TW201143790A - Glucagon superfamily peptides exhibiting nuclear hormone receptor activity - Google Patents

Abstract

Provided herein are glucagon superfamily peptides conjugated with NHR ligands that are capable of acting at a nuclear hormone receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.

Description

201143790 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention provides a glycemic superfamily peptide that binds to a nuclear hormone receptor ligand, which is capable of acting on a nuclear hormone receptor. A computer-readable amino acid sequence listing filed concurrently with the present disclosure and identified below is hereby incorporated by reference in its entirety by reference in its entirety in its entirety: 889, 723-bit ASCII (text) rights for 88922B_SeqListing. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 61/334,435, filed on Jan. 13, 2010, and No. 61. The disclosures of each of the provisional applications are expressly incorporated herein by reference in their entirety. [Prior Art] Nuclear hormone receptor proteins constitute a class of ligand activating proteins which act as opening and closing switches for transcription in the nucleus when bound to specific DNA sequences. These switches control the development and differentiation of skin, bone and brain behavioral centers, as well as the ongoing regulation of reproductive tissues. Nuclear hormone receptor ligands (such as steroids, sterols, retinoids, thyroid hormones, and vitamin D) function to activate nuclear hormone receptors. The interaction of the hormone with the receptor triggers a change in the conformation of the receptor, causing an up-regulation of the gene. The cellular signal transduction activated by the interaction of the ligand with the nuclear hormone receptor is determined by the number of ligands and receptors available for binding, and is determined by the binding affinity between the ligand 15604.doc 201143790 and the receptor. . Multiple ligands and corresponding analogs that bind to nuclear hormone receptors can be used as drugs to treat, for example, Parkinson's disease (NURRl), sleep disorders (RZRP), arthritis, and cerebellar ataxia (RORa) , central nervous system disorders (NOR-1, Rev-ErbAp, Tlx, NGFI-Ββ, HZF-2a, COUP-TFa, COUP-TFP, (: OUR-TFy, NUR77), hypercholesterolemia (LXRa, COR) , obesity (Rev-ErbAa), urinary tract disease (HNF4a), immune disorder (TOR), metabolic disorders (MB67a, SHP, FXR, SF-1, LXRP), as well as infertility and contraception (GCNF, TR2-lla, TR2-llp, TR4, ERa, ERP, ERRa, ERRP) » Pre-proglucagon is a pre-proglucagon with 1 58 amino acids, which is processed in different tissues to form a variety of different derivatives. Peptide from proglucagon, including glycoside, glycosidin-like peptide-1 (GLP-1), glycopeptide-like peptide-2 (GLP-2), and oxyntomodulin (OXM), Isotonic peptides are involved in a variety of physiological functions, including glucose homeostasis, insulin secretion, gastric emptying and intestinal development, and regulation of food intake. a glycosidic amino acid 33 to 61 having a peptide of 29 amino acids, and GLP-1 having a peptide having 37 amino acids corresponding to amino acid 72 to 108 of proglucagon Produced. GLP-1 (7-36) guanamine or GLP-1 (7-37) acid is a biologically effective form of GLP-1 which exhibits substantially equivalent activity to the GLP-1 receptor. Glycosides are used in the acute treatment of severe hypoglycemia. Acid regulating agents have been reported to have appetite and weight loss pharmacological functions. GLP-1 and GLP-1 receptor agonists are used for the treatment of type 2 diabetes Incremental Phosphorus Island 156004.doc 201143790 The analogue-4 (exendin-4) is present in the saliva of the lizard (Gila m〇nster). It is structurally similar to glp-i and is like glucagon and glp_i. Generally, insulin release can be increased. GIP is also known as a glucose-dependent insulinotropic peptide and is a member of the hormone secretagogue family. GIP is derived from the 153 amino acid-derived protein encoded by the GIp gene, and The biological activity has a "peptidic form of the amino acid cycle. The GIP gene is expressed in the small intestine and the salivary gland and is φ weak gastric acid. Inhibitors. In addition to inhibition in the stomach, GIP enhances insulin release from pancreatic p-islet cells when administered in a physiological dose in the presence of glucose. The GIP can act to stimulate pancreatic insulin release and maintain Intestinal factor that plays a physiological role in glucose homeostasis. Osteocalcin is a non-collagen protein found in bone and dentin. It is secreted by osteoblasts and is believed to play a role in mineralization and calcium homeostasis. Osteocalcin has also been reported to act as a hormone in the body, allowing the cells in the pancreas to release more insulin, and at the same time directing the fat cells to release hormones, which increase sensitivity to insulin. . SUMMARY OF THE INVENTION Provided herein are glycoside superfamily peptides that bind to a nuclear hormone receptor ligand ("NHR ligand"). These combinations of multiple activities are suitable for the treatment of a variety of diseases. The glycoside superfamily conjugate of the present invention can be represented by the following formula:

Q-L-Y wherein Q is a glycoside superfamily peptide, Y is a NHR ligand, and L is a bonding group or a bond. 156004.doc 201143790 The glycosidic superfamily peptide (Q) may, in some implementations, exhibit agonist activity at the glycoside receptor, agonist activity at the GLp] receptor, and (10) Agent activity, exhibits eo-agonist activity to the glycemic receptor and GLpq receptor, exhibits co-activator activity to the glycemic receptor and GIp receptor, GUM receptor and (10) A glycoside-related peptide that exhibits co-activator activity or exhibits triple agonist activity at the glycosidic receptor, GIP receptor, and coffee receptor. In some embodiments, the glycoside related property exhibits antagonist activity against the glycoside receptor 'GLP_1 receptor or GIp receptor. The activity of the ghrelin-related peptide on the glycoside receptor, on the GLP4 receptor, or on the Gip receptor can be achieved with any of the teachings set forth herein. In some specific embodiments, the glycosidin-related peptide exhibits at least 0.1% of the activity of the glycoside receptor and is at least 0.1% of the native GLpl exhibited by the GLP-1 receptor. , or the activity exhibited by the GIP receptor is at least 0·1ο/〇 of the native GIP. The NHR ligand (Υ) is fully or partially non-peptide and acts on nuclear hormone receptors with activity according to any of the teachings set forth herein. In some embodiments, the N50 ligand has an EC50 or IC50 of about 1 mM or less, or 100 μΜ or less, or 1 μ μ or less, or i μ μΜ or less. In some embodiments, the 'NHR ligand has a molecular weight of up to about 5000 Daltons or up to about 2000 Daltons, or up to about 1 Dalton' or up to about 500 Daltons. The NHR ligand can act on any of the nuclear phase receptors described herein and has any of the structures described herein. In some embodiments, the 'glucagon-related peptide to the glycoside receptor EC5〇 (or ICso) is an NHR ligand for its nuclear hormone receptor EC5〇*1C5〇-6 - 156004.doc 201143790 Within 100 times, or within about 75 times, or within about 50 times, or about 4 times, 30 times, 25 times, 20 times, 15 times, 10 times or 5 times. In some embodiments, the EC5〇 (or ic5〇) of the 'glycoside-related peptide to GLp】 receptor is within about 1〇〇 of the ECR or ICso of the NHR ligand to its nuclear hormone receptor or is about 75. Within or less than 5 times, or about 4 times, 3 times, 25 times, 20 times, 15 times, 1 time or 5 times. In some embodiments, the glycoside-related peptide to the GIP receptor EC5〇 (or ICso) is within about 100 times, or about 75, of the NHR ligand to its nuclear/hormographic style EC5〇 or 1C5〇 Within a multiple of about 50 times, or about 40 times, 30 times, 25 times, 20 times, 15 times, 1 time or 5 times. In some aspects of the invention, a Q-L-Y prodrug is provided, wherein the prodrug comprises a dipeptide prodrug (A-B) covalently linked to the active site of Q via a guanamine linkage. Subsequent removal of the dipeptide under physiological conditions and in the absence of enzymatic activity restores the full activity of the Q-L-Y conjugate. In some aspects of the invention, a pharmaceutical composition comprising a L L-Y conjugate and a pharmaceutically acceptable carrier is also provided. In other aspects of the invention, a method of administering a therapeutically effective amount of a Q-L-Y conjugate as described herein to treat a disease or medical condition of a patient is provided. In some embodiments, the disease or medical condition is selected from the group consisting of metabolic syndrome, diabetes, obesity, hepatic steatosis, and neurodegenerative diseases. [Embodiment] Definitions In the description and claims of the present invention, the following terms will be used in accordance with the definitions set forth below 156004.doc 201143790. The term "about" as used herein means greater than or less than 1 〇 / of the value or range of values. It is intended that the scope of the value of the value of the value of the value The term "pharmaceutically acceptable carrier" as used herein includes any standard pharmaceutical carrier such as a phosphate buffered saline solution 'water, an emulsion (such as an oil/water or water/oil emulsion) and various types of wetting agents. . The term also covers any agent approved by the regulatory agency of the United States federal government or listed in the US Pharmacopeia for use in animals, including humans. The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound which retains the biological activity of the parent compound and which is not biologically or otherwise undesirable. The various compounds disclosed herein are capable of forming acid and/or base salts due to the presence of amine groups and/or carboxyl groups or the like. Pharmaceutically acceptable base addition salts can be prepared from inorganic bases and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates and the like. Salts derived from organic acids include acetates, propionates, glycolates, pyruvates, oxalates, malates, malonates, succinates, maleates, fubutenes Diacid salt, tartrate salt, citrate salt, benzoate, cinnamate, mandelate, decane sulfonate, ethane sulfonate, p-toluene 156004.doc 201143790 salt, salicylate And its analogues. The term "treating" as used herein includes preventing a particular condition or condition, or alleviating symptoms associated with a particular condition or condition, and/or preventing or eliminating such symptoms. By way of example, the term "treating diabetes" as used herein generally refers to altering blood glucose levels in the direction of normal levels and may include increasing or decreasing blood glucose levels, as the case may be. An "effective amount" or "therapeutically effective amount" of a glycoside peptide as used herein refers to a non-toxic and sufficient amount of the peptide to provide the desired effect. For example, one of the desired effects can be to prevent or treat hypoglycemia, as measured, for example, by elevated blood glucose levels. The desired effects of the replacement of the glycosidic peptide of the present invention include treatment of hyperglycemia, for example, as measured by changes in blood glucose levels closer to normal; or induction of weight loss/prevention of weight gain, for example as measured by weight loss Test; or prevent or inhibit weight gain; or correct body fat distribution. The “effective” amount varies from individual to individual, depending on the age and general condition of the individual, the mode of administration, and the like. Therefore, the exact "effective amount" cannot always be specified. However, an appropriate "effective" amount in any individual condition can be determined by one of ordinary skill in the art using routine experimentation. Sf "parenteral" means not through the digestive tract but by some other means, such as subcutaneous, intramuscular, intraspinal or intravenous. The term "patient" as used herein is intended to cover any domesticated warm-blooded vertebrates (including, but not limited to, domestic animals, horses, babies, dogs, and other pets), mammals, and humans, without further designation. The term "isolated" as used herein means that it has been removed from its natural environment. In some embodiments, the analog is produced via a recombinant method and the analog is isolated from host cell 156004.doc 201143790. The term "purified" as used herein refers to the separation of a molecule or compound in a form substantially free of contaminants 'the contaminants are normally associated with the molecule or compound in a native or natural environment' and the term means The other components of the original composition are separated to increase the purity. The term "purified polypeptide" is used herein to describe a polypeptide that has been separated from other compounds including, but not limited to, nucleic acid molecules, lipids, and carbohydrates. The term "peptide" as used herein encompasses sequences having 2 or more amino acids and typically less than 50 amino acids, wherein the amino acids are naturally occurring or encoded or non-naturally occurring or non-coding amine groups. acid. A non-naturally occurring amino acid refers to an amino acid that does not naturally occur in vivo but can be incorporated into the peptide structures described herein. As used herein, "non-coding" refers to an amino acid that is not an L-isomer of any of the following two amino acids: Ala, cys, Asp, Glu, Phe, Gly, His, lie, Lys, Leu, chest, —,

Pro, Gin, Arg, Ser, Thr, Va, Trp, Tyr. As used herein, "partial non-peptide" refers to a molecule in which a portion of a molecule is a compound or substituent that is biologically active and does not comprise an amino acid sequence. "Non-peptide" as used herein refers to a molecule that is biologically active and does not comprise an amino acid sequence. The terms "polypeptide" and "protein" as used herein are terms used interchangeably and refer to a polymer of an amino acid, regardless of the length of the polymer. Generally, polypeptides and proteins have a polymer length greater than the length of the polymer of the "peptide". In some cases, the protein comprises more than one polypeptide chain covalently or non-covalently linked to each other. 156004.doc 201143790 Throughout this application, all references to a particular amino acid position by a number (eg, position 28) refer to the position in the native glucosinolate (SEQ ID NO: 1601) or any analog thereof. The amino acid at the corresponding amino acid position. By way of example, reference herein to "position 28" means the corresponding position 27 of the glycoside analog in which the first amino acid of SEQ ID NO: 1601 has been deleted. Similarly, reference herein to "position 28" means that the corresponding position of a glycosidic analog of an amino acid has been added before the N-terminus of SEQ ID NO: 1601. 29 "Amino acid modification as used herein. "(1) Amino acid substituted or substituted with a reference amino acid (eg, SEQ ID NO: 1601, 1603, 1607) with a different amino acid (naturally occurring or encoded or non-coding or non-naturally occurring amino acid), (ii) Amino acids (naturally occurring or encoded or non-coding or non-naturally occurring amino acids) are added to a reference peptide (eg SEQ ID NO: 1601, 1603, 1607), or (iii) one or more amine groups The acid is deleted from a reference peptide (eg, SEQ ID NO: 1601, 1603, 1607). In some embodiments, the amino acid is substituted or replaced with a conservative amino acid substitution, eg, positions 1, 2, 5, 7, 8, A conservative substitution of an amino acid on one or more of 1 〇, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28 or 29. The term "conservative amino acid substitution" as used herein is an amino acid substituted with another amino acid having similar properties (eg, size, charge, hydrophobicity, hydrophilicity, and/or aromaticity) and includes the following 5 Exchange within one of the groups: I. Small aliphatic non-polar or slightly polar residues:

Ala, Ser, Thr, Pro, Gly; 156004.doc 201143790 II. Negatively charged polar residues and their guanamines and esters:

Asp, Asn, Glu, Gin, sulfoalanine and high sulfoalanine; III. Positively charged polar residues:

His, Arg, Lys; ornithine (Orn); IV. Large aliphatic non-polar residues:

Met, Leu, lie, Val, Cys, n-leucine (Nle), homocysteine; V. Large aromatic residues:

Phe, Tyr, Trp, acetylated amphetamine. In some embodiments, the amino acid substitution is not a conservative amino acid substitution, such as a non-conservative amino acid substitution. The term "amino acid" as used herein encompasses any molecule containing an amine group and a slow chain functional group, wherein the amine group and the carboxyl group are bonded to the same carbon (alpha carbon). It may have one or two other organic substituents as appropriate. For the purposes of the present invention, the designation of an amino acid in the absence of a specified stereochemistry is intended to encompass the L- or D-form or racemic mixture of the amino acid. However, in the case where the amino acid is named by its three-letter code and includes the superscript number (ie, Ly^), the designation is intended to specify the native amino acid, and is incorporated by the three-letter code and the superscript number. Lowercase d (also known as dLp-)) to specify the type. As used herein, the term "hydroxy acid refers to the absence of a sulphuric acid". Your acesulfame acid is modified to replace the alpha-carbonamine group with a hydroxy group. The term "charged amino acid" as used herein refers to an amine group comprising a side bond having a negative charge (ie, deprotonation) or a positive charge (ie, protonation) under physiological enthalpy in an aqueous solution. acid. For example, the negatively charged sea 156004.doc •12· 201143790 base acids include aspartic acid, face acid, sulfoalanine, high sulfoalanine and glutamic acid, and positively charged amines Base acids include arginine, lysine, and histidine. Charged amino acids include 20 charged amino acids encoding amino acids and atypical or non-naturally occurring or non-coding amino acids. The term "acidic amino acid" as used herein refers to an amino acid comprising a second acidic moiety (other than an amino acid (other than a carboxylic acid) including, for example, a side chain carboxylic acid or a sulfonic acid group). The "deuterated" amino acid is an amino acid comprising a non-native sulfhydryl group for a naturally occurring amino acid, regardless of the manner in which it is produced. An exemplary method for producing deuterated amino acids and deuterated peptides is Known in the art, and including deuterated amino acids, which are then incorporated into the peptide, or peptide synthesis, followed by chemical deuteration of the peptide. In some embodiments, the thiol group has one or more of the following: i) prolonged circulating half-life, (ii) delayed onset time '(iii) extended duration of action, (iv) improved resistance to proteases (such as DPP-IV), and (v) enhanced pair The potency of a glycoside superfamily peptide receptor. As used herein, an "alkylated" amino acid is an amino acid comprising a non-native alkyl group for a naturally occurring amino acid, regardless of the manner in which it is produced. An exemplary method for producing alkylated amino acids and alkylated peptides in this technique It is known in the art and includes an alkylated amino acid, which is then incorporated into the peptide, or peptide synthesis, followed by chemical alkylation of the peptide. Under the circumstance of any particular theory, the salt alkylation peptide can be achieved and deuterated. Peptides are similar (if not identical) effects, such as prolonging circulating half-life, delaying the onset of action, prolonging the duration of action, improving resistance to proteases (such as DPP-IV), and enhancing glycemic excess 156004.doc •13 · 201143790 The efficacy of a family peptide receptor. As used herein, the term "Ci-Cn alkyl" (where n can be from 1 to 18) means a branched or straight chain alkyl group having from 1 to a specified number of broken atoms. By way of example, 'CrC6 alkyl denotes a branched or straight-chain alkyl group having from 1 to 6 carbon atoms. Typical Ci-Cu alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, a butyl group, an isobutyl group, a second butyl group, a tert-butyl group, a pentyl group, a hexyl group, and the like. The group may be, for example, a trans group (〇H), a halogen group, an aryl group, a carboxyl group, or a thio group. , C3-C8 cycloalkyl and amine substituted. The term "C〇-Cn alkyl" as used herein (which Wherein η may be from 1 to 18) represents a branched or straight-chain alkyl group having up to 18 carbon atoms. For example, the term "(CG-C6 alkyl)〇Η" means attached to have up to 6 carbon atoms. The hydroxy parent moiety of the alkyl substituent (eg, 〇Η, -CH2OH, -(:2ϋ4ΟΗ, -C3H6OH, -C4H8〇H, -C5H10〇H, -C6H12OH) » The term "C2_Cn alkenyl" as used herein (wherein n may be from 2 to 18) represents an unsaturated branched or straight chain group having 2 to a specified number of carbon atoms and having at least one double bond. Examples of such groups include, but are not limited to, propylene Base, 2-propenyl (_CH2-CH=CH2), 1,3-butadienyl (_CH=CHCH=CH2), 1-butenyl (_(:Η=(:Η(:ΙΙί2(:ΙΙ3) ), hexyl, pentyl and the like. The alkenyl group may, for example, be substituted with a hydroxy group, a halogen group, an aryl group, a carboxyl group, a thio group, a C3-C8 cycloalkyl group, and an amine group. The term "C2-Cn alkynyl j (wherein n may be from 2 to 18) means an unsaturated branched or straight-chain group having 2 to n carbon atoms and having at least one reference. Examples of such groups include (but not limited to • propynyl, 2-propynyl, indolynyl, 2-butynyl, 1-pentynyl and the like. decynyl groups. I56004.doc -14- 201143790 Carboxyl, The thio group, CrC8 cycloalkane is substituted, for example, by a hydroxyl group (〇H), a dentate group, an aryl group, and an amine group.

The term "aryl" as used herein refers to a monocyclic or polycyclic (e.g., tapered, tricyclic or tetracyclic) aromatic radical. The size of the aryl ring is indicated by the number of carbons specified therein. For example, the term "(CVCA-based) (C6_aryl)" refers to a 6 to / an aryl group attached to the parent moiety via a hydrazine to a 3 member alkyl chain. Unless otherwise indicated, the aryl group may be unsubstituted or substituted with one or more and especially from 1 to 5 groups independently selected from the group consisting of: dentate, alkyl, dilute, hydrazine CF3, N 〇 2. Cn, nc'〇h, ^M^, C02h, (: 3_(:8-cycloalkyl, c(〇)〇alkylaryl, and heteroaryl. Exemplary aryl groups include, but are not limited to, stupid , naphthyl, tetrahydronaphthyl, benzene benzene, dihydrogenated benzyl, fluorenyl, nonylphenyl, decyloxyphenyl, trifluoromethylphenyl, nitro stupyl, 2,4-decyloxy Base gas phenyl and the like. The term "heteroaryl" as used herein refers to a single or multiple ring containing one or more aromatic rings and containing at least one nitrogen, oxygen or sulfur atom in the aromatic ring. The ring system. The size of the heterocyclic ring and the presence of the substituent or linkage & group are indicated by specifying the number of carbons present. For example, the term "((:"(:6 alkyl)) C5_C6heteroaryl) means a 5- or 6-membered heteroaryl group attached to the parent file via a 1 to 6 member alkyl chain. Unless otherwise indicated, the heteroaryl group may be unsubstituted or one or more Especially 1 to 5 independently Substituted from, for example, the following groups: dentyl, alkyl, alkenyl, OCF3, N〇2, CN, NC, 〇H, alkoxy, amine, c〇2H, C3_C8 cycloalkyl, c(〇) 〇alkyl, aryl and heteroaryl. Examples of heteroaryl include, but are not limited to, thienyl, furanyl 'pyridinyl, oxazolyl, quinolyl, thienyl, isoquinolyl,吲156004.doc 201143790 Amidino, triazinyl, triazolyl, isothiazolyl, isoxazolyl, oxazolyl, benzothiazolyl, pyrazinyl, pyrimidinyl, thiazolyl and thiadiazolyl. The term "heteroalkyl" as used herein, refers to a straight or branched chain hydrocarbon containing the indicated number of carbon atoms and containing at least one heteroatom in the backbone of the structure. Heteroatoms suitable for the purposes herein include, but are not limited to, N, S and 〇. Heteroalkyl groups may, for example, be substituted with hydroxy (OH), halo, aryl, sulfhydryl and amine groups. The term "halogen" or "halo" as used herein means fluoro, One or more members of the group consisting of chlorine, indifferent, and broken. As used herein, the term "glycoside-related peptide" refers to glycoside, GLP-1, GLP- 2 and any one or more of the GIP receptors are biologically active (as agonists or antagonists) and comprise native glucosin, native phytotonin, native incretin analogue _4, native GLP- 1. At least one of native GLP-2 or native GIP has at least 4% sequence identity (eg, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%) a 90%, 95%) peptide of the amino acid sequence. Unless otherwise stated, any reference to the position of the amino acid in the glycosidin-related peptide (eg, for a linked NHR ligand, a binding moiety, Hydrophilic polymer, deuterated or alkylated and ») ligated relative to the native glycosyl amino acid sequence (SEq ID N〇 corresponding position). As used herein, the term "molecular selection for a first receptor relative to a second receptor" refers to the ratio of the EC5 of the molecule to the second receptor divided by the ec50 of the molecule to the first receptor. For example, $, for the first receptor, "is n nM and for the first - EC ECw of 100 nM, the first receptor is selected 156004.doc 201143790 is selective for the second receptor Selective 1 〇〇. The term "consistency" as used herein refers to the similarity between two or more sequences. A priming line is measured by dividing the number of identical residues by the total number of residues and multiplying the result by 100 to obtain a percentage. Thus, two copies of exactly the same sequence have a 嶋 consistency, while two sequences with a deletion, addition or substitution of amino acids have a lower degree of agreement. Those skilled in the art should be aware of a number of computer programs (such as computer programs that use algorithms such as BLAST (Basic Local Alignment Search T〇〇1, AUschul et al. (1993) J. Mo/. Ao/. 215:403-410). ) can be used to determine sequence identity. The term "glycoside superfamily peptide" as used herein refers to a group of peptides that are structurally related in the N-terminal and c-terminal regions (see, for example, Sherw〇〇d et al., 21: 619-670 (2000) ). Members of this cohort include all glycoside-related peptides and growth hormone releasing hormone (GHRH; SEQ ID NO: 1619), vasoactive intestinal peptide (VIp; SEQ ID NO: 1620), pituitary adenylate cyclase activating polypeptide 27 (paCAP-27; SEQ ID NO: 1621), peptide histidine acid isoleucine (pHI; SEq ID no: 1642), histidine methionine (ΡΗΜ; SEQ ID NO: 1622), secretion (SEQ ID NO: 1623), and an analog, derivative or conjugate having at most i, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications relative to the native peptide. Preferably, the peptide retains the ability to interact (activator or antagonist) with a receptor of the glycoside receptor superfamily. Unless otherwise stated, any reference to the position of the amino acid in the glycoside superfamily peptide (eg, for a linked NHR ligand, a binding moiety, a hydrophilic polymer, a deuterated or an alkane 156004.doc - 17-201143790) refers to the alignment of the representative glycosidic superfamily peptides relative to the corresponding position of the native glycosyl amino acid sequence (SEQ ID NO: 1601), see Figure 1. The term "glycoglyco agonist peptide" refers to a compound that binds to the glycecan receptor and activates downstream signaling of the glycemic receptor. However, this term should not be construed as limiting the compound to be active only on the glycemic receptor. In fact, the glycosidin agonist peptides of the invention may exhibit additional activity on other receptors, as discussed further herein. "Glycoglycan agonist peptides, for example, may exhibit for GLP-丨 receptors and/or GIP receptors. Activity (eg agonist activity). Similarly, the term "glycoglycogen agonist peptide" should not be considered as a limiting compound as a peptide. In fact, compounds other than peptides are also covered by this term. Therefore, the glycoside agonist is in the form of a peptide (heterodimer, multimer, fusion peptide) peptide, a chemically derived peptide, a pharmaceutical salt of a peptide, a mimetic and analog. The term GLP-1 agonist peptide refers to a compound that binds to the GLP-1 receptor and activates downstream signaling of the GLM receptor. ^, this term should not be construed as limiting the compound to be active only at the GLP-1 receptor. In fact, the GUM promoting (tetra) peptides of the present invention exhibit additional activity on other receptors, as described herein. GLP.1 agonist peptides, for example, can exhibit activity on the glycoside receptor and/or GIP receptor (eg, agonistic gastric "euM agonist peptides" should not be considered as limiting peptides only. In fact, except peptides Compounds other than this are also covered by this term. Thus, the GUM agonist peptide is, in some aspects, a peptide in the form of a conjugate (hetero-octa-hetero-mer, multimer, fusion peptide), a chemically-derived peptide. Pharmacological steps: gas, peptidomimetic and its analogues. 156004.doc •18· 201143790 The term “GIP agonist peptide” refers to a compound that binds to the GIP receptor and activates downstream signaling of the GIP receptor. However, this term should not be taken as limiting. The agent is only active against the GIP receptor. In fact, the Glp agonist peptides of the invention may exhibit additional activity to other receptors, as discussed further herein. The agent peptide can, for example, exhibit activity (e.g., agonist activity) to the GLP-i receptor. Likewise, the term "GIP agonist peptide" should not be considered as a limiting compound as a peptide. In fact, compounds other than peptides are also This term is covered. Therefore, the GIP agonist peptide is in some aspects Peptides in the form of conjugates (heterodimers, multimers, fusion peptides), chemically derived peptides, pharmaceutical salts of peptides, peptidomimetics, and the like. The term "glycoglycan antagonist peptide" refers to the offset a compound that inhibits glycosidic activity or inhibits glycosidic function. For example, a glycoside antagonist exhibits at least a 6% inhibition of the maximum response achieved by a glycoside to a glycosidic receptor (eg, at least 70%, 80%, 90°/. or 90❶/〇 above inhibition.) In a particular embodiment, the glycosidic antagonist exhibits a maximum of glycosidic receptors at the concentration of about 丨μΜ The agonist activity is about 2% or less (for example, about 1% or less). This term should not be regarded as limiting the compound to be active only on the glycosidic receptor. In fact, the glycosidic antagonist of the present invention The peptide may exhibit additional activity on the glycoside receptor (eg, partial agonist) or other receptors. The glycoside antagonist peptide may, for example, exhibit activity (eg, agonist activity) at the GLP-1 receptor. The term "glycoglycemic antagonist peptide" should not be considered as a limiting compound. In fact, compounds other than peptides are also covered by such terms. Therefore, in some aspects, the glycosidin agonist peptide is a peptide in the form of a conjugate, a chemically derived peptide, a pharmaceutical salt of a peptide, and a peptide simulation. And its 156004.doc •19- 201143790 analog. The term “GLP-1 antagonist peptide” refers to a compound that counteracts GLP-1 activity or inhibits GLP-1 function. For example, a GLP-1 antagonist pair by GLP -1 exhibits at least a 60% inhibition of the maximum response achieved by the GLP-1 receptor (eg, at least 70%, 80%, 90%, or more than 90% inhibition). In a particular embodiment, the GLP-1 antagonist About 20% or less (e.g., about 10% or less) of the maximum agonist activity achieved by GLP-1 to the GLP-1 receptor is exhibited at a concentration of about 1 μΜ. The term should not be taken as limiting the compound to be active only at the GLP-1 receptor. In fact, the GLP-1 antagonist peptides of the invention may exhibit additional activity at the GLP-1 receptor (e.g., partial agonist) or other receptors. The GLP-1 antagonist peptide can exhibit activity (e.g., agonist activity) to the glycoside receptor, for example. Similarly, the term "GLP-1 antagonist peptide" should not be considered as a limiting compound as a peptide. In fact, compounds other than peptides are also covered by such terms. Thus, in some aspects, the GLP-1 agonist peptide is a peptide in the form of a binder, a chemically derived peptide, a pharmaceutical salt of a peptide, a peptidomimetic, and the like. The term "GIP antagonist peptide" refers to a compound that counteracts GIP activity or inhibits GIP-1 function. For example, a GIP antagonist exhibits at least a 60% inhibition (e.g., at least 70%, 80%, 90%, or 90% inhibition) on the maximum response achieved by GIP to the GIP receptor. In a particular embodiment, the GIP antagonist exhibits less than about 20% (e.g., about 10% or less) of the maximum agonist activity achieved by GIP to the GIP receptor at a concentration of about 1 μΜ. The term should not be taken as limiting the compound to be active only on the GIP receptor. In fact, the GIP antagonist peptides of the invention may exhibit additional activity on GIP receptors (e.g., for partial efficacies 156004.doc • 20-201143790) or other receptors. GIP antagonist peptides, for example, can exhibit activity (e. g., agonist activity) on a glycoside receptor. Similarly, the term "G-press antagonist peptide" should not be considered as a limiting compound as a peptide. In fact, compounds other than peptides are also covered by such terms. Thus, in some aspects, the GIP agonist peptide is a peptide in the form of a conjugate, a chemically derived peptide, a pharmaceutical salt of a peptide, a peptidomimetic, and the like. The terms "glycosin analog" and "glycoside peptide" as used herein are used interchangeably to refer to a glycoside analog having the indicated activity against a glycopeptide-related peptide receptor. The term "primary glucosin" as used herein refers to a peptide consisting of the sequence of SEQs: 160: 1601. The term "native GLP-丨" as used herein means GLpi(7 36)醯(SEQ ID NO: 1603) > GLP-1(7-37)g^(SEQ ID NO: 1604) or both A generic term for a mixture of compounds. The term "native GIP" as used herein refers to a peptide consisting of SEQ ID N: 16〇7. As used herein, "glycamine potency" or "efficiency compared to native glycosides" refers to the ec5q of the molecule to the glycemic receptor divided by the EC5 of the proglucagon receptor to the glycemic receptor. The resulting ratio. As used herein, "GLP-丨 potency" or "potency compared to native GLP_1" refers to the ratio of the molecule's EC5G to the GLP receptor divided by the Eg5Q of the native GLP-1 to the GLP-1 receptor. As used herein, the "GIP potency" of a molecule or "the efficacy of a native GIP" refers to the ECS of a molecule to a GIP receptor divided by the EC50 of a native GIP to the GIP receptor 156004.doc •21-201143790 ratio. As used herein, "NHR ligand" refers to a hydrophobic or lipophilic moiety that is biologically active (agonist or antagonist) to a nuclear hormone receptor (NHR). The NHR ligand is completely or partially non-peptide. In some embodiments, the NHR ligand is an agonist that binds to NHR and activates NHR. In other embodiments, the NHR ligand is an antagonist. In some embodiments, the lignin is an antagonist that acts by blocking, in whole or in part, the binding of the native ligand to the active site. In other embodiments, the NHIU&position is by binding to the active site. An antagonist that acts at an allosteric site and prevents NHR activation or deactivation. As used herein, "nuclear hormone receptor" (NHR) refers to a ligand-activated protein that sometimes cooperates with other co-activators and co-inhibitors to regulate gene expression in the nucleus. As used herein, "steroid and its derivatives" refers to a naturally occurring or synthetic compound having the structure of formula A:

Wherein R1 and R2, when present, are independently the moiety that allows or promotes the activity of the agonist or antagonist when the compound of formula A binds to the nuclear hormone receptor; and ruler 3 and R4 independently bind the compound of formula A to the nuclear hormone The portion of the receptor that allows or promotes the activity of the agonist or antagonist; and each dashed line indicates the presence of a double bond of 156004.doc -22-201143790 as appropriate. Formula A may further comprise - or a plurality of substituents on one or more of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, u, 12, I4, 15, 16 and 17. Substituents which are optionally included include, but are not limited to, OH, NH2, ketone and CVCu alkyl. Specific non-limiting examples of steroids and derivatives thereof include cholesterol, estradiol cholic acid, steroids, and hydrocortisone. As used herein, "bile acid and its derivatives" refers to the natural presence of hydrazine or Synthetic compound:

Wherein R, R and R17 are each independently a moiety which allows or promotes the activity of the agonist or antagonist when the hydrazine compound is bound to the nuclear hormone receptor. In some embodiments, R15 and R16 are each independently hydrogen, (C〇_C8 alkyl) halo, c18 alkyl, C2-C18 dilute, c2-c18 fast radical, heteroalkyl or hydroxy); And R17 is oh, (C〇-C8 alkyl)NH(C丨-C4 alkyl)S03H or (C0_C8 alkyl)Ni^CVC4 alkyl)COOH. The formula may further comprise one or more substituents on one or more of the positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16 and 17. Non-limiting examples of bile acids include cholic acid, deoxycholic acid, lithocholic acid, chenodeoxycholic acid, bovine cholesteric acid, and glycocholic acid. As used herein, "cholesterol and its derivatives" means a naturally occurring or synthetic compound containing a structure similar to that of a cholinol, as described below: 156004.doc -23- 201143790:

The cholesterol derivative may include an oxysterol such as transbasin cholesterol, hydrazine (8)-hydroxycholesterol, 27-carbyl cholesterol, and cholesterol acid acid. As used herein, "estradiol and its derivatives" are compounds that are synthesized or synthesized:

Wherein R, R and R6 are those which permit or promote the activity of the agonist or antagonist when the compound of formula B is bound to the estrogen receptor. In some embodiments, the structure of Equation B passes through one or more of the four rings (such as positions 1, 2, 4, 6, 7 8 9 11 , 12, 14, ! 5, 16 and 17). Or substituted with multiple substituents. In some cases, the substituent contains a ketone at position 6 ^

156004.doc -24· 201143790 Specific non-limiting examples of estradiol derivatives include beta-estradiol i 7 -acetate, estradiol 17 ~cyclopentanoic acid, P-estradiol 17- Heptanoic acid vinegar, β-estradiol 17-pentanoic acid, β-estradiol 3,17-diacetic acid, p-estradiol 3,17-dipropionate, β-estradiol 3_benzoic acid , estradiol 3_capsules · · n-butyl ISa P estradiol 3-glycidyl hydrazine, β-estradiol 3 曱 ether, p_ estrone 6 _ β-estradiol 3 'shrinkage Glycerol ether, β-estradiolone 6_(〇_carboxycarboxamidine), 16-epitriol, 17_epitriol, 2-methoxymethoxyestradiol, 4-decyloxyestradiol, Estriol 17_phenylpropionic acid vinegar and 17-drastodiol 2-methyl ether, 17«-ethynyl estradiol, megestrol acetate (caffeide 1 acetate) and estriol. What is the "testosterone and its derivatives"? Naturally occurring or synthetic compounds:

Where R1 (when present),! ^, 1^ and 1^ are each independently? a moiety that allows or promotes the activity of an agonist or antagonist when the compound binds to a nuclear hormone receptor; and each dashed line represents a double bond as the case exists, with the proviso that there is at most one carbon-carbon double present as appropriate at position 5. key. In some embodiments, the structure of Formula F is at one or more locations of the four rings (such as positions t, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16 and 17) Substituted by one or more substituents. Specific non-limiting examples of guanidine derivatives include dehydroepiandrosterone, androstenedione, 5·androstenediol, androstenone, and dihydro 156004.doc 25·201143790 testosterone. As used herein, "fatty acid and its derivatives" refers to a ruthenium containing a long unbranched chain (^ to a 28 alkyl or C2 to Cm alkenyl moiety and optionally one or more halo substituents and/or Or optionally, one or more substituents other than a dentate group. In some embodiments, the 'long unbranched bond group or the dilute moiety may be completely substituted with a halo group (eg, all hydrogen is replaced by a halogen atom). The chain fatty acid contains 1 to 5 carbon atoms, the medium chain fatty acid contains 6 to 12 carbons, the long chain fatty acid contains 13 to 22 carbon atoms, and the very long chain fatty acid contains 23 to 28 carbon atoms. Restrictive examples include formic acid, acetic acid, n-hexanoic acid, heptanoic acid, caprylic acid, capric acid, capric acid, eleven acid, lauric acid, dodecanoic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecane Acid, stearic acid, nonadecanic acid, arachidic acid, behenic acid, behenic acid, behenic acid, mead acid, myristoleic acid ), palmitoleic acid, hexadecenoic acid (10) heart acid), oleic acid, linoleic acid, α_linolenic acid , oleic acid, petrose acid, arachidonic acid, dihydroxyeicosatetraenoic acid (DiHETE), octadecathynoic acid, eicosatrinoic acid, eicosadienoic acid, twenty carbon three Alkenoic acid, twenties pentaic acid, heptayl acid, di-high linoleic acid, docosalic acid, docosapentaenoic acid, docosahexaenoic acid and adrenal acid. "Cortisol and its derivatives" means a naturally occurring or synthetic compound of formula C: 156004.doc -26- 201143790

Wherein R 2 , R 3 , R 6 , R 7 , R 8 , R 9 and R 10 are each independently a moiety which allows or promotes the activity of the agonist or antagonist when the SC compound binds to the nuclear hormone receptor; and each dotted line indicates a double Keys In some embodiments, the structure of Formula C is on one or more of the four rings (such as positions 1, 2, 4, 5, 6, 7, 8, 11, 12, 14, and 15). Multiple substituents are substituted. Specific non-limiting examples of cortisol and its derivatives include cortisol, corticosterone acetate, beci〇metasone, prednisone, prednisolone, and prednisolone (prednisolone) Methylprednisolone), betamethasone, trimcinolone and dexamethas〇rie. As used herein, a "bonding group" is a group of molecules or molecules that bind two separate entities to each other. The linking group can provide an optimal spacing between the two entities, or can further provide an unstable linkage that allows the two entities to be separated from one another. The labile linkage includes a hydrolyzable group, a photocleavable group, an acid labile moiety, an alkali labile moiety, and an enzyme cleavable group. The term "prodrug" as used herein is defined as any compound that undergoes chemical modification prior to exhibiting a fully pharmacological effect. A "dipeptide" as used herein is via a peptide bond. The amino acid or alpha-hydroxy acid is linked to the product of another amino acid. The term "chemical cleavage" as used herein encompasses a non-enzymatic reaction that cleaves a covalent chemical bond without any further reference to 156004.doc • 27·201143790. EXAMPLES The present invention provides a glycoside superfamily peptide that binds to an NHR ligand. In some aspects, NHR ligands are capable of acting on nuclear hormone receptors involved in metabolism or glucose homeostasis, and conjugates provide superior metabolism or glucose homeostasis compared to peptides alone or NHR ligands alone. Biological effects. Without being bound by the theory of the present invention, NHR ligands can be used to target a glycoside superfamily peptide to a particular type of cell or tissue; alternatively, a glycoside superfamily peptide can be used to make a NHR ligand Transport of NHR ligands into cells is enhanced by binding to cells or, for example, via peptides to receptors of internalization conjugates. The glycoside superfamily peptide conjugate of the present invention can be represented by the following formula:

Q-L-Y wherein Q is a glycoside superfamily peptide, Y is an NHR ligand, and L is a bonding group or a bond. The glycoside superfamily peptide (Q) may, in some embodiments, exhibit agonist activity at the glycoside receptor, agonist activity at the GLP-1 receptor, and agonist activity at the GIP receptor. , exhibits co-activator activity on the glycoside receptor and GLP-1 receptor, exhibits co-activator activity on the glycosidic receptor and GIP receptor, and promotes co-promoting to the GLP-1 receptor and GIP receptor. Activator activity or a glycosidin-related peptide exhibiting triple agonist activity at the glycosidic receptor, the GIP receptor, and the GLP-1 receptor. In some embodiments, the glycoside-related peptide exhibits antagonist activity at a glycemic receptor, a GLP-1 receptor, or a GIP receptor. The glycoside superfamily peptide (Q) may, in some embodiments, be a glycosidin-related peptide, a growth hormone releasing hormone (GHRH; SEQ ID NO: 1619), 156004.doc -28-201143790 vasoactive intestinal peptide (VIP) SEQ ID NO: 1620), pituitary adenylate cyclase activating polypeptide 27 (PACAP-27; SEQ ID NO: 1621), peptide histidine methionine (ΡΗΜ; SEQ ID NO: 1622) or secretin (SEQ ID NO: 1623;) and/or analogs, derivatives and combinations thereof. The glycoside superfamily peptides may have structural features in common, including, but not limited to, homology within the N-terminal amino acid and/or alpha-helical structure within the C-terminal portion. The C-terminus of the salty letter generally plays a role in receptor binding, and the terminus generally plays a role in receptor signaling. A few amino acids in the terminal part and the C-terminal part are among the members of the glycoside superfamily. Highly conserved, such as Hisl, Gly4, Phe6, Phe22, Val23, Trp25 and Leu26, wherein the amino acid at these positions exhibits a consistent, conservative substitution or similarity of the amino acid side chains. In some embodiments, the glycosidin-related peptide Q is a glycosidic acid (SEQ ID NO: 1601) 'Acetate (SEQ ID NO: 1606), Incretin Analog-4 (SEQ ID NO: 1618) , Aspergillus-like peptide-1 (GLP-1) (amino acids 7 to 37 provided as SEQ ID NOS: 1603 and 1604), glycosidin-like peptide-2 (GLP-2) (SEQ ID NO: 1608) , GIP (SEQ ID NO: 1607), or analogs, derivatives and combinations thereof. In some embodiments, Q, as a glycein-related peptide, comprises a native glycein, a native acid-regulating hormone, a native incretin analog-4, a native (7-37) GLP-1, a native GLP-2, or The corresponding sequence of the native GIP is at least about 40%, 45%, 50%, 55%, 60%, 65%, 70% over the length of the native peptide (or at a position corresponding to the glycein, see, eg, Figure 1). , 75%, 80°/. , 85%, 90% or 95% of the amino acid sequence. In other embodiments, the glycoside superfamily peptide (Q) comprises a native glycoside having up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications, native 156004.doc •29- 201143790 Incretin analogue-4, native (7-37) GLP-1, native GLP-2, native GHRH, native VIP, native PACAP-27, native PHM, native acid regulator, Amino acid sequence of native secretin or native GIP. In other embodiments 'Q contains an amino acid sequence that is a chimera of two or more native glycosidin-related peptide sequences. In some embodiments, q comprises an amino acid that is at least about 50% identical to the native glucagon (SEQ ID NO: 1601) and retains the alpha-helical configuration of the amino acid corresponding to the amino acid 12 to 29 sequence. In a related aspect, the invention provides a peptide conjugate represented by the formula:

QLY wherein Q is bone chemokine, vasopressin, branched starch or analogues, derivatives or conjugates thereof instead of a glycoside superfamily peptide; a ligand; and is a bonding group or a bond . In some embodiments, Q comprises Osteosin (SEQ ID NO: 1644) or at least about 40%, 45 of the length of the native peptide with native osteocalcin. /. , 50%, 55%, 60%, 65%, 70%, 75%, 80°/. , 85°/. , 90% or 95% of the amino acid sequence. Q may comprise an osteocalcification analog having up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications relative to native osteocalcin, or relative to native truncated bone Calcitonin has up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modified truncated osteocalcin analogs (e.g., amino acids 7 to 84). In some embodiments 'Q comprises calcitonin (SEQ ID NO: 1645) or at least about 40%, 45%, 50%, 55%, 60%, 65% of the length of the native peptide with native vasopressin, 70%, 75%, 80%, 85%, 90% or 95% of the amino acid sequence. Q may comprise a calcitonin-like 156004.doc -30-201143790 having up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications relative to native calcitonin. In some embodiments, q comprises amylopectin (SEQ ID NO: 1646) or is at least about 40%, 45%, 50%, 55%, 60%, 65% of the length of the native peptide with native amylopectin, 70%, 75%, 80%, 85%, 90% or 95% of the amino acid sequence. Q may comprise an amylopectin analog having up to 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid modifications relative to native amylopectin. NHR Ligand (Y) In the present disclosure regarding QLY conjugates, Y is for any nuclear hormone receptor (including the "nuclear hormone receptor superfamily" (NHR superfamily) set forth in Table 1. Any of these, or a class or subgroup thereof, that acts as a ligand. This NHR superfamily is composed of structurally related proteins that regulate transcription of genes in cells. These proteins include steroid receptors and thyroid hormone receptors, vitamin receptors, and other "lonely" proteins in which no ligand is found. Nuclear hormone receptors typically include at least one C4 type zinc finger DNA binding domain (DBD) and/or ligand binding domain (LBD). The DBD function is to bind DNA in the vicinity of the target gene, and the LBD binds to and reacts with its homologous hormone. "Classic nuclear hormone receptor" has DBD and LBD (eg estrogen receptor a), while other nuclear hormone receptors only have DBD (eg Knirps, ORD) or only LBD (eg short heterodimer conjugate (SHP) )). Nuclear hormone receptors can be divided into four mechanisms: Type I, Type II, Type III, and Type IV. The binding of a ligand to a type I receptor (NR3 group) causes heat shock protein (HSP) to dissociate from the receptor, the receptor is dimerized, translocates from the cytoplasm into the nucleus, and binds to the inverted repeat of DNA. Sequence Hormone Anti-156004.doc -31 - 201143790 Component (HRE) The nuclear receptor/DNA complex then recruits other proteins that transcribe hre downstream DNA into messenger RNA. The „type receptor (NR1 group) remains in the nucleus and binds to DNA in the form of a heterodimer, usually associated with the retinoid X receptor (RXR). Type II nuclear hormone receptors are often co-repressor proteins. (C〇repreSS〇r protein) complex. The binding of a ligand to a π-type receptor causes the co-inhibitor to dissociate and recruit a co-activated protein. Other proteins are recruited to the nuclear receptor/DNA complex' to transcribe the DNA into a messenger. RNA. The nuclear hormone receptor of type (1) (group NR2) is an orphan receptor that binds to the direct repeat HRE of dna in the form of a homodimer. The iv-type nuclear hormone receptor binds in the form of a monomer or a dimer. To DNA. Type IV receptors are unique in that the single DNA binding domain of the receptor binds to a single half-site hre. The NHR ligand can be of type I, type II, type III or A ligand (eg, acting as an agonist or antagonist) that acts on any one or more of the nuclear hormone receptors. Table 1. Nuclear hormone receptor superfamily nuclear hormone receptor species registration number endogenous NR1 group NR1A1 thyroid hormone receptor a (TRa) human M24748 thyroid gland NR1A2 Thyroid Hormone Receptor β (ΤΙΙβ) Human X04707 NR1B1 Retinoic Acid Receptor a (RARc〇 Human X06538 _Biotin A and Related Compound NR1B2 Retinoic Acid Receptor β (ΙΙΑΙΙβ) Human Y00291 NR1B3 Retinoic Acid Receptor Y(RAR)〇 human M57707 NR1C1 peroxisome proliferator-activated receptor a (PPARa) human L02932 fatty acid, prostaglandin NR1C2 peroxisome proliferator-activated receptor β/δ (ΡΡΑΙΙβ/δ) human L07592 NR1C3 peroxisome proliferation Activator Receptor γ (ΡΡΑΚγ) Human L40904 NR1D1 Rev-ErbAa Human M24898 Heme NR1D2 Rev-ErbAp Human L31785 NR1F1 RAR Related Solitary Acupuncture a(R〇Ra) Human U04897 Cholesterol, all-trans retinoic acid NR1F2 RAR related loneliness Receptor p(R〇Rp) Human Y08639 NR1F3 RAR-related lone receptor Y (R〇Ry) Human U16997 156004.doc -32· 201143790

NR1H2 Liver X Receptor P (LXRP) Human U07132 Oxysterol _ NR1H3 Γ^Dry X Receptor a (LXRo〇 Human U22622 NR1H4 Faneys X Receptor (FXR) Human U68233 NR1I1 Vitamin D Receptor (VDR) Human J03258 Vitamin D NR1I2 Pregnane X Receptor (PXR) Human AF061056 Exotic organism (dexamethasone, rifapicin) NR1I3 Constitutive male alkane receptor a (CARa) Human Z30425 androstenane NR2 Group NR2A1 Hepatocyte Nuclear Factor 4a (HNF4o〇 Human X76930 Fatty Acid NR2A3 Hepatocyte Nuclear Factor 4γ (ΗΝΡ4γ) Human Z49826 Fatty Acid NR2B1 Retinoid X Receptor a (RXRa) Human X52773 Retinoid NR2B2 Retinoid X Receptor P(RXRP) Human M84820 NR2B3 Retinoid X Receptor Y (RXRy) Human U38480 NR2C1 Testicular Receptor 2 (TR2) Human M29960 NR2C2 Testicular Receptor 4 (TR4) Human L27586 NR2E1 Drosophila tailless gene , TLX) Human homologue Human Y13276 NR2E3 Photoreceptor-specific nuclear receptor (PNR) Human AF121129 NR2F1 Chicken ovalbumin upstream promoter Transcription factor I (COUP-TFI) Human XI2795 NR2F2 Chicken egg white White Upstream Promoter Transcription Factor II (COUP-TFII) Human M64497 NR2F6 V-erAA Related Gene (EAR2) Human X12794 NR3 Group NR3A1 Estrogen Receptor a (ERa) Human P03372 Estrogen NR3A2 Estrogen Receptor Beta (ΕΙΙβ) Human AB006590 NR3B1 estrogen-related receptor a (ERRa) human X51416 NR3B2 estrogen-related receptor β (Εΐυΐβ) human AF094517 NR3B3 estrogen-related receptor γ (ΕϊΙΙΙγ) human AF058291 NR3C1 glucocorticoid receptor (GR) human X03225 cortex Alcohol NR3C2 Mineralocorticoid Receptor (MR) Human M16801 Aldosterone NR3C3 Progesterone Receptor (PR) Human M15716 Progesterone NR3C4 Androgen Receptor (AR) Human M20132 Prodosterone NR4 Group NR4A1 Nerve Growth Factor IBA (NGFI-Ba) Human L13740 NR4A2 nerve growth factor IBp (NGFI-Bp) human X75918 NR4A3 nerve growth factor IBy (NGFI_By) human D78579 NR5 group NR5A1 steroidogenic factor 1 (SF1) human U76388 NR5A2 liver receptor homologue-l (LRH-l) human U93553 NR6 Group 156004.doc ·33· 201143790 NR6A1 | Germ Cell Nuclear Factor (GCNF) Human | U64876 NR0B Subgroup (only LBD and 2 F with DBD) NR0B1 DAX1 Human S74720 NR0B2 Short heterodimer conjugate (SHP) Human L76571 Table data was taken from Laudet and Gronemeyer "The Nuclear Receptor Facts Book", Academic Press. The category identification number refers to the classification code of each member, and the registration number refers to the NCBI gene library nucleotide registration code. Activity of NHR Ligand (Y) In some embodiments, Y exhibits an EC5 对 (or IC5 在 in the case of an antagonist) exhibited by nuclear hormone receptor activation of about 10 mM or less, or 1 mM (1000 μΜ) or less than 1 mM (eg, about 750 μΜ or 750 μΜ, about 500 μΜ or 500 μΜ, about 250 μΜ or 250 μΜ, about 100 μΜ or less, about 75 μΜ or 75 μΜ , about 50 μΜ or less than 50 μΜ, about 25 μΜ or 25 μΜ, about 10 μΜ or 10 μΜ, about 7.5 μΜ or 7.5 μΜ, about 6 μΜ or less, about 5 μΜ or less, about 5 μΜ or less 4 μΜ or 4 μΜ or less, about 3 μΜ or 3 μΜ or less, about 2 μΜ or 2 μΜ or less, or about 1 μΜ or less. In some embodiments, the enthalpy exhibits an EC50 or IC50 for the nuclear hormone receptor of about 1000 nM or less than 1000 nM (eg, about 750 nM or 750 nM or less, about 500 nM or less, about 250 nM or 250 nM). Hereinafter, about 100 nM or 100 nM or less, about 75 nM or 75 nM or less, about 50 nM or 50 nM or less, about 25 nM or 25 nM or less, about 10 nM or 10 nM or less, about 7.5 nM or 7.5 nM or less, About 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, or about 1 nM or less. In some embodiments, 156004.doc -34·201143790 Y has an EC50 or IC50 for the nuclear hormone receptor in the picomolar range. Thus, in some embodiments, the ec50 or IC5〇 exhibited by Y to the nuclear hormone receptor is about 1000 pM or less than 1000 pM (eg, about 750 pM or 750 pM or less, about 500 pM or less, or about 250 pM). Or below 250 pM, about 100 pM or 100 pM or less, about 75 pM or 75 pM or less, about 50 pM or less, less than 25 pM or less, about 1 pM or less, about 7.5 pM or 7.5 pM or less, about 6 pM or less, less than 5 pM or less, about 4 pM or less, about 3 pM or less, about 2 pM or less, or about pρΜ or less than 1 ρΜ ). In some embodiments, the ec50 exhibited by the quinone on the nuclear hormone receptor or

The IC5 〇 is about 0.001 pM or more, 0.001 pM or more, about 0.01 pM or more, or about 0.1 pM or more. Nuclear hormone receptor activation (nuclear hormone receptor activity) can be measured in vitro by any assay known in the art. For example, activity on a nuclear hormone receptor can be measured by causing the receptor to behave under the control of a hormone-responsive promoter in a yeast cell that also has a reporter gene (eg, β-galactosidase). Thus, in the presence of a ligand that acts on the receptor, the gene is reported and the activity of the gene product can be reported (eg, by measuring β-galactosidase, such as initially yellowish red) The coloration of β-D-galactopyranoside (cprg) is decomposed into the activity of the red product as measured by absorbance. See, for example, Jungbauer and Beck, /. Chromatog. B, 77: 167-178 (2002) Routledge and Sumpter, 乂 〇 /. chm, 272: 3280- 3288 (1997) » Liu^A, J. Biol. Chem., 274: 26654-26660 (1999). NHR ligands and nuclear hormones The combination of the bodies can be determined using any combination of detections known in the art, such as fluorescence polarization or radioactivity determination. See, for example, Ranamoorthy et al, 138(4): 1520-1527 (1997) In some embodiments, the active phase exhibited by Y on the nuclear hormone receptor About 0.001% or more, about 0.01% or more, about 0.1% or more, about 0.5% or more, about 1% or more, about 5% or 5, for the primary nuclear hormone. % or more, about 10% or more, about 20% or more, about 30% or 30%, above, about 40% or more, about 50% or more, about 60% or 60% Above/❶, about 75% or more, about 100% or more, about 125% or more, about 150% or more, about 175% or more, about 200% or 200 More than %, about 250% or more, about 300% or more, about 350% or 350%, above, about 400% or more, about 450% or more, or about 500% or More than 500% (nuclear hormone potency). In some embodiments, the activity exhibited by Y on the nuclear hormone receptor is about 5000% or 5000% or less or about 10,000% or less than the native nuclear hormone. For the native ligand of the receptor, the activity of Y on the receptor is calculated as the inverse ratio of the EC50 of Y to the EC5〇 of the native ligand. In some embodiments, Y is the native ligand of the receptor. Structure of Ligand (γ) NHR Ligand of the Invention Y) and having partially or completely non-peptide hydrophobic or lipophilic. In some embodiments, the molecular weight of the 'NHR ligand is about 5000 Daltons or less 5,000 Daltons' or about 4000 Daltons or less, or about 3000 Daltons or less. , or about 2000 Dalton 156004.doc • 36-201143790 or less than 2000 Daltons, or about 1750 Daltons or less than 1750 Daltons, or about 1500 Daltons or less 1500 Daltons, or about 1250 Dalton or below 1250 Dalton, or about 1 Dalton or! Below Dalton, or below about 750 Daltons or 750 Daltons, or below about 500 Daltons or 500 Daltons, or below about 250 Daltons or 250 Daltons. The structure of Y can be based on any teachings disclosed herein. In the embodiments described herein, Y is bonded to L (eg, when L is a linking group) or Q (eg, when l is a bond) at any position where gamma is capable of reacting with Q or L. The location and manner of the combination can be readily determined by the skilled artisan in view of the general knowledge and the invention provided herein. In any of the embodiments described herein, wherein γ comprises three 6-membered rings attached to a 5-membered ring of a four-ring backbone or variants thereof (eg, Y acting on a vitamin 〇 receptor) 'carbon atoms of the backbone It is mentioned by the location number, as follows

For example, s, a modification having a ketone at position 6 refers to the following structure:

Li-R ligands that act on type I nuclear hormone receptors 156004.doc -37· 201143790 In some embodiments of the invention, the 'NHR ligand (Y) acts on a type I nuclear hormone receptor. In some embodiments, γ can have any structure that allows or promotes agonist activity when the ligand binds to a Type I nuclear hormone receptor. In other embodiments, γ is a type of nuclear hormone receptor. An antagonist of the body. In an exemplary embodiment, Υ includes a structure as shown in the formula:

Formula A wherein R1 and R2, when present, are independently a moiety that allows or promotes the activity of an agonist or antagonist when a compound of formula A is bound to a type I nuclear hormone receptor; R3 and R4 are independently compounds of formula A A moiety that allows or promotes the activity of an agonist or antagonist when bound to a Type I nuclear hormone receptor; and each dashed line indicates a double bond that is optionally present. Formula A may further include one or more of the positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 14, 15, 16, 17, 18, and 19 Multiple substituents. Substituents which are optionally included include, but are not limited to, hydrazine H, NH2, ketone, and CVCu alkyl. In some embodiments, Y comprises the structure of Formula A, wherein R1 is present and is hydrogen, C丨-C18 alkyl, C2-Ci8 alkenyl, C2-C18 alkynyl, heteroalkyl, (CVC8 alkyl) aryl (C〇-C8 alkyl)heteroaryl, ((: 〇-(:8 alkyl)C(0)Ci-C18 alkyl, (c〇-c8 alkyl)c(o)c2-c18 ene , (c〇-c8 alkyl) C(0)C2-C18 alkynyl, (C(rC8 alkyl)C(0)H, (C(rC8 alkane I56004.doc • 38 · 201143790 base) C(o Aryl, (C(rC8 alkyl)c(o)heteroaryl, (C(rc8 alkyl), (C(rC8 alkyl)c(o)〇c2_cl8 dilute, (c〇_ c8 alkane) ))C(0)〇C2-C18 alkynyl, (C〇-C8 alkyl)C(〇)〇H, ((:〇-<:8 alkyl)c(0)0 aryl, (c 〇-c8 alkyl)c(o)oheteroaryl, (C(rC8 alkyl)C^C^NR^Ci-Cis alkyl, (CQ-C8 alkyl)c(〇)NR24C2-Ci8 alkenyl , (CG-C8 alkyl) c(o)nr24c2-c18 alkynyl, (C(rC8 alkyl) C(0)NR24H2, (C〇-C8 alkyl) C(0)NR24 aryl, (C〇 -c8 alkyl) C(0)NR24 heteroaryl or S03H; R2 is present and is hydrogen, (C〇-C8 alkyl)-yl, C!-C18 alkyl, C2-C18 alkenyl, C2-C18 alkyne Base, miscellaneous , (CQ-C8 alkyl) aryl, (cG-C8 alkyl) heteroaryl, (Co-Cs alkyl) 0 (ν(:18 alkyl, (c〇-C8 alkyl)oc2-Ci8 Alkenyl, (CG-C8 alkyl) OC2-C18 alkynyl, (<:0-(:8 alkyl) fluorene 11, (c〇-C8 alkyl) SH, (C〇-C8 alkyl) NR ^CVCu alkyl, (CG-C8 alkyl) NR24C2-C18 alkenyl, (CG-C8 alkyl) nr24c2-c18 alkynyl, (CG-C8 alkyl) NR24H2, (CG-C8 alkylalkyl, ( (:.-(:8-alkyl)C(0)C2-C18 alkenyl, (Cg-C8 alkyl)c(0)c2-c18 alkynyl, (Cg-C8 alkyl)c(o)h, (C〇_C8 alkyl)C(O)aryl, (C〇-C8 alkyl)c(o)heteroaryl, (CQ-C8 alkyl)alkyl, (C〇-C8 alkyl)c (o) oc2-c18 alkenyl, (c〇-c8 alkyl)c(o)oc2-c18 alkynyl, (c〇-c8 alkyl)c(o)〇H, (c0-c8 alkyl)c (o)oaryl, (c〇-c8 alkyl)c(o)o heteroaryl, (c〇-c8 alkylalkyl, (c〇-c8 alkyl) oc(o)c2-c18 olefin , (cQ-c8 alkyl) oc(o)c2-c18 alkynyl, (c〇-c8 alkyl) C^C^NRWcvCu alkyl, (C()-C8 alkyl) (:0 State 1124 (:2-(:18 alkenyl, (C〇-C8 alkyl) C(0)NR24C2 -C!8 Fast radical, (C〇-C8 alkyl) 156004.doc •39- 201143790 C(0)NR24H2, (c0-c8 alkyl)C(0)NR24 aryl, (C〇_c8 alkyl C(0)NR24 Heteroaryl, (C〇-C8 alkyl) NR24C(0)Ci-C18 alkyl, (c〇-c8 alkyl)nr24c(o)c2-c8 alkenyl or (c〇- C8 alkyl)nr24c(o)c2-C18 alkynyl, (c〇-c8 alkyl)nr24c(o)oh, (c〇-c8 alkyl)alkyl, (c〇-c8 alkyl)oc(o Oc2-c18 alkenyl, (c0-c8 alkyl) 0C(0)0C2-C18 alkynyl, (C〇-C8 alkyl) 0C(0)0H, (C〇-c8 alkylalkyl, (C 〇-C8 alkyl) 〇C(〇)NR24C2·C18 alkenyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkynyl, (c〇-c8 alkyl)〇C(0)NR24H2 (C〇-C8 alkyl) NR'COOCVCis alkyl, (c. - % c8 alkyl) nr24(o)oc2-c18 alkenyl, (c〇-c8 alkyl)NR24(o)oc2-c18 alkynyl or (c〇-c8 alkyl)nr24(o)oh ; R is Hydrogen, (C〇-C8 alkyl) halo, C1-C18 alkyl, C2-C18 dilute, CVC]8 alkynyl, heteroalkyl, (cvc8 alkyl)aryl, (c〇-c8 alkyl Heteroaryl, (C〇-C8 炫•基)0C!-Ci8 alkyl, (Cq-Cs alkyl) OC2-C18 dilute, (Co-Cg alkyl) OC2-C18 fast radical, (C〇 -C8 alkyl)OH, (C〇-Cs alkyl) SH, (C〇-C8 alkyl)alkyl, (c〇-c8 alkyl) NR24C2-Cl8 dilute, (Co-Cg pit based) NR24C2 -Ci8 alkynyl, (C〇-C8 appearance _ group) NR24H2, (C〇.C8 alkyl) (:(0)(^-(^8 alkyl, (c〇-c8 alkyl) C(0) C2-C18 alkenyl, (C()-C8 alkyl) C(0)C2-C18 alkynyl, ((: 〇.(:8 alkyl)c(o)H, (c〇-c8 alkyl) c(o)aryl, (c0-c8 alkyl)c(o)heteroaryl, (C〇-C8 alkyl)qoeCVCu alkyl, (c〇-c8 alkyl)c(o)oc2-cl8 , (cG-c8 alkyl) c(o)oc2-c18 alkynyl, (cG-c8 alkyl) c(o)oh, (c〇-c8 alkyl)c(o)oaryl, (c 〇-c8 alkyl)c(o)oheteroaryl, (c〇-c8 Alkyl) 〇c(o)cvc18 alkyl, (C〇-C8 alkyl) 0C(0)C2- 156004.doc • 40- 201143790 C18 alkenyl, (c〇-c8 alkyl)oc(o)c2 -c18 alkynyl, (C(rC8 alkyl)(^CONRWcVCualkyl, (CQ-C8 alkyl)(:(0 State 1124(:2-(:18 alkenyl, (CVC8 alkyl)c(o) Nr24c2-c18 alkynyl, (CG-C8 alkyl) C(0)NR24H2, (C〇-C8 alkyl) C(0)NR24 aryl, (C〇_c8 alkyl) C(0)NR24 heteroaryl , (C〇-C8 alkyl) NRWqcOCVCu alkyl, (c〇-c8 alkyl) nr24c(o)c2-c8 alkenyl or (c〇-c8 alkyl) nr24c(0)c2-c18 alkynyl, (C()-C8 alkyl)NR24C(0)0H, (C(rC8 alkyl) OC^COOCVCu alkyl, ((:〇-(:8 alkyl)0(:(0)0(:2- (: 18 alkenyl, (c0-c8 alkyl) 0C(0)0C2-C18 alkynyl, (C()-C8 alkyl) 〇c(o)oh, (c〇-c8 alkyl (OCCCONR^CVCu Alkyl, (c〇-c8 alkyl) oc(o)nr24c2-C18 alkenyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkynyl, (Cg-C8 alkyl) oc(o) Nr24h2, (c〇-c8 alkyl)nrAcoocvcualkyl, (c0-c8 alkyl)NR24(0)0C2-C18 alkenyl, (C〇-C8 alkyl)NR24(0)0C2-C18 alkynyl or C〇-c8 alkyl Nr24(o)oh ; R is a mouse, (C〇-Cs alkyl) halide, C1-C18 alkyl, C2-C18 dilute, Ci-Ci8 alkynyl, miscellaneous, (Co-Cs alkyl) Aryl, (C〇-C8), heteroaryl, (C〇-C8), 〇Ci-Ci8, (Cq-Cs) OC2-C!8, (C〇-C8) Alkyl) OC2-C18 alkynyl, (CQ-C8 alkyl) 〇H, (C〇-C8 alkyl) SH, (Cg-C8 alkyl) NRCCI-Cu alkyl, (CQ-C8 alkyl) NR24C2 -C18 dilute, (Cq-Cs alkyl) NR24C2_Ci8 alkynyl, (Co-Cg) NR24H2, (C〇-C8 alkyl^(COCVCu alkyl, (CVC8 alkyl)c(o)c2-c18 Alkenyl, (CG.C8 alkyl) C(0)C2-Ci8 alkynyl, (c〇-c8 alkyl) C(0)H, (c〇-c8 alkyl)c(o)aryl, C0-c8 alkyl)c(o)heteroaryl, (C〇-C8 alkyl)qCOOCVCualkyl, (C〇-C8 alkyl)C(0)0C2-156004.doc •41 - 201143790

Ci8 dilute group, (C〇-C; 8 alkyl) C(0)0C2-Ci8 block, (C〇.C8 alkyl) c(o)oh, (c0-c8 alkyl)c(o)o Aryl, (c〇-c8 alkyl)c(o)o heteroaryl, (c〇-c8 alkylalkyl, (C(rC8 alkyl) oc(o)c2-c18 alkenyl, (Cg- C8 alkyl)oc(o)c2-c18 alkynyl, (c〇-c8 alkyl) C^C^NR^CVCu alkyl, (C()-C8 alkyl) (:0 State 1124(:2) -(:18 alkenyl, (c〇-c8 alkyl)c(0)nr24c2-c18 alkynyl, (CG-C8 alkyl) C(0)NR24H2, (C〇_C8 alkyl)C(0) NR24 aryl, (C0-C8 alkyl) C(0)NR24 heteroaryl, (C〇-C8 alkyl) NRWqCOC^-Cu alkyl, (c〇-c8 alkyl) nr24c(o)c2-c8 Alkenyl or (c〇-c8 alkyl) nr24c(o)c2. c18 alkynyl, (cQ-c8 alkyl) nr24c(o)oh, (c〇_c8 alkyl) 0C(0)0Ci-C18 alkane Base, (c〇_c8 alkyl) oc(o)oc2-c18 alkenyl, (c〇-Cg alkyl) 0C(0)0C2-Ci8 fast radical, (C〇-C8 alkyl) oc(o) Oh, (c〇_ c8 alkyl)oc(o)nr24cvc18 alkyl, (c〇-c8 alkyl) 0C(0)NR24C2-C〗 8 alkenyl, (C〇-C8 alkyl) 0C(0) NR24C2_Ci8 alkynyl, (C(rC8 alkyl)0C(0)NR24H2, (C(rC8 alkyl) NR'COOCV c18 alkyl, (C(rC8 alkyl)nr24(o)oc2-c18 alkenyl, (c〇-c8 alkyl)nr24(o)oc2-c18 alkynyl or (c〇-c8 alkyl) Nr24(o)oh; and R24 is hydrogen or q-Cualkyl. In some embodiments, Y comprises a structure of formula A wherein R1 is present and is argon, CVC7 alkyl, (C〇-C3 alkyl) C (0)C丨_(:7 alkyl, (c〇-c3 alkyl)c(o)aryl or S03H; R2 is present and is hydrogen, halo, 0^ or (:丨-(:7 alkyl) R3 is hydrogen, amide, alkyl; R4 is hydrogen, (C〇-C8 alkyl) dentate, CVC8 alkyl, C2-C8 alkenyl, C2.18 156004.doc -42- 201143790 Fast-radical, hetero-alkane , (C〇-C8 alkyl) aryl, (c〇-c8 alkyl)heteroaryl, (C〇-C8 alkyl WCi-Cs alkyl, (c〇-C8 alkyl) OC2-C8 olefin ''c〇-C8 alkyl) OC2-C8 alkynyl, (CVC8 alkyl)OH, (CG-C8 alkyl) SH, (C〇-C8 alkyl) NR^Ci-Cs alkyl, (c 〇.C8 alkyl)NR24C2-C8 alkenyl, (c0-C8 alkyl) NR24C2-C8 alkynyl, (C〇-C8 alkyl) NR24H2, (C〇-C8 alkyl)alkyl, (cQ-c8 Alkyl)c(o)c2-c8 alkenyl, ((:. -(:8-alkyl)c(o)c2-c8 alkynyl, (CG-C8 alkyl)c(o)H, (cQ-c8 alkyl)c(0) aryl, (C〇-C8 alkane (c)heteroaryl, (C〇-C8 alkyl) ¢: (0) 0 (^-(:8 alkyl, (cG-c8 alkyl) c(o)oc2-c8 alkenyl, (Cq_c8 alkyl) C(0)OC2-C8 alkynyl, (Cg-C8 alkyl)C(0)0H, (CQ-C8 alkyl) c(o)o aryl, (c〇-c8 alkyl c(o)o Heteroaryl, (C(rC8 alkyl)0(:(0)(^-(:8 alkyl, (c〇-c8 alkyl)oc(o)c2-c8 alkenyl, (c〇-c8 alkyl) 0C(0)C2-C18 alkynyl, (C〇-C8 alkyl^(CONR^Ci-Cs alkyl, (cQ-c8 alkyl)c(o)nr24c2-c8 ene , (CG-C8 alkyl) c(o)nr24c2-c8 alkynyl, (c〇-c8 alkyl)c(o)nr24h2, (C〇-C8 alkyl)C(0)NR24 aryl, C〇-C8 alkyl)C(0)NR24 heteroaryl, (c0-c8 alkyl)NR^C^COCVCs alkyl, (C〇-C8 alkyl)NR24C(0)C2-C8 alkenyl or C〇-c8 院基)nr24c(o)c2-c8 alkynyl, (c〇-c8 alkyl)NR24C(0)0H, (Cg-C8 alkyl)0(:(0)0(^-(: 8 alkyl, (c〇-c8 alkyl) 0C(0)0C2-C8 alkenyl, (CcrC8 alkyl) 0C(0)0C2-C8 alkynyl, (C〇-C8 alkyl) 0C(0)0H , C〇-C8 alkylalkyl, (c〇-c8 alkyl) oc(o)nr24c2-c8 alkenyl, (c〇-c8 alkyl) 〇C(0)NR24C2-C8 alkynyl, (C〇- C8 alkyl) 0C(0)NR24H2, (c〇-c8 炫) NR'COOCVCs alkyl, (C〇-C8 alkyl) NR24(0)0C2-C8 ene 156004.doc -43- 201143790 base, ( C〇-c8 alkyl)nr24(〇)〇c2-c8 alkynyl or (c〇.c8 alkyl)nr24(o)oh; and R24 is hydrogen or CVC7 alkyl. In some embodiments, R1 is hydrogen a propionate group, an acetate group, a benzoate group or a sulfate group; R 2 is hydrogen or a methyl group; R 3 is hydrogen or a fluorenyl group; and R 4 is an acetate group or a cyclopentanoate group, a succinate group, a heptanoate group or a propionate group. In an embodiment where Y comprises a structure of formula A, γ is bonded to L at any position of formula a which is capable of reacting with Q or L (eg, when When L is a linking group) or Q (for example, when L· is a bond), those skilled in the art can readily determine the binding position on Formula A and the combination of Formula a in view of the general knowledge and the invention provided herein. The way to Q or L. In some embodiments 'form a is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 of formula a Or any of 20 is bound to l or q. In some embodiments, Formula A is bonded to L or Q at position 1, 3, 6, 7, 12, 1 , 13, 16, 17, or 19 of Formula A » In some embodiments, Y is an estrogen Receptors (eg, ERa, ERp) work. In some embodiments, Y allows or promotes agonist activity on the estrogen receptor, while in other embodiments, Y is an antagonist of ER. In an exemplary embodiment, Y may have the structure of Formula B:

156004.doc • 44-201143790 r R and ^·6 are the parts that allow or promote the activity of an agonist or antagonist when a compound of formula b binds to an estrogen receptor. In some embodiments, the progression of Formula B includes one or more substituents on one or more of positions 1, 2, 4, 6, 7, 8, 9, 11, 12, 14, 15, and 16 (eg, Ketone at position 6). In some embodiments, when γ comprises the structure of formula B, wherein R is fluorene, CVCis alkyl, C2-C18 alkenyl, c2-c18 alkynyl, heptyl, (C〇-C8 alkyl) aryl , (c0-c8 alkyl) heteroaryl, (c〇_c8 alkyl)CHCOCi-Cu alkyl, (Cg_c8 alkyl)c(0)c2_Ci8 alkenyl, (c❶_c8 alkyl)c(o)c2- C18 alkynyl, (c〇-c8 alkyl)c(o)H, (c〇-c8 alkyl)c(0)aryl, (cvc8 alkyl)c(o)heteroaryl, (c<rc8 Alkyl)alkyl, (.C(rC8 alkyl)C(0)0C2-C18 alkenyl, (c0-c8 alkyl)c(o)oc2-c18 alkynyl, (CG-C8 alkyl)C ( 0) 0H, ((: 〇-(:8 alkyl)c(0)0 aryl, (c〇-c8 alkyl)c(o)o heteroaryl, (c0-c8 alkyl)qcONR^C ^-Cu alkyl, (C〇-C8 alkyl) C(0)NR24C2-C18 dilute, (C«rC8 alkyl) C(0)NR24C2-C18 alkynyl, (C〇-C8 alkyl)C (0) NR24H2, (C0-C8 alkyl) C(0)NR24 aryl, (c0-c8 alkyl) C(0)NR24 heteroaryl or S03H; R5 is hydrogen, (C〇-Cs pit base) Halogen, Ci_Ci8 alkyl, C2-C18 dilute, C2_C18 alkynyl, heteroalkyl, (C0-C8 alkyl)aryl, (C〇-C8 alkyl)heteroaryl, (C〇-C8 alkyl) 〇Ci_Ci8 alkyl, (Cq-Cs) OC2-C18 dilute, (C〇-C8 alkyl) OC2-C18 block, (Cg_C8 alkyl) 0H, (C〇 -C8 alkyl) SH, (C()-C8 alkyl) nr24cvc18 alkyl, (CG-C8 alkyl) NR24C2-c18 alkenyl, (C()-C8 alkyl) nr24c2-c18 alkynyl, (c 〇-c8 alkyl)NR24H2, (C〇-C8 alkyl) (XCOCVCu alkyl, (c〇-c8 alkane 156004.doc -45- 201143790 base) C(0)C2-C18 alkenyl, (C(rC8) Alkyl)C(0)C2_C]8 alkynyl, alkyl)C(0)H, (C〇-C8 alkyl)C(0)aryl, (C〇-C8 alkyl)c(〇) Aryl, (C〇-C8 alkyl) C(0)0Cl_Ci8 alkyl, (CVC8 alkyl) C(0)0C2-C18 alkenyl, (C(rC8 alkyl)c(〇)〇C2_Ci8 alkynyl, (c.-c8 base) C(0)0H, (C0-C8 alkyl)c(o)o aryl, (c〇-c8 alkyl)c(o)oheteroaryl, (c〇_ C8 alkyl) 0C(0)Ci_Ci8 alkyl, alkyl) 0C(0)C2-C18 alkenyl, (cQ-C8 alkyl)oc(o)c2-c18 alkynyl' (C〇-C8 alkyl) C(〇)NR24Ci_Ci8 alkyl, (C(rC8), C(0)NR24C2_C18 alkenyl, (c〇-C8 alkyl) (:(0"1124(:2-(:18 alkynyl, C〇-C8 alkyl)C(〇)NR24H2, (C〇-C8 alkyl)C(0)NR24 aryl, (C〇-C8 alkyl)c(〇)NR24 heteroaryl, (C〇 -C8 alkyl) NR^C^COCVCu alkyl, (c〇-C8 alkyl) NR24C(0)C2-C8 alkenyl or (c〇-c8 alkyl)nr24c(o)c2-c18 alkynyl, C〇-c8 alkyl) nr24c(o)oh, (c〇-c8 alkyl)oc(o)oc丨-C18 alkyl, ((:. -(:8-alkyl)oc(o)oc2-c〗8-alkenyl, (c〇-c8 alkyl)oc(o)oc2-c18 alkynyl, (C〇-C8 alkyl)0C(0)0H (C〇-C8 alkyl, (c〇-c8 alkyl) oc(o)nr24c2-c18 alkenyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkynyl, (c〇- C8 alkyl)oc(o)nr24h2 '(C〇-C8 alkyl)NR'COOCVCu alkyl, (C〇-C8 alkyl) nr24(〇)〇c2-c18 alkenyl, (c〇-c8 alkyl Nr24(o)oc2-c18 alkynyl or (c〇-c8 alkyl)NR24(0)0H; (CG-C8 alkyl)alkyl, (C〇-C8 alkyl)C(0)C2-Ci8 Dilute, (C〇-C8 alkyl) C(0)C2-Ci8 fast radical, (CG-C8 alkyl)CHCOOCi-Cu alkyl, (cvc8 alkyl)c(o)oc2-c18 alkenyl, C〇-c8 alkyl)c(o)oc2-c18 alkynyl, (cG-c8 alkane 156004.doc • 46-201143790 base) C(0)0H, (CQ-C8 alkyl)0(:(0) (^-(^ alkyl, (C(rC8 alkyl)0C(0)C2-C18 alkenyl, (CG-C8 alkyl)0C(0)C2-Ci8 alkynyl, (c〇-c8 alkyl) C^CONRWCrCualkyl, (CQ-C8 alkyl) C(0)NR24C2-C18 alkenyl, (cG-c8 alkyl)c(o)nr24c2-c18 alkynyl, (C〇-C8 alkyl)C ( 0) NR24H2, (C〇_C8 alkyl) NRWqCOCVCu alkyl, C〇-C8院) NR24C(0)C2-C8 alkenyl or (C〇-C8 alkyl)NR24C(0)C2-C18 alkynyl or (c〇-c8 alkyl)nr24c(o)oh ; φ R6 is hydrogen, Ci-Ci8 alkyl, c2-c-8 alkenyl, c2-c18 alkynyl, heteroalkyl, (C〇-C8 alkyl)aryl, (c0-c8 alkyl)heteroaryl, (c〇-C8 alkyl) 0: (0) (:, - (:, 8 alkyl, (C(rC8 alkyl) c(o)c2-c18 alkenyl, (c〇-c8 alkyl) C (0) C2-C18 alkynyl, (CVC8 alkyl) C(0)H '(c〇-c8 alkyl)c(o)aryl, (c〇-c8 alkyl)c(0)heteroaryl (c〇-C8 alkyl) (:(0)0(ν(:18 alkyl, (c〇-c8 alkyl)c(o)oc2-c18 alkenyl, (c〇-c8 alkyl)C (0) 0C2_C18 alkynyl, (C〇-C8 alkyl) C(〇)〇H, (C〇-C8 alkyl)c(o)oaryl, (c〇-c8 alkyl)C(〇) Heteroaryl, (c〇_c8alkylφ)C(〇)Nr24ci_Ci8 alkyl, (c〇-c8 alkyl)c(o)nr24c2-c18 alkenyl, (c〇-c8 alkyl)c ( o) nr24c2-c18 alkynyl, (C〇-C8 alkyl) C(0)NR24H2, (C〇-C8 alkyl)c(〇)NR24 aryl, (c0-c8 alkyl)C(0)NR24 Heteroaryl or S03H; and R24 is hydrogen or CVCu alkyl. In some embodiments, Y comprises the structure of formula B, wherein R1 is hydrogen, C^-C? alkyl, (c0-c3 alkyl)alkyl, (c〇-c3 alkyl)c(o)aryl Or so3h; R5 is argon, (C〇-C8 alkyl) insect base, crC8 alkyl, C2-C8 dilute, C2.18 156004.doc • 47- 201143790 alkynyl, heteroalkyl, (Co-Cs alkane (A) aryl, (C〇-C8 alkyl)heteroaryl, ((^-(^ alkyl...^-^ alkyl, (C()-C8 alkyl))0C2_C8 alkenyl, (c〇-c8) Anthracene) OC2-C8 alkynyl group, (CG-C8 alkyl) OH, (CQ-C8 alkyl) SH, (C〇-C8 alkyl) NR24CVC8 alkyl, (C〇-C8 alkyl) NR24C2-C8 Dilute, (C〇-C8 alkyl) NR24C2-C8 alkynyl, (C〇-C8 alkyl) NR24H2, (CcrC8 alkyl)alkyl, (CVC8 alkyl) C(〇)C2-C8 alkenyl, ((: 〇-(:8 alkyl)C(0)C2-C8 alkynyl, (CG-C8 alkyl)C(0)H, (C〇-C8 alkyl)c(o) aryl, ( C〇-C8 alkyl)C(O)heteroaryl, (C〇-C8 alkyl)C(0)OCi-C8 alkyl, (c〇-c8 alkyl)c(o)oc2-c8 alkenyl , (c〇-c8 alkyl), C(0)0C2-C8 alkynyl, (Cg-C8 alkyl) C(〇)〇H, (C〇-C8 alkyl)C(0)0 aryl, (C〇-C8 alkyl) C(0) anthracene aryl, (c0-c8 alkyl) 0C(0)Ci-C8 alkyl, (C〇-C8 alkyl) 0C(0)C2-C8 Base, (c〇_ C8 alkyl) 0C(0)C2-C18 alkynyl, (CQ-C8 alkyl) C^CONR^CVCs alkyl, (c〇-c8 alkyl)c(o)nr24c2-c8 Alkenyl, (C(rc8 alkyl)c(o)nr24c2-c8 alkynyl, (c〇-c8 alkyl)c(0)nr24h2, (c〇-c8 alkyl)C(0)NR24 aryl, (C〇-C8 alkyl) C(0)NR24 heteroaryl, (c0-c8 alkyl) nr24c(o)c, -c8 alkyl, (c〇-c8 alkyl)nr24c(0)c2-c8 · alkenyl or (c〇-c8 alkyl) nr24c(o)c2-c8 alkynyl, (CG-C8 alkyl)NR24C(0)0H, (C〇-C8 alkyl)0(:(0)0 (^-(:8 alkyl, (c〇-c8 alkyl) 〇c(o)oc2-c8 alkenyl, (C〇-C8 alkyl) 0C(0)0C2-C8 alkynyl, (C〇- C8 alkyl)0C(0)0H, (C〇-C8 alkyl)OC^CONR^CrCs alkyl, (C〇-C8 alkyl)0C(0)NR24C2-C8 alkenyl, (C(rC8 alkyl) Oc(o)nr24c2-c8 alkynyl, (c〇-c8 alkyl) 〇c(o)nr24h2, (c〇-c8 alkyl)NR24(0)0Ci-C8 alkyl, (cQ-c8 alkyl) Nr24(o)oc2-c8 ene 156004.doc 48- 201143790 base, (c〇-c8 alkyl) nr24 (o) oc2-c8 alkynyl or (C(rC8 alkyl) nr24(o)oh ; R6 is hydrogen, CrCs alkyl, C2-C8 alkenyl, C2-C8 alkynyl, heteroalkyl, (C〇- C8 alkyl) aryl, (C〇-C8 alkyl)heteroaryl, (c0-C8), C^COCVCs alkyl, (c〇-c8 alkyl) C(0)C2-C8 alkenyl, (<:. -(:8-alkyl)C(0)C2-C8 alkynyl, (C〇-C8 alkyl)C(0)H, (C(rC8 alkyl)C(O)aryl, (c〇-c8 Alkyl)c(o)heteroaryl' (C〇-C8 alkyl)(:(0)04-c8 alkyl, (CQ_C8 alkyl)c(o)oc2-c8 homing, (c〇-C8 Affinity) c(o)oc2-c8 alkynyl, (C〇-C8 alkyl)C(〇)〇H, (CG-C8 alkyl)c(o)oaryl, (c0-c8 alkyl) c(o)oheteroaryl, (c〇_C8 alkyl)C(0)Nr24Ci-C8 alkyl, (CG-C8 alkyl)c(〇)NR24C2-C8 alkenyl, (C〇-C8 alkane Base) C(〇)NR24C2_C8 alkynyl, (Cg C8 alkyl) C(0)NR24H2, (C〇-C8 alkyl) C(0)NR24 aryl or (CQ_C8 alkyl) C(0)NR24 heteroaryl And R24 is hydrogen or a group. For example, R1 is hydrogen, propionate group, acetate group 'benzoate group or sulfate group; R5 is hydrogen, ethynyl group, hydroxyl group; and R6 is B An acid ester group, a cyclopentanoate group, a succinate group, a heptanoate group or a propionate group. Non-limiting examples of the compound of the formula B include 17-estradiol; estradiol; Modified forms such as β-estradiol 17-acetic acid vinegar, β-estradiol 17-cyclopentanopropionate, β-estradiol 17·heptanoate,|3_estradiol η·valerate, ρ·estradiol 3,17-diacetate, β-estradiol 3,17-dipropionate, and estradiol 3_ benzoate, β-estradiol 3_benzoate 17_n-butyrate, β•estradiol 3·glycidyl ether, β-estradiol 3_methyl ether, β-estradiol 6•ketone, estradiol 3_ 156004.doc • 49· 201143790 glycidol, β-estradiol 6__ 6-(〇- drum-based fat), 16-epitriol, 17-epitriol, 2-methoxyestradiol, 4-methoxyprogesterone, estradiol 17-phenylpropionate and 17β-estradiol 2_anthracene, 17α-ethynyl estradiol, acetate Progesterone, estriol, and derivatives thereof. In some embodiments 'carbon 17 has a ketone substituent and R5 and R6 are absent (e.g., estrone). ^ Some of the compounds of formula B above are shown below:

In an embodiment where Y comprises a structure of formula B, γ is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position of formula b capable of reacting with q or L Those skilled in the art will readily be able to determine the binding position on Formula 3 and the manner in which Formula B is bonded to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, Formula B is in Formula b. Position ι, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 ' 12, 13, 14, 15, 16, 17, 18, 19 or 20 to ^ or In some embodiments, Formula B binds to B or E in position 3 or 17 of Formula B. In other embodiments, Y acts on the estrogen receptor but is not covered by Formula 8. Non-limiting examples of ligands that function and are not covered by Formula B are shown below: 156004.doc -50· 201143790

In some embodiments, Y acts on a glucocorticoid receptor (GR). In some embodiments, the oxime comprises any structure that allows or promotes the activity of the agonist of GR. In other embodiments, hydrazine is an antagonist of GR. In the exemplary embodiment, Υ contains the structure of equation C:

Wherein R2, R3, R6, R7, R8, R9 and each are independently a moiety which allows or promotes the activity of the agonist or antagonist when the compound of formula c is bonded to the GR; and each dotted line represents a double bond as the case may be. In some embodiments, formula c further comprises one or more substituents (e.g., a hydroxyl group or _ at position 丨丨) on one or more of the positions. In some embodiments, Y comprises a structure of formula C, wherein R 2 is hydrogen, (Co-Cs alkyl)dentate, Cl_Cl 8 alkyl, C 2 -Ci 8 alkenyl, C 2 -cu alkynyl, heteroalkyl, (c 〇 _ C8 alkyl)aryl, ((VC8 alkyl)heteroaryl 156004.doc •51·201143790 base, (C()-C8 alkyl)oq-Cualkyl, (C()-C8 alkyl)oc2- C18 alkenyl, (c〇-c8 alkyl) 〇C2-C丨8 alkynyl, (c〇-c8 alkyl)〇H, (cG-c8 alkyl)SH, (Co-C8) NR24Ci- C18 alkyl, (C〇-C8 alkyl) NR24c2. c18 alkenyl, (cG-c8 alkyl) nr24c2-cI8 alkynyl, (cG-c8) nr24h2, (c〇-c8 alkyl) c ( o) c丨-c18 alkyl, (c〇-c8) C(0)C2-C18 alkenyl, (cG_C8 alkyl)c(0)c2-c18 alkynyl, (C〇-c8 alkyl) C(0)H, ((VC8 alkyl)C(O)aryl, (C〇-C8 alkyl)C(0)heteroaryl, (C〇-C8 alkyl)CCCOOCVCis alkyl, (c〇 -c8 alkyl)C(0)0C2-C18 alkenyl, (CQ-C8 alkyl)C(0)OC2-C18 alkynyl, (CV c8 alkyl)C(0)0H, (c〇-c8 alkane Base) c(o)o aryl, (c〇-c8 alkyl) C(0)0 heteroaryl, (c0-C8 alkylalkyl, (C〇-C8 burned) Oc(o)c2-c18 alkenyl, (c〇-c8 alkyl) 〇c(o)c2-c18 alkynyl, (c〇-c8 alkyl) (^(^NRWcVCu alkyl, (c〇-) C8 alkyl) C(0)NR24C2-C18 alkenyl, (C〇-C8 alkyl) (: (0 State 1124 (: 2-(:18 alkynyl, (C〇-C8 alkyl) C(0) NR24H2, (C〇-C8 alkyl) C(0)NR24 aryl, (CVC8 alkyl) C(0)NR24 heteroaryl, (c〇-C8 alkyl) NRWc^COCVCu alkyl, (cQ-c8 Alkyl)nr24c(o)c2-c8 alkenyl or (C〇-C8) NR C(0)C2-Ci8 block, (Co-Cg alkyl)NR24C(0)0H' (C〇-C8 Alkyl) 0C(0)0C丨-C18 alkyl, (CVC8 alkyl) 0C(0)0C2-Cis dilute, (Cq-C8 alkyl) OC(0)OC2-C18 alkynyl, (CG-C8 Alkyl) 0C(0)0H, (C〇-C8 alkyl)OqCONR^Ci-C^ alkyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkenyl, (c〇-c8 alkane Base) 0C(0)NR24C2-C18 alkynyl, (c〇-c8 alkyl)oc(o)nr24h2, (c0-c8 alkyl)NR'COOCVCu alkyl, (CG-C8 156.004.doc •52· 201143790 base) nr24(o)oc2-c18 alkenyl, (c〇-c8 alkyl)nr24(o)oc2-c18 alkynyl or (c〇-c8 alkyl)NR24(〇)〇H; R3 is hydrogen, (C(rC8 alkyl) , CrCu alkyl, C2-C18 alkenyl, C2_Ci8 alkynyl, heteroalkyl, (C〇-C8 alkyl) aryl, (C〇-C8 alkyl) heteroaryl, (C()-C8 alkane a group WCVCu alkyl, (CG-C8 alkyl) OC2-C18 alkenyl, (C〇-C8 alkyl) OC2-C18 alkynyl, (C〇-C8 alkyl) OH, (CVC8 alkyl) SH, ( C〇-C8 alkyl) NR^CVCu alkyl, (CQ-C8 alkyl) NR24C2-c18 alkenyl, (cG-c8 alkyl) nr24c2-c18 alkynyl, (cQ-c8 alkyl) NR24H2, C〇-C8 alkyl)C^COCVCu alkyl, (c〇-c8 alkyl)c(o)c2-c18 alkenyl, (c〇-c8 alkyl)c(o)c2-c18 alkynyl, Cvc8 alkyl)C(0)H, (C〇-C8 alkyl)c(0)aryl, (CcrC8 alkyl)C(O)heteroaryl, (C〇-C8 alkyl)C^COOC^ -Cu alkyl, (CcrC8 alkyl) C(0)0C2-C18 alkenyl, (Cq-C8 alkyl) C(0)0C2-C18 alkynyl, (CV c8 alkyl)c(o)oh, C〇-c8 alkyl)c(o)o aryl, (c〇-c8 alkyl)C(0)0 heteroaryl, (C〇-C8 alkylalkyl, (C〇-C8 φ alkyl) ) 0C(0)C2-C18 alkenyl, (c〇-c8 alkyl)oc(o)c2-c18 alkynyl, (c〇-c8 alkyl) (^conrMcvc^ alkyl, (CQ-C8) Base) c(o)nr24c2-c18 alkenyl, (cG-c8 alkyl)c(o)nr24c2-c18 alkynyl, (C〇-C8 alkyl)C(0)NR24H2, (C〇-C8 alkyl C(0)NR24 aryl, (c0, C8 alkyl) C(0)NR24 heteroaryl, (C0-C8 alkyl) NR^C^COCi-Cu^, (c〇_c8 alkyl) Nr24c(0)c2-c8 dilute group or (C(rC8 alkyl)nr24c(o)c2-c〗8 alkynyl, (c〇-c8 alkyl)nr24c(o)oh, (c0_ c8 alkyl)00 (0)00:,-0:,8 alkyl, (c〇-c8 alkyl)oc(o)oc2-c18^, (CQ-C8 alkyl)0C(0)0C2-C18 alkynyl, Cq-C8 alkyl) 156004.doc -53·201143790 0C(0)0H, (C()-C8 alkyl)OC(0)NR24Ci-Ci8 alkyl, ((:. -<:8 alkyl)oc(o)nr24c2-c18 alkenyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkynyl, (c〇-c8 alkyl)oc(o)nr24h2 (c〇-c8 alkyl) NR24(0)0C--C18 alkyl, (C〇-C8 alkyl) NR24(0)0C2-Ci8 alkenyl, (c〇-c8 alkyl)nr24(o)oc2 -c18 alkynyl or (cQ-c8 alkyl) NR24(0)0H; R6 is nitrogen, C1-C18 alkyl, C2-C18 dilute, C2-C18 fast radical, heterodyne, (c〇-c8 alkane Aryl, aryl, (c〇-c8 alkyl)heteroaryl, (c〇-c8 alkyl) C(0)Ci-Ci8 alkyl, (〇.-〇8 alkyl)C(0)C2- Ci8 dilute, (C〇-C8 alkyl) c(o)c2-c18 alkynyl, (C〇-C8 alkyl) C(0)H, (c〇-c8 alkyl)c(0)aryl (C(rC8 alkyl)c(o)heteroaryl, (c〇-c8 alkylalkyl, (cvc8 alkyl)C(0)OC2-Ci8 alkenyl, (Co-c8 alkyl)C ( 0) 0C2_C18 alkynyl, (CQ-C8 alkyl) C(0)〇H, (C()-C8 alkyl)c(o)oaryl, (c〇-c8 alkyl)c(o)o Heteroaryl, (c〇-c8 alkyl)alkyl, (C()-C8 alkyl)C(〇)NR24C2-Ci8 alkenyl, (C()-C8 alkyl)c(o)nr24c2-c18 Alkynyl, (c〇-c8 alkyl) C(0)NR24H2, (C〇-C8 alkyl C(0)NR24 aryl or (C«)-C8 alkyl)C(0)NR24 heteroaryl; R7 is hydrogen, CrCw alkyl, C2-C18 alkenyl, c2-c18 alkynyl, heteroalkyl' (c〇-c8 alkyl)aryl, (c〇-c8 alkyl)heteroaryl, (c〇-c8 alkyl)alkyl, (c〇-c8 alkyl)C(0)C2-C18 olefin , (CQ-C8 alkyl) C(0)C2-C18 alkynyl, (C(rC8 alkyl)C(0)H, (C〇_C8 alkyl)c(0)aryl, (c〇 -c8 alkyl)C(0)heteroaryl, (C〇-C8 alkylalkyl, (c〇, c8 alkyl) c(o)oc2-c18 alkenyl, (Co-156004.doc •54- 201143790 c8 alkyl)C(0)0C2-C18 alkynyl, (c〇-c8 alkyl)C(0)0H, (CG-C8 alkyl)C(0)0 aryl, (C〇-C8 institute (C)-C (〇) 〇 、, (Cq-Cs alkyl ^ (CONR ^ CVCu alkyl, (c 〇 - c8 alkyl) 〇 (0 state 1124 (: 2- (: 18 alkenyl, (c 〇-c8 alkyl)C(〇)NR24C2-C18 fast radical, (C〇-C8 alkyl) C(0)NR24H2, (C〇-C8 alkyl)C(〇)NR24 aryl or (c〇- C8 alkyl) C(0)NR24heteroaryl; R8 is hydrogen, (C〇-C8 alkyl)halyl, Ci-Ci8 alkyl, C2-C18 alkenyl, CVC18 alkynyl, heteroalkyl, (Co -Cs alkyl)aryl, (c -C8 alkyl)heteroaryl; R9 is hydrogen, (C〇-C8 alkyl)halo, CVCualkyl, c2_C18 alkenyl, C2_C-8 alkynyl, heterodole, (Cq-Cs alkyl) aryl a base '(c〇-C8 alkyl)heteroaryl; R10 is hydrogen, (CQ-C8 alkyl)i, CVCualkyl or (c〇-C8 alkyl)〇H; and R24 is hydrogen or Ci- Ci8 base. In some embodiments, Y comprises the structure of formula C, wherein R 2 is hydrogen, halo, alkyl; R 3 is hydrogen, halo, alkyl; R 6 is hydrogen, (VCg alkyl, C 2 -C 8 alkenyl, C 2 -C8 alkynyl, heteroalkyl, (c〇-c8 alkyl)aryl, (C〇-C8 alkyl)heteroaryl, (c〇_c8 alkyl)C(0)CVC8 alkyl, (C 〇-C8 alkyl)C(0)C2-C8 alkenyl, (C()-C8 alkyl)C(0)c2-C8 alkynyl, (C()-C8 alkyl)C(0)H, (C(rC8 alkyl)C(0) aryl, (C〇-C8 alkyl)C(〇)heteroaryl, (c0_c8 alkyl)(^(COOCi-Cs alkyl, (C〇-C8 burned) Base) C(〇)〇C2-C8 dilute group, ((VC8 alkyl) 156004.doc •55· 201143790 C(0)0C2-C8 alkynyl, (CG-C8 alkyl)C(0)〇H, (CVC8 alkyl) c(o)oaryl, (c0-c8 alkyl)c(o)oheteroaryl, (cvc8 alkyl) C(0)NR24Ci-C8 alkyl, (CG_C8 alkyl)C (〇)NR24C2-C8 alkenyl, (C〇-C8 alkyl) C(0)NR24C2-C8 alkynyl, (Cq_C8 alkyl) C(0)NR24H2, (C0-C8 alkyl) C(0)NR24 Aryl or (C{rc8 alkyl) C(0)NR24 heteroaryl; R7 is hydrogen, C^-Cg alkyl, C2-C8 alkenyl, C2-C8 alkynyl, heteroalkyl, (C〇- C8 alkane Aryl, aryl (C〇-C8 alkyl)heteroaryl, (c〇alkyl)(:(〇)(:!-c8 alkyl, (C.alkyl)C(0)C2-C8 olefin Base, (C. alkyl) c(〇)C2-C8 alkynyl, (c0)c(o)aryl, (c〇)c(o)heteroaryl, ((:0)(:(〇) 〇(:1_(:8 alkyl, (c〇alkyl)c(o)oc2-c8 alkenyl, (cQ alkyl)c(〇)〇c2_C8 alkynyl or (Co alkyl)C(0)0H R is nitrogen or C1-C7 alkyl; R is nitrogen or C1-C7 alkyl; R1 (> is hydrogen or OH; and R24 is hydrogen or CVC7 alkyl. For example, R2 is hydrogen or methyl; R3 is hydrogen, fluorine, chlorine or methyl; r6 is hydrogen or alkyl; R7 is hydrogen, c(〇)CH3 or C(〇)CH2CH3; R8 is hydrogen or methyl; r9 is hydrogen or methyl; 〇 is a basis. Non-limiting examples of the structure of formula c include · 156004.doc • 56· 201143790

also

Betamethasone and its derivatives

H3c Et Ο A

. In the embodiment of the formula, Y is bonded to L at any position capable of reacting with Q or L (e.g., when L is a linking group) or _ such as when L is '. Those who are familiar with this technology #于-general knowledge and this article

The present invention provides for the ease of determining the binding position on Formula C and the manner in which Formula c is combined to Q or L. In some embodiments, the formula c is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 〇, U, 12, 13, 14, B, 16, 17, 18, 19, 20, 21, 22 or 2

Also in the U - the combination of 爻 L or Q. In some embodiments 'Formula C' is bonded to L or Q at position 3, 1 〇, 16 or 17 of 沬r -, Formula C. 156004.doc -57- 201143790 In some embodiments, Y acts on the mineralocorticoid receptor (MR). In the examples, 'Υ contains any structure that allows or promotes the activity of the agonist of MR, while in other embodiments, Y is an antagonist of MR. In the illustrative embodiment +, γ contains the structure of formula D:

Wherein R, R, R and r1q are each independently a moiety which allows or promotes the activity of the agonist or antagonist when the compound of formula D is bonded; and the dotted line indicates the double bond which is optionally present. In some embodiments, Formula D further comprises one or more substituents on one or more of positions j, 2, 4, 5, 6, 7, 8, 11, 12, 14, 15, 16 and 17. . In some embodiments, Y comprises the structure of formula D, wherein R is hydrogen, (C〇-C8 alkyl) halo, Ci_Ci8 alkyl, C2-C18 dilute, C2_Ci8 alkynyl, heteroalkyl, (C〇 -C8-based) aryl, (C〇-C8 alkyl)heteroaryl, (C〇-C8 炫)〇Ci_Ci8 炫•基, (Cq-Cs alkyl) OC2-C18 dilute base, (C〇 -C8 alkyl) OC2-C18 fast radical, (Cg-Cs alkyl) 〇H, (C〇-C8 alkyl) SH, (C〇-C8 alkyl) NR^CVCu alkyl, (CQ-C8 alkane Base) NR24C2-C18 alkenyl, (C〇-C8 alkyl) NR24C2-C18 alkynyl, (C〇-C8 alkyl) NR24H2, (C〇_C8 alkyl) C^COCrCu alkyl, (CG-C8 Alkyl)C(0)C2-C〗8 alkenyl, (C()-C8 alkyl)c(o)c2-c18 alkynyl, (c〇-c8 alkyl)c(o)h, (c0 -c8 alkyl)c(o)aryl, (C〇-C8 alkyl)c(o) hetero 156004.doc • 58 · 201143790 aryl, (C〇-C8 alkyl) CXCOOCVCu alkyl, (C( rC8 alkyl) c(o)oc2-c18 alkenyl, (cQ_c8 alkyl)c(o)oc2_c18 alkynyl, (c〇-c8), c(o)〇H, (c〇-c8 alkyl) c(o)o aryl, (c0-c8 alkyl) c(0)0 heteroaryl, (c〇_c8 alkyl) 0C(0) Cl_Cl8 alkyl, ((^(^alkyl)oc(o)c2-c18 alkenyl, (c〇-c8 alkyl)oc(o)c2-c18 alkynyl, (c〇-匚8 alkyl)C (0) NR24Ci-Ci8 alkyl, (C〇-C8 alkyl) C(0)NR24C2-Ci8 alkenyl, (cQ-c8 alkyl)c(o)nr24c2-c18 alkynyl, (cG-c8 alkyl C(0)NR24H2, (C0-C8 alkyl) C(0)NR24 aryl, (c0-c8 alkyl) C(0)NR24 heteroaryl, (C〇-C8 alkyl)alkyl, ( C〇-c8 alkyl)nr24c(o)c2-c8 alkenyl or (c〇-c8 alkyl)nr24c(o)c2-c18 alkynyl, (c〇-c8 alkyl)nr24c(o)oh, C〇-C8 alkyl)0(:(0)0(:,-c18 alkyl, (CG-C8 alkyl)0C(0)0C2-C18 alkenyl, ((3〇-(:8 alkyl)) Oc(o)oc2-c18 alkynyl, (c〇-c8 alkyl)oc(o)oh, (CG-C8 alkylalkyl, (C〇-C8 alkyl) 0C(0)NR24C2-C18 alkenyl , (c〇-c8 alkyl) oc(o)nr24c2-c18 alkynyl, (cG_c8 alkyl) oc(o)nr24h2, (c0_c8 alkyl)nr24(o)oc丨-c18 alkyl, (c〇- C8 alkyl)NR24(0)0C2-C18 alkenyl, (CG-C8 alkyl)NR24(0)0C2-C18 block or (c〇-c8 alkyl)nr24(o)oh; R3 is hydrogen, ( C〇-C8 alkyl) halogen, C1-C18 yard, C2-Ci8 , CVCu alkynyl, heteroalkyl, (CVC8 alkyl) aryl, (C〇-C8 alkyl)heteroaryl, (C〇-C8 炫)〇Ci_Ci8 alkyl, (Co-Cs alkyl) OC2 -C18 dilute group, (c〇-c8 alkyl) OC2-C18 alkynyl group, (C〇-C8 alkyl) OH, (c〇-c8 alkyl) SH, (CG-C8 alkyl) NRWCrCu alkyl, (C〇-C8 alkyl) NR24c2_ c18 alkenyl, (Cg-C8 alkyl) NR24C2-C18 alkynyl, (Cg-C8 alkyl) 156004.doc -59- 201143790 nr24h2, (CG-C8 alkyl) :(0)(^-(:,8 alkyl,(C()-C8 alkyl)C(〇)C2-C18 alkenyl, (Cq_c8 alkyl)c(0)c2_c18 alkynyl, ((:〇 -(:8 alkyl)c(o)H, (C〇-C8 alkyl)c(o)aryl, (c0-c8 alkyl)c(o)heteroaryl, (CG-C8 alkyl) C(0)0Cl-C18 alkyl, (C()-C8 alkyl) C(0)0C2-C18 alkenyl, (c〇-c8 alkyl)c(o)oc2-c18 alkynyl, (cG- C8 alkyl)C(0)0H, (C0-C8 alkyl)C(0)0 aryl, (C〇-C8 alkyl)c(0)0 heteroaryl, (C〇-C8 alkyl alkane , (c0-c8 alkyl) 0C(0)C2-C18 alkenyl, (Cg-C8 alkyl)OC(0)C2-Ci8 alkynyl, (c0-c8 alkyl)C^CONR^CVCu alkyl , (Cg-C8 alkane C(0)NR24C2-C18 alkenyl, (c〇-c8 alkyl)c(0)nr24c2-c18 alkynyl, (c〇-c8 alkyl) C(0)NR24H2, (c0-c8 alkyl) C(0)NR24 aryl, (c0-c8 alkyl) C(0)NR24 heteroaryl, (C〇_c8 alkyl) NR24c(〇)Ci_Ci8 alkyl, (c〇_ c8 alkyl)nr24c ( o) c2-c8 alkenyl or (c〇-c8 alkyl) nr24c(o)c2-c18 alkynyl, (c〇-c8 alkyl)nr24c(o)oh, (C〇-C8 alkyl)0 ( :(0)0(:"c18 alkyl, (C()-C8 alkyl) 〇c(o)oc2-c18 alkenyl, (c〇_c8 alkyl) oc(o)oc2-c丨8 alkyne Base, (C〇-C8 alkyl) 0C(0)0H, ((:. -(:8 alkyl)0C(0)NR24Ci-C18 alkyl, (C〇-C8 alkyl) 〇c(o)nr24c2-c18 alkenyl, (C()-C8 alkyl) 〇c(〇) Nr24c2-c18 alkynyl, (c〇-c8 alkyl) 0C(0)NR24H2, (C〇-C8 alkyl) NR'COOCVCu alkyl, (C0-c8 alkyl) NR24(0)OC2-Ci8 alkenyl , (C()-C8 alkyl) nr24(o)oc2-c18 alkynyl or (CVC8 alkyl)nr24(〇)〇h ; R7 is hydrogen, (VCu alkyl, c2-c18, c2-c18 Fast-group, heteroalkyl, (C〇-C8 alkyl)aryl, (C〇-C8 alkyl)heteroaryl, (c0-C8 alkyl)C^COCVCu alkyl, (C〇-C8 alkyl) c(0)c2-c18 alkenyl, (C(rC8 156004.doc •60-201143790 alkyl)C(0)c2-C18 alkynyl, (C〇-C8) C(0)H, ( C〇-Cs 炫·基)c(0)aryl, (C(rc8 alkyl)c(0)heteroaryl, (C(rC8 alkyl) C(0)0C1-C18 alkyl, (Cg_c8 alkane) Base) c(o)oc2-c18 alkenyl, (C❶-c8 alkyl) C(0)0C2-C18 alkynyl, (C〇-C8 alkyl) C(〇)〇H, (C〇_C8 burned Base) c(o)o aryl, (c〇_c8 alkyl) C(0)0 heteroaryl, (c0-C8 alkyl)c(o)nr24cvc18 alkyl, (cG_c8 alkyl)c(〇 )nr24c2-c丨8 alkenyl, (C -C8 alkyl)C(0)NR24C2-C18 alkynyl, (CVC8 alkyl) C(〇)Nr24h2, (C(rC8 alkyl)C(0)NR24 aryl or (C〇-C8 alkyl)C (0) NR24 heteroaryl; R10 is hydrogen, (C〇-C8 alkyl) halo, C^-Cu alkyl or (Co-Cs) 〇H; and R24 is hydrogen or CrCu alkyl. In some embodiments, γ comprises a structure of formula D, wherein R2 is hydrogen, a dentate group, an OHiCi-c? alkyl group; R3 is hydrogen, a dentate group, an alkyl group; R7 is hydrogen, a CrCs alkyl group, a C2-C8 olefin , c2-C8 alkynyl, heteroalkyl, (C〇-C8 yl) aryl, (c〇-C8 alkyl)heteroaryl, (c〇alkyl)〇:(0)(:"c8 Alkyl, (CQ alkyl) c(0)c2-c8 alkenyl, (C.alkyl) (:(0)(:2-(:8 alkynyl, (C0)C(O)aryl, ( Co)C(O)heteroaryl, (coc^COOCi-Ce alkyl, (C〇alkyl)C(0)0C2-C8 alkenyl, (Cq alkyl)C(0)0C2_C8 alkynyl or (Co Alkyl)C(0)0H; R1() is hydrogen or OH; and R24 is hydrogen or CVC7 alkyl. For example, R2 is hydrogen or fluorenyl; R3 is hydrogen, fluoro, chloro or methyl; R7 156004.doc -61·201143790 is hydrogen, c(o)ch3 or C(0)CH2CH3; and R1. It is a hydroxyl group. Non-limiting examples of compounds of formula D include:

Deoxycorticoacetate retention, and its derivatives. In an embodiment where Y comprises a structure of formula D, γ is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position of formula D capable of reacting with Q or L. Time). Those skilled in the art will readily be able to determine the binding position on Formula D and the manner in which Formula d is combined to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, the formula 1、 is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 of the formula d , 20' 21, 22, 23 or 24 is combined to L or Q. In some embodiments, the formula is bonded to L or Q at position 3, 1 〇, 13 or 17 of formula D. In some embodiments, Y acts on a progesterone receptor (PR). In some embodiments, Y comprises any structure that permits or promotes agonist activity against Pr, while in other embodiments, ¥ is an antagonist of PR. In the exemplary embodiment, Y contains the structure of equation E: 156004.doc • 62· 201143790

Wherein R2, R3, R4 and R7 are each independently a moiety which allows or promotes the activity of the agonist or antagonist when the compound of formula E is bonded to 1>11; and the dotted line indicates the double bond which is present as the case may be. In some embodiments, Formula E further comprises one or more substituents on one or more of positions 1, 2, 4, 5, 6, 7, 8, 11, 12, 14, 15, 16 and 17. (eg methyl at position 6). In some embodiments, Y comprises a structure of formula E, wherein R 2 is hydrogen, (C〇-C8 alkyl) halo, CVCu alkyl, C 2 -C 18 alkenyl, C 2 -C 1 S alkynyl, heteroalkyl, CVCs alkyl)aryl, (C〇-C8 alkyl)heteroaryl, (C〇-C8 alkyl)〇Ci-Ci8 alkyl, (Cq-Cs) OC2-C18 dilute, (C〇 -C8 alkyl) OC2-C18 alkynyl, (Cg-C8 alkyl) OH, (CG-C8 alkyl) SH, (C〇-C8 alkyl) NF^CVCu alkyl, (C〇-C8 alkyl NR24c2_C18 alkenyl, (C〇-C8 alkyl) NR24C2-C18 alkynyl, (CVC8 & base) NR24H2, (C〇-C8 alkyl) C^COCVCu alkyl, (C〇-C8 alkyl) C(0)C2-C18 alkenyl, (C()-C8 alkyl)C(0)C2-C18 alkynyl, (C0-c 8 alkyl)C(0)H, (CVC8 alkyl)C( O) aryl, (C〇-C8 alkyl) C(O)heteroaryl, (C0-C8 alkylalkyl, (c〇-c8 alkyl) c(o)oc2-c18 alkenyl, (C 〇-C8 alkyl)C(0)0C2-C18 alkynyl, (c0-c 8 alkyl)C(0)0H, (c〇-c8 alkyl)c(o)o aryl, (c0-c8 Alkyl) c(0)0 heteroaryl, (C〇-C8 alkylalkyl, (CVc8:|^ 156004.doc • 63·201143790 base) oc(o)c2 -c18 alkenyl, (c〇-c8 alkyl) oc(o)c2-c18 alkynyl, (c〇-c8 alkyl) C(0)NR24Ci-C18 alkyl, (c〇-c8 alkyl)c (0) nr24c2-c18 alkenyl, (C()-C8 alkyl)c(o)nr24c2-c18 alkynyl, (c〇-c8 alkyl) C(0)NR24H2, (C0-C8 alkyl)C (0) NR24 aryl, (〇0_(:8 alkyl)C(0)NR24 heteroaryl, (C〇-C8 alkyl)NRWc^COCVCu alkyl, (c〇-c8 alkyl)nr24c(o ) c2-c8 alkenyl or (C(rC8 alkyl)nr24c(0)c2-c18 alkynyl, (c〇-c8 alkyl)nr24c(o)oh, (c〇-c8 alkyl) 0C(0) 0Ci-C18 alkyl, (c〇-c8 alkyl) oc(o)oc2-c 丨8 alkenyl, (c〇-c8 alkyl) oc(o)oc2-c18 alkynyl, (C〇-C8 alkane Base) 0C(0)0H, (C.-call C8 alkyl eC^CONRMcVCu alkyl, (C〇-C8 alkyl) 0C(0)NR24C2-C18 alkenyl, (c〇-c8 alkyl)oc ( o) nr24c2-c18 alkynyl, (<:. -(:8 alkyl)0C(0)NR24H2, (C〇-C8 alkyl)NR'COOCVCu alkyl, (c0-c8 alkyl)nr24(o)oc2-c18 alkenyl, (c〇-c8 alkane Base) nr24(o)oc2-c18 alkynyl or (C〇-C8 alkyl)NR24(0)0H; R24 is hydrogen or Ci-C18 alkyl; R3 is hydrogen, (C()-C8 alkyl)_ Base, alkyl, c2-C18 alkenyl, CVCi8 alkynyl, heteroalkyl, (Co-Cg alkyl) aryl, (c〇-C8 alkyl) heteroaryl, (C〇-C8 alkylalkyl , (C〇-C8 alkyl) 0C2-C18 alkenyl, ru (C〇-C8 alkyl) OC2-C18 alkynyl, (CG-C8 alkyl) 0H, (C(rC8^))SH, (Cq -C8 alkyl)nr24c丨-c18 alkyl, (c〇-c8 alkyl)nr24c2_C18 alkenyl, (cG_c8 alkyl)nr24c2-c18 alkynyl, (c〇-c8 alkyl)nr24h2, (c〇- C8 alkyl)(:(o)(ν(:18 alkyl,(c〇-c8 alkyl)C(0)C2-C18 dilute, (Cq-C8 alkyl)C(0)C2-C18 alkyne Base, (C0-c alkyl) C(0)H, (C0-C8 alkyl)C(O)aryl, (c0-c8 alkyl)C(〇)hetero(), (C〇- C8 炫 base) C(0)0Ci-Ci8 alkyl, (C〇-C8 appearance 156004.doc ·64·201143790 base) c(o)oc2-c18 alkenyl, (C(rC8 alkyl)C(0) 0C2_ Cl8 alkynyl, (c〇_ c8 alkyl) C(0)0H, (Cq-C8 alkyl)c(o)o aryl, (c0-c8 alkyl)C(0)0 heteroaryl, C0-c8 alkyl group WCCCOCi-Cu alkyl, (c〇-c8 alkyl) OC(0)C2-C18 alkenyl, (cQ-C8 alkyl)oc(o)c2-c18 alkynyl, (C〇- C8 alkyl)alkyl, (C〇-C8 alkyl) C(0)NR24C2-C18 alkenyl, (Co-Cs alkyl)c(o)nr24c2-c18 alkynyl, (C〇-C8 alkyl) C(0)NR24H2, (C〇-C8 alkyl)C(0)NR24 aryl, (c0-c8 alkyl)C(0)NR24 heteroaryl, (C〇-C8 alkyl)NR24C(0) C1-C18 alkyl, (c〇-c8 alkyl) nr24c(o)c2-c8 alkenyl or (CG-C8 alkyl) nr24c(o)c2-c18 alkynyl, (c〇-c8 alkyl) NR24C (0) OH, ((: 〇-(:8 alkyl)0(:(0)0(^-(:,8 alkyl, (cG-c8 alkyl)oc(o)oc2-c18), (C〇-C8 alkyl) oc(o)oc2-c18 alkynyl, (C〇-C8 alkyl) 0C(0)0H, (C〇-C8 alkyl WC^CONRWCkCu alkyl, (C(rC8 alkane) Base)oc(o)nr24c2-c18 alkenyl, (C〇-C8 alkyl) 0C(0)NR24C2-C18 alkynyl, (C〇-C8 alkyl) 0C(0)NR24H2, (C〇-C8 alkane Base) nr24 (〇)〇Ci-Ci8 alkyl, (C〇-C8 alkyl) NR24 (〇)〇C2-C18 alkenyl, (c0_c8 alkyl)nr24(o)oc2-c18 alkynyl or (C〇-C8 alkyl)NR24(〇)〇H; R4 is hydrogen, (C〇-C8 Acryl group, G-Cm alkyl group, c2-C18 fluorenyl group, C2_C1S fast group, miscellaneous group, (Co-Cg alkyl) aryl group, (c0-C8 alkyl) heteroaryl group, (C〇 -C8院基)0Ci-Ci8 alkyl, (C〇-C8) 〇C2-C18 dilute, (C〇-C8 alkyl)〇C2-Ci8 alkynyl, (C〇-C8 alkyl)〇 H, (C〇-C8 alkyl) SH, (C〇_C8 alkyl) NR Ci-Ci8 alkyl, (C〇-C8 alkyl) NR24c2· Ci8 dilute, (C〇-C8 yard) NR24C2 -Ci8 alkynyl, (Cg-Cs) NR 、:, (Cg-Cs alkyl) C(0)Ci-C18, (Cq-Cs alkyl) 156004.doc -65- 201143790 C(0 C2-c18 alkenyl, (Cq_C8 alkyl) C(0)c2_Cl8 alkynyl, ((:()_(:8 alkyl)C(0)H, (C〇-C8 alkyl)c(o) Aryl, (c〇-c8 alkyl)c(o)heteroaryl, (C()-C8 alkyl)alkyl, (cG-c8 alkyl)c(o)oc2-c18 alkenyl, (C 〇-C8 alkyl)c(o)oc2-c18 alkynyl, (CG-C8 alkyl)C(0)0H, (CVC8 alkyl)c(o)oaryl, (c〇-c8 alkyl) c(o)o heteroaryl (CVC8 alkylalkyl, (c〇-c8 alkyl) oc(o)c2-c18 alkenyl, (cG-c8 alkyl) oc(o)c2-c18 alkynyl, (c〇-c8 alkyl^ (C^NR^CVCu alkyl, (C〇-C8 alkyl) C(0)NR24C2-C18 alkenyl, (c〇-c8 alkyl)c(o)nr24c2-c18 alkynyl, (CG-C8 alkane Base) C(0)NR24H2, (c0-c8 alkyl) C(0)NR24 aryl, (C0-C8 alkyl) C(0)NR24 heteroaryl, (c〇-C8 alkyl) NRMC^COCi -Cu alkyl, (c〇-c8 alkyl) nr24c(o)c2-c8 alkenyl or (c〇-c8 alkyl) nr24c(o)c2-c18 alkynyl, (Co-Cs alkyl)NR24C ( 0) 0H, (C〇-C8 alkyl) OC(0)OCi-C18 alkyl, (C(rC8 alkyl)0C(0)0C2-C18 alkenyl, (c〇-c8 alkyl)oc(o Oc2-c〗 8 alkynyl, (c〇-c8 alkyl) oc(o)oh, (C〇-C8 alkyl, (C(rC8 alkyl) 0C(0)NR24C2-C18 alkenyl, (C〇_C8 alkyl) 0(:(0"1124(:2-(:18 alkynyl, (C〇-C8 alkyl)0C(0)NR24H2, (C〇-C8 alkyl)NR24(0 ) 0Ci-c18 alkyl, (c〇-c8 alkyl) nr24(o)oc2-c18 alkenyl, (cG-c8 alkyl) NR24(0)OC2-Ci8 alkynyl or (C〇-C8 alkyl) Nr24(〇)〇h ; R7 is hydrogen, C1-C18 alkyl, C2-C18 Alkenyl 'C2-C18 alkynyl, heptyl, (c〇-c8 alkyl)aryl, (c〇-c8 alkyl)heteroaryl, (c〇-C8 alkyl)alkyl, (C〇 -C8 alkyl)C(0)C2-C18 alkenyl, (Cq-Cs alkyl)c(o)c2-c18 alkynyl, (c〇-c8 alkyl)c(o)h, (c〇- C8 alkane 156004.doc -66 - 201143790 base) c(0) aryl, (C〇_c8 alkyl) c(o)heteroaryl, (CVC8 alkyl)¢:(0)0(^-(: , 8 alkyl, (c〇-c8 alkyl) c(o)oc2_c18 alkenyl, (c〇_ c8 alkyl) c(o)〇c2-c18 alkynyl, (c〇-c8 alkyl) C ( 0) 0H, (cg_C8 alkyl) c(o)o aryl, (CVC8 alkyl) c(0)0 heteroaryl, (C(rC8 alkyl)c^conrWcvc^alkyl, (C(rC8) Base)(:(0 State 1124(:2-(:18), (c〇-c8 alkyl)c(o)nr24c2-c18 alkynyl, (C()_C8 alkyl)C(0)NR24H2 (C〇-C8 alkyl) C(0)NR24 aryl or (c〇_c8 alkyl) C(0)NR24 heteroaryl; and R24 is hydrogen or CVCu alkyl. In some embodiments, Y comprises a structure of formula E, wherein R2 is hydrogen, halo, OHSCVCt alkyl; R3 is hydrogen, li, 0114(:,-(:7 alkyl; R is hydrogen, (Co- Cg alkyl), Ci-Cg alkyl, C2-C8 dilute, C2 18 alkynyl, heteroalkyl, (C〇-C8 alkyl)aryl, (Co-Cs alkyl)heteroaryl, (c0-c8 alkyl group WCi-Cs alkyl group, (CQ-C8 alkyl) oc2-c8 dilute group, (c〇_C8 alkyl group) OC2-C8 alkynyl group, (CG-C8 alkyl group) 〇H, ( CG-C8 alkyl) SH, (c0-cs alkyl) NRMCVC8 alkyl, (c0-C8 alkyl) nr24c2-c8 dilute, (c0-c8 alkyl) NR24C2-C8 alkynyl, (Cg_c8 alkyl) NR24H2, (6) cardinyl) (: (0) (ν(: 8 alkyl, (CQ-C8 alkyl) C(0)C2-C8 alkenyl, ((: 〇-(:8 alkyl) C ( 0) c2-c8 alkynyl, (CQ-C8 alkyl) C(0)H, (c〇-c8 alkyl)c(o) aryl '(C〇-C8 alkyl)C(〇)heteroaryl Base, (c〇_C8 alkyl)c(〇)〇Ci_C8 alkyl, (C(rC8 alkyl)C(〇)〇C2_C8 alkenyl, (Cq_C8 alkyl)C(0)〇C2-C8 fast radical , (C()_C8 alkyl)c(〇)〇H, (C(rC8 alkyl)c(0)0 aryl, (CVc8 alkyl)c(〇)〇 aryl, ( C〇C8 alkane 156004.doc -67- 201143790 base) OC(0)Ci-C8 alkyl, (CG-C8 alkyl)oc(o)c2-c8 alkenyl, (c〇-c8 alkyl)oc ( o) c2-c〗 8 alkynyl, (cG-c8 alkyl) c(o)nr24c丨-(:8 alkyl, (cQ-c8 alkyl)c(o)nr24c2-c8 alkenyl, (c〇 -c8 alkyl)C(0)NR24C2-C8 alkynyl, (Cq-C8 alkyl)C(0)NR24H2, (CcrC8 alkyl)C(0)NR24 aryl, (C〇-C8 alkyl)C (0) NR24 heteroaryl, (C〇-C8 alkyl) NR^C^COCVCs alkyl, (C〇-C8 alkyl) NR24C(0)C2-C8 alkenyl or (C()-C8 alkyl Nr24c(o)c2-c8 alkynyl, (c〇-c8 alkyl)NR24C(0)0H, (C〇-C8 alkyl)OCnCOOCrCs alkyl, (C«rC8 alkyl)oc(o)oc2- C8 alkenyl, (cG-c8 alkyl) oc(o)oc2-c8 alkynyl, (C0-C8 alkyl) OC(0)OH, (C〇-C8 alkylalkyl, (C()-C8 Alkyl)oc(o)nr24c2-c8 alkenyl, (cG-c8 alkyl) oc(o)nr24c2_c8 alkynyl, (c〇-c8 alkyl)oc(o)nr24h2, (c〇-c8 alkyl) NR'COOCVCs alkyl, (Cq-C8 alkyl) NR24(0)0C2-C8 alkenyl, (c〇-c8 alkyl)NR24(0)0C2-C8 alkynyl or (cQ-c8 alkyl) nr24 ( 〇)〇h ; R7 is hydrogen, Ci-Cs alkane , c2-c8 dilute, C2-C8 alkynyl, heteroalkyl, (c〇-c8 alkyl)aryl, (c〇-c8 alkyl)heteroaryl, (c〇alkyl)c(〇) Cl_C8 alkyl, (CQ alkyl) C(0)C2-C8 alkenyl, (cG alkyl) (:(〇)0:2-(:8 alkynyl, (C〇)C(0)aryl (c〇)c(0)heteroaryl, (C〇)C(0)OC1_C8 alkyl, (Coalkyl)C(0)0C2-C8 alkenyl, (cQ alkyl)c(〇)〇 C2-C8 alkynyl or (Coalkyl)C(0)0H; and R24 is hydrogen or Ci-C7 alkyl. For example, R 2 is hydrogen or methyl; R 3 is hydrogen or fluorenyl; R 4 is ((: 1 alkyl) C(0)C - C4 alkyl, acetate, cyclopentanoate, Succinic acid 156004.doc •68· 201143790 Ester, heptanoate, + = & roll or propionate group; and ruler 7 is hydrogen, c(o)ch3 or C(0)CH2CH3. Non-limiting examples of oral materials include

CH,

〇

Me Hydrazine Progesterone and Its Derivatives In an embodiment where Y comprises a structure of formula E, γ is bonded to L at any position of formula E capable of reacting with Q or L (eg, when l is a linking group) ) or Q (for example, when L is a key). Those who are familiar with this technology in view of general knowledge and this article

The present invention provides for the ease of determining the binding position on Formula E and the manner in which Formula E is bonded to Q or L. In some embodiments, formula e is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18' 19 of formula e Binding to L or Q on any of 20, 21, 22, 23 or 24. In some embodiments, Formula E is bonded to L or Q via position 3 or 17 of Formula E. In other embodiments, gamma acts on the progesterone receptor but is not covered by Formula E. For example, Y can include the following structures and their likes... 156004.doc •69· 201143790

Norethindrone. In some embodiments, Y acts on the androgen receptor (AR). In some embodiments, Y comprises any structure that permits or promotes activity against an eight-foot agonist, while in other embodiments, γ is an antagonist of AR. In an exemplary embodiment, Y contains the structure of equation F·

Wherein R1 (when present), R2, R3&r6 are each independently a moiety that allows or promotes the activity of the agonist or antagonist when the formula is bound to the AR; and each dashed line represents a double bond as the case may be The constraint is that there is at most one carbon-carbon double bond present at position 5 as appropriate. In some embodiments, Formula F is further in position! One or more of the 2, 4, 5, 6, 7, 8, 8, U, 12, ΐ4, Μ, 16 and 17 include one or more substituents. In some embodiments, Y comprises a structure of formula F, wherein - is present and is hydrogen, C _C18 alkyl, C2-C 丨 8 alkenyl, C 2 -C18 fast radical, heteroalkyl (C 〇 'C8 fen) Aryl, (C〇-C8 alkyl)heteroaryl, (c〇-c8^)c(〇)Ci-c, (c〇-c8 alkyl)c(0)C2_Ci8 alkenyl, (VC8 alkyl) c(o)cvCi8 fast radical, (c〇_C8 alkyl) c(9)H, (CA alkyl)c(〇)aryl, (C〇-C8) C(9)heteroaryl, (CVC8 Alkane 156004.doc 201143790 base KCCOOCi-Cu alkyl, (cG-c8 alkyl) c(o)oc2-c18 alkenyl, (c〇, c8 alkyl) c(o)oc2-c18 alkynyl, (c〇 -c8 alkyl)C(0)0H, (c〇-c8 alkyl)c(o)oaryl, (c0-c8 alkyl)c(0)0 heteroaryl, (C0-C8 alkyl) C^C^NR^Ci-Cis alkyl, (C〇-C8 alkyl) C(0)NR24C2-C18^, (cG-c8 alkyl)c(0)nr24c2-c18 alkynyl, (cQ- C8 alkyl) C(0)NR24H2, (c0-c8 alkyl) C(0)NR24 aryl, (C0_C8 alkyl) C(0)NR24 heteroaryl or S03H; R2 is hydrogen, (C〇-C8 Alkyl group, a Ci-C18 alkyl group, a C2-C18 dilute group, a C2-C1S block group, a miscible group, a (Cq-Cs pit group) aryl group, (C〇-C8 alkyl group) Heteroaryl, (C〇-C8 alkylalkyl, (cG-c8 alkyl) oc2-c18 alkenyl, (c〇-c8 alkyl) oc2-c18 alkynyl, (C〇-C8 alkyl) fluorene H, (cQ-c8 topography) SH, (C〇-C8 alkyl) NRMCVCu alkyl, (c〇-c8 alkyl) NR24c2-C18 alkenyl, (cG-c8 alkyl) nr24c2-c18 alkynyl, (C()-C8 alkyl) NR24H2, (c〇-c8 alkyl) (:(0)(^-(:,8 alkyl,(c〇-c8 alkyl)c(o)c2-c18 olefin , (Cg-C8 alkyl) c(0)c2_Cl8 alkynyl, (CVC8 alkyl) c(o)h, (c〇-c8 alkyl)c(o)aryl, (c〇-c8 alkyl c(o)heteroaryl' (CG-C8 alkyl)C(〇)〇Ci-C18 alkyl, (cG-c8 alkyl)c(o)oc2-

Cl8, (Cq-Cs), C(0)0C2-Ci8, fast (C〇-C8 alkyl) C(0)0H, (cvc8 alkyl)c(o)oaryl, (C0 -C8 alkyl)c(o)o Heteroaryl, (C〇-C8 alkyl) 0(:(0)(^-(^8 alkyl, (c〇-c8 alkyl)0C(0)C2 -C18 alkenyl, (Cq-C8 alkyl) oc(o)c2-c18 alkynyl, (c〇-c8 alkyl) qC^NR^CVCw alkyl, (C〇-C8 alkyl) C(0) NR24C2-C18 alkenyl, (Cg-C8 leu) C(0)NR24C2-C18 alkynyl, (CcrC8 alkyl) C(0)NR24H2, (c0-c8 alkyl) C(0)NR24 aryl, (:〇-<:8-alkane 156004.doc -71- 201143790 base) C(0)NR24 heteroaryl, (C〇-C8 alkyl)NR^C^COCVCu alkyl, (C〇-C8 alkyl Nr24c(o)c2-c8 alkenyl or (C〇-C8 alkyl)NR24C(0)C2-c18 alkynyl, (C〇-C8 alkyl)NR24C(0)0H, (C()-C8 alkane Base) 00(0)0(^-(:,8 alkyl,(C()-C8 alkyl)oc(o)oc2-c18 alkenyl, (C〇-C8 alkyl)0C(0)0C2- C18 alkynyl, (C(rC8 alkyl)0C(0)0H, (C〇-C8 alkyl)oqCONRMCVCw alkyl, (C(rC8 alkyl)0C(0)NR24C2-Ci8 alkenyl, (c〇- C8 alkyl)oc(o)nr24c2-c18 alkynyl, (C〇-C8 alkyl)oc(o Nr24h2, (c〇-c8 alkyl) NR24(〇)〇c丨-Cualkyl, (C〇-C8 alkyl)NR24(〇)〇C2-C18 alkenyl, (c〇-c8 alkyl) Nr24(o)oc2-c18 alkynyl or (cvc8 alkyl)NR24(〇)〇H; R is hydrogen, (C〇-C8 alkyl)halide, C1-C18 alkyl, C2-C18 dilute, G -Ci8 fast radical, miscible base, (C〇-C8 alkyl) aryl, (Co-Cs alkyl) heteroaryl, (C〇-C8 alkyl) OCI_C!8 alkyl, (C〇-C8 Anthracene) OC2-C18 dilute group, (c〇-c8 alkyl) oc2-c18 alkynyl group, (c〇-c8 alkyl) 〇H, (c〇-c8^ group) SH, (C()-C8 Alkyl)nr24c "c18 alkyl, (C〇-C8 alkyl) NR24C2-C18 alkenyl, (c〇-c8 alkyl) nr24c2-c丨8 alkynyl, (cvc8 alkyl) NR24H2, (C〇- C8 alkyl^(COCVCu alkyl, (CQ_C8 alkyl) C(0)C2_Ci8 alkenyl, (Co-Cg leu) C(0)C2-C18 alkynyl, (cQ-C8;^yl)c(o H, (c0-c8 alkyl) c(o)aryl, (c〇-c8 alkyl)c(〇)heteroaryl, (C〇-C8 alkyl)C^COOCVCualkyl, (C〇 -C8 alkyl)C(〇)〇c2_ c18 alkenyl, (c〇-c8 alkyl)c(o)oc2-c18 alkynyl, (C(rc8 alkyl)C(0)0H, (c0 -c8 alkyl)c(o)oaryl, (c〇-c8 alkyl)c(0)0 heteroaryl, (C〇-C8 alkyl)0(:(0)(^-(:, 8 alkyl, (c〇-c8 alkyl) 156004.doc • 72· 201143790 oc(o)c2-c18 alkenyl, (c〇-c8 alkyl)oc(o)c2-c18 alkynyl, (C〇 -C8 alkyl)C^CONRWcVCualkyl, (C〇-C8 alkyl) (:(0"1124(:2-(:18 alkenyl, (c〇-c8 alkyl)c(o)nr24c2-c18 Alkynyl, (c〇-c8 alkyl) C(0)NR24H2, (C〇-C8 alkyl) C(0)NR24 aryl, (C〇-C8 alkyl) C(0)NR24 heteroaryl, (C〇-C8 alkyl) NRWCiCOCVCM alkyl, (c〇-c8 alkyl) nr24c(o)c2-c8 alkenyl or (c〇-c8 alkyl) nr24c(o)c2-c18 alkynyl, (c 〇-c8 alkyl)nr24c(o)oh, (Cq-C8 alkyl)0(:(0)0(^-(^8 alkyl, (c〇-c8 alkyl)oc(o)oc2-c18 Alkenyl, (c〇-c8 alkyl) oc(o)oc2-c18 alkynyl, (c〇-c8 alkyl)oc(o)oh, (C0-C8 alkyl WC^CONRWCi-Cis alkyl, ( C()-C8 alkyl) oc(o)nr24c2-c18 alkenyl, (c〇-c8 alkyl)oc(o)nr24c2-c18 alkynyl, (C(rC8 alkyl)0C(0)NR24H2( C()-C8 alkyl)NR'COOC, -c18 alkyl, (C〇-C8 alkyl) NR24 ( 0) OC2-C18 alkenyl, (<:〇-(:8 alkyl)nr24(o)oc2-c18 alkynyl or (C0-C8 alkyl)NR24(〇)〇H; R6 is hydrogen, C1- C18 alkyl, C2-C18 dilute, C2-C18 alkynyl, heteroalkyl, (C〇-C8 alkyl) aryl, (Co-Cg alkyl) heteroaryl, (C〇-C8) C(0)Ci-Ci8 alkyl, (Co-Cg alkyl) 0(0)02-(^8 dilute, (C〇-Cs alkyl) C(0)C2-Ci8 alkynyl, (Co- Cg alkyl) C(0)H, (C〇-C8 alkyl) c(0) aryl, (c〇-c8 alkyl)c(o)heteroaryl, (C(rc8 alkyl)C( 0) 0Ci-C18 alkyl, (c〇-c8 alkyl) c(o)oc2-c18 alkenyl, (c0-C8 alkyl) C(0)0C2-C!8 alkynyl, (Cq-Cs burned Base)C(0)0H, (Co-Cs alkyl)c(o)oaryl, (c0-c8 alkyl)c(o)oheteroaryl, (c〇_C8 alkyl)c^conrMcvCu Alkyl, (Cg-C8 alkyl) (:(〇- 厌24(:2-(:18-alkenyl), (C〇-C8 alkyl)C(0)NR24C2-C18 block, (c〇-C8 Calcination) 156004.doc • 73· 201143790 C(0)NR24H2, (C0-C8 alkyl) C(0)NR24 aryl, (C〇-C8 alkyl) C(0)NR24 heteroaryl or S03H; And R24 is hydrogen or C, -C18 alkyl. In some embodiments, Y comprises the structure of Formula E, wherein R1 is hydrogen, alkyl, (C〇-C3 alkyl)alkyl, (C〇_C3 alkyl)c(o)aryl or S03H; R2 Is hydrogen, halo, 011 or <: 1-(:7 alkyl; R3 is hydrogen, functional, alkyl; R6 is hydrogen, Ci-Cg alkyl, C2-Cg dilute, C2-C8 alkynyl ,hetero,(c〇-c8 alkyl)aryl, (c〇-c8 alkyl)heteroaryl, (C(rc8 alkyl)C^COCi-Cs leuco, (C〇-C8 fluorenyl) C(0)C2-C8 alkenyl, (Co-Cs alkyl)C(0)C2-C8 alkynyl, (C〇-C8) C(0)H, (c〇-C8 alkyl) c(o) aryl, (C〇-C8 alkyl) (3(0) hetero), (C〇-C8 alkyl) alkyl, (C(rC8 alkyl)c(o)oc2-c8 Alkenyl, (Cg_C8 alkyl) C(0)0C2-C8 alkynyl, (C〇-C8) C(〇)〇H, (c〇_c8 alkyl)c(o)oaryl, C〇-c8 alkyl)c(0)0heteroaryl, (c〇c8 alkyl)C(〇)NR24Cl-C8, (cvc8 alkyl)C(0\NR24C2°_C88^, (C 〇-C8 alkyl) C(0)NR24C2-C8 block, (c〇-C8 alkyl) C(0)NR24H2, (C0-C8 alkyl)c(〇)NR24 Guan Shishi or (C 〇-C8 alkyl) C(0)NR And a C. Non-limiting examples of compounds include: 156004.doc -74- 201143790

derivative. In an embodiment where Y comprises a structure of formula F, γ is bonded to L at a position where k can be bonded to L (for example, when L is a linking group) or hydrazine (for example, when L is a bond) The present invention can readily determine the binding position on Formula F and the manner in which Formula F is combined to Q or L. In some embodiments, Formula f is in the position of Formula f.丄, 2, 3, 4, 5, 6, 7, 8, 9, 1 〇, u, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 Binding to L or q. In some examples, Formula F binds to l or Q at position 3 or 17 of Formula F. In some embodiments, binding of the NHR ligand to a Type I nuclear hormone receptor will occur Producing agonist activity (or antagonist activity) in some but not all cells or tissues of type I nuclear hormone receptors. NHR ligands acting on type II nuclear hormone receptors in some embodiments of the invention In one embodiment, the NHR ligand (Y) acts on a type II nuclear hormone receptor. In some embodiments, Y can have an agonist that allows or promotes binding of the ligand to a type II nuclear hormone receptor. Any of the 156004.doc-75·201143790 structures of activity, while in other embodiments, Y is an antagonist of a type II nuclear hormone receptor. In an exemplary embodiment, Υ to thyroid hormone receptor (TR), visual Raffin receptor (RAR), peroxisome proliferator-activated receptor (PPAR), liver X receptor (LXR), farnesyl X receptor (FXR), vitamin D receptor (VDR) and/or pregnane The X receptor (PXR) exhibits agonist (or antagonist) activity. In some embodiments, Υ acts on a sigmoid receptor (eg, TRa, TRp). In some embodiments, Y contains an allowable or Any structure that promotes the activity of the agonist of TR, while in other embodiments, Y is an antagonist of TR. Non-limiting examples of Y include the following compounds:

Thyroxine (T4) trisulfothyronin (Τ3), and its derivatives in which Y contains a structure that allows or promotes the activity of an agonist or antagonist of TR, Y is capable of reacting with Q or L in Y. Bind to L at any position (eg, when L is a linking group) or Q (eg, when L is a bond). Those skilled in the art will readily be able to determine the binding position on Y and the manner in which Y is bound to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, Y is bonded to L or Q via any position of Y. In some embodiments, Y is bonded to L or Q via a carboxylic acid or alcohol moiety as indicated below: 156004.doc -76- 201143790

Gonadotropin (T<0 In some embodiments, Y acts on retinoic acid receptors (e.g., RARa, RARP, RAR/y). In some embodiments, Y comprises a stimulatory effect that allows or promotes RAR Any structure of agent activity, while in other embodiments, hydrazine is an antagonist of RAR. In an exemplary embodiment, Υ contains the structure of formula G··

Wherein R11 is the moiety which allows or promotes the activity of the agonist or antagonist when the compound of formula G is bound to the RAR, and one represents the stereochemistry of the £ or quinone type. In some embodiments, Υ comprises a structure of formula G, wherein R11 is C(0)0H, CH2OH, or C(0)H. In some embodiments, hydrazine comprises a structure of formula G wherein R11 is a carboxylic acid derivative (e.g., a sulfhydryl vapor, an anhydride, and an ester). Non-limiting examples of compounds of formula G include:

All-trans retinoic acid retinol 156004.doc •77 201143790

Things. In an embodiment where Y comprises a structure of formula G, Y is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position of formula G capable of reacting with Q or L Time). Those skilled in the art will readily be able to determine the binding position on Y and the manner in which Y is bound to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, Y is bonded to L or Q via any position of Y. In some embodiments, Formula G binds to L or Q at R11. In some embodiments, Y acts on a peroxisome proliferator-activated receptor (eg, PPARa, ΡΡΑΙΙβ/δ, PPAR/y). In some embodiments, Y comprises any structure that allows or promotes agonist activity on PPAR, while in other embodiments, Y is an antagonist of PPAR. In some embodiments, Y is a saturated or unsaturated, toothed or undonated free fatty acid (FFA) as described by the formula: ΗΟ R12 (R12) Na 0 R12 where η is 0 to 26 And each R12, when present, is independently a moiety that allows or promotes the activity of the agonist or antagonist when the hydrazine compound is bound to the PPAR. In some embodiments, Y comprises a structure of the formula wherein n is from 0 to 26 and each R12, when present, is independently hydrogen, (^-(:7 alkyl or halogen. In some 156004.doc •78. 201143790 In the example, Formula B is saturated, such as formic acid, acetic acid, n-hexanoic acid, heptanoic acid, octanoic acid, citric acid, citric acid, undecanoic acid, lauric acid, tridecanoic acid, myristic acid, fifteen Alkanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecinal acid, arachidic acid, twenty-one yard acid, twenty-two succinic acid, succinic acid, perfluorodecanoic acid (see below), Perfluorooctanoic acid (see below), and derivatives thereof. In some embodiments, the formula is unsaturated and has cis or trans stereochemistry, such as eicosatrienoic acid, myristate, palmitic acid , hexadecenoic acid, oleic acid, linoleic acid, α-linolenic acid, oleic acid, petroselinic acid, arachidonic acid, dihydroxyeicosatetraenoic acid (DiHETE), octadecane Acid, eicosatrinoic acid, eicosadienoic acid, eicosatrienoic acid, eicosapentaenoic acid, sinapic acid, di-high linoleic acid, twenty Carbon triple acid, docosapentaenoic acid, docosahexaenoic acid, adrenic acid and derivatives thereof.

In an embodiment of the structure comprising Y, γ is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position capable of reacting with Q or L. Time). Those skilled in the art, given the general knowledge and the invention provided herein, can readily determine the binding position on the formula and the manner in which the formula is bonded to Q or L. In some embodiments, any of the formulas η on the formula η Bind to L or q in position. In some embodiments, the formula η is bonded to L or Q via a terminal carboxylic acid moiety. In some of these embodiments, γ is a terpenic acid. In the specific example of 156004.doc •79·201143790, γ is a prostaglandin or a leukotriene. In some exemplary embodiments, 'Υ is a serotonin having a sister structure as described by the formulas j丨 to j 6: ki HO K1 HO Μ: ?d: r13 δ U HO αρη Formula J1 Formula J2 J3 Formula J4 Formula J5 Formula J6 ~~ wherein each R13 is independently a moiety which allows or promotes the activity of the agonist or antagonist when the compound of formula j is bound to ppAR (for example, PGJ2 as shown below):

OH

In some embodiments 'when Y comprises the structure of any of formulas J1 to J6, each R13 is independently (VC: 8 alkyl, C7_C8 alkenyl, C7_C8 alkynyl or heteroalkyl. In the embodiment of the alkanoic acid, γ is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a - bond) at any position of the decyl-like acid capable of reacting with q or L. Those skilled in the art will readily be able to determine the binding position on Y and the manner in which gamma binds to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, gamma is coupled to l via any position of gamma Or Q. In some embodiments, the decanoic acid is bonded to L or Q via a terminal carboxylic acid moiety or via a pendant alcohol moiety. 156004.doc 201143790 In some exemplary embodiments, γ is a leukotriene having A structure as described in the form of a derivative of the formula:

Wherein each R14 is independently a moiety that allows or promotes the activity of the agonist or antagonist when the hydrazine compound is bound to ppAR (e.g., leukotriene B4 as shown below):

OH 〇 In some embodiments, when Y comprises a structure of formula κ, each R!4 is independently c3-c13, c3_Cl3, c3_Ci3 alkynyl or heteroalkyl. In an embodiment where Y comprises a structure of formula K, γ is bonded to L at any position of the formula κ capable of reacting with Q or L (eg, when l is a linking group) or Q (eg, when L is a bond) Time). Those skilled in the art will readily be able to determine the binding position on Formula K and the manner in which K is combined to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, the formula κ binds to L or Q at any position on the formula κ. In some embodiments, the formula κ is bonded to L or q via a terminal carboxylic acid moiety or via a pendant alcohol moiety. In some exemplary embodiments, Y is a thiazolidinedione comprising a structure as described by Formula L:

156004.doc 81-201143790 Non-limiting examples of compounds of formula L include:

Rosiglitazone

Troglitazone and its derivatives. In an embodiment where Y comprises a structure of formula L, Y is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position of formula L capable of reacting with Q or L Time). Those skilled in the art will readily be able to determine the binding position on Formula L and the manner in which Formula L is combined to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, Formula L is bonded to L or Q at any position on Formula L, such as a pendant alcohol moiety or via an aromatic substituent. In some embodiments, Y acts on RAR-associated orphan receptors (eg, RORa, RORP, ROR/y). In some embodiments, Y comprises any structure that allows or promotes agonist activity against ROR, while in other embodiments, Y is an antagonist of ROR. Non-limiting examples of Y include:

Cholesterol melatonin 156004.doc -82- 201143790

, V3 CGP 52608

Things.

In embodiments where Y is effective for ROR, Y is bonded to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position where Y is capable of reacting with Q or L. . Those skilled in the art will readily be able to determine the binding position on Y and the manner in which Y is bound to Q or L in view of the general knowledge and the invention provided herein. In some embodiments, Y is bonded to L or Q via any position of Y, such as any of the locations previously described herein. In some embodiments, Y acts on the liver X receptor (LXRa, LXRP). In some embodiments, Y comprises any structure that allows or promotes agonist activity against LXR, while in other embodiments, Y is an antagonist of LXR. In an exemplary embodiment, Y is an oxysterol (i.e., an oxidative derivative of cholesterol). Non-limiting examples of Y in these examples include 22(R)-hydroxycholesterol (see below), 24(S)-hydroxycholesterol (see below), 27-hydroxycholesterol, cholesterol acid, and derivatives thereof.

In embodiments where Y acts on LXR, Y binds to L (e.g., when L is a linking group) or Q (e.g., when L is a bond) at any position where Y is capable of reacting with Q or L. . Those skilled in the art will readily be able to determine the binding position on gamma and the manner in which Y is bound to Q or L, given the general knowledge and the teachings of the present invention, 156,004.doc, 83-201143790. In some embodiments, γ is at positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, Binding to L or Q in any of 20, 21, 22, 23, 24, 25 or 26 In some embodiments, the formula ρ is bonded to L or Q at position 3 or 17 of formula F. In some embodiments, Y acts on the farnesoid X receptor (FXR). In some embodiments, gamma comprises any structure that allows or promotes agonist activity on FXR. In other embodiments, Y is an antagonist of FXR. In some of these embodiments, Y is a bile acid. In the exemplary embodiment, 'Y has the structure of the formula.

Wherein R15, R16 and R17 are each independently a moiety which allows or promotes the activity of the agonist or antagonist when the hydrazine compound is bound to the FXR. In some embodiments, when Υ comprises a structure of the formula, R 15 and R 16 are each independently hydrogen, (C〇-C8 alkyl) halo, CrCu alkyl, C 2 -C 18 alkenyl, C 2 -C 18 alkynyl. , heteroalkyl or (C〇-C8 alkyl)OH; and R17 is OH, (C0-C8 alkyl) NH(Ci-C4 alkyl)S〇3H or (C〇-C8 alkyl)alkyl) COOH. In some embodiments, when γ comprises a structure of a river, 'R15 and R16 are each 156004.doc • 84· 201143790 The site is hydrogen or OH; and r17 is 〇H, ΝΗ((ν(:2 alkyl)S03H Or NHCCVCz alkyl) COOH. Non-limiting examples of hydrazine compounds include:

Gentiochoic acid

Chenodeoxycholic acid

And its derivatives. In the case where the structure of the Υ Υ 会 丨 丨 丨 丨 丨 丨 ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? ? To L (for example, when L is a linking group) or Q (for example, when L is a bond). Those skilled in the art will be able to readily ascertain the position of the binding on the cymbal and the manner in which the formula μ binds to Q or L in view of the general knowledge and the invention provided herein. In the second instance of this police, the position of the formula is 1, 2, 3, 4, 5, 6, 7, ", 〇8 9, 10, 11, 12, 13, 14, 15, 16 Any of 156,004.doc -85 - 201143790, 17, 18, 19, 20, cm, 22, 23, 24, or 25 is combined to L or Q. In some embodiments, the formula is combined to l or Q at position 3, 7, 12 or 17 of the formula. In some embodiments, gamma acts on the vitamin D receptor (VDr). In some embodiments, 'Υ contains any structure that allows or promotes agonist activity against VDR'. In other embodiments, γ is an antagonist of VDR. In the exemplary embodiment, 'Υ has the structure of the formula:

Wherein R18, R19, R20, R2, R22 and R23 are each a moiety which allows or promotes the activity of an agonist or antagonist when the compound of formula ν is bound to VDR, such as, for example, Bouillon et al., ZieWew®, 16 (2) ): Any of the vitamin D compounds in 200-257 (1995).

In some embodiments, wherein Y comprises the structure of formula N, R18 and R19 are each independently hydrogen, (C〇-C8 alkyl) halo, (C〇-C8 alkyl)heteroaryl or (C〇- C8 alkyl) 〇H; both R2G are hydrogen or two R2Q together form =CH2; R21 and R22 are each independently CkG alkyl; and R23 is C4-C18 alkyl, C4-C18 dilute, C4- Ci8 fast radical, heteroalkyl, (C4-C18 alkyl)aryl, (C4-C18 alkyl)heteroaryl, (C〇-C8 alkyl)OCV C 18 alkyl, (C 〇- C 8 Dilute base) 0 C 1 - c 1 8 alkyl group, (CQ - C 8 fast group) 0 C 1 - C 1 8 156004.doc • 86· 201143790 alkyl, (C〇-C8 alkyl) OC2-C18 olefin Base, ((:.-(:8 alkyl) fluorene (: 2-(:18 alkynyl, (C6-C18 alkyl) OH, (C6-C18 alkyl) SH, (C6-C18 dilute) 〇 H, (C6-C18 alkynyl) OH, (C〇-C8 alkyl)alkyl, ((: 〇-(:8) NR^CVCu alkyl, (C〇-C8 alkynyl) NI^CVCu Alkyl, alkyl)NR24C2-C18 alkenyl, (C()-C8 alkyl)NR24C2-C18 alkynyl, (c〇-c8 alkyl) (^(COCVCu alkyl, (cQ-c8 alkyl)c (o) c2-c18 alkenyl, (c〇-c8 alkyl) c(o)c2-c18 alkynyl , (c〇-c8 alkyl) C(0)H, (c〇-c8 alkyl) C(O)aryl, (C〇-C8 alkyl)C(O)heteroaryl, (C〇- C8 alkyl) (:(0)0(ν(:18 alkyl, (c〇-c8 alkyl)c(o)oc2-c18 alkenyl, (c〇-c8) C(0)OC2- C18 fast radical, (C〇-C8 alkyl) C(0)0H, (C〇-C8 alkyl) C(0)0 aryl, (C0-C8 alkyl) C(0)0 heteroaryl, (c0-c8 alkyl) 00(0) (:, -(^8 alkyl, (c〇-c8 alkyl) 〇c(o)c2-c18 alkenyl, (C〇-c8 alkyl) oc ( o) c2-c18 alkynyl, (c〇-c8 alkyl, (c〇-c8 alkyl) c(o)nr24c2-c18 alkenyl, (cvc8 alkyl) C(0)NR24C2-C18 alkynyl, (C〇-C8 alkyl) c(o)nr24h2, (C〇-C8 alkyl) C(0)NR24 aryl, (C〇-C8 alkyl) C(0)NR24 heteroaryl, (C〇 -c8-based) NR^CiWCVCu alkyl, (Cg-C8 alkyl) NR24C(0)C2-C8 alkenyl or (c〇-c8 alkyl)nr24c(o)c2-c18 alkynyl, (Cg_C8 alkyl Nr24c(o)oh, (c〇-c8 alkyl)oc(o)oc丨-Ci8 alkyl, (C❶-c8 alkyl)0C(0)0C2-C18 alkenyl, (C〇-C8 alkyl) )〇c(〇)〇c2-C18# base, (C〇-C8 alkyl) 0C(0)0H, (C〇-C8 alkyl) 00(0)1^24(^-( ^8 alkyl, (c〇-cs alkyl) oc(o)nr24c2-c18 alkenyl, (C(rC8 alkyl alkynyl, (C〇-C8) 〇c(0)NR24H2, (C〇 _C8 alkyl)^24(0)0(^-0^8 alkyl, (C(rC8 alkyl) 156004.doc -87- 201143790 NR24(9)0C"Cl8 alkenyl, (c〇_C8 炫) nr24( 〇) 〇C2_Cu block group or (C〇-C8 alkyl) NR24(〇)〇h; and R24 is hydrogen or cvc18 alkyl. Non-limiting examples of compounds of formula N include:

And its derivative 0 In an embodiment in which Y comprises a structure of formula N, γ is bonded to L at any position where the formula can react with hydrazine or ^ (for example, when L is a linking group) or hydrazine (for example, when L When it is a key). Those skilled in the art will readily be able to determine the binding position on Formula N and the manner in which Formula n is combined to Q or L. in view of the general knowledge and the invention provided herein. In some embodiments, the formula n is at positions i, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 of the formula n Binding to L or Q on any of 20, 21, 22, 23, 24, 25 or 26. In some embodiments, formula n is bonded to L or Q at position 1, 3, 19 or 25 of formula N. In some embodiments, Y acts on a pregnane X receptor (PXR). In some embodiments, Y comprises any structure that permits or promotes agonist activity on PXR, while in other embodiments, Y is an antagonist of PXR. In some embodiments 'Y is a steroid, an antibiotic, an antifungal agent, a bile acid, a petal gold 156004.doc-88-201143790 a hyperforin or an herbal compound. In an exemplary embodiment, γ is a compound that induces CYP3A4, such as dexamethasone and rifampicin. In embodiments where gamma comprises a structure that acts on PXR, gamma binds to L (e.g., when l is a linking group) or Q (e.g., when L is one) at any position where gamma is capable of reacting with q or L. When the key is pressed). Those skilled in the art will readily be able to determine the binding position on gamma and the manner in which gamma binds to Q or L. in view of the general knowledge and the invention provided herein. In some embodiments, ¥ is bonded to L or Q at any position on the raft. Modification of NHR Ligand (Y) In some embodiments, the NHR ligand is derivatized or otherwise chemically modified to comprise a ability to react with a glycoside superfamily peptide (q) or a linking group. Reactive part. In the examples described herein, gamma is derivatized at any position where gamma is capable of reacting with Q or L. The location of the derivatization on gamma is evident to those skilled in the art and will depend on the type of NHR ligand used and the activity desired. For example, in an embodiment where γ has a structure comprising three four-membered rings connected to a five-membered ring or a variant thereof, Y can be at positions 1, 2, 3, 4, 5 Derivatization of any of 6, 7, 8, 9, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25. Other derivatization locations can be as previously described herein. The N H R ligand can be derivatized using any reagent known to those skilled in the art or as described herein (see, for example, the oxime-based iron moiety and the ugly ♦ portion of g and/or y). For example, estradiol can be derivatized with succinic acid, succinic anhydride, benzoic acid, ethyl 2-bromoacetate or iodoacetic acid to form the following females capable of knotting 156004.doc •89- 201143790 to Q or L A diol derivative.

Succinic acid or succinic acid sj/ Me pH

Ethyl 2-bromoacetate or iodoacetic acid

Likewise, any of the above NHR ligands can be derivatized by methods known in the art. Additionally, certain derivatized ligands are commercially available and are commercially available from chemical companies such as Sigma-Aldrich. Glucagon Super Family Peptide (Q) In the Q-L-Y conjugate described herein, Q is a glycoside superfamily peptide. The glycosidic superfamily peptide refers to a group related to the structure of the N-terminal and/or C-terminal regions (see, for example, Sherwood et al., 5, c/ocr/we 21: 619-670 (2000)). . The C-terminus of the salty letter generally plays a role in receptor binding, and the N-terminus generally plays a role in receptor signaling. A small amount of amino acid in the N-terminal and C-terminal regions is highly conserved among members of the glycoside hyperfamily. Some of the amino acids in these conservative amino acids include His 1, Gly 4 , Phe 6 , Phe 22 , Val 23 , Trp 25 and Leu 26 , wherein the amino acids at these positions exhibit the consistency and conservation of the amino acid side chains thereof. Replace or similarity. Glycosin superfamily peptides include glycosidin-related peptides, growth hormone release 156004.doc -90- 201143790 ermen (GHRH; SEQ ID NO. 1619), vasoactive intestinal peptide (VIP; SEQ ID NO: 1620 Pituitary adenylate cyclase activating polypeptide 27 (PACAP-27; SEQ ID NO. 1621), peptide histidine isokinetic acid (PHI; SEQ ID NO: 1542), peptide histamine methylthioamide Acid (ΡΗΜ; SEQ ID NO: 1622), secretin (SEQ ID NO: 1623) and/or its analogs, derivatives or conjugates. In some embodiments, Q comprises a native glucomannan having at least 1, 2, 3' 4, 5, 6, 7, 8, 9, or 10 amino acid modifications, a native incretin analog-4, native Amino acid sequence of GLP-1 (7-37), native GLP-2, native GHRH, native VIP, native PACAP-27, native PHM, native acid-regulating hormone, native secretin or native GIP. In some aspects of the invention, Q is a glycosidin-related peptide, such as a glycoside (SEQ ID NO: 1601), a acid-regulator (SEQ ID NO: 1606), an incretin analog-4 (SEQ) ID NO: 1618), a glycopeptide-like peptide-1 (GLP-1) (amino acid 7-36 provided as SEQ ID NO: 1603; amino acid 7-37 provided as SEQ ID NO: 1604), Glucagon-like peptide-2 (GLP-2, SEQ ID NO: 1608), gastric inhibitory peptide (GIP, SEQ ID NO: 1607), or analogs, derivatives and combinations thereof. The glycoside-related peptide is biologically active (as an agonist or antagonist) for any of the glycosidic receptor, the GLP-1 receptor, the GLP-2 receptor, and the gip receptor, and includes the native liter At least one of a glycoside, a native sophoronin, a native incretin analog _4, a native GLP-1 (7-3 7), a native GLP-2, or a native GIP is in the length of the peptide (or in correspondence) At the position of glycosidic, see, for example, Figure 共有) a total of at least 2% sequence identity (eg 25%, 30%, 35%, 4%, 45%, 5%, 156004.doc •91-201143790) 5 5% ' 60% ' 65% ' 70%, 75%, 80% ' 85% ' 90% ' 95% ) The amino acid sequence β should be understood to cover all possible active subsets of the glycein-related peptide, eg The peptide is biologically active (as an agonist or antagonist) for any one or more of the glycoside receptor or GLP-1 receptor or GIP receptor; and is consistent with the sequence of each of the listed native peptides All possible subsets, such as peptides, comprise at least 20%, 25%, 30%, 35% '40% '45% > 50% '55% '60 of the length of native GLP-1 over native GLP-1. % ' 65% ' 70% ' 75% ' 80%, 85%, 90% or 95% The amino acid sequence of columns consistency. In some embodiments of the invention, the glycosidin-related peptide has a glycosidic receptor agonist activity, a GLP-1 receptor agonist activity, a GIP receptor agonist activity, a glycosidic receptor/ GLP-1 receptor co-activator activity, glycosidic receptor/(卟卟 receptor co-activator activity, GLP-1 receptor/GIP receptor co-activator activity, glycosaminoglycan receptor/GLP a peptide of the -1 receptor/GIP receptor triple agonist activity, a glycoside receptor antagonist activity or a glycoside receptor antagonist/GLP-1 receptor agonist activity. In some embodiments, the peptide is The alpha-helical configuration is retained in the C-terminal half of the molecule. In some embodiments, the peptide retains a position involved in receptor interaction or signaling 'eg, position 3 of glycosidin, or GLP-1 (7-3 7) Position 7, 10, 12, 13, 15, or 17. Therefore, the glycoside-related peptide may be a class 1, a second class, a third class, a fourth class, and/or a fifth class peptide, each of which is Further described herein. Q can also be any of the glycoside superfamily peptides known in the art, some of which are disclosed herein by way of non-limiting examples. A variety of GLP-1 analogs in Known in the art, and the present invention glycemic 156004.doc -92 · 201143790 hormone related peptide, see, e.g. WO 2008023050, WO 2007030519,

WO 2005058954, WO 2003011892, WO 2007046834, WO

Each of the sequences or structural disclosures of GLP-1 analogs or derivatives is incorporated herein by reference in its entirety. In any embodiment, Q can be a glycosidin related peptide as disclosed in the following patent: WO 2007/056362, WO

2008/086086 'WO 2009/155527 > WO 2008/101017 'WO 2009/155258, WO 2009/058662, WO 2009/058734, WO 2009/099763, WO 2010/011439, PCT Patent Application No. US 09/68745 And U.S. Patent Application Serial No. 61/187,5, the entire disclosure of each of which is incorporated herein by reference. In certain embodiments, Q is a Class 1, Class 2, Class 3, Class 4, or Class 5 glycosidin related peptide as detailed herein. In any of the embodiments described herein, Q is any one of SEQ ID NOs: 1-760, 801-919, 1001-1275, 1301-1371, 1401-1518, 1601-1650. In some embodiments, Q is any one of SEQ ID NOs: 1647-1650. Activity of the Glycosin Superfamily Peptide (Q) Activity on the Glycoglycan Receptor In some embodiments, Q exhibits EC5 对 (or agonist to the glycemic receptor) exhibited by glycosidic receptor activation. The displayed IC5G) is about 10 mM or less, or about 1 mM (1000 μΜ) or less than 1 mM (for example, about 750 μΜ or 750 μΜ, about 500 μΜ or less, about 250 μΜ or less than 250 μΜ) , about 100 μΜ or less, about 75 μΜ or 75 μΜ to {;: 156004.doc •93- 201143790, about 50 μΜ or less than 50 μΜ, about 25 μΜ or less, about 10 μΜ or 10 μΜ Below, about 7·5 μΜ or 7.5 μΜ, about 6 μΜ or 6 μΜ, about 5 μΜ or 5 μΜ, about 4 μΜ or 4 μΜ, about 3 μΜ or 3 μΜ, about 2 μΜ or 2 μΜ Below, or about 1 μΜ or less than 1 μΜ). In some embodiments, the Q exhibits an EC50 or IC50 of about 1000 nM or less than 1000 nM (eg, about 750 nM or 750 nM or less, about 500 nM or less, about 250 nM or 250, for the glycosidic receptor). nM or less, about 100 nM or 100 nM or less, about 75 nM or 75 nM or less, about 50 nM or 50 nM or less, about 25 nM or 25 nM or less, about 1 〇 nM or less, or about 7.5. nM or 7.5 nM or less, about 6 nM or 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, or about 1 nM Or 1 nM or less). In some embodiments, 'Q is in the Pimol range for the EC5D or IC5Q of the glycemic receptor. Thus, in some embodiments, q exhibits EC5〇 or IC5 to the glycemic receptor. Above about 1000 pM or less than 1000 pM (eg, about 750 pM or less than 750 pM, about 500 pM or less, about 250 pM or 250

Below pM, about 1〇〇1)1^ or 1〇〇pM or less, about 75 pM or 75 pM or less, about 50 pM or 50 pM or less, about 25 pM or less, less than about 1 pM or less than 10 pM , about 7.5 pM or 7.5 pM or less, about 6 pM or less, about 5 pM or less, about 4 pM or less, about 3 pM or less, about 2 ρ or less than 2 ρΜ, or About i ρΜ or i ρΜ below). In some embodiments, the Q exhibits an ec5Q or ic50 of about 0.001 pM or 0.001 pM, about p1 pM or 〇〇1 pM at 156004.doc-94-201143790, or about 0.1 pM or more. Glycoglycan receptor activation (glucagon receptor activity) can be detected by in vitro detection of cAMP induction in HEK293 cells overexpressing the glycosidic receptor, for example, as described in Example 2, encoding a glycoside The recipient's DNA and HEK293 cells co-transfected with the luciferase gene linked to the c AMP response element were measured.

In some embodiments, the activity exhibited by Q on the astaxanthin receptor is about 0.001% or 0.001% relative to the native glyce. Above, about 0.01% or more, about 0.1% or more, about 0.5% or more, about 1% or more, about 5% or more, about 10% or more, About 20% or more, about 30°/. Or 30°/. Above, about 40% or 40°/. Above, about 50% or more, about 60% or more, about 75% or more, about 100% or more, about 125% or more, about 150% or more, About 175% or more, about 200% or more, about 250°/. Or 250% or more, about 300% or 300°/. Above, about 350°/. Or more than 350%, about 400°/. Or more than 400%, about 450% or more, or about 50,000% or more (glycin potency). In some embodiments, the activity exhibited by Q on the ghrelin receptor is about 5000% or less or about 10,000% or less relative to the native glyce. The activity of Q on the receptor relative to the native ligand of the receptor is calculated as the inverse ratio of EC5Q of Q to EC5g of the native ligand. In some embodiments, Q exhibits substantial activity (potency) only to the glycemic receptor and exhibits little or no activity to the GLP-1 receptor or GIP receptor. In some embodiments, the Q system is considered to be a "pure glycoside receptor agonist" or not as a "glycoside receptor/GLP-1 receptor co-activator" or "glycoside 156004.doc" -95- 201143790 50 Receptor/GIP Receptor Co-agonist γ exhibits any activity or potency described herein in some embodiments. Q has substantially less activity on the glycoside or GIP receptor ( In the ~~GLIM receptor, the EC5 exhibited by Q to the GLP-1 receptor. For: - some examples

_ times or (10) times or more. In some embodiments, the EC exhibited by the masking receptor ΡΓt Q is more than 1 doubling the ec^ of the glycoside receptor or the GLP-I receptor for the GIP receptor. Activity In some embodiments, the EC50 exhibited by Q for GRP-1 receptor activation by private rTD (or 1 for GLP-1 receptor antagonism):

J mM or less than 10 mM, or about 1 mM (l〇〇〇μΜ) or less than i mM (for example, about 75 〇 750 μ Μ or less, about 500 μ Μ 4 500 μ Μ or less, about 25 〇 μ Μ * 25 〇 μ Μ or less, about 100 4 PCT or 1 〇〇μΜ, about 75 or less, about 50 μΜ or 50 μΜ, about 25 μΜ or 25 μΜ, about 1〇μΜ or 10 μΜ, about 7·5 μΜ or 7.5 μΜ, About 6 μΜ or 6 μΜ or less, about 5 μΜ or 5 μΜ or less, about 4 μΜ or 4 μΜ or less, about 3 μΜ or 3 μΜ or less, about 2 μΜ or less, or about 1 μΜ or less. In some embodiments, the EC50 or IC5〇 exhibited by Q for GLP-1 receptor activation is about looo nM or less than 1000 nM (eg, about 750 nM or 750 nM or less, about 5 〇〇 nM or less, about 500 nM or less, about 250 nM or 250 nM or less, about 100 nM or 100 nM or less, about 75 nM or 75 nM or less, about 50 nM or less, less than 25 nM or less, about 10 nM or less, about 7.5 n. nM or 7.5 nM or less, about 6 nM or 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, or about 1 nM or 1 nM or less). In some 156004.doc • 96·201143790 example towels, Q to the GLiM receptor EC5〇s1UC5〇 is in the picomolar range. Thus, in some embodiments, the QSfGLp_K body activates the exhibited EC5. Or IC5. Is about 1000 pM or less 〇0 〇 pM or less (eg, about 75 〇pM or 750 pM or less, about 500 pM or less, about 25 〇pM or less, about 100 pm or less, about 75 pm, about 75 pm pM*75 below pM, about 50 PM or less, about 25 pM or less, about 1〇

pM or less than 10 pM, about 7.5 pM or 7.5 pM or less, about 6 pM or less, less than 5 PM or less, about 4 pM or less, about 3 pM or less, about 2 pM or 2 pM or less, or about i pM or i pM or less). In some embodiments, Q exhibits an ec5G or IC50 for the GLP-1 receptor of about 0.001 pM or 0.001 pM or more, about 〇·〇ι pM or 0.01 pM or more, or about 0.1 pM or more. GLP-1 receptor activation (GLP-1 receptor activity) can be detected by in vitro detection of cAMP induction in HEK293 cells overexpressing the GLP-1 receptor, for example, the coding GLP-1 as described in Example 2. The recipient's DNA and HEK293 cells co-transfected with the luciferase gene linked to the cAMP response element were measured. In some embodiments, the activity exhibited by Q on the GLP-1 receptor is about 0.001% or 0.001% relative to native GLP-1. Above, about 0.01% or more, about 0.1% or 0.1%. Above, about 0.5% or more, about 1% or more, about 5% or more, about 10% or more, about 20% or more, about 30% or more, About 40% or more, about 50% or more, about 60% or more, about 75°/. Or more than 75%, about 100% or 100. /. Above, about 125% or 125°/. Above, about 150% or 150% is 156004.doc -97-201143790, about 175% or more, about 200% or more, about 250% or 250°/. Above, about 300% or 300°/. Above, about 350% or more, about 400% or 400. /. Above, about 450°/. Or more than 450% or about 500% or more (GLP-1 potency). In some embodiments, the activity exhibited by q on the glP-Ι receptor is about 5000% or less or about 10,000% or 10,000°/% relative to native GLP-1. The following (GLP-1 performance). In some embodiments 'Q exhibits only substantial activity (potency) to the GLP-1 receptor and exhibits little or no activity to the glycoside receptor or GIP receptor. In some embodiments, 'Q is considered to be a "pure GLp_i receptor agonist" or not as a "glycoside receptor/GLP-1 receptor co-agonist" or "GLP·1/GIP co-promoting Effect agent." In some embodiments, q exhibits any activity or potency as described herein for the glP-Ι receptor but has substantially less activity (potency) for the glycosidic receptor or GIP receptor. In some embodiments, the ECso exhibited by Q to the glycemic receptor is 100-fold or more than the EC5G of the GLP-Ι receptor. In some embodiments, the ECso exhibited by q for the GIp receptor is 1 or more than 1 to about the EC5 of the GLP-Ι receptor. Activity against GIP receptors In some embodiments, 'Q for ge5G exhibited by GIP receptor activation (or ic5〇 exhibited by GIP receptor antagonism) is about 1〇11^ or less than 1〇mM or about 1 mM (1000 μΜ) or less than 1 mM (eg, about 750 μΜ or 750 μΜ, about 500 μΜ or 500 μΜ, about 250 μΜ or 250 μΜ, about 100 μΜ or less, about 75 μΜ or 75 μΜ Below, about 50 μΜ or 50 μΜ, about 25 μΜ or 25 μΜ, about 10 μΜ or 10 μΜ, about 7.5 μΜ or 7.5 μΜ, about 6 μΜ or less, 156004.doc -98- 201143790

About 5 μΜ or 5 μΜ, about 4 μΜ or 4 μΜ, about 3 μΜ or 3 μΜ or less, about 2 μΜ or 2 μΜ or less, or about 1 μΜ or less. In some embodiments, the EC50 or IC50 of the Q-to-GIP receptor is 1000 ηΜ or less, 900 ηΜ or less, 800 ηΜ or less, 700 ηΜ or less, 600 ηΜ or less, 500 ηΜ or less, 400 ηΜ or less, 300 ηΜ or less, or 200. Below ηΜ. In some embodiments, the EC50 or IC50 of the Q-to-GIP receptor is about 100 η Å or less, such as about 75 η Μ or 75 η Μ, about 50 η Μ or 50 η Μ or less, about 25 η Μ or 25 η Μ or less, about 10 ηΜ or 10 ηΜ or less, about 8 η Μ or 8 η Μ or less, about 6 η Μ or 6 η Μ or less, about 5 η Μ or 5 η Μ or less, about 4 η Μ or 4 η Μ or less, about 3 η Μ or 3 η Μ or less, about 2 η Μ Or 2 ηΜ or less, or about 1 ηΜ or 1 ηΜ or less. In some embodiments, the EC5〇 or IC50 exhibited by Q for GIP receptor activation is in the picomolar range. In an exemplary embodiment, the EC50 or IC50 of the Q-to-GIP receptor is 1000 pM or less, 900 pM or less, 800 pM or less, 700 pM or less, 600 pM or less, 500 pM or less, 400 pM or less, 300 pM or less, 200. Below pM. In some embodiments, the EC5〇 or IC5〇 of the Q to GIP receptor is about 100 pM or less, such as about 75 pM or 75 pM or less, about 50 pM or less, about 25 pM or less. , about 10 pM or less, about 8 pM or less, about 6 pM or less, about 5 pM or less, about 4 pM or less, about 3 pM or less, about 3 pM or less 2 pM or less, or about 1 pM or less. Receptor activation can be detected by in vitro detection of cAMP induction in HEK293 cells overexpressing GIP receptors, for example, detection of DNA encoding the receptor and luciferase linked to cAMP response elements as described in Example 2. Gene co-transfected HEK293 fine 156004.doc -99- 201143790 Cellular assays In some embodiments of the invention, the activity exhibited by Q on the GIP receptor is at least or about 0.1% of the native GIP. In an exemplary embodiment, the activity exhibited by q on the GIP receptor is at least about 0.2%, at least or about 0.3%, at least or about 0.4%, at least or about 0.5%, at least or about 0.6% of the native GIP, At least or about 0.7%, at least or about 0.8%, at least or about 0.9%, at least or about 1%, at least or about 5%, at least or about 10%, at least or about 2%, at least or about 30%, at least Or about 40%, at least or about 50%, at least or about 60%, at least or about 70%, at least or about 75%, at least or about 80%, at least or about 90%, at least or about 95%, or at least or About 100%. In some embodiments of the invention, Q exhibits greater activity to the GIP receptor than native GIP. In an exemplary embodiment, the activity exhibited by q on the GIP receptor is at least about 101%, at least or about 105%, at least or about 110%, at least or about 125%, at least or about 150% of the native GIP, At least or about 175%, at least or about 200%, at least or about 300%, at least or about 400%, at least or about 500%, or more than 500%. In some embodiments, the activity exhibited by Q on the GIP receptor is at most 1000 Å/〇, 10,000%, 100,000%, or 1,000,000% relative to the native GIP. The activity of the peptide against the GIP receptor was calculated as the inverse ratio of the EC5G of the GIP agonist peptide to the EC5〇 of the native GIP relative to the native GIP. In some embodiments, Q exhibits only substantial activity (potency) to the GIP receptor and exhibits little or no activity to the glycoside receptor or GLP-1 receptor. In some embodiments, the Q system is considered to be a "pure GIP receptor agonist" or not as a "glycoside receptor/GIP receptor co-activator" or "GLP-1/GIP co-promoted 156004.doc • 100. 201143790 efficacy agent. In some embodiments, the 0 pair of 〇11> receptors exhibit any activity or potency as described herein, but have substantially less activity on the glycoside receptor or GLpq receptor (efficiency in some embodiments) 'Q is expressed as a glycoside receptor at 1〇〇 or ι〇〇 times the GIP receptor and is expressed at the GLP-1 receptor. Ec 100 is the GIp receptor. Times or more than 100 times. 50 Temple GLP receptor and glycosidic receptor activity

In some embodiments, the _GUM receptor and the glycemic receptor activity ("glucagon receptor/GUM receptor co-activator"). In the case, the activity of the (4) glucosamine receptor (e.g., % or ^) is about 50 times greater than the activity of the 辄P· 咖 (e.g., or relative activity or effect). 4〇 times, about 3〇 times about 2〇 times 2•101- 1 times. In some embodiments, the glucagon performance of the 'q differs by a factor of about 25 times, more than about 2 times, about 10 times, or about 5 times less than or equal to the sail performance. . In some embodiments, the relative activity of Q to the glycemic receptor is: the relative activity of the energy receptor divided by an i receptor: the ratio is less than X or about X, wherein x is selected from the group of 4 〇, 3. ,, —. In some embodiments, the EC5 of the binary body. Or the efficacy or relative activity divided by (4) (10)] ', again: the ratio of energy or relative activity is about 5 or less (for example, or about 2, about υ. In some embodiments, Q rises J-, (10)] The ratio is less than z, ^ is compared to Q _, 75, 6 〇, 50, 40, 3 〇, 2 〇, l5 where Z is selected from and 1. In some implementations 156004.doc 201143790 case 'Q rise The ratio of glycin potency to Q<GLp i potency is less than 5 (e.g., about 4, about 3, about 2, about 1). In some embodiments, the EC50 of the 'Q for the glycemic receptor is for GUM. The receptor is called twice as much as 〇 (for example, 2 times 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 1 times times). In the embodiment, Q is affected by GLIM. The relative activity or potency of the body or the EC50 divided by the relative activity or potency of the glycosidic receptor to the glycemic receptor or the ratio obtained by ec50 is less than v, or about v, which is selected from (10), is, 60 , 50, 40, 30, 20, or 5» In some embodiments 'Q for the GLP-1 party EC5〇 or potency or relative activity divided by q for the ec50 of the glycemic receptor or potency or relative The ratio obtained by the activity is less than 5 (example) Is about 4, about 3, about 2, about 1). In some embodiments, the ratio of the efficacy of the sinking effect to the glycemic potency of Q is less than..., or about trade, wherein the W is selected from 100, 75, 6〇, 5〇, 4〇, 3〇, 2〇, 15, 1〇 and /. In some embodiments, the ratio of GLpq efficacy of Q to the glycemic potency of Q is Less than 5 (eg, about 4, about 3, about 2, about 丨). In some embodiments, the ECw of Q to the GLP-1 receptor is about 2 to about 10 to the EC5 升 of the glycemic receptor. Multiple (eg, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold). In some embodiments, the activity exhibited by Q on the GLP-1 receptor is native. At least 1.1% of GLP-1 (eg, about 05% or more than 5%, about 1% or more, about 5% or more, about 1%, or more than 10%, or higher). (GLp i potency)' and its activity on the glycoside receptor is at least 0.1 ° / (for example about 0.5 ° / ❶ or 0.5%, about 1% or more, About 5°/〇 or more, about 101⁄4 or more, or higher) (glycoside potency) 156004.doc •102- 20114 3790 <220><223>Synthetic peptide <220><221> MOD.RES <222> (2)..(2) <223> Xaa is Aib <400>

His Xaa Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Arg Arg Ala Gin Asp Phe Val Gin 20

Trp Leu 25

Ser Met

Lys

Asn

Tyr Leu Thr Gly 30

Asp Glu 15 Pro Ser

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 >>>> 0 12 3 2 22 2 <<<< 1263 40 PRT Artificial Sequence <220><223> Synthetic Peptide <220>;<221> MISCJ <223> MT-34. _FEAT\JRE 345 <220><221> MOD RES <222> (2)..(2) <223> Xaa is Aib <220>;<221> MOD RES <222> (40)..(40) <223> 〇4 fat 醯 based brewing <220><221> M0D.RES <222> (40). (40) <223> Alanine <400> 1263 His Xaa Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Gin Ala Ala Lys Glu Phe lie Cys 20

Trp Leu 25

Ser Met

Lys

Asn

Tyr Leu Gly Gly 30

Asp Glu 15 Pro Ser

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1264 <211> 40 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide-526 156004·Sequence Table.doc 201143790 <220><221> MISC FEATURE <223> ΛΤΓ-346 <220><221> MOD RES <222> (2) 7. (2) <223> Xaa is Aib <220><221> MOD RES <222> (40)..(40) <223>imidization <400> 1264

His Xaa Gin Gly Thr Phe Tht Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

<210> 1265 <211> 40 <212> PRT < 213 > artificial sequence <220><223> synthetic peptide <220><221> MISC FEATURE <223> MT-347 <220><221> MOD.RES <222> (2)..(2) <223> Xaa is Aib <220><221> MOD.RES <222> (16)..(16 <223> Xaa is Aib <220><221> M0D.RES <222> (40)..(40) <223> by (:14 fat-based hydrogenation <220><221> MOD RES <222> (40)..(40) <223>mysylated <400> 1265

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 -527· 156004 Sequence Listing.doc 201143790 <210> 1266 <211> 40 <212> PRT <213> Artificial Sequence <220><223> Synthesis Peptide <220><221> MISC FEATURE <223> MT-348 <220><221> MOD RES <222> (2)..(2) <223> Xaa is Aib <220>;<221> MOD RES <222> (16)..(16) <223> Xaa is Aib <220><221> MOD RES <222> (40)..(40) <223> Amination <400> 1266

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1267 <21I> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> MT-349 <220><221> MOD RES <222> (2)..(2) <223> Xaa is Aib <220><221> MOD RES <222> (24).. (24) <223> Covalently bonded to the thioether produced by the reaction of the peptide with the gingival-activated PEG to 40 kDaPEG <220><221> M0D_RES <222> (40).. (40) <223> with (:14 fat-based hydrogenation <220><221> MOD RES <222> (40).. (40) <223> amidation-528-156004· Sequence Listing.doc 201143790 <400> 1267

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1268 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATTJRE <223> OT-350 <220>

<221> MOD.RES <222> (2)..(2) <223> Xaa is Aib <220><221> M0D.RES <222> (24)..(24) <;223> Covalently bonded to the 40kDaPEG via the peptide-functional thiol-activated PEG reaction to 40kDaPEG <220><221> MOD-RES <222> (40)..(40) <223> Amination <400> 1268

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 0123 Column 69T, 240 is a person <220><223> Synthetic peptide <220><221> MISC FEATURE <223> MT-351 <220>;221> MODJRES <222> (2)..(2) <223> Xaa is Aib 156004-sequence table.doc -529· 201143790 <220><221> MOD.RES <222> (16 (16) <223> Xaa is Aib <220><221> MOD RES <222> (24)..(24) <223> via peptide reaction with guanidinium-activated PEG The thioether is covalently bonded to 40 kDa PEG <220><221> MOD RES <222> (40).. (40) <223> with C14 fat 醯匕 醯匕 <220><22i> MOD RES <222> (40)..(40) <223>mysylated <400> 1269

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15 6 s r0 py 1 o G 3 y G1 nst Me u Le p Γ 5 T2 ssy yo c L4 6 Γ — e I s £ oh Γ Ppuo G p $ o yo Γ L2 pd ed 1 1 5 A A3 B y A1G, nr 1 e G s

<210> 1270 <211> 40 <212> PRT < 213 > artificial sequence <220><223> synthetic peptide <220><221> MISC FEATURE <223> MT-352 <220>

<221> M0D_RES <222> (2)..(2) <223> Xaa is Aib <220><221> MOD RES <222> (16)..(16) <223> Xaa is Aib <220><221> MOD RES <222> (24)..(24) <223> covalently bonded to 40 kDaPEG via a thioether produced by peptide reaction with dentate-activated PEG; 220><221> MOD RES <222> (40)..(40) <223>mysylated <400> 1270

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15 530- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1271 <400> 1271 000 <210> 1272 <211> 40 <212> PRT < 213 > Artificial Sequence <220><223> Synthetic peptide <220><221> MISC.FHATURE <223> MT-361

<220><221> MOD RES <222> (2) 7. (2) <223> Xaa is Aib <220><221> MOD RES <222> (16).. (16 <223> Xaa is Aib <220><221> MOD RES <222> (40).. (40) <223> Amination <400> 1272

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1273 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC A FEATURE <223> ΝΓΓ-362 <220><221> MOD RES <222> (2)..(2) <223>Xaa is Aib <220>

<221> MOD.RES 531 · 156004 - Sequence Listing.doc 201143790 <222> (16)..(16) <223> Xaa is Aib <220><221> M0D-RES <222> (40).. (40) <223> with (:16 fat-based hydrogenation <220><221> MOD-RES <222> (40).. (40) <223><400> 1273

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1274 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MI SC FEATTJRE <223> MT-363 <220><221> MOD RES <222> (2) 7. (2) <223> Xaa is Aib <220><221> MOD RES <222> (40)..(40) <223>mysylated <400> 1274

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1275 <211> 40 <212> PRT <213>Artificial Sequence <220><223>Synthetic Peptide <220>

<221> M1SC.FEATURE 532-

156004-Sequence List.doc 201143790 <223> ΛΓΓ-364 <220><221> MOD RES <222> (2)7.(2) <223> Xaa is Aib <220><221>; MOD RES <222> (40)..(40) <223> Condensed with C16 fat base <220><221> MOD RES <222> (40)..(40) <223> Amination <400> 1275

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1276 <400> 1276 000 <210> 1277 <400> 1277 000 <210> 1278 <400> 1278 000 <210> 1279 <400> 1279 000 <210> 1280 <400> 1280 000 <210> 1281 <400> 1281 000 <210> 1282 <400> 1282 000 <210> 1283 <400> 1283 000 <210> 1284 <400> 1284 000 156004_ Sequence Listing.doc - 533 - 201143790 <210> 1285 <400> 1285 000 <210> 1286 <400> 1286 000 <210> 1287 <400> 000 <210> 1288 <400> 1288 000 <210> 1289 <400> 1289 000 <210> 1290

<400> 1290 000 <210> 1291 <400> 1291 000 <210> 1292 <400> 1292 000 <210> 1293 <400> 1293 000 <210> 1294 <400><210> 1295

<400> 1295 000 <210> 1296 <400> 1296 000 <210> 1297 <400> 1297 000 <210> 1298 <400> 1298 000 <210> 1299 <400> 1299 000 156004-Sequence List.doc •534·201143790 <210> 1300 <400> 1300 000 <210> 1301 <213> 29 <212> PRT <213> Homo sapiens <400> 1301

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1302 <211> 28 <212> PRT <213>

<220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> Glycoside analogue <220><221> MISC.FEATURE <222> (8)..( 8) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <400> 1302

Ser Gin Gly Thr Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg 1 5 10 15

Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1303 <211> 27 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220>;221> MISC FEATURE <223>glycoside analogue <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is aspartic acid, glutamic acid , sulfoalanine or high sulfoalanine <400> 1303

Gin Gly Thr Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg 1 5 10 15

Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 156004-Sequence Listing.doc 535- Γ h 201143790 The selectivity of Q for the glycecan receptor relative to the GLP4 receptor can be described as relative glycoside/GLP-i activity. Ratio (Q relative to the activity of the native glycein to the glycoside receptor divided by the activity of the analog relative to native GLP-1 to the GLP-1 receptor). For example, the activity exhibited by the glycoside receptor is 60% of the native glucosamine and the activity exhibited by the GLp-i receptor is 60/ of the native GLp-丨. The Q has a 1:1 glucosin/GLp_丨 activity ratio. An exemplary glucosin/GLP-1 activity ratio includes about 1.5:1, 2:1, 3:1, 4:1, 5:1, 6.1 7.1, 8:1, 9:1 or l〇:i ' Or about 1:1 〇, 1:9, 1:8, 17, 1.6, 1.5, 1:4, 1:3, 1:2, or 1:1 5. For example, the glycoside/GLP-1 activity ratio of l〇:i is greater than the selectivity to the glycemic receptor for the selectivity of the GLp·^ receptor. Similarly, the (10) glucomannan activity ratio of (4) is 1 倍 times less selective for GLP-1 steroids than for the glycosidic receptor. In some embodiments, (p-glycoside receptor and GLpq receptor exhibit substantial activity (potency) and exhibit little to no activity to the GIP receptor. In some embodiments, Q versus glycoside The receptor and (10)] receptor exhibit any activity or potency as described herein, but have substantially more activity than the VIII receptor |± (potency). In some embodiments, q is expressed by the (10) receptor. The EC50 is 丨〇〇 or more than 100 times that of the EC5〇 of the glycemic receptor and the EC5Q of the GUM receptor. The activity of the GLP-1 receptor and the G1p receptor is in the case of 'Q pair Both the GLIM receptor and the Gip receptor exhibit activity ("(10) receptor/GUM receptor co-activator"). In some embodiments, Q is active against GIP (eg, EC5 〇 or relative activity or potency) Rather, 156004.doc •103·201143790 20 25 <210> 1304 <211> 26 <212> PRT <213>Artificial sequence <220><2«>Synthetic polypeptide <220><221> MISC.FEATURE <223> Glycemic > Analogs <220><221> MISC.FEATURE <222> (2)..(6) <223> Xaa is aspartic acid, noodles Acid, sulfo or high sulfo alanine-alanine < 400 > 1304

Cly Thr Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala 15 10 15

Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1305 <211> 25 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221>; MISC^FEATURE <223> Glycoside analogue <220><221> M1SC FEATURE <222> (5)..(5) <223> Xaa is aspartic acid, glutamic acid, Sulfoalanine or high sulfoalanine

<400> 1305

Thr Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin 15 10 15

Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1306 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC.FEATURE <223> Glycosides <220> •536-156004-sequence table.doc 201 143790 <221> MISC.FEATURE <222> (4).7(4) <223> Xaa is glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Leu4Nle <400> 1306

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr 20 ^ >>> Q 1 z 3 ofc 2 ΛΖ 2 V <\z < 1307 24

PRT artificial sequence <220><223> synthetic polypeptide 01^3 o]z 3 2222 2222

MOD RES trans-substrate replacement MISC FEATURE (4).7(4) Xaa is aspartic acid glutamic acid, sulfoalanine or high sulfoalanine <220>

<221> MISC.FEATURE <222> (22)..(22) <223> Xaa is li/iet, Leu or Nle <400> 1307

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr 20

<210> 1308 <211> 24 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (22)..(22) <223> kaa is ivlet, Leu or Nle <220>;<221> MOD RES - 537· 156004 - Sequence Listing.doc 201143790 <222> (24)..(24) <223> α«αcarboxylate group via decylamine replacement <400> 1308

Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt FEATURE <223> Glycosin analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221>; MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220> <221> MISC_FEATTJRE <222> (7).7(7) <223> Xaa is Lys or Aig <220><221> MISC-FHATURE <222> (11) 7. (11) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is lilet, Leu or Nle <400> 1309

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Xaa Arg Arg Ala Gin Asp l 5 10 15

"health polypeptide <220> &lt FEATURE <223> Glucose Female Analog 538·

156004-Sequence List.doc 201143790 <220><221> M0D.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <220><221> MISC .FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <;222> (7)..(7) <223> Xaa is Lys or Aig <220><221> MISC FEATURE <222> (16)..(16) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu*Nle

<400> 1310

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Xaa 15 10 15

"health sequence <220> &lt FEATORE < 223 > sucrose > analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <220>221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Arg <220><221> MISC FEATURE <222> (19)..(19) <223> Xaa^ Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Ivlet, Leu or Nle -539· 156004-sequence table.doc 201143790 <400> 1311

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220><223>glycoside analogue <220><221><222><223>

MOD RES (l)T.(l) N-terminal amine & hydroxy substitution <220><221> M1SC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid , glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Arg <220><221> MISC FEATURE <222> (11)..(11) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC FEATURE <222> (19)..(19) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220>

<221> MISC.FEATTJRE <222> (22) 7. (22) <223> 3Caa is I^4et, Leu or Nle <400> 1312

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 1 5 10 15

"health peptide <220> &lt

<221> MISC.FEATURE 540-156004-sequence table.doc 201143790 <223>glycoside analogue <220>

<22]> M0D.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4). (4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MOD.RES <222> (11).. ( 11) <223> PEGylation <220><221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <400> 1313

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Cys Arg Arg Ala Gin Asp

"health sequence <220> &lt FEATIJRE <223> Glycemic analogue <220><221> M0D_RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement

<220><221> MISC FEATURE <222> (4).7(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220>;<221> M0D.RES <222> (19)..(19) <223> PEGylation <220>

<221> MISC FEATURE <222> (22)..(22) <223> Xaa is Leu or Nle <400> 1314

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Cys Trp Leu Xaa Asn Thr 20 541 - 156004 - Sequence Listing.doc 201143790 <210> 1315 <2Π> 24 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide<223>;220><221> MISC.FEATURE <223> Glycoside analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group Hydroxy substitution <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <;220><221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Met, Leu*Nle <220><221> MOD RES <222> (241. (24) <223> PEGylation <400> 1315

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt FEATURE <223> Lactose Analog <220>

<221> MOD.RES

<222> (1) T. (D < 223 > N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is Aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MOD RES <222> (19).. (19) <223> PEGylation 542 -

156004· Sequence Listing.doc 201143790 <220><221> MISC FEATURE <222> (22) 7. (22) <223> Xaa is Met, Leu or Nle <400> 1316

Phe Thr Ser Xaa Tyr Ser Arg Tyr Leu Asp Ser Arg Arg Ala Gin Asp 1 5 10 15

"health sequence <220> &lt

<221> MISC.FEATURE <223> Glycoside analogue <220>

<221> MOD-RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4).7 ( 4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220>

<221> M0D.RES <222> (11)..(11) <223> PEGylation <220><221> MISC FEATURE <222> (22) 7. (22) <;223> Xaa is Met, Leu4Nle <400> 1317

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Cys Arg Arg Ala Gin Asp 15 10 15

"health polypeptide <220> &lt FEATURE <223>升^去相相<220><221> MOD RES <222> (l)T.(l) 543 · 156004·SEQ ID NO.doc 201143790 <223> N-terminal amine group Hydroxy substitution <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <;220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu4Nle <220><221> MOD RES <222> (24)..( 24) <223> (: terminal steroidal acid group substituted by decylamine <400> 1318 Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Glu Cys Arg Arg Ala Gin Asp 15 10 15

"health peptide <220> &lt MISC FEATURE <223> represents a peptide fragment of 10 amino acids at the carboxy terminus of the insulin-free analog-4 <400> 1319 Gly Pro Ser Ser Gly Ala Pro Pro Pro 1 5 10 <210> 1320 < 211 > 8 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223> represents 8th amino group of carboxy terminal Acid peptide fragment <400> 1320 Lys Arg Asn Arg Asn Asn lie Ala on213<v <v 1321 4 PRT artificial sequence <220><223> Synthetic polypeptide 156004 - Sequence Listing.doc 544-201143790 <220&gt ;

<221> MISC.FEATURE <223> represents a peptide fragment of a carboxyl group of 4 amino acids of the carboxy terminal of <400> 1321 Lys Arg Asn Arg <210> 1322 <211> 24 <212> PRT <2]3>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC.FEATURE <223> Glycoside analogue <220>

<221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Aig <220><221> MISC.FEATURB <222> (11)..(11) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC^FEATTJRE <222> (19)..(19) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <400> 1322

Phe Thr Ser Arg Tyr Ser Xaa Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 15 10 15

Phe Val Xaa Trp Leu Met Asn Thr 20 <210> 1323 <211> 34 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC_FEATURE <;M3> Glycosides analog <220><221> MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine Or high sulfoalanine <220><221> MISC_FEATURE <222> (7)..(7) <223> Xaa is Lys or Aig - 545 - 156004. Sequence Listing.doc 201143790 Sex (eg EC5 or relative activity or potency) differs (higher than ^; 'spoon 5 〇, about 40 times, about 30 times, about 20 times, about 1 〇 times or about 5 or less. Gip potency is equal to or lower than its gum potency by about 25 times, about 2 times, about 15 times about 1 () times or about %. In the column, the relative activity of Q to GIP receptor or EC50 or effect Month & divided by the relative activity or potency of Q to the GUM receptor yields a ratio less than X or about X, which causes the illusion to be selected from (10), 75 6〇5〇4〇, 30^20' 15' 1Ω+ < Preparation or 5. In some embodiments, Q is 5 to the GIP receptor. The ratio of the effect I or the relative activity divided by the ε~ or potency or relative activity of the Q*GLp·receptor is about 5 or less (for example, about 4, about 3, about). In one embodiment, the GIP of Q The ratio of potency to GLp_J potency of Q is less than z, or about Z, where z is selected from _, 5〇40, 30, 20, 15, 10, and 5. In some embodiments, the GIP performance of Q is less than 5 compared to kGUM performance (e.g., about 4' about 3, about 2, ^). In some embodiments, the (IV) ECso is 2 to 1 fold greater than the EC of the GLP-1 receptor (eg, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold) , 9 times, 1 〇 times in some implementations such as J towel, Q relative activity or potency of GLP-1 receptor or EC ^ divided by the relative activity or potency of Q to GIP receptor or e ^ yield is less than V Or about V, wherein v is selected from the group consisting of 100, 75, 6 〇, 5 〇, 4 〇, 30 20 15 , 1 〇 or 5. In some embodiments, q is for the glp 1 receptor: Or the ratio of potency or relative activity divided by q to ec5g or potency or relative activity of the GIp receptor is less than 5 (eg, about 4, about 3, about 2, about 丨). at 156004.doc •104- 201143790 <;220><221> MISC FEATURE <222> (16)..(16) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MISC_FEATURE <222> (22)..(22) <223> Xaa is Met, Leu4Nle <400> 1323 Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Xaa 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210><211><212><213><220><223> 1324 32 PRT artificial sequence synthesis polypeptide <220><221><223><220>;221><222><223> MISC.FEATURE Glycosyl analogue MISC.FEATURE (4)..(4) Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfopropylamine Acid <220><221><222><223><220><221><222><223><220><221><222><223><;220><221><222><223><400> MISC FEATURE (7).7(7) Xaa is Lys or Ar^ MISC FEATURE (19)7.(19) Xaa is Lys, Cys ,Om, homocysteine or acetaminophen MOD RES (19)..(19) PEGylated MISC FEATURE(22)..(22) 3(aa is Met, Leu or Nle 1324 Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Xaa Trp Leu Xaa Asn Thr Lys Arg Asn Arg Asn Asn lie Ala 20 25 30 <210> 1325 <211> 34 156004-sequence table.doc -546- 201143790 <212> PRT <213><220><223>Synthetic polypeptide <220>221> MISC FEATURE <223> Glycoside analogue <220><221> MISC FEATURE <222> (4).7(4 <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (7).. (7) <223> Xaa is Lys or Aig <220><221> MISC FEATURE <222> (19)..(19)

<223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MOD.RES <222> (19)..(19) <223> PEGylation <220><221> MISC.FEATTJRE <222> (22)..(22) <223> Xaa is l^iet, Leu or Nle <400> 1325

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Xaa Trp Leu Xaa Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1326 <211>32 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220><221> MISC FEATURE <223> Analog <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine<lt ;220><221> MISC.FEATURE <222> (7)..(7) <223>;kaa is Lys or Arg 547· 156004-sequence table.doc 201143790 <220><221> MISC FEATURE <222> (16) 7. (16) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MOD RES <222> (16)..(16) <223> PEGylation <220><221> M1SC.FEATORE <222> (22)..(22) <223> Xaa is 14 over, 1^ 11 or 1'^ <400> 1326

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Xaa 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Lys Arg Asn Arg Asn Asn lie Ala 20 25 30 <210> 1327 <211> 28 <212> PRT <213>Artificial sequence <220><223><220><221> MISC FEATURE <223> Glycoside analogue <220><221> MISC.FEATTJRE <222> (4)..(4) <223> Xaa is winter Amine acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Aig <220><221> MISC FEATURE <222> (16)..(16) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221>; MOD RES <222> (16T..(16) <223> PEGylation <220><221> MISC.FEATURE <222> (22)..(22) <223> Xaa For Met, Leu4Nle <400> 1327

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Xaa 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Lys Arg Asn Arg 20 25 <210> 1328 -548·

156004-sequence table.doc 201143790 <211> 28 <212> PRT <213>Artificial sequence<220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> Analog <220><221><222><223> MISC FEATURE (4).. (4) Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine

<220><221> MISC FEATURE <222> (7)..(7) <223> jiaa is Lys or Arg <220><221> MISC FEATURE <222> (19)7. (19) <223> Xaa is Lys, Cys, Om, homocysteine or acetylated amphetamine <220><221> MOD RES <222> (19)..(19) <;223>Pegylated<220><221> MISC FEATURE<222> (22)..(22) <2b> Xaa is l^let, Leu or Nle <400> 1328

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser 1 5 10

Arg Arg Ala Gin Asp 15

Phe Val Xaa Trp Leu Xaa Asn Thr Lys Arg Asn Arg 20 25

<210> 1329 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223><220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> ), (4) <223> Xaa is aspartic acid, tyrosine, reductive alanine or homo-propargyl acid <220><221>MISC.FEATURE<222> (22).. (22 156004· Sequence Listing.doc 549- 201143790 <223> Xaa is Met, Leu or Nle <400> 1329

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1330 <211>32 <212> PRT <213>Artificial sequence<220><223>Synthetic polypeptide <220><221> Mi SC FEATURE <223> Prime analog <220><221> MOD.RES <222> (l).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220> <221> MISC FEATURE <222> 22)..(22) <223> Xaa is Ivlet, Leu or Nle <400> 1330

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gla Trp Leu Xaa Asn Thr Lys Arg Asn Arg Asn Asn lie Ala 20 25 30 <210> 1331 <211> 28 <212> PRT <213>Artificial sequence <220><223><220><221> MISC FEATURE <223> Glycoside analogue <220>

<221> M0D_R£S <222> (1)..(1) <223> N-terminal amine group is replaced by a hydroxyl group <220>

<221> MISC.FEATURB 550-

156004· Sequence Listing.doc 201143790 <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE<222> (22)..(22) <223> ^Caa is Klet, Leu or Nle <400> 1331 Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Cys 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Lys Arg Asn Arg 20 25 >>>> 012 3 <21<21<21<21 1332 29 PRT Artificial Sequence <220><223> Synthetic Polypeptide<220><221> MISC FEATURE <223> Glycosin analogue <400> 1332 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1333 <211> 39 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> Glycemic Tone Analog <400> 1333 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pto Pro Ser 35 012 3 n 11 1—1— 2 Λζ ΛΖ 2<vv < 1334 29 PRT Artificial Sequence <220> 156004-Sequence List.doc 551 - 201143790 <223>Synthetic Peptide<220><221> MISC.FEATURE <223> Glycosin analogue <220><221> M0D.RES <222> (24)..(24) <223> via cysteine Thiol group-bonded 2·butyrolactone <400> 1334

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1335 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> M1SC FEATURE <223> Glycoside analogue <220><22l> MOD.RES <222> (24)..(24) <223> mercaptan via cysteine Carboxymethyl group <400> 1335

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1336 <211> 24 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC „FEATORE < 223 > sucrose ^ analog <220><22l> M0D_RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or sulphonyl alanine <220> 552- 156004 · Sequence Listing.doc 201143790

<221> MISC.FEATIJRB <222> (22)..(22) <223> Xaa is ^let, Leu or Nle <400> 1336

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Glu Ser Arg Arg Ala Gin Asp 15 10 15

"health peptide <220&gt

<22l> MISC FEATURE <223> Glycose > Analog <220>

<221> MOD RES <222> (1)..(1) <223> N-terminal amine group substituted by hydroxyl group <220>

<221> MISC FEATURE <222> (22)..(22) <223> Xaa is l^et, Leu or Nle <400> 1337

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <223&gt Glycoside analog <220><22> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220>

<221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Met, Leu*Nle <400> 1338

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Ser Arg Arg Ala Gin Asp 1 5 10 15 - 553 - 156004 - Sequence Listing.doc 201143790

Phe Val Gin Trp Leu Xaa Asn Thr 20 012 3 2 ΛΖ 2 2 vv < 1339 24

PRT artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223>glycoside analogue <220><221> MISC FEATURE <222> (1). (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> M1SC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, drum Amine acid, sulfoalanine or university arginine <220><221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> M1SCLFEATURE <222> (23)..(23) <223> Xaa is Asn, Asp, Glu, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <;222> (24)..(24) <223> Xaa is Thr, Asp, Glu, sulfoalanine or high sulfoalanine <400> 1339

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health polypeptide <220> &lt <223> Glycemic female analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..(4) 554-156004·SEQ ID NO.doc 201143790 <223> xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220>

<221> MISC-FEATURE <222> (10)..(10) <223> Xaa is Glu, contiguous alanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATURE <222> (23), (23) <223> Xaa is Asn or acid amino acid <220><221> MISC.FEATTJRE <222> (24)..(24) <223> Xaa is Thr or acidic amino acid ' <400> 1340

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt FEATURE <223> sucrose per analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl substitution <220>221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (10)..(10) <223> Xaa is Glu, mercaptoalanine, high-fat acid or high-performance propylamine <220><221> MISC FEATURE <222> )..(22) <223> Xaa is l^et, Leu or Nle <220><221> MISC.FEATURE <222> (23)..(23) <223> Xaa is human sn , Asp or Glu <220><221> MISC FEATURE <222> (24)..(24) - 555 - 156004 · Sequence Listing.doc 201143790 In some embodiments, Q GLP-1 performance is compared to The ratio of GIP efficacy of Q is less than W, or about W, where W is selected from 100, 75, 60 50, 40,30,20,15,10 and 5. In some embodiments, the ratio of GLP-1 efficacy of Q to GIP efficacy of Q is less than 5 (e.g., about 4, about 3, about 2, about 1). In some embodiments, q is equivalent to the gum receptor (5 〇 is about 2 to about 1 〇 to the ECso of the GIP receptor (eg, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7x, 8x, 9x, 1x). In some embodiments, the activity exhibited by Q on the GLP-1 receptor is at least 〇_1% of native GLP-1 (eg, about 0.5% or 0.5%) Above, about 1% or more, about 5% or 5% or more, about 1% or 1% above or above) (glim potency), and it is exhibited by GIP receptors The activity is at least 〇1% of the native GIP (eg, about 0.5°/. or 0.5% or more, about 1% or more, about 5% or more, about 10% or more, or higher). (〇ΐρ potency) Q selectivity of GIP receptor relative to GLP-1 receptor can be described as relative GIP/GLP-1 activity ratio (Q vs. native GIP activity against GIP receptor divided by the analog Relative to the activity of the native GLP-1 to the GLP-1 receptor), for example, the activity exhibited by δ 'on the GIP receptor is 6 % of the native gip and the activity exhibited by the glP-1 receptor is the native GLP- 60% of the q has a 1:1 GIP/GLP-1 activity ratio. The exemplary GIP/GLP-1 activity ratio includes about 丨:i, 1.5:1 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 1〇:1, or about 1:10, 1:9, 1:8 , 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 or 1.1.5. For example, &,1 〇: 1 GIP/GLP-1 activity ratio indication for Gip The selectivity of the body is 1〇 times that of the GLP-1 receptor. Similarly, the GLP-1/GIP activity ratio of 1〇:1 indicates that the selectivity to the GLP-1 receptor is GIP receptor 156004. Doc -105- 201143790 <223> Xaa is Thr, glu or Asp <400> 1341

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220><223&gt FEATURE <223> Glycein} analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <220><221>; MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (10)..(10) <223> Xaa is Glu, sulfoalanine, high-facial acid or high sulfoalanine <220><221> MISC FEATTJRE (72) ( 22) <223> XaaAMet, Leu or Nle <220>

<221> MISC.FEATURE <223> Xaa^Asn or acidic amino acid <220><22l> MISC.FEATURE <222> (24)7.(24) <223> Xaa is Thr or Acidic amino acid <400> 1342

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt

156004-Sequence List.doc 201143790 <220><221> MISC FEATURE <223> Glycemic} Analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine Or high sulfoalanine <220><221> MISC FEATURE <222> (10) 7. (10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfonate Alkalamine <220><221> MOD RES <222> (11)..(11)

<223> 20kDaPEG group linked to Xaa at position 11 <220><221> MISC.FEATURE <222> (22) 7. (22) <223> Xaa is 1^ 〖,! ^11 or 1'^ <220><221> MISC FEATURE <222> (23)..(23) <223> Xaa is Asn or acidic amino acid <220><221> MISC. FEATURE c〇2〇s (7ά) (Οά) <223> Xaa^Thr or acid amino acid <400> 1343

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Cys Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt FEATIJRE <223> Glycose > Analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220>22\> MISC FEATURE <222>(4):(4) <223> Xaa is an aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine-557- 156004-sequence. Doc 201143790 <220><221> MISC.FEATURE <222> (10)..(10) <223> Xaa is Asp, Glu, mercapto alanine, glutamic acid or high sulfopropylamine <lt;220><221> MOD RES <222> (16)..(16) <223> 20kDaPEG group connected to Xaa at position 16 <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATOE <222> (23)..(23) <223> Xaa is Asn or acidic Amino acid <220><221> MISC FEATURE <222> (24) 7. (24) <223> Xaa is T Hr or acidic amino acid <400> 1344

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Cys 15 10 15

Phe Val Gin Trp Leu Xaa Xaa Xaa 20 <210> 1345 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> Glucagon analog <220><221> MOD-RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221>; MISC FEATURE <222> (4).7(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (10) 7. (10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220><221> M0D.RES <222> (19)..(19) <223> PEGylation <220><221> MISC FEATURE (21^ (22) <223> Xaa^Met, Leu or Nle -558- 156004- Sequence Listing .doc 201143790 <220><221> MISC FEATURE <222> (23) 7. (23) <223> Xaa is Asn or Acid Amino Acid <220><221> MISC FEATURE <;222> (24)7.(24) <223> Xaa is Thr or acidic amino acid <400 > 1345

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15 xa na xa Aa a X u Le pro T 2 s cy va c ph Column order 46i 1335PR person 0 > 1 > 2 > 3 >21<21<21<21<220><223>Syntheticpolypeptide<220><221><223> MISC.FEATURE annihilation warning <220><221> M0D_RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATTJRE <222> (4)..(4) <223> Xaa is day Aspartic acid glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (10)..(10) <223> Xaa is Asp, Glu sulfo group Alanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (22) 7. (22) <223> Xaa is Met, Leu or Nle <220><221> MISC.FEATURE ✓999^ (2^ <223> Xaai Asn or Acid Amino Acid <220><221> MISC.FEATURE <222> (24) 7. (24) <223> Xaa is Thr or acidic amino acid <220><221> MISC FEATURE <222> (25) 7. (25 <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <220><221> MOD.RES <222> (25)..(25) <223> Pegylated 156004 - Sequence Listing. doc -559- 201143790 <400> 1346

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Xaa Xaa Xaa Gly Pro Ser Ser Gly Ala Pro 20 25 30

Pro Pro Ser 35 <210> 1347 <211> 35 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><22l> MISC FEATURE <223> Glycoside analogue <220><221> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><22l> MISC_FEATURE <222> (\ 0)..(\0) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (22) 7. (22) <223> Xaa is I^Iet, Leu or Nle <220> <22]> MISC FEATURE <222> (23)., (23) <223> Xaa is Asn or Acid Amino Acid <220><221> MISC FEATURE <222> (24)..(24) <223> Xaa is Thr or Acidic Amino Acid <220><221> MISC.FEATURE <;222> (35)..(35) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <2 20><221> MOD RES <222> (35)..(35) <223> PEGylation <400> 1347

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 1 5 10 15 •560·

156004-sequence table.doc 201143790

Phe Val Gin Trp Leu Xaa Xaa Xaa Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser Xaa 35 <210> 1348 <211> 39 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> Sugar > Analogs <400> 1348

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 1349 <211> 35 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <;223> sucrose analog <220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group <221> MISC FEATURE <222> (4).. (4) <223> Xaa is aspartic acid, glutamic acid, sulfopropylamine or homosulfopropionic acid <220> <221> MISC FEATURE <222> )..(7) <223> Xaa is Lys or Aig <220>

<221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATURE <222> (35) 7. (35 <223> Xaa is Lys, Cys, Om, homocysteine or acetyl phenylalanine <220> -561 - 156004-sequence table.doc 201143790 <221> f^DJES <222> 35)..(35) <223>PEGylation <400> 1349

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser Xaa 35 <210> 1350 <211> 24 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223> Glycoside analogue <220><22!> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <400>

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Val Gin Trp Leu Met Asn Thr 20 <210> 1351 <211> 20 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <;223>glycoside analogue <400> 1351

Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp Phe Val Gin Trp 15 10 15

Leu Met Asn Thr 20 0123 03 1111 22 Λ / 2 Λζ 2 2 V < V V << 1352 24

PRT artificial sequence synthetic polypeptide -562· 156004-sequence table.doc 201143790 <220><221> MISC.FEATORE <223> sucrose > analogue <220><221> MISC_FEATURE <222> 4)..(4) <223> Xaa is high sulfoalanine <400> 1352

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr 20 <210> 1353 <211> Π <212> PRT <213> artificial sequence <220><223>

<220>

<221> MISC.FEATURE <223> represents a peptide fragment of 10 amino acids at the carboxy terminus of insulinotropic analog-4 <220><221> MISC FEATURE <222> (11)7. 11) <223> Xaa is Lys, Cys, Om, homocysteine or acetylalanine <400> 1353 1 5 <210> 1354 <2\\> 6 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <222> (6).7(6) <223> Xaa is phenyl lactic acid <400> 1354 His Ser Gin Gly Thr Xaa 1 5 <210> 1355 <211> 5 <212> PRT <213> Artificial Sequence <220><223><220> Synthetic polypeptide

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Xaa •563 - 156004. Sequence Listing.doc 201143790 <221> MISC.FEATliRE <222> (5)..(5) <223> Xaa is Phenyl Lactic Acid <;400> 1355

Ser Gin Gly Thr Xaa 1 5 <210> 1356 <211> 4 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220><221> MISC.FEATORE <;222> (4)..(4) <223> Xaa is phenyl lactic acid <400> 1356

Gin Gly Thr Xaa <210> 1357 <211> 3 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> Ml SC FEATURE <222> (3)..(3) <223> Xaa is phenyl lactic acid <400> 1357

Gly Thr Xaa <210> 1358 <211> 2 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <222> )..(2) <223> Xaa is phenyl lactic acid <400> 1358

Thr Xaa <210> 1359 <211> 6 <212> PRT < 213 > artificial sequence 156004 · Sequence Listing. doc 201143790 <220><223> Synthetic polypeptide <220>

<221> MISC FEATURE <222> (1).. (1) <223> is selected from the group consisting of: His, D-histamine, hydrazine> (!-dimercaptoimidazoleacetic acid ( DMIA) 'N-mercapto histidine, α-mercapto histidine, imidazoleacetic acid 'deaminated histidine, hydroxy-histidine, etidyl-histidine and <220>

<221> MISC_FEATURE <222> (2)..(2) <223> xaa is selected from the group consisting of Ser, D-serine, D-alanine, Val, Gly, N-曱Baseline acid, N-mercaptoalanine and aminoisobutyric acid (AEB) <220><221> MISC FEATURE <222> (3)..(3)

<223> xaa is selected from the group consisting of Glu or Gin <220>

<221> MISC FEATURE <222> (6)..(6) <223> Xaa is phenyllactate <400> 1359

Xaa Xaa Xaa Gly Thr Xaa <210> 1360 <211> 5 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MISC FEATURE <222> (1)..(1) <223> xaa is selected from the group consisting of Ser ' D·serine, D·alanine, Val, Gly, N- Methyl serine, N-mercaptoalanine and aminoisobutyric acid (AIB)

<221> MISC FEATURE <222> (2)..(2) <223> Xaa' is selected from the group consisting of Glu or Gin <220><221> MISC FEATURE <222> (5). (5) <223> Xaa is phenyl lactic acid <400> 1360

Xaa Xaa Gly Thr Xaa <210> 1361 <211> 4 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide-565 - 156004-Sequence List.doc 201143790 Selective Ίο倍. Activity against the Glucagon Receptor and GIP Receptors In some embodiments, 'Q exhibits activity on both the glycoside receptor and the (10) receptor ("GIP receptor/glycoglycin receptor co-activator") . In some embodiments, the activity of the '(10)(10) receptor (eg, % or relative activity or potency) differs from the potency of the glycoside receptor (eg, EC5〇 or (4) activity or potency) (above or below) 50 times, about division, (four) times, (four) times, about ι〇 times or times, in some embodiments, Q (10) efficacy differs from its glycosidic effect by about 25 times, about 2 times, about 2 The 〇 is about 15 times (7) times or less than about 5 times. In some embodiments, the relative activity or % of Q to the GIp receptor. Or the effect is divided by the relative activity of Q on the glycemic receptor. Or the ratio obtained by potency is less than X or about X, wherein X is selected from the group consisting of 100, 75, 60, 50, 40, 30 2, 15, 10 or 5. In some embodiments (iv) (10) the receptor or A8 or relative activity divided by the ratio of Q to the glycemic receptor or the potency or relative activity is about 5 or less (eg, about 4, about 3, about L). In some embodiments, the GIP potency of Q is less than 2, or about ζ, compared to the glycemic sugar of Q, where 2 lines are selected from 100, 〇5Q, 4G, 3G, 2G. , 15, 1G and 5. The ratio of the efficacy of the examples to the glycosidic potency of sputum is less than about 4, about 3, about 2, about 1}. In some embodiments, (10) the HC50 of the body. 2 to 1 fold times the EC5 of the glycosidic receptor (eg 2 °, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 fold, 9 fold, 10 fold in the example 'Q Relative activity or potency to the glycemic receptor or 156004.doc •106 201143790 <220> <221> MISCJFEATURE <222> (1)..(1) <223> Xaa is selected from Glu and Gin The group of composition <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is phenyllactate <400> 1361 Xaa Gly Thr Xaa <210> 1362 <211> 24 <212> PRT <213> Column <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220>221> MOD RES <222> (24)..(24) <223> C-terminal alpha tetamine group as appropriate by indoleamine replacement <400> 1362 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Ding rp Leu Met Asp Thr 20 0123 03 «I 1 11 ΛΖ 2 2 2 2 2 2 << V V << 1363 28 PRT Artificial Sequence Synthetic Peptide

<220><221> M0D.RES <222> (28)..(28) <223> C-terminal alpha tetamine group as appropriate by indoleamine replacement <400> 1363 Ser Gin Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg 15 10 15

Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 2 Λζ ΛΖ 2<vv < 1364 28 PRT Artificial Sequence 156004 - Sequence Listing. doc 566- 201143790 <220><223> Synthetic Polypeptide<220><221> MISC FEATURE <222> (4) (5) <223> The sulphate at position 4 and the phenyl lactic acid at position 5 are linked via an ester bond <220><221> MISC.FEATURE <222> (5)..(5) <223> Xaa is phenyl lactic acid <220><221> MOD RES <222> (28).. (28) <223> Optionally, the C-terminal α-carboxylate group is substituted with decylamine <220><221> M0D.RES <222> (28)..(28) <223> C-terminal α-ester group Condition by indoleamine replacement <400> 1364

Ser Gin Gly Thr Xaa Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg 15 10 15

Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1365 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic polypeptide-linked Lyt bond ester The lactic acid-based benzene JL-6 is set with the acid amine JRE Su TUI of FEA1 (6) 5h ΪΙ · 5 sc). MI (5-position 0 > 1 > 2 > 3 > 22 22 22 22 <<<<<220>

<221> MISC FEATURE <222> (6).. (6) <223> Xaa is phenyl lactic acid <220><221> M0D_RES <222> (29).. (29) <223> C-terminal alpha tetamine group as appropriate by indoleamine replacement <400> 1365

His Ser Gin Gly Thr Xaa Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 <21<21<21<21 1366 24

PRT artificial sequence • 567 - 156004 - Sequence Listing. doc 201143790 <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1)..(1) <223> N The terminal amino group is replaced by a hydroxyl group <220><221> M1SC FEATURE <222> (11) 7. (11) <223> Xaa is aminoisobutyric acid <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <400> 1367

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr 20 <2I0> 1368 <211> 6 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MISC FEATURE <222> m_.(n <223> xaa is selected from the group consisting of: His, D-histamine, o^x-dimercaptoimidazoleacetic acid (DMIA), Ν· Methylhistamine, ct.methylhistamine, imidazoleacetic acid, deaminated histidine, hydroxy-histidine, acetyl-histidine, and <220><221> MISC.FEATURE <;222> (2)..(2) <223> xaa^ is selected from the group consisting of Ser, D-serine, D. alanine, Val, Gly, N-mercapto-silicic acid, hydrazine Methylalanine and Aminoisobutyric acid (AIB) <220><221> MISC.FEATTJRE <222> (3)..(3) 568-

156004-sequence table.doc 201143790

<223> Xaa is selected from the group consisting of Glu or Gin <400> 136S

Xaa Xaa Xaa Thr Gly Phe 1 5 <210> 1369 <211> 5 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC.FEATURE <222> (1).7(1) <223> Xaa is selected from the group consisting of Ser, D-serine, D-alanine, Val, Gly, N-methylserine, N-mercaptoalanine and aminoisobutyric acid (AIB) <220>

<221> MISC FEATURE <222> (2)..(2) <223> Xaa' is selected from the group consisting of Glu or Gin <400> 1369

Xaa Xaa

Thr Gly Phe <210> 1370 <211> 4 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC.FEATURE <222> 1), 7(1) <223> Xaa is selected from the group consisting of Glu or Gin <400> 1370 Xaa Thr Gly Phe

<210> 1371 <211> 24 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (24) 7. (24) <223> C-terminal α-carboxylate group as the case may be Indoleamine replacement <400> 1371 156004-sequence table.doc 569- 201143790

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

1 1 <400> 000 1372 &lt ; 000 1375 <210> 1376 <400> 000 1376 <210> 1377 <400> 000 1377 <210> 1378 <400> 000 1378 <210> 1379 <400> 000 1379 <210&gt 1380 <400> 000 1380 <210> 1381 <400> 000 1381 <210> 1382 <400> 000 1382 <210> 1383 <400> 000 1383 <210> 1384 <400> 000 1384 <210> 1385

• 570-156004 • Sequence Listing.doc 201143790 <400> 1385 000 <210> 1386 <400> 1386 000 <210> 1387 <400> 1387 000 <210> 1388 <400> 1388 000 <;210> 1389 <400> 1389 000 <210> 1390 <400> 1390

<210> 1391 <400> 1391 000 <210> 1392 <400> 1392 000 <210> 1393 <400> 1393 000 <210> 1394 <400> 1394 000 <210> 1395 <;400> 1395 <210> 1396 <400> 1396 000 <210> 1397 <400> 1397 000 <210> 1398 <400> 1398 000 <210> 1399 <400> 1399 000 <210> 1400 156004. Sequence Listing. doc -571 - 201143790 <400> 1400 000 <210> 1401 <211> 29 <212> PRT <213> Homo sapiens <400> 1401

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1402 <211> 24 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE < 223 > sucrose > analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <400> 1402

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr 20 <210> 1403 <211> 31 <212> PRT <213> Homo sapiens <400> 1403

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 <210> 1404 <211> 30 <212> PRT <213> Homo sapiens <400> 1404

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg 20 25 30 •572·

156004· Sequence Listing.doc 201143790 <210> 1405 <211> 24 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide <220><221> MISCJFEATURE <223>; 弁 ― 告 类似物 <220><221> MOD RES <222> (l)T.(l) <223> N-terminal amine group via hydroxyl substitution <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr 20 0123 <21<21<21<21 1406 24 PRT artificial sequence <220><223> Synthetic polypeptide <220><221> MOD.RES <222> 1).. (1) <223> N-terminal amine group via hydroxyl group <400> 1406 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 1 5 10 15 Phe Val Gin Trp Leu Met Asn Thr 20 <210> 1407 <211> 24 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223> Analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> 11) 7.(11) <223> 3iaa is Ser Glu 156004-sequence, doc • 573 - 201143790 <400> 1407

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Lys Asp 15 10 15

Phe Val Glu Trp Leu Met Asn Thr 20 012 3 1i 1ί 1ί 1i 2 ΟΛ 2 2 <v << Column ^08T Worker 1424 Quad <220><223> Synthetic Peptide <220><221> MISC FEATURE < 223 > sucrose < analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl substitution <220><221> MISC.FEATURE <222> (11)..(11) <223> Xaa is Ser or Glu <400> 1408

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 15 10 15

Phe Val Glu Trp Leu Met Lys Thr 20 <210> 1409 <211> 24 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> Glucagon analog <220><221> MOD RES <222>(1).. (1) <223> N-terminal amine group via hydroxyl group <220><221> MISC.FEATURE <222> (7)..(7) <223> Xaa on stand 7 is Lys or Glu <220><221> MISC FEATURE <222> (10)..( 10) <223> Xaa is Asp, Glu, homofacial acid, sulfoalanine or high sulfoalanine <220> <221> MISC_FEATORE <222> (11).. (11) <223> Xaa is Ala, Ser, Glu, Lys, high-fat acid or homo-alanine-574·156004-sequence table.doc 201143790 <220><221> MISC FEATURE <222> (15)7. 15) <223> Xaa is Gin, Glu or Lys <220><221> MISC FEATURE <222> (19) 7. (19) <223> Xaa is Ala, Gin, Lys or Glu < 220> <221> MISC.FEATORE <222> (23)..(23) <223> Xaa'Asn, Ly s or acid amino acid <220><221> MISC FEATURE <222> (24) 7. (24) <223> Xaa is Thr or acidic amino acid <400>

Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Xaa Arg Arg Ala Xaa Asp 15 10 15

"health sequence <220><223>LoseSugar> Analogs <220>

<221> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11)..( 11) <223> Xaa is Ala, Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (15) 7. (15) <223> Xaa is όΐη or Lys <220><221> MISC FEATURE <222> (19)7.(19) <223> Xaa is Ala, Gin or Glu <220><221> MISC. FEATURE <222> (23)7.(23) <223> Xaa is Asn, Lys or Acid Amino Acid <400> 1410

Phe Tht Ser Asp lyx Sct Lys Tyr Leu Asp Xaa Arg Arg Ala Xaa Asp 15 10 15 -575- 156004 · Sequence Listing.doc 201143790 The ratio of Q to GIP receptor relative activity or potency or ECsg is less than v ' or Approximately V, wherein V is selected from the group consisting of 100, 75, 60, 50, 40, 30, 20, 15, 1G or 5 » In some embodiments, the ECw or potency or relative activity of q to the glycemic receptor The ratio obtained by dividing E to the Ec^ or potency or relative activity of the GIp receptor is less than 5 (for example, about 4, about 3, about 2, about). In some embodiments, the ratio of G glucagon potency to GIp potency of 〇 is less than W, or about w, wherein w is selected from the group consisting of 1〇〇, & 6〇, %, 40'30' 20, 15, 1 and 5. In some embodiments, the ratio of the glycosidic effect of 'Q to the GIP potency of Q is less than 5 (e.g., about 4, about 3, about 2, about 1). In some embodiments, the oxime to the glycosidic receptor is about 2 to about 1 fold greater than the ECm of the GIP receptor (eg, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold) , 8 times, 9 times, 1 time). In some embodiments, the activity exhibited by Q on the glycemic receptor is at least 0.1% of the native glycein (eg, about 5% or more than 5%, about 1% or more, about 5%). Or 5% or more, about 1% or more, or higher) (glycoside φ potency), and its activity on the GIP receptor is at least 〇1% (for example, about 0.5%) of the native GIP. Or 0.5% or more, about 1% or more, about 5% or more, about 10% or 10% or more, or higher) (GIp potency). The selectivity of Q for the GIP receptor relative to the glycosidic receptor can be described as the relative GIP/glycoglycegic activity ratio (Q relative to the native gip activity against the GIP receptor divided by the analog relative to the native glycoside) Activity on the glycoside receptor). For example, the activity exhibited by the GIP receptor is 60% of the native gip and the activity exhibited by the glycosidic receptor is 60% of the native glycosidic acid has iq GIP/glycoside activity ratio The ratio of sexual GIP/glycoside activity includes about 丨:工, 156004.doc •107· 201143790

"health sequence <220> &lt FEATURE <223> Glucosin Analog <220>

<221> M0D_RES <222> (1)..(1) <223> N-terminal amine tomb replacement by hydroxyl group <220>

<221> Ml SC FEATURE <222> (11) 7. (11) <223> Xaa is Ala, Ser, Glu, Gin, homofacial acid or high sulfoalanine <220><221>; MISC FEATURE <222> (15)7.(15) <223> Xaa is όΐη or Lys <400> 1411

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Xaa Asp 15 10 15

"health peptide <220> &lt FEATORE <223> Ascending Sugar i Analog <220><221><222><223>

MOD.RES 经 via base replacement <220><221> MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine Or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <22 3> 3iaa is Ly s or Aig <220> <221> MISC FEATURE <;222> (15)..(15) <22]> Xaa is Lys or Gin 576-156004-sequence table.doc 201143790 <220><22\> MI SC FEATURE <222> (16 (16) <223> Xaa is Lys, Cys, Om, homocysteine or acetylated amphetamine <220><221> MOD RES <222> (16).. ( 16) <223> PEGylation <220><221> MISC FEATURE <222> (19)..(19) <223> Xaa^Lys, Cys, Om, homocysteine or Ethyl phenylalanine <220><221> M0D_RES <222> (19)..(19) <223> PEGylation <220>

<221> MISC FEATURE <222> (22)..(22) <223> Xaa is I^iet, Leu or Nle

<400> 1412

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Asp Glu Arg Arg Ala Xaa Xaa 15 10 15

"health sequence <220> &lt <223> Ligose female analog <220><221> MOD.RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><22】> MISC-FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, a face acid, a tranyl alanine or a high sulfoalanine <220><221>; MISC FEATTJRE <222> (15)..(15) <223> Xaa is death ys or Gin <220><221> MISC.FEATURE <222> (16)..(16) <223> Xaa is Cys, Om, homocysteine or acetylalanine <220><221> MOD.RES <222> (16)..(16) <223> PEGylation -577- 156004 - Sequence Listing.doc 201143790 <220><221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Klet, Leu or Nle <400> 1413

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Xaa Xaa 15 10 15

"health sequence <220> &lt FEATURE <223> Glycosin analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221>; MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC .FEATTJRE <222> (15)..(15) <223> Xaa is Lys or Gin <220><221> MISC FEATURE <222> (19)..(19) <223> Xaa It is 0 ys, Om, homocysteine or acetyl phenylalanine <220><221> M0D_RES <222> (19)..(19) <223> PEGylation <220><;221> MISC FEATURE <222> (22)..(22) <223> Xaa is l^fet, Leu or Nle <400> 1414

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Xaa Asp 15 10 15

Phe Val Xaa Trp Leu Xaa Asn Thr 20 <210> 1415 <211> 24 <212> PRT <213>Artificial Sequence <220> -578-

156004. Sequence Listing.doc 201143790 <223>Synthetic Peptide<220><221> MISCJFEATURE <223> Glycoside Analog <220><221> MOD RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid , sulfoalanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Glu <220>;<221> MISC FEATURE <222> (10)7.(10)

<223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (11)..(11) <223> Xaa is Ala, Ser, Glu, Lys, Gin, glutamic acid or high sulfoalanine <220><221> MISC.FEATURE <222> (15)..(15) <223> Xaa is ig, Gin, Glu or Lys <220><221> MISC.FEATURE <222> (19)7.(19) <223> Xaa is Ala, Gin, Lys or Glu <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is ]^let, Leu or Nle <220>

<221> MISC FEATURE <223> Xaa^Asn, Lys or Acid Amino Acid <220> <221> MISC FEATURE <222> (24)..(24) <223> Xaa is Thr or Acid Amino Acid <400> 1415

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Xaa Xaa Arg Arg Ala Xaa Asp 15 10 15

Phe Val Xaa Trp Leu Xaa Xaa Xaa 20 <210> 1416 <211> 24 <212> PRT <213> Artificial sequence 579·156004-sequence table.doc 201143790 <220><223>Syntheticpolypeptide<223>;220><221> MISC_FEATORE <223>glycoside analogue <220>

<221> MOD RES <222> (1)..0) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATORE <222> (7).. (11 <223> Linking the indole bridge of residue 7 to residue 11 <220>

<221> MISC FEATURE <222> (10)..(10) <223> Xaa is 01u or Asp <220>

<221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATURE <222> (23).. (23 <223> Xaa is Asn, Asp or Glu <220><221> M0D_RES <222> (24).. (24) <223> C-terminal α-acid ester group is replaced by decylamine <400> 1416

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Gin Asp 15 10 15

"health sequence <220><223&gt<223> Glycosin analogue <220>

<221> MOD RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATORE <222> (10) 7. (10) <223> Xaa is Asp or Glu <220><221> MISC.FEATURE <222> (11)..(15) <223> Linking residue 11 and residue 15 within the guanamine bridge Key 156004 - Sequence Listing.doc -580-

201143790 <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is ^/iet, Leu or Nle <220><221> MISC FEATURE <222> (23)..(23) <223> Xaa is Asn, Asp or Glu <220><221> MOD RES <222> (24)..(24) <223> C-terminal α-rebel Ester group replaced by decylamine <400> 1417

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Xaa Xaa Thr 20 ^ >>> 0 12 3 <21<21<21<21 1418 24 PRT Artificial Sequence <220〉 <223> Synthetic Peptide <220><221>;<223><220><221><222><223><220><221><222><223><220><221><222> MISC FEATURE sucrose ^ analogue MOD RES (1).. (1) N-terminal amine group via hydroxyl substitution MISC.FEATURE (10).. (10) Xaa is Asp or Glu

MISC.FEATTJRE (11)7.(11.) Xaa is Ser or Glu <220><221><222><223><220><221><222><223><;220><221><222><223><220><221><222><223><400> MISC.FEATURE (15)7. (19) Linking residue 15 And the residue of the indoleamine bridge MISC FEATURE (07) (22) Xaa is Met, Leu or Nle MISC.FEATORE (23) 7. (23) Xaa is Asn, Asp or Glu MOD.RES (24). (24) C-terminal alpha tickerate group substituted by decylamine 1418 156004 · Sequence Listing. doc 581 - 201143790

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa Arg Arg 1 5 10

Lys Asp 15

"health sequence <220><223&gt<223> Glucagon analog <220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group <220><221> MISC.FEATURE <222> (10)..(10) <223> Xaa is Asp or Glu <220><221> MISC FEATURE <222> (11)..(11) <223> Xaa is Ser or Glu <220><221> MISC FEATURE <222> (19)..(23) <223> Linking residue 19 to the phthalamide bond in residue 23 <220>;221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu4Nle <220><221> MISC.FEATURE <222> (24)..(24) <;223> Xaa is Thr or Glu <220><221> M0D.RES <222> (24)..(24) <223> C-terminal ester group is replaced by indoleamine <400> 1419 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa Arg Arg 1 5 10

Gin Asp 15

"health sequence <220> &lt <220><221> MISC.FEATURE <223> Glycoside analogue <220><221> MOD-RES <222> (1)..(1) <223> N-terminal amine Substituted by hydroxyl group <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, proline, sulfoalanine or high sulfopropylamine Acid <220><221> MISC.FEATURE <222> (7).7(7) <223> 3caa is Lys or Glu <220><221> MISC FEATURE <222> (10) ..(10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine

<220><221> MISC FEATURE <222> (11)..(11) <223> Xaa is Ala, Ser, Glu, Lys, Gin, glutamic acid or homocysteine <220><221> MISC.FEATURE <222> (15)..(15) <223> Xaa is Ai^, Gin, Glu or Lys <220><221> MISC.FEATURE <223> kaa4Ala, Gln, Lys4Glu <220><221> MISC.FEATURE <222> (22) 7. (22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATURE <;222> (23)..(23) <223> Xaa'Asn, Lys, Asp, Glu, arginine or high-base alanine <220><221>MISC FEATURE <222> 24)..(24) <223> Xaa is 1111*, Ba Yin, 0111, sulfoalanine and high sulfoalanine <400> 1420

Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Xaa Xaa Arg Arg Ala Xaa Asp 15 10 15

Phe Val Xaa Trp Leu Xaa Xaa Xaa 20 <210> 1421 <21]> 10 <212> PRT <213>Artificial Sequence<220><223> Synthesis of Polypeptide-583 - 156004-Sequence Listing. Doc 201143790 <220>

<221> MISC FEATURE <223> represents a peptide fragment of 10 amino acids without a carboxy terminal of the insulin-promoting analog 4. <400>

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 <210> 1422 <211> 24 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220>221> MISC.FEATURE <223> Glycosin analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl substitution <220>;<221> MISC.FEATTJRE <222> (4)..(4) <223> Xaa is aspartic acid, face acid, primate levulinic acid or thioglycolic acid <220> <221> MISC FEATURE <222> (7).7(11) <223> Linking residue 7 to the indole bridge of residue 11 <220><221>MISCLFEATTJRE<222> (10). (10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine <220><221> MISC FEATURE <222> (22).. (22 ) <22》> Xaa is ]^fet, Leu or Nle <400> 1422

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt FEATURE <223> Ascending Sugar i Analog <220> 584·

156004. Sequence Listing.doc 201143790 <221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl substitution <220><221> MISC.FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220>

<221> MISC FEATORE <222> (10)..(10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine <220><221>; MISC.FEATIJRE <222> (11)..(15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MISC FEATURE <〇〇〇>; (22) (22) <223> Xaa^Met, Leu or Nle

<400> 1423

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Lys Asp 15 10 15

"Phe < 211 &gt FEATURE <223> Glucosin Analog <220>

<221> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..( 4) <223>xaa>^aspartic acid, face acid, sulfoalanine or high sulfoalanine <220>

<221> MISC FEATURE <222> (10)..(10) <223> xaa is Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine <220><221>; MISC FEATURE <222> (15)..(19) <223> Linking residue 15 to the indole bridge of residue 19 <220><22i> MISC_FEATURE <222> (22)7 (22) <223> Xaa is Met, Leu or Nle -585 - 156004-sequence table.doc 201143790 6:1, 7:1, 8:1, 9:1 or ι〇:ι, 1:6, 1:5, 1:4, 1:3, 1:2 or 1·5·1, 2:1, 3:1, 4:1, 5·1 or approximately 1:10, 1:9, υ, 1 :7 1:1.5. For example, a 10:1 GIP/glycoglycemic activity ratio is H) times greater than a selectivity to a GIP receptor for selectivity to a glycemic receptor. Similarly, a 10:1 glucosin/GIP activity ratio indicates that the selectivity to the glycoside receptor is 1 to 10 times that of the (10) receptor. River π 褥 又 “ “ π 又 又 又 又 姐 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在

Body: Both exhibit activity ("glycoside receptor/gum receptor/GIP receptor double agonist"). In some implementations, Q (such as EC5 ° or relative activity or potency) and its GUM receptor 1 GIP are subject to =: EC5. Or relative activity or efficacy) difference (above 2 about: times, times, times, times, about 4. times -

* The tongue of the body is two or less than about 5 times. In some embodiments, _GUM: and two = C5° or relative activity or potency differ from their relative activity or potency to glycosidic (higher u times about 75 times, about 6 times, 5 times about 3 inches). Times, about 20 times, about 1 time or about 5 times - this mouth

Activity against the GIP receptor (e.g., in the two embodiments, Q-glycoside receptor and GUM receptor = activity or potency) and its activity on the ascending phase (e.g., heart or relative activity or efficacy)

Heart difference (heart or below) about _ times, about 75 times, qing, J about 4 times, about 30 times, about 2 times, about ι times or about $ times by two or two differences or can be expressed as above 4 Special / prime / GUM ratio. ^GUM/GIp or sucrose 156004.doc •108· 201143790 <400> 1424

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt FEATURE <223> Glucosin Analog <220>

<22\> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> (4). (4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220>

<221> MISC.FEATURE <222> (10).. (10) <223> Xaa is Asp, Glu, sulfoalanine, homofacial acid, and island-based alanine <220>221> MISC-FEATURE <222> (19)..(24) <223> Linking residue 19 to the indole bridge of residue 24 <220>

<221> MISC^FEAOJRE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <400> 1425

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Gin Asp 15 10 15

"health peptide <220> &lt

<22l> MISC.FEATURE <223> represents a peptide fragment of 8 amino acids at the carboxy terminus of the acid-adjusting hormone <400> 1426 586-

156004· Sequence Listing.doc 201143790

Lys Arg Asn Arg Asn Asn lie Ala <210> 1427 <211> 4 <212> PRT <213> Artificial sequence <220> Synthetic polypeptide <220>

<221> MISC FEATURE <223> represents a peptide fragment of a carboxy group of 4 amino acids of citrate citrate <400> 1427 Lys Arg Asn Arg

<210> 1428 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC FEATURE <223> Object <400> 1428

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1429 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC.FEATURE <222> ) (11) <223> linking the residue to the indole bridge of residue 7 <400> 1429

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30 156004-Sequence List.doc •587«

S 201143790

Pro Ser <210> 1430 <211> 34 <212> PRT <213>Artificial sequence <220><M3>Synthetic polypeptide <220><221> MISC.FEATOE <223>> Analog <220><221> MISC.FEATURE <222> (11)..(15) <223> Linking residue 11 to the indole bridge of residue 15 <400> 1430

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1431 <21l> 34 <212> PRT <2>3>Artificial sequence<220><223>Synthetic polypeptide <220><221> MISC FEATURE <223> Sugar > Analog <220><221> MISC FEATURE <222> (7)..(11) <223> Linking residue 7 to the indoleamine bridge of residue 11 <400> 1431

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1432 <211> 34 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide -588-

156004· Sequence Listing.doc 201143790 <220><221> MISC FEATURE <223> Glycoside Analog <220><221> M0D.RES <222> (1)7.(1) <;223> N-terminal amine group via hydroxyl group replacement <220><22t> MISC FEATURE <222> (7)..(11) <223> linking residue 7 and residue 11 in the guanamine bridge <400> 1432

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 3 5 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1433 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MISC_FEATURE <223><220><221> MODJRES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) ..(15)

<223> Linking residue 11 to the indole bridge of residue 15 <400> 1433

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1434 <211> 24 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide•589-156004-Sequence List.doc 201143790 <220><221> MISC FEATURE <223> Glycoside analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220&gt FEATURE <223> sucrose to analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl substitution <220><221>; MISC FEATURE <222> (7).7(11) <223> Linking residue 7 to the indole bridge of residue 11 <400> 1435

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

"health polypeptide <220> &lt <223> Glycoside analog <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <220><221> MISC FEATURE <222> (11) 7. (15) <223> Linking residue 11 to the indoleamine bridge of residue 15 156004. Sequence Listing.doc 590-

201143790 <400> 1436 Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt FEATURE <223> Ascending Sugar Analog <400> 1437 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ala Arg Tyr Leu Asp Ala 15 10 15

Arg Arg Ala Arg Glu Phe lie Lys Trp Leu Val Arg Gly Arg Gly 20 25 30 >>>> 012 3 V < 1438 24 PRT Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE < 223 > sucrose|analog <220><221>M0D.RES<222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> M0D.RES <222> (24)..(24) <223> C-terminal alpha tetamine group via decylamine replacement <400> 1438 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr 20 <210> 1439 <211> 24 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide 156004 - Sequence Listing.doc •591- 201143790 <220><221> MISC.FEATURE <223>glycoside analogue <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group Hydroxyl substitution <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC FEATURE <222> (10)..(10) <223> Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220>;<221> MISC FEATURE <222> (22)7.(22) <223> Xaa is Met, Leu4Nle <220><221> MOD RES <222> (24)..(24) <223> (: terminal carboxylic acid ester group substituted by decylamine <400> 1439

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt <223> Glycosides <400> 1440

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1441 <211> 39 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220> -592-

156004· Sequence Listing.doc 201143790 <221> MISC-FEATURE <223> Glycosin Analogs <4〇〇> 1441

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 1442 <211> 29 <212> PRT <213> artificial sequence <220><223>

<220><221> MISC FEATURE <223> Glycosin analogue <220><221> MOD RES <222> (22)..(24) <223> via cysteine Thiol group-bound 2-butyrolactone <400> 1442

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1443 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC.FEATURE <223> sucrose analog <220><22l> M0D_RES <222> (21)..(21) <223> thiol group via cysteine Combined carboxy thiol <400> 1443

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Met Asn Thr 20 25

<210> 1444 <211> 39 <212> PRT .593 · 156004 · Sequence Listing.doc 201143790 <213> Homo sapiens <400> 1444

His

Arg

Ser Gin Gly Thr Phe 5 Arg Ala Gin Asp Phe 20

Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 10 15

Val Gin Trp Leu Arg Asn Thr Gly Pro Ser

Ser

Gly Ala Pro Pro Pro 35

Ser <210> 1445 <21l> 35 <212> PRT <213>Artificial sequence<223>Synthetic polypeptide<220><221> MISC.FEATORE <223> Glycoside analogue <220><221> M0D_RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (4)..( 4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MISC_FEATURE <222> (7).. (11) <223> Linking residue 7 to the indole bridge of residue 11 <220><221> MISC FEATURE <222> (10)..(10) <223> Xaa is Asp, Glu, sulfo group Alanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC_FEATURE <222> (23) 7. (23) <223> Xaa is Asn ' Lys, Asp, Glu, sulfoalanine, and high sulfoalanine <220><221> MISC .FEATURE <222> (24)..(24) <223> Xaa is Thr, Asp, Giu, sulfoalanine and High sulfoalanine <220><221> MISC FEATURE <222> (25) 7. (25) <223> Xaa is Cys, Om, homocysteine or acetyl phenylalanine <220><221> M0D.RES <222> (25)..(25) <223> PEGylation 594-

156004-sequence table.doc 201143790 <400> 1445

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 1 5 10 15

Phe Val Gin Trp Leu Xaa Xaa Xaa Xaa Gly Pro Ser Ser Gly Ala Pro 20 25 30

Pro Pro Ser 35 <210> 1446 <211> 35 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MISC FEATURE < 223 > sucrose g; analogue <220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl substitution <;220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is aspartic acid, glutamic acid, sulfoalanine or high sulfoalanine <220> .

<221> MISC.FEATURE <222> (10)..(10) <223> Xaa is Asp, Glu, sulfoalanine, homotosine or homosulfoalanine <220><221> MISC FEATURE <222> (11) 7. (15) <223> Linking residue 11 to the indole bridge of residue 15 <220>

<221> MISC.FEATURE <222> (22)..(22) <223> Xaa is Met, Leu or Nle <220><221> MISC FEATORE <222> (23)..( 23) <223> Xaa is Asn, Lys, Asp, Glu, sulfoalanine, and high sulfoalanine <220><221> MISC FEATURE <222> (24).. (24) <223> Xaa is Thr, Asp, Glu, sulfoalanine, and high sulfoalanine <220><221> MISC FEATURE <222> (35) 7. (35) <223> Xaa is Cys, Orr, homocysteine or acetylated amphetamine <220><221> M0D.RES <222> (35)..(35) <223> PEGylation - 595 - 156004- Sequence Listing.doc 201143790 Structure of Glycosin Superfamily Peptide (Q) The glycoside superfamily peptide (Q) described herein may comprise an amino acid sequence based on the following amino acid sequence: native human glucosin (SEQ ID NO: 1601), native human GLP-1 (SEQ ID NO: 1603 or 1604) or native human GIP (SEQ ID NO: 1607). Based on native human glycosides In some aspects of the invention, the glycoside superfamily peptide (Q) comprises an amino acid sequence based on the amino acid sequence of the native human glucosinolate (SEQ ID NO: 1601). In some aspects 'Q comprises a modified amino acid sequence SEQ m NO: 1601 comprising 1, 2, 3, 4, 5, ό, 7, 8, 9, 10, 11, 12, 13, 14 15 at 'and in some cases contains 16 or more (eg 17, 17, 18, 20, 21, 22, 23, 24, 25, etc.) amino acid modifications. In some embodiments 'Q relative to the native human glucagon sequence (SEQ ID NO: 1601) comprises a total of 1, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7 Up to 8, up to 9 or up to 10 amino acid modifications. In some embodiments, the modifications are any of the modifications described herein, for example, for positions 1, 2, 3, 7, 10, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 27, The amino acid of one or more of 28 and 29 is deuterated, alkylated, PEGylated, truncated at the C-terminus, and substituted. In some embodiments, Q comprises at least 25 ❶/ of the amino acid sequence of native human glucosinolate (SEQ ID NO: 1601). Sequence-equal amino acid sequence. In some embodiments, Q comprises at least 30%, at least 40%, at least 50%, at least 6%, at least 70%, at least 156004.doc -109·201143790 <400> 1446 with SEq ID NO: 1601

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Ser Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Xaa Xaa Xaa Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser Xaa 35 <210> 1447 <211> 24 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> Sugar Female Analog <220><221> MISC FEATURE <222> (4)..(4) <223> Xaa is glutamic acid, glutamic acid, sulfoalanine or high sulfopropylamine Acid <220><221> MISC^FEATIJRE <222> (7)..(11) <223> Linking residue 7 to the indole bridge of residue 11 <220><221> (10) <223> Met, Leu or Nle <220><221> MISC FEATURE <222> (23)..(23) <223> Xaa is into sn, Asp or Glu <400> 1447

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt <223> Ligose I analogue 596·

156004-Sequence List.doc 201143790 <220><221> MISC FEATURE <222> (4).7(4) <223> Xaa is glutamic acid, glutamic acid, sulfoalanine or high Sulfoalanine <220><221> MISC FEATURE <222> (10) 7. (10) <223> Xaa is Asp or Glu <220><221> MISC.FEATORE <222> (11) 7. (15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MISC FEATURE <222> (22) 7. (22) <223> Xaa is l^let, Leu or NIe <220><221> MISC FEATURE <222> (23)7.(23) <223> Xaa is Asn, Asp or Glu

<400> 1448

Phe Thr Ser Xaa Tyr Ser Lys Tyr Leu Xaa Glu Arg Arg Ala Lys Asp 1 5 10 15

"health sequence <220> &lt FEATORE <223> Glycoside analogue <4〇〇> 1449

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp Phe 15 10 15

Val Gin Trp Leu Met Asp Thr 20 <210> 1450 <2U> It <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220>

<221> MISC FEATURE <223> represents a peptide fragment of 10 amino acids of the carboxy terminal of the ruthenium oxytocin analog _4 plus an additional amino acid <220> 597-156004-sequence table.doc 201143790 <221> MISC FEATURE <222> (11)..(11) <223> Xaa is selected from the group consisting of (^, 0〇1, 1^, homocysteine and acetopheniric acid) Group <400> 1450

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Xaa 1 5 10 <210> 1451 <211> 24 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220>;221> MISC FEATURE <223> Glycoside analogue <220><221> MOD RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl substitution <220>;<221> MISC FEATURE <222> (4)..(4) <:223> Xaa is aspartic acid, glutamic acid, sulfoalanine, glutamic acid or high sulfoalanine <220><221> MISC FEATURE <222> (7)..(7) <223> Xaa is Lys or Glu <220><221> MISC FEATURE <222> (10).. (10) <223> Xaa is Asp, Glu, arginine, lysine or arginine <220><221> MISC.FEATURE <222> (11) 7. (11 <223> Xaa is Ala, Ser, Glu, Lys, Gin, glutamic acid or high sulfoalanine <220><221> MISC.FEATURE <222> (15)..(15) <223> Xaa is Arg, Gin, Glu or Lys <220><221> MISC^FEATURE (193⁄4 <223& Xaa is Ala, Gin, Lys or Glu <220><221> MISC FEATURE <222> (22) 7. (22) <223> Xaa is I^let, Leu or Nle <220><221> MISC.FEATTJRE <222> (23)..(23) <223> Xaa is Asn, Lys or Acid Amino Acid <220><221> MISC FEATURE <222> (24) ..(24) • 598· 156004 - Sequence Listing.doc 201143790 <223> Xaa is Thr, Gly or Acid Amino Acid <400> 1451 Phe Thr Ser Xaa Tyr Ser Xaa Tyr Leu Xaa Xaa Arg Arg Ala Xaa Asp 15 10 15 Phe Val Xaa Trp Leu Xaa Xaa Xaa 20 >>>> 012 3 220Λ2 << V < 1452 6 PRT Artificial Sequence <220><223> Synthetic Peptide <220>;221> MISC.FEATURE <222> (6)..(6) <223> Xaa is phenyl lactic acid <400> 1452 His Ser Gin Gly Thr Xaa

<210> 1453 .- <211> 5 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <222> (5) .7(5) <223> Xaa is phenyl lactic acid <400> 1453 Ser Gin Gly Thr Xaa 1 5 <210> 1454 <211> 4 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <222> (4).. (4) <223> iCaa is phenyl lactic acid <400> 1454 Gin Gly Thr Xaa 1 <210> 1455 <211> 3 <212> PRT 156004. Sequence Listing. doc 599-201143790 <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <222> (3)..(3) <223> Xaa is phenyl lactic acid <400> 1455

Gly Thr Xaa <210> 1456 <211> 2 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MISC FEATURE <222> (2)..(2) <223> Xaa is phenyllactate <400>

Thr Xaa <210> 1457 <211> 6 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> Ml SC FEATURE <222> (1).. (1) <223> Xaa is selected from the group consisting of His, D-histidine, and α^α-dimethyl-myzolacetic acid (DMIA), Ν-methylhistamine, α-mercapto histidine, imidazoleacetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histamic acid, and <220>

<221> MISC.FEATURE <222> (2)..(2) <223> Xaa is selected from the group consisting of strontium: Ser, D-serine, D-alanine 'Val' Gly, N-mercaptosine, N-methylalanine, and amine tocoisobutyric acid (AIB) <220><221> MISC.FEAHJRE <222> (3)..(3) <223> Xaa is selected from the group consisting of Glu or Gin <220>

<221> MISC FEATURE <222> (6)..(6) <223> Xaa is phenyllactate <400> 1457

Xaa Xaa Xaa Gly Thr Xaa 600-

156004. Sequence Listing. doc 201143790 <210> 1458 <211> 5 <212> PRT < 213 > Artificial Sequence <220><223> Synthetic Peptide <220><221> M1SC FEATURE <222> (1)..(1) <223> Xaa is selected from the group consisting of Ser, D. serine, D-alanine, Val, Gly, N-methylserine, N- Mercaptoalanine and amine tomb isobutyric acid (AIB) <220><221> MISC FEATURE <222> (2)..(2) <223> Xaa% is selected from the group consisting of Glu or Gin<;220>

<221> MISC.FEATURE <222> (5)..(5) <223> Xaa is phenyllactate <400>

Xaa Xaa Gly Thr Xaa 1 5 <210> 1459 <211> 4 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC.FEATURE <;222> (l).T(l) <223> (10) is a group of free Glu or Gin <220><221> MISC.FEATURE <222> (4).7(4) <;223> Xaa is phenyl lactic acid <400> 1459

Xaa Gly Thr Xaa <210> 1460 <211> 24 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MOD RES <222> 1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220> •601·156004·SEQ ID NO:doc 201143790 <221> MISC FEATURE <222> (11)..(15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MOD RES <222> (24)..(24) <223> C-terminal ester group Indoleamine replacement <400> 1460

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

"health polypeptide <220> &lt <222> (1) T. (l) <223> N-terminal amine group via hydroxyl group replacement <220><221> MOD RES <222> (24)..(24) <223> Terminal alpha tetreate group replaced by decylamine <400> 1461

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <223&gt (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATORE <222> (4)., (7) <223><220><221> MOD_RES <222> (24)..(24) <223> C-terminal α-acidate group via decylamine replacement <400> 1462

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 602· 156004· Sequence Listing.doc 201143790 15 10 15

"health sequence <220> &lt FHATURE <222> (15) 7. (19) <223> Linking residue 15 to the indole bridge of residue 19 <220><221> MOD RES <222> (28).. (28) <223> C-terminal α-acid ester group replaced by decylamine

<400> 1463

Ala Glu Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg 15 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1464 <211> 28 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220>;221> MISC FEATURE <222> (4).7(5) <223> The sulphate at position 4 and the phenyl lactic acid at position 5 are linked via an ester bond <220><221> MISC FEATURE <222> (5)..(5) <223> Xaa is phenyllactate <220><221> MISC FEATURE <222> (15)7.(19) <223> The indole bridge of the base 15 and the residue 19 <220><221> M0D_RHS <222> (28)..(28) <223> C-terminal alpha tetamine group by decylamine replacement <4〇〇> 1464

Ala Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg 15 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 -603 - 156004 · Sequence Listing.doc 201143790 <210> 1465 <211> 28 <212> PRT <213>Artificial Sequence<220>;223>Synthetic polypeptide <220>221> MISC_FEATURE <222> (15)..(19) <223> Linking residue 15 to the indoleamine bridge in residue 19 <220>221> MOD RES <222> (28)..(28) <223> C-terminal α-obturate group via decylamine replacement <400>

Ser Gin Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg 15 10 15

Arg A, a Lys Asp Phe Va. Gin Trp Leu Met Asp <210> 1466 <211> 28 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>;221> MISC.FEATURE <222> (4)..(5) <223> The sulphonic acid at position 4 and the phenyl lactic acid at position 5 are linked via an ester bond <220><221> (5) <223> Linking residue 15 to the indole bridge of residue 19 <220><221> MOD RES <222> (28)..(28) <223> C-terminal alpha tetamine group Replacement <400> 1466

Ser Gin Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg 15 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1467 <211> 24 <212> PRT <213>Artificial Sequence<220> • 604·156004 Sequence Listing.doc 201143790 &lt ;223> Synthetic polypeptide <220><221> M0DJRES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> (5)..(5) <223> covalently linked to the cholesterol acid moiety <220><221> MISC FEATURE <222> (11)..(15) <223> The indole bridge of the group 11 and the residue 15 <220><221> MOD RES <222> (24)..(24) <223> C-terminal α-carboxylate group substituted by decylamine <;400> 1467

Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 1 5 10 15

"health sequence <220> &lt <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> Residue 11 and the indole bridge of residue 15 <220><221> MISC FEATURE <222> (25)..(25) <223> covalently bonded to the cholesterol acid moiety <220>;<221> M0D.RES <222> (25)..(25) <223> C-terminal α-acid ester group replaced by decylamine <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asp Thr Lys 20 25

<210> 1469 <211> 35 <212> PRT-605-156004-sequence table.doc 201143790 80%, at least 85%, at least 90°/. Or an amino acid sequence having more than 90% sequence identity. In some embodiments, the amino acid sequence of Q having a percent sequence identity as referred to above is the full length amino acid sequence of Q. In some embodiments, the amino acid sequence of Q having a percent sequence identity as referred to above is only one of the Q partial amino acid sequences. In some embodiments, Q comprises a reference amine that is at least 5 contiguous amino acids of SEQ ID NO: 1601 (eg, at least 6, at least 7, at least 8, at least 9, at least 10 amino acids) The amino acid sequence has an amino acid sequence of about A% or more % sequence identity, wherein the reference amino acid sequence begins with the amino acid at position C of SEQ ID NO: 1601 and ends with SEQ ID NO: 1601 Amino acid at position D, wherein A is 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99; C is 1, 2, 3, 4, 5, ό, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, and D is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 , 21, 22, 23, 24, 25, 26 '27, 28 or 29. Any and all possible combinations of the above parameters are contemplated, including but not limited to, for example, where eight is 9〇% and C and D are 1 and 27, or 6 and 27, or 8 and 27, or 1〇 and 27, Or 12 and 27, or 16 and 27. Based on native human GLP-1 In some aspects of the invention, the glycoside superfamily peptide (Q) comprises an amino group based on the amino acid sequence of the native human GLP-1 (SEQ ID N: 16〇3) Acid sequence. In some aspects, Q comprises a modified amino acid sequence seq 156004.doc • 110· 201143790 <213> artificial sequence <220><223> synthetic polypeptide <220><221> MOD RES <;222> (l) T. (i) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> The indole bridge of the group 11 and the residue 15 <220><221> MISC FEATTJRE <222> (35) 7. (35) <223> covalently bonded to the cholesterol acid moiety <220><221> MOD RES <222> (35)..(35) <223> C-terminal alpha tickerate substituted by decylamine <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asp Thr Gly Pro Ser Ser Gly Ala Pro Pro

Pro Ser Lys 35 <210> 1470 <211> 28 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <222> 1).. (1) <223> Xaa is aminoisobutyric acid <220><221> MISC.FEATURE <222> (4).7(5) <223> Amino acid and phenyl lactic acid at position 5 are bonded via an ester bond <220><221> MISC.FEATURE <222> (5)..(5) <223> Xaa is phenyl lactic acid <220><221> MISC FEATURE <222> (15)..(19) <223> Linking residue 15 to the indole bridge of residue 19 <220><221> MOD RES <222> (28)..(28) <223> C-terminal α-propionate group substituted with decylamine-606· 156004-sequence table.doc 201143790 <400> 1470

Xaa Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1471 <211> 34 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>;221> MOD.RES <222> (34)..(34) <223> C-terminal alpha carboxylate group substituted with decylamine <400>

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp l 5 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1472 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220>

<221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><22l> M0D.RES <222> (34)..( 34) <223> C-terminal alpha tickrate group substituted with decylamine <400> 1472

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp

10 IS

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1473 <211> 34 <212> PRT <213> artificial sequence•607- 156004-sequence table.doc 201143790 Synthetic polypeptide <220><221> MISC^FEATORE <222> (11).. (15) <223> linking the residue 11 and the indole bridge of the residue 15 <220><221> MOD RES <222> (34).. (34) <223> C-terminal alpha tetamine group substituted with decylamine <400>

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1474 <211> 34 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MOD.RES <222> (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11)..(15) <223> Indoleamine bridge <220><221> MOD RES <222> (34)..(34) <223> C-terminal α-carboxylate group via indoleamine replacement <400>

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1475 <211> 24 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide -608-

156004-Sequence List.doc 201143790 <220><221> MOD RES <222> (l)T.(l) <m> N-terminal amine group via hydroxyl substitution <m><221> MISC FEATURE <222> (7).7(11) <223> Linking the indole bridge of residue 7 to residue 11 <220><221> MOD RES <222> (24)..( 24) <223> C-terminal α-carboxylate group substituted with decylamine <400>

Phe Thr Ser Asp Tyr

Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 10 15

Phe Val Gin Trp Leu Met Asp Thr 20

<210> 1476 <211> 24 <212> PRT <213>Artificial sequence <220><m> Synthetic polypeptide <220><221> MOD RES <222> (l) T. (l) <223> N-terminal amino group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> Linking residue 11 to residue 15 Indole bridge <220><221> MOD RES <222> (24)..(24) <223> C-terminal alpha carboxylate group via decylamine replacement <400>

Phe Thr Ser Asp Tyr Ser 1 5 Phe Val Gin Trp Leu Met 20

Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 10 15

Asp Thr

<210> 1477 <211> 24 <212> PRT <213> Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD RES <222> (l) T. (l) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE -609· 156004 - Sequence Listing.doc 201143790 <222> (15)..(19) <223> Linking the residue 15 and the indole bridge of the residue 19 <220><221> MOD.RES <222> (24)..(24) <223> C-terminal α-carboxylate group Indoleamine replacement <400> 1477

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATTJRE <222> (19)..(23) <223> Linking the indole bridge of residue 19 to residue 23 <220><221> M0D.RES <222> (24)..(24) <223> (: terminal oxime 1 carboxylate Base guanamine replacement <400> 1478

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Glu Trp Leu Met Lys Thr 20 <210> 1479 <211> 24 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide<220><221> M0D_RES <;222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC.FEATURE <222> (7)..(11) <223> The indole bridge of residue 7 and residue 11 <220><221> MOD.RES <222> (24)..(24) <223> Indoleamine replacement 156004 - Sequence Listing. doc 610-

201143790 <400> 1479

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp G!u Gin Ala Ala Lys Asp 15 10 15

Phe lie Ala Trp Leu Met Asp Thr 20 <210> 1480 <211> 24 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220>

<221> MOD RES <222> (1)..(1) <223> N-terminal amine group substituted by hydroxyl group <220>

<221> MISC.FEATURE <222> (11)..(15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MOD RES <222>; (24)..(24) <223> 0-terminal 〇 1 tetamine group via decylamine replacement <400> 1480

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Gin Ala Ala Lys Glu 15 10 15

Phe lie Ala Trp Leu Met Asp Thr 20 <210> 1481 <211> 28 <212> PRT <213>Artificial sequence <220><223>

<221> MISC FEATURE <222> (15)..(19) <223> Linking the residue 15 to the indole bridge of residue 19 <220><221> M0D.RES <222> (28),. (28) <223> C-terminal α-carboxylate group substituted with decylamine <400>

Ala Glu Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg )5 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1482 <2H> 28 -611 - 156004 - Sequence Listing.doc 201143790 <212> PRT <213>Artificial Sequence<220>;223>Syntheticpolypeptide>>>>>>>> 0123 0123 2222 2222 <400> MISC.FEATORE (15)..(19) Linking residue 15 to residue 19 Indole bridge MOD RES (28)..(28) C-terminal ct- oxalate group via guanamine replacement 1482

Ala Glu Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Gin 15 10 15

Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 <210> 1483 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220>;221> MISC FEATURE <222> (16).. (20) <223> Linking residue 16 to the indole bridge of residue 20 <220><221>M0D'RES<222> (29)..(29) <223> C-terminal α-carboxylate group substituted with decylamine <400> 1483 his Ala Glu Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1484 <211> 29 <212> PRT <2丨3> Artificial sequence <220> A ... <223><220><221> MI SC FEATURE <222> (16).. (20) <223> : Linking the residue to the indole bridge of residue 16 and residue <220><221> MDD.RES <222> (29)..(29) <223> C-terminal alt acid ester group via decylamine substitution 156004 - Sequence Listing. doc 612-201143790 <400> 1484

His Ala Glu Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu 15 10 】5

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 <210> 1485 <211> 26 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <222> (13)..(17) <223> Linking residue 13 to the indole bridge of residue 17 <220>

<221> MOD RES <222> (26)..(26) <223> 0: terminal oxime 1 acid ester group replaced by decylamine <400>

Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala 1 5 10 15

Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1486 <211> 28 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <222> (5)..(6) <223> The sulphate at position 5 and the phenyl lactic acid at position 6 are linked via an ester bond <220><221> MISC FEATURE <;222> (15)..(19) <223> Linking residue 15 to the indole bridge of residue 19 <220><221> MOD RES <222> (28).. (28 <223> C-terminal α-carboxylate group substituted with decylamine <400> 1486

Ser Gin Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg 10 15

Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1487 -613- 156004 - Sequence Listing.doc 201143790 <211> 29 <212> PRT <213>Artificial Sequence<220>;223>Synthetic polypeptide <220><221> MISC.FEATURE <222> (5)..(6) <223> sulphate at position 5 and phenyl lactic acid at position 6 via ester bond Link <220><221> MISC FEATURE <222> (6)..(6) <223> Xaa is phenyllactate <220><221> MISC FEATURE <222> (16) .. (20) <223> Connecting the tomb 16 and the residue of the amide in the residue 20 <220><221> MOD RES <222> (29)..(29) <223> Ester group replaced by decylamine <400> 1487

His Ala Glu Gly Thr Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 <210> 1488 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (7).7 (11 <223> Linking the indole bridge of residue 7 to residue 11 <220><221> MOD-RES <222> (19)..(19) <223> PEGylation <220><221> MOD RES <222> (24)..(24) <223> C-terminal α-carboxylate group substituted with decylamine <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Cys Trp Leu Met Asp Thr -614-

156004-Sequence List.doc 20 201143790 <210> 1489 <211> 35 <212> PRT <213>Artificial Sequence<220><223>SyntheticPolypeptide<220><221> MOD RES <;222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (7).7(11) <223> The indole bridge of the base 7 and the residue 11 <220><221> M0D.RES <222> (35)..(35)

<223> PEGylation <221> MOD RES <222> (35T..05) <223> C-terminal α-carboxylate group substituted with decylamine <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Trp Leu Met Asp Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser Cys 35 <210> 1490 <211> 24 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MOD.RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) (15) linking residue 11 and residue 15 The indoleamine bridge <220><221> M0D.RES <222> (19)..(19) <223> PEGylation <220><221> MOD RES <222> (24)..(24) <223> C-terminal alpha tetamine group via decylamine substitution 615-156004. Sequence Listing, doc 201143790 NO: 1603, which contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 , 11, 12, 13, 14, 15 and in some cases 16 or more (eg 17, 18, 19, 20, 21, 22, 23, 24, 25, etc.) amino acid modification. In some embodiments, Q comprises 1 total, up to 2, up to 3, up to 4, up to 5, up to 6, and up to 7 relative to the native human GLP-1 sequence (SEQ ID NO: 1603) Up to 8, up to 9 or up to 10 amino acid modifications. In some embodiments, the modifications are any of the modifications described herein, for example, for positions 1, 2, 3, 7, 10, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 27, The amino acid of one or more of 28 and 29 is deuterated, alkylated, PEGylated, truncated at the C-terminus, and substituted. In some embodiments 'Q comprises an amino acid sequence having at least a 25% sequence identity to the amino acid sequence of native human GLP-1 (SEQ ID NO: 1603). In some embodiments 'Q comprises at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or 90% with SEQ ID NO: 1603 The above sequence is consistent with the amino acid sequence. In some embodiments, the amino acid sequence of Q having a percent sequence identity as referred to above is the full length amino acid sequence of Q. In some embodiments, the amino acid sequence of q having the percent sequence identity referred to above is only one of the Q partial amino acid sequences. In some embodiments, Q comprises a reference to at least 5 contiguous amino acids of SEQ ID NO: 1603 (eg, at least 6, at least 7, at least 8, at least 9, at least 1 胺 amino acid) The amino acid sequence has an amino acid sequence of about A% or more than about A%, wherein the reference amino acid sequence begins at SEq ID NO: 156004.doc • 111- 201143790 <400> 1490 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 Phe Val Cys Trp Leu Met Asp Thr 20

Arg Arg Ala

Lys 15 >>>> 0123 <21<21<21<21 1491 35 PRT artificial sequence <220><223> Synthetic polypeptide <220><221> MOD.RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11)..(15) <223> Indole bridge in residue 15 <220><221> MOD.RES <222> (35)..(35) <223> PEGylation <220><22l> MOD RES <222> (35)..(35) <223> 〇: terminal (1 phthalate group by decylamine substitution <400> 1491 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10

Phe Val Gin Trp Leu Met Asp Thr Gly Pro Ser 20 25

Arg Arg Ala Ser Gly Ala 30

Lys 15

Pro

Asp Pro

Pro Ser Cys 35 <210> 1492 <211> 24 <212> PRT <2丨3>Artificial Sequence<220><223>SyntheticPeptide<220><221> MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MOD.RES <222> (1).. (1) <223> Covalent connection To C16 fatty acid <220><221> MISC FEATURE <222> (11)..(15) 616-156004-sequence table.doc 201143790 <223> linking residue 11 with indoleamine 15 Bridge key <220><221> MOD RES <222> (24)..(24) <223> C-terminal alpha tetamine group via decylamine replacement <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asp Thr 20 <210> 1493 <211> 24 <212> PRT <213> Artificial sequence <220><223>

<220><221> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> M0D_RES <222> (5) .. (5) <223> linked to C16 fatty acid via a Glu residue <220><221> MISC FEATURE <222> (11)..(15) <223> The indole bridge in the base 15 <220><221> MISC FEATURE <222> (15)7.(15) <223> is linked to the C16 fatty acid via the Glu residue <220><221>; M0D.RES <222> (24)..(24) <223> C-terminal alpha tetamine group via decylamine replacement <400>

Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt RES <222> (1)7.(1) <223> N-terminal amine group via hydroxyl group replacement 617-156004-sequence table.doc 201143790 <220><221> MISC.FEATURE <222> 15) 7. (15) <223> linked to C16 fatty acid via a Giu residue <220><221> M0D.RES <222> (24)..(24) <223> C-terminal α Carboxylic acid ester group substituted with decylamine <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr 1 5

Phe Val Gin Trp Leu Met Asp Thr 20

Leu Asp GIu Arg Arg Ala Lys Asp 10 15 <210> 1495 <211> 24 <212> PRT <213> Artificial Sequence <220>

<223> Synthetic polypeptide <220><221><222><223>

MOD.RES is transposed by the base <220> <221> MISC.FEATURE <222> (11)..(15) <223> linking the residue 11 with the indole bridge of residue 15 <220><221> MISC.FEATTJRE <222> (19)..(19) <223> Linked to C16 fatty acid <220><221> M0D.RES <222> via Giu residue 24)..(24) <223> C-terminal alpha carboxylate group substituted with decylamine <400> 1495

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu Arg Arg Ala Lys Asp 15 10 15

"health sequence <220> &lt RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group <220>

<221> MISC.FEATTJRE 618-156004. Sequence Listing. doc 201 143790 <222> (11)..(15) <223> Linking residue 11 with a guanamine bridge in residue 15 <220><221> MISC FEATURE <222> (24) 7. (24) <223> Linked to C16 fatty acid via Glu residue <220><221> MOD RES <222> (24) ..(24) <223> C-terminal α-acid ester group substituted by decylamine <400> 1496 Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

"health sequence <m> &lt 222><223><220><221><222><223> MOD.RES(1)7.0) N-terminal amine group via hydroxyl group MISC FEATURE (11) 7. (11) Xaa is an amine Isobutyric acid!>>>> 012 3 2222 <2<2<2<2 <400> MOD RES (24)..(24) C-terminal alpha tickate group substituted by decylamine 1497

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 1 5 Phe Val Gin Trp Leu Met Asn Thr 20

Asp Xaa Arg Arg Ala Gin Asp 10 15 <210> 1498 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD RES <222> (1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC-FEATURB <222> (11) 7. (11) <220> 156004-Sequence List.doc 619- 201143790 <221> MISC FEATURE <222> (15)..(15) <223> Xaa is α isobutyric acid <220><221> MOD RES <222> (24)..(24) <223> 0-terminal (1 carboxylate group substituted by decylamine <400> 1498

Phe Thr Ser Asp Lys Ser Lys Tyr Le\i Asp Xaa Arg Arg Ala Xaa Asp 15 10 15

Phe Val Cys Trp Leu Met Asn Thr 20

<210> 1499 <211> 24 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MOD RES <222> (1).. (1) <223> N-terminal amine tomb hydroxy substitution <220><221> MOD RES <222> (24)..(24) <223> 0: terminal oxime 1 ester ester group Indoleamine replacement <400> 1499

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

"health peptide <220> &lt

<221> MOD.RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MOD.RES <222> (24).. (24) <223> C-terminal α-carboxylate group substituted with decylamine <400> 1500

Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu Arg Arg Ala Gin Asp 15 10 15

Phe Val Cys Trp Leu Met Asn Thr 20 620-

156004-Sequence List.doc 201143790 <210> 1501 <211> 24 <212> PRT <213>Artificial Sequence<220><223>SyntheticPolypeptide<220><221> MISC FEATURE <222> (4)..(7) <223> Linking the indole bridge of residue 4 and residue 7 <220><22l> MOD.RES <222> (11).. (11 <223> Xaa is α isobutyric acid <220><221> MOD RES <222> (24)..(24) <223> C-terminal carboxylate group is replaced by decylamine <400>; 1501

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 1 5 10 15

"health sequence <220> &lt FEATORE <222> (4)..(7) <223> Linking residue 4 to the indole bridge of residue 7 <220><221> MOD RES <222> (11).. (11) <223> Xaa is α isobutyric acid <220><221> M0D_RES <222> (24).. (24) <223> C-terminal carboxylate group is replaced by decylamine <400> 1502

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Xaa Arg Arg Ala Gin Asp 15 10 15

Phe Val Gin Ding rp Leu Met Asn Thr 20 <210> 1503 <211> 24 <212> PRT <213> Artificial sequence 621 - 156004 · Sequence Listing.doc 201143790 <220><223><220><221> MOD RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> Linking the indole bridge between residue 11 and residue 15 <220><221> MOD RES <222> (24)..(24) <223> Terminal α-acid ester group replaced by decylamine <400> 1503

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Glu 15 10 15

"health sequence <220> &lt MOD RES <222> (1) 7. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MOD RES <222> (24)..(24) <223>; C-terminal α fumarate group replaced by decylamine <400> 1504

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Gin Ala Ala Lys Glu 15 10 15

"health sequence <220&gt <222> (347..(34) <223> (: terminal 〇 1 tetamine group by decylamine replacement <400> 1505

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp -622- 156004 - Sequence Listing.doc 201143790 15 10 15

Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser <210> 1506 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MOD RES <222> (1)..(1) <223> N-terminal amine group is replaced by a hydroxyl group

<220><221> MISC FEATURE <222> (5).. (5) <223> Linked to C16 fatty acid via a Glu residue <220><221> MISC.FEATORB <222> (Ί). ΛΊ) <223> linkage to C16 deer fatty acid via a Glu residue <220><221> M0D_RES <222> (24)..(24) <223> C-terminal carboxylic acid Ester group replaced by decylamine <400> 1506

Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 1.5 10 15

"health peptide <220>

<221> MISC FEATURE <222> (1)..(1) <223> The aal line is freely composed of the following groups: His, D-histidine, c^a-dimercapto Acetic acid (DMIA), N-mercapto histidine, a-methyl histidine, imidazoleacetic acid, adenosine histidine, hydroxy-histidine, etidyl histidine, and <220>

<221> MISC FEATURE <222> (2).. (2) <223> Xaa is selected from the group consisting of Ser, D-serine, D-alanine, proline, glycine Acid, N-methylserine and aminoisobutyric acid (AIB) 623 - 156004-sequence table.doc 201143790 <220><221> MISC.FEATTJRE <222> (3)..(3) <223> Xaa is selected from the group consisting of Glu or Gin <400> 1507 Xaa Xaa Xaa Thr Gly Phe <210> 1508 <21i> 5 <212> PRT <213> Artificial Sequence <220><223> Synthetic polypeptide <220><221><222><223> MISC FEATURE (l).T(l) Xaa is selected from the group consisting of D-alanine, proline, Glycine aminoisobutyric acid (AIB)

Ser, D-serine, • N-methyl serine and <220><221> MISC FEATURE <222> (2)..(2) <223> Xaai is selected from Glu or Gin Group <400> 1508 Xaa Xaa Thr Gly Phe <210> 1509 <211> 4 <2I2> PRT <213>Artificial Sequence<220><2U>SyntheticPeptide>>>> 012 3 2222 2 2 ΟΛ 2 <<v <<400> MISC FEATURE (l).T(l) Xaa is a group of freely composed Glu or Gin 1509

Xaa Thr Gly Phe <210> 1510 <211> 24 <212> PRT < 213 > artificial sequence <220><223> synthetic polypeptide <220><221> MOD RES <222>;223> by base substitution <220><221> MOD.RES <222> (24)..(24) 156004. Sequence Listing.doc 624· 201143790 <223> C-terminal alpha carboxylate group Replacement with decylamine <400> 1510

Phe Thr Set Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 15 10 15

"health sequence <220> &lt <222> (28)..(28) <223> c-terminal alpha-propionate group substituted by decylamine

<400> 1511

Ser Gin Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg 15 10 15

Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1512 <211> 28 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC.FEATORE <222> (4)..(5) <223> The sulphate at position 4 and the phenyl lactic acid at position 5 are linked via an ester bond <220><221> (4) <223>; C-terminal alpha tetamine group replaced by decylamine <400> 1512

Ser Gin Gly Thr Xaa Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser Arg 15 10 15

Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <2]0> 1513 <211> 29 <212> PRT <213>Artificial Sequence -625-156004 · Sequence Listing.doc 201143790 1603 Location Amino acid on C, and amino acid 'end' at position D of SEQ ID NO: 1603 where a is 25' 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 , 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99; C is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 , 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, and D is 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29. Any and all possible combinations of the above parameters are contemplated, including but not limited to, for example, where A is 90% and C and D are 1 and 27, or 6 and 27, or 8 and 27, or 10 and 27, or 12 And 27, or 16 and 27.

Based on native human GIP In some embodiments of the invention 'Q is a similar to native human GIP', the amino acid sequence thereof is provided herein as SEQ ID NO: 1607. Thus 'in some embodiments' Q comprises an amino acid sequence based on SEq ID NO: 1607' but modified to have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and, in some cases, having 16 or more (eg 17, 18, 19, 20, 21, 22, 23, 24, 25, etc.) amino acid modified amino acids sequence. In some embodiments, Q comprises a total of 1 position, up to 2 places, up to 3 places, up to 4 places, up to 5 places, up to 6 places, up to 7 places, up to 7 relative to the native human GIP sequence (SEQ ID NO: 1607) 8, up to 9 or up to 10 amino acid modifications. In some embodiments 'modified as any of the modifications described herein, for example for positions 1, 2, 3, 7, 10, 12, 15, 16, 17, 18, 19, 20, 21, 23, 24, 156004. Doc • 112 201143790 <220><223>SyntheticPeptide<220><221> MISC_FEATURE <222> (5)..(6) <223> Position 5 on threonine and position 6 The phenyl lactic acid is linked via an ester bond <220><221> MISC FEATURE <222> (6)..(6) <223> Xaa is phenyl lactic acid <220><221> M0D. RES <222> (29)..(29) <223> C-terminal alpha tetamine group via decylamine replacement <400> 1513

His Ser Gin Gly Thr Xaa Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 1514 <2U> 24 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide<220><221> M0D_RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11)..(15) <223> Linking residue 11 and the indole bridge of residue 15 <220><22> M0DJES <222> (19)..(19) <223>PEGylation<;220><221> MOD RES <222> (24)..(24) <223> (: end 〇 1 tetamine group via guanamine replacement <400> 1514

Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Cys Trp Leu Met Asn Thr 20 <210> 1515 <211> 24 <212> PRT <213> Artificial Sequence • 626· 156004 - Sequence Listing.doc 201143790 <220><223>

<220><221> MOD RES<222> (1)..(1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11). (15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MISC FEATURE <222> (19)..(19) <223> Pegylated PEGylation <220><221> MOD RES <222> (24).. (24) <223> C-terminal alpha carboxylate group substituted with decylamine <400> 1515 Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 10 IS

Phe Thr Ser Asp Tyr Ser 1 5

Phe Val Lys Trp Leu Met

Asp Thr <210> 1516 <211> 24 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221><222><223> MOD -RES transmembrane replacement

<220><221> MISC FEATURE <222> (11) 7. (15) <223> Linking residue 11 to the indole bridge of residue 15 <220><221> MOD RES <222> (19).. (19) <223> PEGylation via rigid spacers <220><221> MOD RES <222> (24)..(24) <223> C-terminal α-decanoate group replaced by decylamine <400> 1516

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Lys Trp Leu Met Asp Thr 20 <210> 1517 <211> 35 156004-sequence table.doc .627. 201143790 <212> PRT <213> Artificial Sequence <220><223> Synthetic polypeptide <220><221> MISC FEAnJRE <222> (l).T(l) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> linking the residue 11 to the indole bridge of the residue 15 <220><221> MOD RES <222> (35)..(35) <223> Ethylene glycolate <220><221> MOD RES <222> (35).. (35) <223> C-terminal alpha carboxylate group via decylamine replacement <400>

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15

Phe Val Gin Trp Leu Met Asp Thr Gly Pro Gly Pro Gly Pro Gly Pro 20 25 30

Gly Pro Cys <210> 35 1518 <211> 35 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD RES <222> 1).. (1) <223> N-terminal amine group via hydroxyl group replacement <220><221> MISC FEATURE <222> (11) 7. (15) <223> The guanamine bridge in the base 15 <220><221> MOD RES <222> (35)..(35) <223> PEGylation <220><221> MOD RES <222> (35)..(35) <223> C-terminal alpha treate group via decylamine S for <400> 1518

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu Arg Arg Ala Lys Asp 15 10 15 628- 156004 - Sequence Listing.doc 201143790

Phe Val Gin Ττρ Leu Met Asp Gly Gly Ρτο Ser Ser Gly Ala Pro Ρτο 20 25 30

15th &lt ;210> 1523 <400> 000 1523 <210> 1524 <400> 000 1524 <210> 1525 <400> 000 1525 <210> 1526 <400> 000 1526 <210> 1527 <400> 000 1527 <210> 1528 <400> 000 1528 <210> 1529 <400> 000 1529 <210> 1530 <400> 000 1530 <210> 1531 <400> 000 1531 <210> 1532 - 629- 156004 - Sequence Listing. doc 201143790 <400> 1532 000 <210> 1533 <400> 1533 000 <210> 1534 <400> 1534 000 <210> 1535 <400> 1535 000 <210> 1536 <400> 1536 000 <210> 1537 <400> 1537 000 <210> 1538 <400> 1538 000 <210> 1539 <400> 1539 000 <210> 1540 <400> 1540 000 <210> 1541 <400> 1541 000 <210> 1542 <400> 1542 000 <21 0> 1543 <400> 1543 000 <210> 1544 <400> 1544 000 <210> 1545 <400> 1545 000 <210> 1546 <400> 1546 000 <210> 1547 -630 156004 - Sequence Listing.doc 201143790 <400> 1547 000 <210> 1548 <400> 1548 000 <210> 1549 <400> 1549 000 <210> 1550 <400> 1550 000 <210><400> 1551 000 <210> 1552

<400> 1552 000 <210> 1553 <400> 1553 000 <210> 1554 <400> 1554 000 <210> 1555 <400> 1555 000 <210> 1556 <400> 1556 000 <210> 1557 <40〇> 1557 000 <210> 1558 <400> 1558 000 <210> 1559 <400> 1559 000 <210> 1560 <400> 1560 000 <210&gt 1561 <400> 1561 000 <210> 1562 <400> 1562 -631 - 156004 - Sequence Listing.doc 201143790 000 <210> 1563 <400> 1563 000 <210> 1564 <400> 000 <210> 1565 <400> 1565 000 <210> 1566 <400> 1566 000 <210> 1567 <400> 1567 000

<210> 1568 <400> 1568 000 <210> 1569 <400> 1569 000 <210> 1570 <400> 1570 000 <210> 1571 <400> 1571 000 <210> 1572 <;400> 1572 000

<210> 1573 <400> 1573 000 <210> 1574 <400> 1574 000 <210> 1575 <400> 1575 000 <210> 1576 <400> 1576 000 <210> 1577 <;400> 1577 156004. Sequence Listing.doc -632-201143790 000 <210> 1578 <400> 1578 000 <210> 1579 <400> 1579 000 <210> 1580 <400> 1580 000 <210> 1581 <400> 1581 000 <210> 1582

<400> 1582 000 <210> 1583 <400> 1583 000 <210> 1584 <400> 1584 000 <210> 1585 <400> 1585 000 <210> 3586 <400><210> 1587 <400> 1587 000 <210> 1588 <400> 1588 000 <210> 1589 <400> 1589 000 <210> 1590 <400> 1590 000 <210> 1591 <;400> 1591 000 <210> 1592 <400> 1592 • 633 · 156004 - Sequence Listing.doc 201143790 000 <210><400> 000 <210><400> 000 <210><400> 000 <210><400> 000 <210><400> 000 <210><400> 000 <210><400> 000 <210> 9 9 9 9 9 9 9 9 9 9 9 9 9 9 5 5 5 5 5 5 5 5 5 5 5 5 5 5 <400> 1600 000 <210> 1601 <211> 29 <212> PRT <213> Homo sapiens<220><221> MOD RES <222> (29)..(29) <223> terminal amidation <400> 1601 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys 1 5 10

Arg Arg Ala Gin Asp Pro Val Gin Trp Leu Met Asn 20 25

Tyr Leu Asp Ser 15 Thr <210> 1602 <211> 24 <212> PRT <213> Artificial sequence <220><223> Glycoside analogue <220><221> RES <222> (1)..(1) <223> N-terminal amine group via hydroxyl group 156004 - Sequence Listing. doc 634-201143790 <400> 1602

Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gin Asp 1 5 10 15

Phe Val Gin Trp eu eu Met Asn Thr 20 <210> 1603 <211> 31 <212> PRT <213> Homo sapiens <400>

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu G]y 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 04T People 1630PR 智0>]>2>3><220><221> MOD RES <222> (30).. (30) <223> Alanine <400> 1604 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg 20 25 30 <210> 1605 <211> 28 <212> PRT <2B> Homo sapiens <400> 1605 His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu 15 10 15

Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly 20 25 >>·>> Q 1 z 3 <21<21<21<21 <400> 1606 37 PRT Homo sapiens 1606

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr Lys Arg Asn 20 25 30 156004-Sequence List.doc -635 - 201143790 One or more of 27, 28 and 29 amino acids are deuterated, alkane Basicization, PEGylation, truncation at the C-terminus, substitution. Exemplary GIP receptor agonists are known in the art. See, for example, Irwin et al., P/iarm awe?

Ther 314(3): 11 87-1194 (2005) ; Salhanick et al.

Med Chem Lett 15(18): 4114-4117 (2005); Green et al, DAeiej 7(5): 595-604 (2005); O'Harte et al., /5 165(3): 639-648 ( 2000); O'Harte et al., Diakio/oya 45(9): 1281-1291 (2002); Gault et al., 5/oc/iew ·/ 367 (Pt3): 913-920 (2002); Gault et al. , / 176: 133-141 (2003);

Irwin ,, Diabetes Obes Metab. 11(6): 603-610 (epub 2009)° In some embodiments, Q comprises at least 25% sequence with the amino acid sequence of native human GIP (SEQ ID NO: 1607) Consistent amino acid sequence. In some embodiments, Q comprises at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, or 90% with SEQ ID NO: 1607 The above sequence is consistent with the amino acid sequence. In some embodiments, the amino acid sequence of Q having a percent sequence identity as referred to above is the full length amino acid sequence of Q. In some embodiments, the amino acid sequence of Q having a percent sequence identity as referred to above is only one of the Q partial amino acid sequences. In some embodiments, Q comprises a reference amine that is at least 5 contiguous amino acids of SEQ ID NO: 1607 (eg, at least 6, at least 7, at least 8, at least 9, at least 10 amino acids) The amino acid sequence has an amino acid sequence of about A% or more than about A%, wherein the reference amino acid sequence begins at SEQ ID NO: 156004.doc • 113-201143790

Arg Asn Asn lie Ala 35 <210> 1607 <211> 42 <212> PRT <213> Homo sapiens <400> 1607 Tyr Ala Glu Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Va) Asn Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Asp Trp Lys His Asn lie Thr Gin 35 40 <210> 1608 <21I> 33 <212> PRT <213> Homo sapiens <400> 1608 His Ala Asp Gly Ser Phe Ser Asp Glu Met Asn Thr He Leu Asp Asn 15 10 15 Leu Ala Ala Arg Asp Phe lie Asn Trp Leu He Gin Thr Lys lie Thr 20 25 30

Asp ^ >>> 012 3 2222 <400> 1609 49 PRT Homo sapiens 1609

Tyr Leu Tyr Gin Trp Leu Gly Ala Pro Val Pro Tyr Pro Asp Pro Leu 15 10 15

Glu Pro Arg Arg Glu Val Cys Glu Leu Asn Pro Asp Cys Asp Glu Leu 20 25 30

Ala Asp His lie Gly Phe Gin Glu Ala Tyr Arg Arg Phe Tyr Gly Pro 35 40 45

Val <210> 1610 <211> 10 <212> PRT <213>Artificial sequence<223> represents an incretin analog "4 carboxy terminal 10 amino acid synthetic peptide fragment 156004- Sequence Listing.doc -636- 201143790 <400> 1610 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 <210> 1611 <211> 10 <212> PRT <213>Artificial Sequence<220><223> A peptide fragment representing 10 amino acids of the carboxy terminal of the intestinal melanin analog 4 <220><221> M0D.RES <222> (10).. (10) < 223 > amide <400> 1611 Gly Pro Ser Ser Gly Ala Pro Pro Pro 1 1 10 10 >>>> p7 0123 03 n 1 - n 11 ofc < 2 < 2 < 2 < 2 <2<2 1612 11 PRT artificial sequence representing a peptide fragment of 10 amino acids of the carboxy terminal of incretin analogue 4 <220><221><222><223> MOD RES (11)..( 11) PEGylation <400> 1612 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Cys 1 5 10 <210> 1613 <211> 13 <212> PRT <213> Artificial Sequence <220><223> represents GIP A peptide fragment of 13 amino acids at the carboxy terminus <400> 1613 Lys Gly Lys Lys Asn Asp Trp Lys His Asn lie Thr Gin 1 5 10 <210> 1614 <211> 8 <212> PRT <213> Artificial sequence <220><223> represents a peptide fragment of 8 amino acids at the carboxy terminus of the acid-regulating hormone <400> 1614 Lys Arg Asn Arg Asn Asn lie Ala 156004 - Sequence Listing. doc • 637-201143790 <2]0> 1615 <211> 6 <212> PRT <213> Artificial sequence <220><223> Glycoside analogue <220><221> MOD RES <222> (6) 7. (6) <223> C-terminal guanamine <400> 1615 His Thr Arg Gly Thr Phe <210> 1616 <211> 6 <212> PRT <213> Artificial sequence <220><223> Glucagon analog <220><221> MOD RES <222> (1) 7. (1) <223> d-histidine <220><221> MOD RES <222> (2) 7. (2) <223> d-threonine <220><221> MOD RES <222> (3) 7. (3) <223> d - arginine <220><221> MOD RES <22 2> (5)..(5) <223> d-threonine <220><221> MOD RES <222> (6): (6) <223> d-phenylalanine <;220><221> MOD RES <222> (6)..(6) <223> C-terminal amide hydration <400> 1616 Xaa Xaa Xaa Gly Xaa Xaa 1 5 <210> 1617 < 211 > 30 <212> PRT < 213 > Artificial Sequence <220><223> Glycoglycan Analog 638 156004 - Sequence Listing.doc 201143790 <220><221> MOD.RES <222> (24)..(24) <223> PEGylation <400> 1617

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly Arg 20 25 30 <210> 1618 <211> 39 <212> PRT <213> Poisonous <400> 1618

His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gin Met Glu Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Lys Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 1619 <211> 29 <212> PRT <213> Homo sapiens <400> 1619

Tyr Ala Asp Ala lie Phe Thr Asn Ser Tyr Arg Lys Val Leu Gly Gin 15 10 15

Leu Ser Ala Arg Lys Leu B eu Gin Asp lie Met Ser Arg 20 25 <210> 1620 <211> 28 <212> PRT <213> Homo sapiens <220><221> MOD.RES <222> (28)..(28) <223> Amination <400> 1620

His Ser Asp Ala Val Phe Thr Asp Asn Tyr Thr Arg Leu Arg Lys Gin 15 10 15

Met Ala Val Lys Lys Tyr Leu Asn Ser lie Leu Asn 20 25 <210> 1621 <211> 27 <212> PRT <213> Homo sapiens <400> 1621 •639· 156004 Sequence Listing.doc 201143790

HisSer Asp Gly lie Phe Asp Ser Tyr Ser Arg Tyr Arg LyS Gin

Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu 20 25 <210> 1622 <211> 27 <212> PRT <2]3>%人<220><221> MOD-RES <222>; {27)..(27) <223> Amination <400> 1622

His Ala Asp Gly Val Phe Thr Ser Asp Phe Ser Lys Leu Leu Gly Gin 15 10 15

Leu Ser Ala Lys Lys Tyr Leu Glu Ser Leu Met 20 25 <210> 1623 <211> 27 <212> PRT <213> Homo sapiens <220><221> MOD.RES <222> 27)..(27) <223> Amination <400> 1623

His Ser Asp Gly Thr Phe Thr Ser Glu Leu Ser Arg Leu Arg Glu Gly 15 10 15

Ala Arg Leu Gin Arg Leu Leu Gin Gly Leu Val 20 25 <210> 1624 <211> 30 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220>221> MOD RES <222> (2)..(2)

<223> Xaa is ABB <220><221> MOD RES <222> (24).. (24) <223> Cys residue bonded to 40 kDaPEG via maleimide ;220><221> M0DJES <222> (30),. (30) <223> C-terminal amide-640-

156004· Sequence Listing.doc 201143790 <400> 1624

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr Asn 20 25 30 <210> 1625 <211> 29 <212> PRT <213> Artificial sequence <220><223> Synthetic peptide <220><221> MOD RES <222> (2) 7. (2) <223> Xaa is AJB <220><221> MISC FEATURE <222> f24)T.f24) <223> Covalently bound to 40 K PEG <220><221> MOD RES <222> (29).. (29) <223> amidation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 <210> 1626 <211> 31 <212> PRT <213>Artificial Sequence <220><223>Synthetic Peptide <220>

<221> MOD RES <222> (1)., (1) <&:3> d_Amino acid <220> <221> MOD RES <222> (2) 7. 2) <223> Creatine (N-methylglycine) <220><221> MOD RES <222> (4) 7. (4)

<223> Xaa is AIB <220><221> MOD.RES <222> (24)..(24) <223> Covalently bonded to 40 kDaPEG via a thioether <220>

<221> M0D_RES 641 - 156004· Sequence Listing.doc 201143790 <222> (31)..(31) <223> Amylation <400> 1626

Lys Gly His Xaa Glu G]y Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 30 <210> 1627 <211> 31 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide<223> 220> <221> MOD RES <222> (1)..(1) <223> d-lysine <220><221> MOD RES <222> (2)..( 2) <223> N-hexylglycine <220><221> MOD RES <222> (4)..(4)

<223> Xaa is AIB <220><221> MOD RES <222> (24).. (24) <223> Covalently bonded to 40 kDaPEG via maleimide [220] <221> MOD-RES <222> (31)..(31) <223>mysylated <400>

Lys Gly His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr <210> 1628 <211> 31 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MOD RES <222> (1)..(1) <223> d·Amino acid <220><221> M0D.RES <222> (2)..(2) <223>N-methylphenylalanine 642-156004-sequence table.doc 201143790 <220><221> MOD RES <222> (4)7.(4) <223> Xaa is AIB <220><221> MOD RES <222> (24)., (24) <223> Covalently bonded via thioether to 40 kDa PEG <220><221> MOD RES <222> )..(31) <223> Amination <400> 1628

Lys Phe His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 15

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 30

<210> 1629 <211> 29 <212> PRT <213> Artificial sequence <220> Synthetic peptide <220><221> MOD_RES <222> (2) 7. (2)

<223> Xaa is AIB <220><221> MOD.RES <222> (24)..(24) <223> Covalently bonded to 40 kDaPEG <400> via maleimide ; 1629

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr <210> 1630 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220>221> MOD.RES <222> (1)..(1)

<223> Xaa is DMA <220><221> MISC FEATURE <222> (16).. (20) <223> The indoleamine ring between the amino acid side chains <220>

<221> M0DJRES 643-156004-sequence table.doc 201143790 <222> (24)..(24) <223> Covalently bonded to 40 kDaPEG via <220><221>; M0D.RES <222> (29)..(29) <223> C-terminal amidation <400> 1630

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 1631 <211> 30 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD.RES <222> (30)..(30) <223> C-terminal amidation <400> 1631

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr Asn 20 25 30 <210> 1632 <211> 8 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide<220>

<221> MOD RES <222> (1) 7. (1) <223> Xaa is Phe, trans-Phe, Gly, trans-Gly, Ala, Cys, Ser, Lys, Glu, dehydrogenation -Val, Pro, d-Pro, ATO, L. Aminocyclohexane decanoic acid, 1-aminocyclopropane decanoic acid, N-Me-AIB, α-α-diethyl-Gly, trans-base-AIB ^d-Lys <220>

<221> M0D.RES <222> (2),.(2) <223> XaaiPro, d-Ριυ, N-mercapto-Gly, N-hexyl-Gly, azetidin-2- Formic acid, N-methyl-Ala or Ν·methyl-Phe <220><221> MOD RES <222> (3)..(3) <223> Xaa is His, d-His, Ala Or N-methyl-His <220>

<221> MOD RES <222> (8)..(8) <223> 〇: terminal amidation 644·

156004-sequence table.doc 201143790 <400> 1632

Xaa Xaa Xaa Ser Arg Gly Thr Phe l 5 <210> 1633 <211> 31 <212> PRT <2Π>Artificial sequence<220><223> Synthetic peptide <220><221> MOD RES <222> (1)..(1) <223> d-Lys <220><221> MOD RES <222> (2)..(2) <223> Xaa is Sar <;220>

<221> MOD.RES <222> (4)..(4) <223> Xaa is Affl <220><221> MOD RES <222> (26).. (26) <223> covalently linked via maleic acid, 4〇kDaPEG <400> 1633

Lys Xaa His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 15

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 30 <210>]634 <211> 32 <212> PRT <213>Artificial sequence <220><223><220><221> MOD RES <222> (1)..(1) <223> d-Lys <220><221> MOD RES <222> (2)..(2 ) <223> Xaa is Sar <220><221> MOD RES <222> (4)..(4)

<223> Xaa is AIB <220><221> M0D_RES <222> (26)..(26) <223> Cys residue bonded to 40 kDaPEG via maleimide ;220> 645·156004·SEQ ID NO.doc 201143790 1607 Amino acid at position C, and ending at amino acid at position D of SEQ ID NO: 1607, where A is 25, 30, 35, 40, 45, 50, 55, 60, 65 '70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99; C is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ' 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28, and D is 5 6, 6, 8, 9, 9, 1 , 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 20, 27, 28 or 29. It is contemplated that any and all possible combinations of the above parameters include, but are not limited to, for example, where A is 9〇% and Lu C and D are 1 and 27' or 6 and 27, or 8 and 27, or 10 and 27, Or 12 and 27, or 16 and .27. In the case where Q is a glycosidin-related peptide, q may comprise a modified native glycosyl amino acid sequence (SEQ ID NO: 1601) in an exemplary embodiment.

In the case, the glycoside-related peptide may comprise a total of i, at most 2, at most 3, at most 4, at most 5, at most 6, at most 7, at most 8, at most 9, relative to the native glycosidic sequence. At or at most 10 amino acid modifications, such as conservative or non-conservative substitutions. In some aspects, the modifications and substitutions described herein are made at specific positions in the oxime, the numbering of which corresponds to the numbering of the glycoside (SEQ ID NO: 16G1). In some embodiments, the location 2, 5, 7, 10, u, 12, 13, l4, i7, i8, i9, 2〇, ^^^(3)(10) is performed on any of Conservative substitutions 'and at most one of these positions are carried out at most moth-step conservative substitutions. In some implementations, at position 丨16, 156004.doc -114- 201143790 <221> MODJ^ES <222> (32)..(32) <223> C-terminal amide hydration <400> 1634 Lys Xaa His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser 1 5 10

Lys Tyr Leu 15

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met 20 25

Asn Thr Asn 30 <210> 1635 <211> 31 <212> PRT <213> artificial sequence <220><223> synthetic peptide

<220><221> MOD RES <222> (1)..(1) <223> d-Lys <220><221> MOD RES <222> (2)..(2 <223> Xaa is Sar <220><221> mDJRBS <222> (3)..(3) <223> Xaa is DMIA <220> <221> MISC FEATURE <222><223> The inner amine ring <220><221> MOD RES <222> (26)..(26) <223> is coupled to 40 kDa PEG via maleimide ;220><221> MOD RES <222> (31)..(31) <223> (: terminal amination <400> 1635

6 s s Ly p $ Γ 60 SI Γ Th e ph Γ y G1 n g15 Γ 6 s na xa E na s Lyl

Lys Tyr Leu 15 r8M u 5 p s s ΓΟ A2 u Le Φ Tr s cy Λα5 V2 e ph p s s Ly

Asn Thr 30 <210> 1636 <211> 31 <2I2> PRT < 213 > artificial sequence <220><223> synthetic peptide <220><221> MOD RES <222> )..(1) 646- 156004· Sequence Listing.doc 201143790 <223> d-Lys <220>

<221> M0D.RES <222> (2)..(2) <223> N-hexyl-Gly <220><221> M0D.RES <222> (4)..(4 )

<223> Xaa is AIB <220><221> MISC_FEATURE <222> (26)..(26) <223> Covalently bonded to 40KPEG <220><221> MOD via thioether. RES <222> (31)..(31) <223>mysylated <400> 1636

Lys Gly His Xaa GIu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 IS

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 30 <210> 1637 <211> 32 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <;220>

<221> MOD RES <222> (1)..(1) <223> d-Lys <220>

<221> MOD.RES <222> (2)..(2) <223> N-hexyl-Gly

<220><221> MOD_RES <222> (4)..(4)

<223> Xaa is ABB <220><221> MOD.RES <222> (26)..(26) <223> Cys residue bonded to 40 kDaPEG via maleimide <220><221> MOD_RES <222> (32)..(32) <M3> C-terminal amidation <400>

Lys Gly His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 15

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr Asn 20 25 30-647- 156004-sequence table.doc 201143790 <210> 1638 <2I1> 31 <212> PRT <213><220><223> Synthetic peptide <220><221><222><223> MOD RES (1)..(1) d-Lys <220><221><222>;<223> MOD RES (2)..(2) N-hexyl-Gly <220><221><222><223> MOD RES (3)7.(3) Xaa is DMIA <;220><221><222><223> MISC FEATURE (18) 7. (22) The indoleamine ring between the amino acid side chains <220><221><222>;223> MOD RES (26).. (26) Covalently bound to 40 kDa PEG <220><221><222><223> MOD RES (31) via maleimide. (31) C-terminal amides <400> 1638

Lys Gly Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu 15 10 15

Asp Glu Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 30 <210> 1639 <2ll><212><213> 31 PRT Artificial Sequence <220><223> Synthetic Peptide <223>;220><221><222><223> MOD RES (l)T.(1) d-Lys <220><221><222><223> MOD RES (2)7 (2) N-methyl-Phe <220><221><222><223><220> MOD RES (4)..(4) text aa is ΑΪΒ • 648. 156004-preface List .doc 201143790 <221> MOD.RES <222> (26)..(26) <223> Covalently bound to 40 kDaPEG via <400> 1639 via maleimide

Lys Phe His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 15

Asp Glu Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 30 <210> 1640 <211> 32 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <;220>

<221> MOD RES <222> (1) 7. (1) <223> d-Lys <220><221> MOD.RES <222> (2).. (2) <223> N-曱基-Phe <220><221> MOD-RES <222> (4)..(4)

<223> Xaa is AIB <220><221> MOD.RES <222> (26)..(26) <223> Cys bonded to 40 kDa PEG via maleimide Residue <220><221> MOD RES <222> (32)..(32) <223> C-terminal amidation <400> 1640

Lys Phe His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu 15 10 15

Asp Glu Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr Asn 20 25 30 <210> 1641 <211> 31 <212> PRT <213> Artificial Sequence <220><223><220><221> MOD.RES <222> (1) 7. (1) <223> d-Lys <220><221> MOD.RES <222> (2).. (2) 649-156004-sequence table.doc 201143790 <223> Ν·methyl-Phe <220>

<221> MOD RES <222> (3)..(3) <223> Xaa is DMIA <220><221><222><223>

MISC.FEATURE (18)..(22) The indoleamine ring between the amine toluene acid side chains <220><221> MOD RES <222> (26)..(26) <223> The maleimide is covalently bonded to 40 kDaPEG <220><221> M0D_RES <222> (31)..(31) <223> C-terminal amide hydration <400>

Lys Phe Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu 15 10 15

Asp Glu Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 30 <210> 1642 <211> 27 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <;400> 1642

His Ala Asp Gly Val Phe Thr Ser Asp Phe Ser Lys Leu Leu Gly Gin 15 10 15

Leu Ser Ala Lys Lys Tyr Leu Glu Ser Leu Met 20 25 <210> 1643 <211> 4 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <400> 1643 Lys Arg Asn Arg <210> 1644 <211> 100 <212> PRT <213> Homo sapiens <400>

Met Arg Ala Leu Thr Leu Leu Ala Leu Leu Ala Leu Ala Ala Leu Cys 15 10 15 650- 156004 · Sequence Listing.doc 201143790 lie Ala Gly Gin Ala Gly Ala Lys Pro Ser Gly Ala Glu Ser Ser Lys 20 25 30

Gly Ala Ala Phe Val Ser Lys Gin Glu Gly Ser Glu Val Val Lys Arg 35 40 45

Pro Arg Arg Tyr Leu Tyr Gin Trp Leu Gly Ala Pro Val Pro Tyr Pro 50 55 60

Asp Pro Leu Glu Pro Arg Arg Glu Val Cys Glu Leu Asn Pro Asp Cys 65 70 75 80

Asp Glu Leu Ala Asp His lie Gly Phe Gin Glu Ala Tyr Arg Arg Phe 85 90 95

Tyr Gly Pro Val 100 16432PRT 164 <210><211><212><213><400>

Cys Gly Asn Leu Ser Thr Cys Met Leu Gly Thr Tyr Thr Gin Asp Phe 15 10 15

Asn Lys Phe His Thr Phe Pro Gin Thr Ala He Gly Val Gly Ala Pro 20 25 30 <210> 1646 <211> 37 <212> PRT <2B> Homo sapiens <400>

Lys Cys Asn Thr Ala Thr Cys Ala Thr Gin Arg Leu Ala Asn Phe Leu 15 10 15

Val His Ser Ser Asn Asn Phe Gly Ala lie Leu Ser Ser Thr Asn Val 20 25 30

Gly Ser Asn Thr Tyr 35 <210> 1647 <211> 40 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <220>

<221> MOD.RES <222> (2)..(2) <223> Xaa is AIB <220><221> MOD.RES <222> (40)..(40) 651 · 156004 Sequence Listing.doc 201143790 <223> 0-terminal amidation <400> 1647

His Xaa Glu Gly Thr Phc Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu i 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1648 <211> 40 <212> PRT <213>Artificial Sequence <220><223>Synthetic Peptide <220>

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC.FEATTJRE <222> (40).. (40) C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1649 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD RES <222> (1)..(1) <223> D-Ala <220>

<221> MOD.RES <222> (2)..(2) <223> Xaa is AIB <220><221> M0DJES <222> (3)..(3) <223>; D-Glu <220>

<221> MOD-RES 652-156004-sequence table.doc 201143790 <222> (5)., (5) <223> D-Thr <220><221> MOD RES <222> 6)..(6) <223> D-Phe <220><221> MOD RES <222> (7)..(7) <223> D-Thr <220><221>; MOD RES <222> (8)..(8) <223> D-Ser <220><221> MOD-RES <222> (9)..(9) <223> D -Asp <220>

<221> MOD RES <222> (10)..(10) <223> D-Val <220><221> MOD RES <222> (11)..(11) <223> D-Ser <220><221> MOD RES <222> (12)..(12) <223> D-Ser <220><221> MOD RES <222> (13) ..(13) <223> D-Tyr <220><221> MOD.RES <222> (14)..(14) <223> D-Leu <220><221> MOD RES <222> (15)..(15) <223> D-GIu <220><221> MOD.RES <222> (17)..(17) <223> D- Gln <220><221> MOD RES <222> (18)..(18) <223> D-Ala <220><221> MOD RES <222> (19)..( 19) <223> D-Ala <220><221> MOD RES <222> (20)..(20) <223> D-Lys <220>

<221> MOD.RES • 653 · 156004· Sequence Listing.doc 201143790 <222> (21)..(21) <223> D-Glu <220><221> MOD RES <222> (22)..(22) <223> D-Ala <220><221> MOD RES <222> (23)..(23) <223> D-lle <220><221> MOD RES <222> (24)..(24) <223> D-Ala <220><221> MOD RES <222> (25)..(25) <223> D -Trp <220><22l> MOD RES <222> (26)..(26) <223> D-Leu <220><22i> MOD RES <222> (27).. (27) <223> D-Val <220><221> MOD RES <222> (28)..(28) <223> D-Lys <220><221> MOD RES <;222> (31)..(31) <223> D-Pro <220><221> MOD RES <271> (32)..(32) <223> D-Ser <220>;<221> MOD RES <222> (331..(33) <223> D-Ser <220><221> MOD RES <222> (35)..(35) <223> D-Ala <220><221> MOD RES <222> (36)..(36) <223> D-Pro <220><221> MODJES <222> (37)..(37) <223> D-Pro <220><221> MOD RES <222> (38)..(38) <223> D- Pro <220>

<221> MOD.RES 654 156004. Sequence Listing. doc 201 143790 <222> (39)..(39) <223> D-Ser 0>1>2>3> 2222 <2<2<2<2 MOD RES (40).. (40) C-terminal amide hydration <400> 1649 Ala Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1650 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD RES <222> (2) 7. (2) <223> Xaa is AIB <220><221> MOD-RES <222> (24)..(24) <223> via thioether Covalently bound to 40 kDaPEG <220><221> M0D.RES <222> (40).. (40) <223> C-terminal amide hydration <400> 1650 His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1651 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD RES <222> (2)7.(2) <223> Xaa is AIB <220> 156004-sequence.doc -655 - 201143790 Amino acid is modified in 1, 2 or 3 amino acids And 1, 2 or 3 amino acid modifications are made in the amino acids at positions 17 to 26. In some embodiments 'Q retains at least 22, 23, 24, 25, 26, 27 or 28 naturally occurring amino acids in the corresponding positions in the native glucagon (eg, 1 with respect to the naturally occurring glycoside) Modification of DP P-IV resistance to 7, 1 to 5 or 1 to 3 In some embodiments where Q is a glycosidic superfamily peptide, Q comprises a modification at position 1 or 2 to reduce dipeptide Peptidase IV (Dpp_IV) causes the possibility of cleavage. More specifically, in some embodiments 'the position of Q' (e.g., selected from those in Figure 1) is via an amino acid selected from the group consisting of Substitution: D_histamine, α, (Χ-dimercaptoimidazoleacetic acid (DMIA), N-methylhistamine, α-methylhistamine, imidazoleacetic acid, desaminohistidine, hydroxyl - histidine, ethenyl-histamine and homohistidine. More specifically, in some embodiments, position 2 of q is substituted with an amino acid selected from the group consisting of D-silylamine Acids: 〇-alanine, lysine, glycine, N-methylserine, and aminoisobutyric acid. In some embodiments, position 2 of the glycein-related peptide is not D- Amino acid. Glycoside modification at position 3 The class 1 to class 3 ghrelin-related peptides described herein can be modified at position 3 (based on the amino acid number of wild-type glycoside) to maintain or Enhancing activity on the glycoside receptor. In some embodiments where Q is a Class 1, Class 2 or Class 3 glycosidic-related peptide, the position 3 can be modified by using a glutamate analog. Gin is used to maintain or enhance the activity of the glycemic receptor. For example, at position 3, 156004.doc -115· 201143790 <221> MOJRES <222> (40)..(40) <223&gt ; 3 position covalently bonded to β-estradiol via an ether bond <220><221> M0D.RES <222> (40).. (40) <22> C-terminal amide hydration <400> 1651

His Xaa GIu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

<210> 1652 <211> 40 <212> PRT < 213 > Artificial Sequence <220><223> Synthetic Peptide <220><221> M0D RES <222> (2). .(2)

<223> is AIB <220><221> MOD-RES <222> (40)..(40) <223> Covalently bonded to β-estradiol via ether bond 3 <;220><221> MOD RES <222> (40)..(40) <223> C-terminal amidation <400> 1652

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1653 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD RES <222> (1)..(1) <223> D-Ala 156004·Sequence List.doc -656- 201143790

<220><221> MOD RES <222> (2)..(2) <223> Xaa is AIB <220><221> MOD RES <222> (3)..(3 <223> D-Glu <220><221> MOD RES <222> (5)..(5) <223> D-Thr <220><221> MOD RES <222> (6)..(6) <223> D-Phe <220><221> MOD RES <222> (7)7.(7) <223> D-Thr <220><;221> MOD RES <222> (δ)..(8) <223> D-Ser <220><221> MOD RES <222> (9)..(9) <223> D-Asp <220><221> MOD RES <222> (10)..(10) <223> D-Val <220><221> MOD RES <222> (11). (11) <223> D-Ser <220><221> MOD RES <222> (12)..(12) <223> D-Ser <220><221> MOD RES <222> (13)..(13) <223> D-Tyr <220><221> MOD RES <222> (14)..(14) <223> D-Leu <220><221> MOD RES <222> (15)..(15) <223> D-Glu <22 0><221> MOD RES <222> (17)..(17) <223> D-Gln <220><221> MOD RES <222> (18)..(18) <;223> D-Ala 156004. Sequence Listing.doc -657- 201143790 <220> <221> M0D_RES <222> (19)..(19) <223> D-Ala <220><221> M0D.RES <222> (20)..(20) <223> D-Lys <220><221> M0D.RES <222> (21)..(21) <223>; D-Glu <220><221> M0D.RES <222> (22)..(22) <223> D-Ala <220><221> MOD.RES <222> 23)..(23) <223> D-lle <220><221> MOD RES <222> (24)..(24) <223> D-Ala <220><221> M0D-RES <222> (25)..(25) <223> D-Trp <220><221> M0D.RES <222> (26)..(26) <223> D-Leu <220><221> M0D „RES <222> (27)..(27) <223> D.Val <220><221> MOD RES <222> (28) ..(28) <223> D-Lys <220><221> MOD^RES <222> (31)..(31) <223> D-Pro <220≫<221> MOD RES <222> (32)..(32) <223> D-Ser <220><221> M0D.RES <222> (33)..(33) <223> D-Ser <220><221> MOD RES <222> (35)..(35) <223> D-Ala <220><221> MOD RES <222> (36)..(36) <223> D-Pro 658 156004-sequence table.doc 201143790 <220><221> MOD RES <222> (37)..(37) <223> D -Pro <220><221> MOD RES <222> (38)..(38) <223> D-Pro <220><221> MOD.RES <222> (39). (39) <223> D-Ser <220><221> M0D.RES <222> (40)..(40) <223> Covalently bound to β-estradiol via a puzzle bond 3 position <220> <221> MOD RES <222> (40).. (40) C-terminal amide amination

<400> 1653

Ala Xaa Glu Gly Thr Phe Thr Ser Asp Va] Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1654 <211> 40 <212> PRT <213>Artificial Sequence <220><223>Synthetic Peptide <220>

<221> M0D.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> M0D_RES <222> (24).. (24) <223> Covalently bonded to 40 kDaPEG via thioether <220><221> MOD RES <222> (40).. (40) <223> Covalently bonded to the 3 position of β-estradiol via the S4 bond <220><221> M0D.RES <222> (40). (40) <223> C-terminal amidation <400> 1654

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15 -659- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1655 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><22>; MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD RES <222> (40).. (40) <223> Covalently bonded to the 17 position of β-estradiol via an ester bond <220><221> MOD RES <222> (40)..(40) <223> C-terminal amidation <400> 1655

His Xaa Glu Gly Thr Fhe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe Me Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1656 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> M0D .RES <222> (2)..(2)

<223> Xaa is AIB <220><221>MOD RES <222> (40).. (40) <223> Covalently bonded to the ? position of ?-estradiol via an ester bond <220><221> MOD RES <222> (40)..(40) <223> C-terminal amidation <400> 1656-660-

156004· Sequence Listing.doc 201143790

His Xaa G] u Gly 1

Gin Ala Ala Lys 20

Thr Phe Thr Ser 5

Glu Ala lie Ala

Asp Val Ser Ser Tyr Leu Glu Gly 10 15

Trp Leu Val Lys Gly Gly Pro Ser 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1657 <211> 40 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide <220><221> M0D „RES <222> (1)..(1) <223> D-Ala

<220>

<221> M0D „RES <222> (2) 7. (2) <223> Xaa is AEB <220><221> MOD.RES <222> (3)..(3) <;223> D-Glu <220><221> M0D.RES <222> (5)..(5) <223> D-Thr <220><221> MOD.RES <222> (6)..(6) <223> D-Phe <220><221> MOD.RES <222> (7)..(7) <223> D-Thr <220><221> MOD RES <222> (8)..(8) <223> D-Ser <220><221> MOD RES <222> (9)..(9) <223> D-Asp <220><221> MOD RES <222> (10)..(10) <223> D-Val <220><221> MOD RES <222> (11) ..(11) <223> D-Ser <220><221> MOD RES <222> (12)..(12) <223> D-Ser 661 - 156004 - Sequence Listing.doc 201143790 <220><221> MOD RES <222> (13)..(13) <223> D-Tyr <220><221> MOD RES <222> (14)..(14 <223> D-Leu <220><221> MOD.RES <222> (15)..(15) <223> D-Glu <220><221> MOD RES ≪222> (17)..(17) <223> D-Gln <220><221> MOD RES <222> (18)..(18) <223> D-Ala <220>

<221> MOD.RES <222> (19)..(19) <223> D-Aia <220><22ί> MOD.RES <222> (20)..(20) <;223> D-Lys <220><221> MOD.RES <222> (2lT..(21) <223> D-Glu <220><221> MOD.RES <222> (22)..(22) <223> D-Aia <220><22l> MOD RES <222> (23)..(23) <223> D-IIe <220>

<221> MOD.RES <222> (24)..(24) <223> D-Ala <220><221> MOD RES <222> (25)..(25) <223> D-Trp <220><221> MODJES <222> (26)..(26) <223> D-Leu <220><221> MOD„RES <222> (27 ),.(27) <223> D-Val <220>

<221> MOD RES <m> (28)..(28) <223> D-Lys 156004-sequence table_doc 662·201143790 <220><221> MOD RES <222> (31 )..(31) <223> D-Pro <220><221> MOD.RES <222> (32)..(32) <223> D-Ser <220><221>; MOD RES <222> (33)..(33) <223> D-Ser <220><221> MOD RES <222> (35)..(35) <223> D- Ala <220><221> MOD RES <222> (36)..(36) <223> D-Pro <220>

<22]> MOD RES <222> (37)..(37) <223> D-Pro <220>. <221> MOD RES <222> (38)..(38) <223> D-Pro- <220><221> MOD RES <222> (39)..(39) <223> D-Ser <220><221> MOD.RES <222> (40).. (40) <223> 17-position covalently bonded to β-estradiol via an ester bond <220><221> MOD RES <222> (40).. (40 ) <223> C-terminal amide <400> 1657

Ala Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1658 <211> 40 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide-663- 156004-Sequence Listing.doc 201143790 <220>

<221> MOD_RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD.RES <222> (407..(40) <223> covalently bonded to 17.Ethyl-β-estradiol via an ester bond 3 position <220> <221> MOD RES <222>(40)..<40)<223> (: terminal amination <400> 1658

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1659 <2ll> 40 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide <220><221> MOD RES <222> (1)..(1) <223> D-Ala <220><221> MOD RES <222> (2)..(2) <223> Xaa is ΑΪΒ <;220><221> MOD RES <222> (3)..(3) <223> D-Glu >>>> 012 3 2 222 2 Λζ 2 < VV <

MOD-RES (5)..(5) D-Thr <220> <221> MOD RES <222> (6)7.(6) <223> D-Phe <220><221>; MOD.RES <222> (7)..(7) <223> D-Thr <220><221> MOD RES <222> (8)..(8) <223> D -Ser <220> •664· 156004 - Sequence Listing.doc 201143790 <221> MOD RES <222> (9)..(9) <223> D-Asp <220><221> MOD RES <222> (10)..(10) <223> D-Val <220><221> MOD.RES <222> (11)..(11) <223> D-Ser <220><221> MOD RES <222> (12)..(12) <223> D-Ser <220><221> MOD RES <222> (13)..( 13) <223> D-Tyr <220>

<221> MOD.RES <222> (14)..(14) <223> D-Leu <220><221> MOD_RES <222> (15)..(15) <223> D-Glu <220><221> MOD RES <222> (17)..(17) <223> D-GIn <220><221> MOD.RES <222> (18 (18) <223> D-Ala <220><221> MOD RES <222> (19)..(19) <223> D-Ala <220><221> MOD RES <222> (20)..(20) <223> D-Lys <220><221> MOD.RES <222> (21)..(21) <223> D- Glu <220><221> MOD.RES <222> (22)..(22) <223> D-Ala <220><221> MOD RES <222> (23).. (23) <223> D-Ile <220><221> MOD RES <222> (24)..(24) <223> D-Ala <220> 156004-sequence table.doc 201143790 The activity exhibited by the diterpenoid, class 2 or class 3 ghrelin-related peptide comprising a face valeric acid analog to the glycosidic receptor may be about the activity of the native glucagon (SEQ NO: 1601). 5%, about 1%, about 2%, about 5%, or about 85% or more. In some embodiments, the activity of the first, second or third type of ghrelin-related peptide comprising a bran-loading tyrosine analog at position 3 for a glycosidic receptor can be in addition to position 3 About 20%, about 50%, about 75%, about 1% of the activity of the corresponding glycosidic peptide having the same amino acid sequence as the coated amino acid analog except the modified amino acid. , about 200 〇 / 〇 or about 5003⁄4 or more than 500%. In some embodiments, the Class 1, Class 2, or Class 3 ghrelin-related peptide comprising a bran-loading tyrosine analog at position 3 exhibits enhanced activity on the glycoside receptor' but the enhanced activity Up to 1000 activities of the activity of the native glycein or the activity of the corresponding glycosidin-related peptide having the same amino acid sequence as the peptide comprising the citrate analog except for the modified amino acid at position 3. /. , 10,000%, 100,000〇/. Or 1,000 000 〇 / 〇. In some embodiments, the glutamyl acid analog is a naturally occurring or non-naturally occurring amino acid comprising a side chain of structure I, II or III: 0 such as R1-CH2-X 丄R2 structure I 〇•b r'-chAy structure II 0

j-R1—CH2-S-CH2-R4 Structure III 156004.doc • 116- 201143790 <221> MOD.RES <222> (25)..(25) <223> D-Trp <220><221> MOD RES <222> (26)..(26) <223> D-Leu <220><221> MOD RES <222> (27)..(27) <223> D-Val <220><221> MOD RES <222> (28)..(28) <223> D-Lys <220><221> MOD RES <222> (31) ..(31) <223> D-Pro <220><221> MOD RES <222> (32)..(32) <223> D-Ser <220><221> MOD RES <222> (33)..(33) <223> D-Ser <220><221> MOD RES <222> (35)..(35) <223> D-Ala <;220><221> MOOES <222> (36)..(36) <223> D-Pro <220><221> MOD RES <222> (37)..(37) <;223> D-Pro <220><221> MOD RES <222> (38)..(38) <223> D-Pro <220><221> MOD RES <222> 39)..(39) <223> D-Ser <220><221> M0D_ RES <222> (40).. (40) <223> 3 position covalently bonded to 17-acetamido-β estradiol via an ester bond <220><221> MOD.RES <222> (40)..(40) <223> C-terminal amidation

<400> 1659

Ala Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15 -666- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Ala lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1660 <2Π> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD .RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD.RES <222> (24)..(24)

<223> Covalently bonded via thioether to 40 kDa PEG <220><221> M0D_RES <222> (40)., (40) <223> Covalently bonded to the 3 position of cholesterol via a guanamine bond <;220><221> M0D.RES <222> (40)..(40) <223> 03⁄4 amination <400> 1660

His Xaa Glu Gly Thr Phe Thr Ser Asp Yal Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1661 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> M0D .RES <222> (2)..(2)

<223> is ABB <220><221> MOD RES <222> (40).. (40) <223> Covalently bonded to the 3 position of cholesterol via the guanamine bond <220>221> MOD RES <222> (40)..(40) <223> C-terminal amide 667- 156004-sequence table.doc 201143790 <400> 1661

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1662 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MOD .RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD-RES <222> (40)..(40) <223> Covalently bonded to 17 positions of estradiol via a hydrazone bond <220>;<221> M0D.RES <222> (40)..(40) <223> C-terminal amidation <400> 1662

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe He A, a Trp Leu Va! Lys Gly Gly Pro Ser

Ser Gly Ala Pro Pro Pro Ser Cys <210> 1663 <211> 40 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> M0D RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD.RES <222> (40)..(40) <223> Covalently bonded to β-girl via an amino phthalate disulfide bond 17 position of diol <220> 668-156004-sequence table.doc 201143790 <22]> MOD-RES <222> (4〇T..(40) <223> (: terminal amination <400> 1663

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> 1664 <211> 40 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD RES <222> (40)..(40) <223> xaa is β,β-dimercaptocysteine <220><221> M0D.RES <222> (40).. (40) <223> π position covalently bonded to estradiol via a urethane disulfide bond <220><221> MOD.RES <222> (40)..(40) <2U> c-terminal amidation <400> 1664

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 <210> 1665 <211> 40 <212> PRT <213>Artificial Sequence <220><223>Synthetic Peptide <220>

<221> M0D_RES <222> (2)..(2) <223> Xaa is AIB-669- 156004-sequence table.doc 201143790 <220><221> MOD^KES <222> 40).. (40) <223> Covalently bonded to β-estradiol via the diaminoethane-Phe-Lys bond at position 17 >>& 1 64 3 2222 <400> MOD RES (40)..(40) C-terminal amide hydration 1665

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 <210> 1666 <2I1> 40 <212> PRT <2)3>Artificial Sequence <220><223> Synthetic Peptide <220>

<221> MOD RES <222> (2)..(2)

<223> xaa is AIB <220><221> M0D_RES <222> (40).. (40) <223> Covalently bonded to the 3 position of estrone via an ester bond <220>221> MOD RES <222> (40)..(40) <223> C-terminal amide <400> 1666

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 012 3 22 20^ <<< ν Column 67τ Worker 1640 Quadruple <220><223> Synthetic Peptide <220><221> MOD RES <222> (2) 7. (2) 670 - 156004 - Sequence Listing.doc 201143790 <223> Xaa is AIB <220><221> MOD RES <222> (40)..(40) <223> 17-position covalently bonded to the estradiol via an amino phthalate linkage <220><221> MOD RES <222> (40).. (40) <M3> terminal amidation <;400> 1667

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

<210> 1668 <211> 40 <212> PRT .<213> Artificial sequence <220><223> Synthetic peptide <220>

<221> MOD.RES <222> (2)..(2)

<223> is AIB <220><221> MOD RES <222> (40).. (40) <223> Covalently bonded to the amine cumyl alcohol bond via diaminoethyl-Phe_Lys 17-position of β-estradiol <220><221> MOD RES <222> (40)..(40) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 】5

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 •671 · 156004 - Sequence Listing.doc 201143790 where R1 is C〇.3 alkyl or C0.3 heteroalkyl; R2 is NHR^Cw alkyl; R3 is a heart alkane R4 is an alkyl group; χ is ΝΗ, Ο or S; and Y is NHR4, SR3 or OR3. In some embodiments, X is ΝΗ or Υ is NHR4. In some embodiments, Ri is C〇_2 alkyl or Cl heteroalkyl. In some embodiments 'R2 is 1^11114 or (:1 alkyl). In some embodiments, R4 is 11 or (:1 alkyl. In Q is a Class 1, Class 2, or Class 3 sucrose In an exemplary embodiment of a prime-related peptide, an amino acid comprising a side chain of structure I is provided, wherein R1 is CH2-S, X is NH' and R2 is CH3 (acetamidomethyl-cysteine' C(Acm)); R1 is CH2, X is NH, and R2 is CH3 (acetamidodiaminebutyric acid, Dab(Ac)); R1 is C. alkyl, X is NH, and R2 is NHR4, and R4 is hydrazine (amine mercaptodiamine propionic acid, Dap (urea)); or R1 is CH2-CH2 'X is NH' and R2 is CH3 (acetoxine acid, Orn (Ac)). In an illustrative embodiment, an amino acid comprising a side chain of structure II is provided wherein Ri is CH2, Y is NHR4' and R4 is CH3 (methyl brasic acid, Q(Me)); in an exemplary embodiment Providing an amino acid comprising a side chain of the structure ,, wherein R1 is CH2 and R4 is hydrazine (hydrazinine-arylene, M(O)); in a particular embodiment, the amino acid at position 3 Dab(Ac) substitution. 0^ 醯 is related to glycosidin-related peptides (eg, type 1 glucosamine related peptide, class 2 glucosamine) In some embodiments of the peptide, the third type of glucosinoid related peptide, the fourth type of glucosinoid related peptide, the fourth type of glucosin related peptide group, or the fifth type of glucosinoid related peptide, Q is modified to include The thiol group may be directly covalently bonded to the amino acid of the peptide q or indirectly via a spacer to the amino acid of Q, wherein the spacer is located between the amino acid of Q and the thiol group. The same amino acid value is set at the 156004.doc-117·201143790 of the hydrophilic portion of the linkage or is brewed at a different amino acid position. As described herein, Q may be a glycoside superfamily peptide, a glycoside. Related peptides (including class 1, class 2, class 3, class 4 or class 5 ghrelin-related peptides), or osteocalcin calcitonin, amylopectin or analogues, derivatives or combinations thereof For example, 5 'Q may be one of Class 1, Class 2, Class 3, Class 4, or Category 5' and may include non-native sulfhydryl groups for naturally occurring amino acids. Deuteration can be performed at any position within Q. In the case where Q is a glycoside-related peptide, it can be in any position (including any of positions 1 to 29, C-terminal extension ^ and the position Or deuteration on the c-terminal amino acid, with the proviso that the activity exhibited by the undeuterated ginseng-related peptide is retained after deuteration. For example, if the undeuterated peptide has sucrose The agonist peptide retains the glycosidic agonist activity. For example, if the unpigmented peptide has a glycosidic antagonist activity, the deuterated peptide retains glycosidic antagonism. Agent activity. For example, if the undeuterated peptide has (} £ 1 > 1 agonist activity, the deuterated peptide retains GLPd agonist activity. Non-limiting examples include at positions 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28 or 29 (based on the amino group of wild-type glycoside) Deuteration is carried out on the acid number). For diterpenoid, class 2, and class 3 glycosidin-related peptides, at positions 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27 Deuteration is carried out on any of 28, 29, 30, 37, 38, 39, 40, 41, 42 or 43 (based on the amino acid number of wild type glucosinolate). For glycosidic related peptides (eg, diterpenoids, class 2, class 3, class 4, or class 5), other non-limiting examples include at position 10 (based on the amino group of wild-type glycoside) Acid numbering is carried out on 156004.doc •118- 201143790 and in the c-terminal part of the glycemic peptide - or multiple positions (eg position ... 28 or 29 (according to the amino acid of wild-type glycoside) Numbering)), in the c-terminal extension or on the C-terminus (eg, via PEGylation via addition. In the i-state of the invention, peptide Q (eg, glycosidin super-family peptide, sucrose) a related peptide, an old, a second, a third, a fourth or a fifth type of ghrelin-related peptide, or a bone dance, a morphemin, a branch powder, or an analogue or derivative thereof The conjugate is modified to contain a thiol group by directly enlarging an amine, hydroxyl or thiol of the amino acid side chain of hydrazine. In some embodiments, Q is via a side chain amine, hydroxy or sulphur of an amino acid. Alcohol is directly deuterated. In some embodiments, where Q is a glycosidin-related peptide, at position 丨〇, 2〇, 24 or 29 (according to the amine of wild-type glycosides) The glucosinolate-related peptide may comprise an amino acid sequence SEq ID NO: 1601, or a modification thereof comprising one or more of the amino acid modifications described herein. An amino acid sequence wherein at least one of the amino acids at positions 1 〇, 2 〇, 24, and 29 (based on the amino acid number of the wild type glucosinolate) is modified to form a side chain amine, a hydroxyl group Or any amino acid of a thiol. In some specific embodiments of the invention wherein Q is a glycosidic related peptide, the amino acid on position 1 (based on the amino acid of wild type glucosinolate) Q is directly brewed with a side chain amine, a thiol or a thiol. In some embodiments, 'peptide Q (eg, a glycoside superfamily peptide, a glycoside related peptide, a first, a second, a third) Amino acid containing a side chain amine of a class 4, a Category 5 or a Category 5 ghrelin-related peptide 'or osteocalcin, calcitonin, amylopectin, or an analogue, derivative or conjugate thereof) Amino acid of I: 156004.doc •119· 201143790 Η

Η2Ν"-C-COOH (CH2)n

I νη2 wherein η = 1 to 4 [Formula I] In some exemplary embodiments, the amino acid of the formula 为 is an amino acid of 11 (Lys) or an amino acid of η of 3 (〇Γη). In other embodiments, the amino acid of the peptide q comprising a side chain hydroxyl group is an amino acid of the formula π: ,, Η Η 2Ν--c - COOH CH2)n

I

OH wherein n = 1 to 4 [Formula] In some exemplary embodiments, the amino acid of formula H is an amino acid (Ser) wherein n is 1. In other embodiments, the amino acid comprising a side chain thiol of peptide q is an amino acid of formula m: u Η

Η2Ν·-c-COOH CH2)n

I

SH wherein n=l to 4 [formula] 156004.doc 201143790 In some exemplary embodiments, the amino acid of formula m is an amino acid of 11 to 1 (Cys). In other embodiments, peptide Q An amino acid comprising a side chain amine, a hydroxyl group or a thiol is a disubstituted amino acid which comprises the same formula, a formula π or a formula m. The exception is an amine bonded to a phantom, a formula or an amine of the formula m. The gas of the alpha carbon of the base acid is replaced by the second side chain.

In some embodiments of the invention, the deuterated peptide paste such as a glycoside superfamily peptide, a glycoside related peptide, a diterpenoid, a second, a third, a fourth, or a fifth a glycopeptide-related peptide 'or osteocalcin, calcitonin, amylopectin, or an analogue, derivative or conjugate thereof) in a peptide and a hydrazine, in some embodiments, the valency is bonded to a spacer; The shell is bonded to the brewing base. In * itb /S|| ajL·. # , » In an example of inferiority, the Q system is modified to contain a mercapto group by an amine, a mercapto or a mercaptan of a deuterated spacer, the spacer ( Wherein Q is a glycoside-related peptide, such as a diterpenoid, a second class, a class or a class 5) linked to a position of a glycein-related peptide at a position of 1〇, 2〇, 24 or 29 (according to wild-type glycosides) The amino acid is on the side chain of the amino acid or is attached to the C-terminal amino acid. The amino acid of the linking spacer of peptide Q can be any amino acid comprising a moiety that allows linkage to the spacer. For example, an amino acid (e.g., Lys, 〇rn, Ser, AsP or Glu) comprising a side chain -NH2, -OH or _C00H is suitable. Amino acids of peptide Q comprising a side bond 2, hc 〇〇 h (for example, a single "substituted or double alpha substituted amino acid" (for example, Lys, Orn, Ser 'Asp or Glu) are also suitable. In some embodiments where Q is a glycosidic related (eg, old, class 2, class 3, class 4, or class 5), the glycosidin-related peptide may comprise an amino acid sequence seq Mn〇: 156004.doc -121. 201143790 1601, or a modified amino acid sequence comprising one or more of the amino acid modifications described herein, wherein positions 10, 20, 24 and 29 (according to wild-type glucosamine At least one of the amino acids on the amino acid number is modified to any amino acid comprising a side chain amine, hydroxyl or carboxylate. In some embodiments, the spacer between peptide Q and sulfhydryl is an amino acid comprising a side chain amine, a hydroxyl group or a thiol, or a dipeptide comprising an amino acid containing a side chain amine, hydroxyl or thiol or Tripeptide. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments, the dipeptide spacer is not γ_〇1ιι·γ-Glu. When deuterated via the amine group of the amino acid of the spacer, it can be carried out via an alpha amine or a side chain amine of the amino acid. In the case of deuterated alpha amines, the spacer amino acid can be any amino acid. For example, the spacer amino acid can be a hydrophobic amino acid such as Gly 'Ala, Val, Leu, lie, Trp, Met, Phe, Tyr. In some embodiments, the spacer amino acid can be, for example, a hydrophobic amino acid such as Gly, Ala, Val, Leu, lie, Trp, Met, Phe, Tyr, 6-aminocaproic acid, 5-amino group Valeric acid, 7-aminoheptanoic acid, 8-aminooctanoic acid. Alternatively, the spacer amino acid can be an acidic residue such as Asp and Glu. In the case of a side chain amine of a deuterated spacer amino acid, the spacer amino acid is an amino acid comprising a side chain amine, such as an amino acid of formula I (e.g., Lys or Orn). In this case, it is possible to deuterize the α-amine of the spacer amino acid and the side chain amine to deuterize the peptide. Embodiments of the invention include such dimeric molecules. The amino acid of the amino acid or the dipeptide or the tripeptide may be an amino acid of the formula II when it is subjected to a brewing via a transbasic amino acid. In a specific example, 156004.doc • 122- 201143790, the amino acid is Ser. When deuterated by a thiol group of an amino acid of a spacer, an amino acid of the amino acid or dimorph or tripeptide may be an amino acid of the formula. In a specific exemplary embodiment, the amino acid is Cys. In some embodiments, the spacer comprises a hydrophilic bifunctional spacer. In a particular embodiment, the spacer comprises an amine poly(alkoxy)carboxylate. In this regard, the spacer may comprise, for example, NH2(CH2CH20)n(CH2)mC00H, wherein m is any integer from 1 to 6, and η is any integer from 2 to 12, such as 8-amino-3,6-one Oxyoctanoic acid, available from Peptides International, Inc. (Louisville, KY). In some embodiments, the spacer between peptide Q and thiol comprises a hydrophilic bifunctional spacer. In certain embodiments, the 'hydrophilic bifunctional spacer comprises two or more reactive groups, such as an amine, a hydroxyl group, a thiol, and a carboxy group, or any combination thereof. In certain embodiments, the hydrophilic bifunctional spacer comprises a hydroxyl group and a carboxylic acid ester. In other embodiments, the hydrophilic bifunctional spacer comprises an amine group and a carboxylic acid ester. In other embodiments, the hydrophilic bifunctional spacer comprises a thiol group and a tracing acid. In some embodiments, the spacer between peptide Q and sulfhydryl is a hydrophobic bifunctional spacer. Hydrophobic bifunctional spacers are known in the art. For example, Bioconjugate Techniques, G. T. Hermanson (Academic Press' San Diego, CA, 1996)' is incorporated herein by reference in its entirety. In certain embodiments, the hydrophobic bifunctional spacer comprises two or more reactive groups, such as an amine, a hydroxyl group, a thiol, and a carboxyl group, or any combination thereof. In certain embodiments, the hydrophobic bifunctional 156004.doc • 123- 201143790 spacer comprises an m group and (d) a self. In its (iv), the hydrophobic bifunctional spacer comprises an amine group and m (tetra). In other embodiments, the hydrophobic dual-functional spacer comprises a thiol group and a oleic acid vinegar. Suitable hydrophobic bifunctional spacers comprising a slow acid vinegar and a thiol or thiol group are known in the art and include, for example, 8-hydroxyoctanoic acid and 8-mercaptooctanoic acid. In some embodiments, the difunctional spacer is not a dicarboxylic acid comprising between 1 and 7 methylene carbon atoms of the unbranched chain between the slow acid vine groups. In some embodiments, the bifunctional spacer is a diacid acid comprising between 1 and 7 methylene carbon atoms of the unbranched chain between the carboxylate groups. In a particular embodiment where Q is a Class 1, Class 2, or Class 3 glycosidic-related peptide, a spacer (eg, an amino acid, a dipeptide, a tripeptide, a hydrophilic bifunctional spacer, or a hydrophobic bifunctional) The spacer is 3 to 1 atom in length (for example, 6 to 10 atoms, for example, 6, 7, 8, 9 or 1 atom). In a more specific embodiment of the genus, class 2 or class 3 ghrelin-related peptide, the spacer has a length of from about 3 to 10 atoms (eg, 6 to 10 atoms) and the base is C12. To a C18 fatty thiol group such as a C14 fatty sulfhydryl group, a C16 fatty sulfhydryl group, such that the total length of the spacer group and the thiol group is 14 to 28 atoms, for example, about 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27 or 28 atoms. In some embodiments in which Q is a class 2, class 2 or class 3 glycosidic related peptide, the length of the spacer and the thiol group is 17 to 28 (for example, 19 to 26, 19 to 21) atoms. According to certain embodiments of Q, which are Class 1, Class 2 or Class 3 glycosidic related peptides, the bifunctional spacer may be a synthetic amino acid or a naturally occurring amino acid (including but not limited to) Any of the amino acids described above, 156004.doc • 124· 201143790 comprising an amino acid backbone having a length of from 3 to 10 atoms (eg, 6-aminohexanoic acid, 5-amino group) Valeric acid, 7-aminoheptanoic acid and 8-aminooctanoic acid). Alternatively, the spacer attached to the class 1, class 2 or class 3 glycosidin-related peptide may be a dipeptide or a tripeptide having a peptide backbone of 3 to 10 atoms in length (for example, 6 to 10 atoms). Peptide spacer. Each of the amino acids linked to the dipeptide or tripeptide spacer of the class 1, class 2 or class 3 ghrelin-related peptide may be the same as or different from the other amino acids of the dipeptide or the tripeptide, and may be independent Selected from the group consisting of naturally occurring and/or non-naturally occurring amino acids including, for example, naturally occurring amino acids

Any of the D or L isomers of Ala, Cys 'Asp, Glu, Phe, Gly, His, lie, Lys, Leu, Met, Asn, Pro, Arg, Ser, Thr, Val, Trp, Tyr), Or any D- or L-isomer of a non-naturally occurring amino acid selected from the group consisting of β-alanine (β-Ala), Ν-α-mercapto-alanine (Me-Ala) Aminobutyric acid (Abu), α-aminobutyric acid (γ·Abu), aminohexanoic acid (ε-Ahx), aminoisobutyric acid (Aib), amidinopyrrolecarboxylic acid, amine base bite Formic acid, aminoserminic acid (Ams), amine tetrahydropyrazine-4-decanoic acid, arginine N-decyloxy-N-decylamine, β-aspartic acid (β_Asp), nitrogen Heterocyclic butanecarboxylic acid, 3-(2-benzothiazolyl)alanine, α-t-butylglycine, 2-amino-5-glycosyl-n-valeric acid (citrulline, cit), β-Cyclohexylalanine (Cha), acetaminomethyl-cysteine, diaminobutyric acid (Dab), diaminopropionic acid (Dpr), dihydroxyphenylalanine (D〇pA) ), dimercaptothiazolidinium (DMTA), γ-glutamic acid (γ-Glu), homoserine (Hse), hydroxyproline (Hyp), isoleucinate-decyloxy-Ν-曱Guanamine, M-isoleucine (Melle), isopiperidinecarboxylic acid (isn), methyl-leucine (MeLeu), methyl-isoamine, dimethyl-isoamine, tridecyl-isoamine 156004 .doc -125· 201143790 Acid, methanoproline, methionine-mesh (Met(O)), methionine-sulfone (Met(02)), norleucine ( Nle), methyl-norglycine (Me-Nle), n-proline (Nva), ornithine (Orn), p-aminobenzoic acid (PABA), penicillamine (Pen), sulfhydryl Phenylalanine (MePhe), 4-epoxyphenylalanine (Phe(4-Cl)), 4-fluorophenylalanine (Phe(4-F)), 4-nitrophenylalanine (Phe) (4-N02)), 4-cyanophenylalanine ((Phe(4-CN)), phenylglycine (Phg), piperidinyl alanine, piperidinylglycine, 3,4 - dehydroproline, pyrrolidinyl alanine, sarcosine (Sar), mercaptocysteine (Sec), 0-phenylmercapto-phosphoric acid, 4-amino-3-hydroxyl -6-methylheptanoic acid (Sta), 4-amino-5-cyclohexyl-3-hydroxyvaleric acid (ACHPA), 4-amino-3-hydroxy-5-phenylpentanoic acid (AHPPA), 1 , 2,3,4,-tetraman-isoindolin-3-carboxylic acid (Tic), Hydrogen glucosamine, phenyl methionine (Thi), 0-phenylhydrazino-phosphotyrosine, 〇-phosphate tyrosine, decyl tyrosine, ethoxy tyrosine, 〇_(bis-didecylamino-subretinal)·tyrosine, tetrabutylamine tyrosinate, mercapto-proline (MeVal), 1-amino-1·cyclohexane Acid (Acx), valeric acid, β-cyclopropyl-alanine (Cpa), propargylglycine (Prg), allylglycine (Alg), 2-amino-2-ring Hexyl-propionic acid (2_Cha), tetrabutylglycine (Tbg), vinylglycine (Vg), amine d-cyclopropanecarboxylic acid (Acp), 1-amino-1-cyclopentanoic acid (Acpe) ), alkylated 3 · thiopropionic acid, 1 -amino-1-cyclobutanecarboxylic acid (Acb). In some embodiments where Q is a Class 1, Class 2 or Class 3 glycosidic-related peptide, the spacer comprises a total negative charge, for example comprising one or two negatively charged amino acids. In the case where Q is one of the class 1, class 2 or class 3 glycosidic related peptides 156004.doc -126· 201143790, in some embodiments, the peptide is not a dipeptide of the general structure A_B, Wherein A is selected from the group consisting of Gly, Gln, Shi, Xin, Asp, Asn, 仏, Leu, Val, Phe and Pro, wherein the B is selected from the group consisting of: His, Trp. In some embodiments wherein Q is a third, third or third type of glycosidic related peptide, the dipeptide spacer is selected from the group consisting of: Ala-Ala, p-Ala-p-Ala, Leu -Leu, Pro-Pro, γ-aminobutyric acid-γ-aminobutyric acid and y-Glu-y-Glu. The Φ peptide Q can be modified to contain a thiol group by deuteration of a long chain alkane. In a particular aspect, the long chain alkane comprises an amine, hydroxyl or thiol group (e.g., octadecylamine, tetradecanol, and hexadecanethiol) that reacts with the carboxyl group of peptide Q or an activated form thereof. The carboxyl group of Q or an activated form thereof may be part of the side chain of the amino acid of Q (e.g., glutamic acid, aspartic acid) or may be part of the peptide backbone. In certain embodiments, peptide Q is modified to include a thiol group by deuteration of a long chain alkane with a spacer attached to Q. In a particular aspect, the long chain alkane comprises an amine, hydroxyl or thiol group reactive with the carboxyl group of the spacer or an activated form thereof. Suitable spacers comprising a tick or an activated form thereof are described herein and include, for example, bifunctional spacers such as amino acid 'dipeptides, tripeptides, hydrophilic bifunctional spacers, and hydrophobic bifunctional spacers. . The term "activated form of a carboxy group" as used herein refers to a carboxy group having the formula R(C=0)X, wherein hydrazine is a leaving group and RgQ or a spacer. For example, the activated form of the carboxy group can include, but is not limited to, sulfhydryl vapor, acid liver, and vinegar. In some embodiments, the activated carboxyl group is an ester having a N-hydroxybutanediamine (NHS) leaving group. For such aspects of the invention, wherein the long chain alkane is brewed from the peptide Q or the intermediate I56004.doc -127-201143790 spacer, the 'long chain burned hydrocarbons can be of any size and can comprise carbon chains of any length. Long-chain hydrocarbons can be straight or branched chain. In some aspects, the long chain hydrocarbon is a C4 to C30 hydrocarbon. For example, the long-chain hydrocarbon may be a C4 hydrocarbon, a C6 alkane, a C8 alkane, a C10 alkane, a C12 alkane, a C14 alkane, a C16 alkane, a C18 alkane, a C20 alkane, a C22 alkane, a C24 alkane, a C26 alkane, a C28 alkane or Any of C30 alkanes. In some embodiments the 'long chain alkane comprises a C8 to C20 alkane, such as a C14 alkane, a C16 alkane or a C18 alkane. In some embodiments, the amine, hydroxyl or thiol group of Q is deuterated with cholesterol. In a particular embodiment, the peptide is linked to the cholesterol acid via an alkylated de-amino Cys spacer (i.e., an alkylated 3-cyanopropionic acid spacer). Suitable methods for deaminating peptides via amines, hydroxyl groups and thiols are known in the art. See, for example, Miller, and es Cowmw« 218: 377-382 (1996); Shimohigashi and Stammer, /w J Pepi Pro...19: 54-62 (1982); and Previero et al., 5/0/7; ^ dcM 263: 7-13 (1972) (about the method of oximation via hydroxy); and San and Silvius, ·/ Pepi 66: 169-180 (2005) (about the method of brewing via mercaptan); C/zew. Chemical Modifications of Proteins: History and Applications", pp. 1, 2-12 (1990) 'Hashimoto et al., P/iar/wacMei/ca/ Λβ·?. "Synthesis of Palmitoyl Derivatives of Insulin and their

Biological Activity, Vol. 6, No. 2, pp. 171-176 (1989). The thiol group of the deuterated peptide Q can have any size, such as any carbon chain length, 156004.doc -128-201143790 and can be a direct bond or a branched bond. In some particular embodiments of the invention, the thiol group is a C4 to C30 fatty acid. For example, the thiol group can be a C4 fatty acid, a C6 fatty acid, a C8 fatty acid, a C10 fatty acid, a C12 fatty acid, a C14 fatty acid, a C16 fatty acid, a C18 fatty acid, a C20 fatty acid, a C22 fatty acid, a C24 fatty acid, a C26 fatty acid, a C28 fatty acid or a C30 fatty acid. Either. In some embodiments, the thiol group is a C8 to C20 fatty acid, such as a C14 fatty acid or a C16 fatty acid. In an alternate embodiment, the thiol group is a bile acid. The bile acid can be any suitable bile acid including, but not limited to, cholic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, taurocholic acid, glycocholic acid, and cholesterol acid. The deuterated peptide Q described herein can be further modified to comprise a hydrophilic moiety. In some particular embodiments, the hydrophilic moiety can comprise a polyethylene glycol (PEG) chain. Incorporation of the hydrophilic moiety can be achieved via any suitable method, such as any of the methods described herein. In some embodiments relating to a Class 1, Class 2, Class 3, Class 4 or Class 5 ghrelin-related peptide, the brewed glycoside-related peptide may comprise SEQ ID NO: 1601, Any of the modifications described herein including at least one of the amino acids at positions 10, 2, 24, and 29 (based on the amino acid number of the wild type glucosinolate) comprise a sulfhydryl group, and positions 16, 17 , 21, 24 or 29 (according to the amino acid number of the wild type glycein), at least one of the amino acid or the c-terminal amino acid at the position within the c-terminal extension is modified to Cys, Lys , 〇 rn, high _Cys or Phe ' and the side chain of the amino acid is covalently bonded to the hydrophilic moiety (eg pEG). In some embodiments relating to a Class 1, Class 2, Class 3, Class 4 or Class 5 ghlylin-related peptide, the thiol-based condition is via cys, 156004.doc -129·201143790 〇 The spacer of rn, high-Cys or Ac-Phe is attached to position 1 (numbered according to the amino acid of wild-type glycemic acid) and the hydrophilic moiety is incorporated at the Cys residue at position 24. Alternatively, the deuterated peptide (Q) may comprise a spacer wherein the spacer is deuterated and modified to comprise a hydrophilic moiety. Non-limiting examples of suitable spacers include spacers comprising one or more amino acids selected from the group consisting of:

Cys, Lys, Orn, high-Cys and Ac-Phe. Alkylation of Q In some embodiments, Q is modified to comprise an alkyl group. The alkyl group may be directly covalently bonded to the amino acid of peptide Q or to the amino acid of q via a spacer, wherein the spacer is located between the amino acid of Q and the alkyl group. The alkyl group can be alkylated, for example, via a mystery, thiol or amine linkage to Q at the same amino acid position of the bonded hydrophilic moiety or at a different amino acid position. As described herein, Q may be a glycoside superfamily peptide, a glycoside-related peptide (including a class 1, a second class, a third class, a fourth class, or a fifth class of a glycein-related peptide), or Osteocalcin, calcitonin, amylopectin or an analogue, derivative or combination thereof. For example, Q can be a third, third or third type of glycein-related peptide, and can comprise a non-native alkyl group for a naturally occurring amino acid. Alkylation can be carried out at any position within Q. In the case where Q is a glycosidin-related peptide, alkylation can be carried out at any position (including any of positions i to 29, a position in the C-terminal extension or a c-terminal amino acid), and the restriction conditions To maintain the agonist activity of the unalkylated peptide for the glycosidic receptor, GLP-1 receptor, GIP receptor or other glycosidic peptide receptor after alkylation. In some embodiments, the alkylated peptide retains glycosidic agonist activity if the unalkylated peptide has a glycosidic 156004.doc • 130-201143790 agent activity. In some embodiments, an alkylated peptide retains GLP-1 agonist activity if the unalkylated peptide has Glp-1 agonist activity. Non-limiting examples include at position 5, 7, 1, 、, 11, 12, 13, 14, 16, 17, 18, 19, 2, 21, 24, 27, 28, or 29 (according to wild-type glycoside The alkylation is carried out on the amino acid number. For Class 1, Class 2, and Class 3 Glycanin-related peptides, 'can be at positions 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24 Alkylation at 27, 28, 29, 30, 37, 38, 39, 40, 41, 42 or 43 (based on the amino acid number of wild-type glucosamine). For glycosidic related peptides (eg, class 1, class 2, class 3, class 4, or class 5), other non-limiting examples include at position 1 (based on the amine of wild-type glucosamine) Alkylation on the base acid numbering and at one or more positions in the c-terminal portion of the glycein-related peptide (eg, position 24, 28 or 29 (based on the amino acid number of wild-type glycosidic acid)) PEGylation is carried out in the c-terminal extension or on the c-terminus (for example via the addition of a c-terminal Cys). In a particular aspect of the invention, the peptide Q (eg, a glycoside superfamily peptide, a glycoside related peptide, a first, a second, a third, a fourth, or a fifth type of glycosidin) a related peptide, or osteocalcin, calcitonin, amylopectin, or an analogue, derivative or conjugate thereof thereof, by direct alkylation of a side chain amine, hydroxyl or thiol of the amino acid of q Modified to include an alkyl group. In some embodiments, Q is directly alkylated via a side chain amine, hydroxyl or thiol of an amino acid. In some embodiments, in the case where Q is a glycosidin-related peptide, alkylation is carried out at position 1, 20, 24 or 29 (based on the amino acid number of wild-type glycoside). In this regard, the 'alkylated ghrelin-related peptide may comprise an amino acid sequence 156004.doc • 131 · 201143790 SEQ ID NO. 1601 or a modified amine comprising one or more of the amino acid modifications described herein a base acid sequence in which at least one of the amino acids at positions 1, 20, 24, and 29 (based on the amino acid number of the wild-type glycemic acid) is modified to include a side chain amine, a hydroxyl group, or a sulfur Any amino acid of an alcohol. In some specific embodiments of the invention wherein Q is a glycoside-related peptide, a pendant amine, hydroxyl or thiol pair of amino acid via position 1 (based on the amino acid of wild-type glycemic acid) Q is directly alkylated. In some embodiments 'peptide Q (eg, a glycoside superfamily peptide, a glycoside related peptide, a class 1, a class 2, a class 3, a class 4, or a class 5 a glycosidin-related peptide, The amino acid comprising a side chain of either osteocalcin, calcitonin, amylopectin, or an analogue, derivative or combination thereof is an amino acid of the formula. In some exemplary embodiments, the amino acid of the formula is an amino acid of η & 4 (1^8) or an amino acid of Orion (11). In other embodiments, the amino acid of the peptide q comprising a side chain hydroxyl group is an amino acid of the formula 。. In some exemplary embodiments, the amino acid of formula π is an amino acid (Ser). In other embodiments, the amino acid of the peptide Q comprising a side chain thiol is an amino acid of the formula _. In some exemplary embodiments, the amino acid of formula III is an amino acid (Cys) having a η of 1. In other embodiments, the amino acid of the peptide Q comprising a side chain amine, a hydroxyl group or a thiol is a disubstituted amino acid comprising the same formula of formula I, formula η: or formula m, with the exception of bonding To the style! Hydrogen of the alpha carbon of the amino acid of formula π or formula m is replaced by a second side chain. In some embodiments of this month, alkylated peptide Q (eg, glycoside super 156004.doc • 132- 201143790)

a family peptide, a glycoside-related peptide, a third, a second, a third class of a 'sentimental or a fifth type of ghrelin-related peptide, or (iv) a chemical, a (tetra), a branched starch, or an analogue thereof, The derivative or conjugate) comprises a spacer between the peptide and the alkyl group. In some embodiments, Q is covalently bound to a spacer and the gastric spacer is covalently bonded to an alkyl group. In some exemplary embodiments, 'peptide Q is modified to include an alkyl group by an alkylation of an amine, hydroxyl or thiol of a spacer, wherein Q is a glycosidin related peptide, such as a first class , Class 2, Class 3, Class 4 or Class 5) The side of the amino acid attached to the position of Q, 1 〇, 2 〇, 仏 cut (based on the amino acid number of wild type glucosinolate) chain. The amino acid of the interstitial linker of the peptone may be any amino acid comprising a moiety that allows linkage to the spacer. The amino acid of the linking spacer of peptide Q may be any amino acid (e.g., an alpha monosubstituted amino acid or an alpha, alpha double substituted amino acid) that allows for linkage to a portion of the spacer. The amino acid of peptide Q comprising a side chain - ΝΗ2, -ΟΗ or -COOH (for example, Lys, 〇rn, Ser, Asp or Glu) is suitable. "Q is a glycein-related peptide (for example, class 1, number In some embodiments of class 2, class 3, class 4 or class 5), the alkylated Q may comprise an amino acid sequence SEq ID NO: 1601, or it comprises one or more of the amine groups described herein Acid-modified modified amino acid sequence 'at least one of the amino acids at positions 10, 20, 24, and 29 (based on the amino acid number of wild-type glycemic acid) is modified to include a side chain amine Any amino acid of a hydroxy or carboxylic acid ester. In some embodiments, the spacer between the peptide Q and the alkyl group is an amino acid comprising a side chain amine, a hydroxyl group or a thiol, or a dipeptide comprising an amino acid containing a side chain amine, a hydroxyl group or a thiol or Tripeptide. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments, the dipeptide spacer is not Y_Giu_Y_156004.doc •133·201143790

Glu 〇 When alkylated via an amine group of an amino acid of a spacer, alkylation can be carried out via an alpha amine or a side chain amine of an amino acid. In the case of alkylating an alpha amine, the spacer amino acid can be any amino acid. For example, the spacer amino acid can be a hydrophobic amino acid, such as Gly, Ala, Val, Leu, lie, Trp, Met, Phe, Tyr » or 'the spacer amino acid can be an acidic residue, for example Asp and Glu. In an exemplary embodiment, the spacer amino acid can be a hydrophobic amino acid 'eg, Gly, Ala, Val, Leu, lie, Trp, Met, Phe, Tyr, 6-aminocaproic acid, 5-amino group Valeric acid, 7-aminoheptanoic acid, 8-aminooctanoic acid. Alternatively, the spacer amino acid can be an acidic residue, for example, Asp and Glu' are limited to alkylation on the alpha amine of the acidic residue. In the case of a side chain amine of an alkylated spacer amino acid, the spacer amino acid is an amino acid comprising a side chain amine, such as an amino acid of formula I (eg Lys or Orn) » in this case It is possible to alkylate the alpha amine of the spacer amino acid and the side chain amine to dialkylate the peptide. Embodiments of the invention include such dialkylated molecules. When alkylating via the hydroxyl group of the amino acid of the spacer, the amino acid of the amino acid or spacer may be an amino acid of the formula. In a specific exemplary embodiment, the amino acid is Ser » when alkylated via a thiol group of a spacer amino acid, the amino acid of the amino acid or spacer may be Amino acid. In a specific exemplary embodiment, the amino acid is Cys. In some embodiments, the spacer comprises a hydrophilic bifunctional spacer. In a particular embodiment, the spacer comprises an amine poly(alkoxy)carboxylate. 156004.doc • 134· 201143790 In this case, the spacer may comprise, for example, NH2(CH2CH20)n(CH2)mCOOH, wherein m is any integer from 1 to 6 and η is any integer from 2 to 12, such as 8-amine Glycosyl-3,6.dioxaoctanoic acid' is commercially available from Peptides Internati(R), Inc (Louisville, KY). In some embodiments, the spacer between the peptide Q and the alkyl group is a hydrophilic bifunctional spacer. In certain embodiments, the hydrophilic bifunctional spacer comprises two or more reactive groups, such as an amine, a hydroxyl group, a thiol, and a carboxyl group φ, or any combination thereof. In certain embodiments, the hydrophilic bifunctional spacer comprises a hydroxyl group and a carboxylic acid ester. In other embodiments, the hydrophilic bifunctional spacer comprises an amine group and a carboxylic acid ester. In other embodiments, the hydrophilic bifunctional spacer comprises a thiol group and a carboxylate β. In some embodiments, the spacer between the peptide Q and the alkyl group is a hydrophobic bifunctional spacer. In certain embodiments, the hydrophobic bifunctional spacer comprises two or more reactive groups, such as an amine, a trans group, a thiol, and a suspending group, or any combination thereof. In certain embodiments, the hydrophobic bifunctional spacer is coated with a base and a slow acid vinegar. In other embodiments, the hydrophobic bifunctional spacer comprises an amine group and a carboxylic acid vinegar. In other embodiments, the hydrophobic bifunctional spacer comprises a thiol group and a slow acid brew. Suitable hydrophobic bifunctional spacers comprising diacid vinegar and a thiol or thiol group are known in the art and include, for example, 8-hydroxyoctanoic acid and 8-mercaptooctanoic acid. In a particular embodiment where Q is a Class 1, 2, or 3 glycosidic relationship, a spacer (eg, an amino acid' di-, tri-, hydrophilic, bifunctional, or hydrophobic bifunctional The spacer is 3 to 1 atom in length (for example, 6 to 10 atoms 'for example, 6, 7, 8, 9 or 1 atom). In a more specific example, 156004.doc -135. 201143790, the spacer attached to the steroid, class 2 or class 3 ghrelin-related peptide is from about 3 to 10 atoms in length (eg, 6 to 1) 〇 one atom), and the alkyl group is a C12 to C18 building group, such as a C14 alkyl group, a C16 building group, and thus the total length of the spacer and the alkyl group is 14 to 28 atoms, for example, about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 or 28 atoms. In some embodiments where Q is a Class 1, Class 2 or Class 3 glycosidic-related peptide, the 'spacer and alkyl group are 17 to 28 (eg, 19 to 26, 19 to 21) atoms in length. . According to some of the foregoing examples wherein Q is a Class 1, Class 2 or Class 3 glycosidic related peptide, the bifunctional spacer may be a synthetic amino acid or a non-naturally occurring amino acid comprising a length of 3 Up to 10 atomic amino acid backbone (eg, 6-aminohexanoic acid, 5-aminopentanoic acid, 7-aminoheptanoic acid, and 8-aminooctanoic acid) or 'connected to Class 1, 2 The spacer of the class or class 3 asphyticin-related peptide may be a dipeptide or tripeptide spacer having a peptide backbone of 3 to 10 atoms in length (e.g., 6 to 10 atoms). A dipeptide or tripeptide spacer attached to a steroid, class 2 or class 3 ghrelin-related peptide may be a naturally occurring and/or non-naturally occurring amino acid (including, for example, any of the amino acids taught herein) ) constitutes. In some embodiments where Q is a Class 1, Class 2 or Class 3 glycosidic-related peptide, the spacer comprises a total negative charge, for example comprising one or two negatively charged amino acids. In some embodiments wherein Q is a Class 1, Class 2 or Class 3 glycosidic-related peptide, the dipeptide spacer is selected from the group consisting of: Ala-Ala, β-Ala-β-Ala, Leu -Leu, Pro-Pro, γ-aminobutyric acid-γ-aminobutyric acid and Y-G1u-y-G1u. In some embodiments, the dipeptide spacer is not γ-Glu-y-Glu 〇156004.doc • 136·201143790 Suitable methods for amine, hydroxyl, and thiol-derived peptides are known in the art as examples of p For example, Williamson ether synthesis can be used to form an ether linkage between the glycoside-related peptide and the alkyl group. Similarly, nucleophilic substitution of the peptide with an alkyl dentate can result in any of an ether, thioether or amine linkage. The alkyl group of the alkyl group Q may have any size, such as any carbon bond length, and may be a linear or branched alkyl group. In some embodiments of the invention, the alkyl group is a C4 to C30 alkyl group. For example, the alkyl group can be C4 alkyl, C6 alkyl, C8 alkyl, C10 alkyl, C12 alkyl, C14 alkyl, C16 alkyl, C18 alkyl, C20 alkyl 'C22 alkyl, C24 alkane Any of a C26 alkyl group, a C28 alkyl group or a C30 alkyl group. In some embodiments, the institutional group is a C8 to C20 alkyl group, such as a C14 alkyl group or a C16 alkyl group. In some particular embodiments, the alkyl group comprises a sterol moiety of a bile acid (e.g., bile acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid, taurocholic acid, glycocholic acid, and cholesterol glycolic acid). • In some embodiments of the invention, peptide Q is modified to comprise an alkyl group by reacting a nucleophilic long chain alkane with Q, wherein Q comprises a leaving group suitable for nucleophilic substitution. In a particular aspect, the nucleophilic group of the long chain alkane comprises an amine, hydroxyl or thiol group (e.g., octadecylamine, tetradecanol, and hexadecanethiol). The leaving group of Q may be a part of the amino acid side chain or may be a part of the peptide backbone. Suitable leaving groups include, for example, N. hydroxybutanediamine, halogen and sulfonate groups. In a second embodiment, peptide Q is modified to comprise a decyl group by reacting a nucleophilic long-chain hydrocarbon with a link to a k-spacer, wherein the spacer comprises a radical from 156004.doc • 137·201143790. In a particular aspect, a long chain hydrocarbon contains an amine, a trans- or a thiol group. In certain embodiments, the spacer comprising a leaving group can be any of the spacers described herein further comprising a suitable leaving group, such as an amino acid, a dipeptide, a tripeptide, a hydrophilic bifunctional spacer, and a hydrophobic group. Sexual bifunctional spacer. For such aspects of the invention 'where long chain hydrocarbons are formed from a Q or a spacer base', the long bond soot may be of any size and may comprise carbon chains of any length. The long chain hydrocarbon may be a linear or branched bond hydrocarbon. In some aspects, the 'long chain hydrocarbons are C4 to C30 hydrocarbons. For example, the long-chain hydrocarbons may be C4 alkanes, C6 alkanes, C8 alkanes, C10 alkanes, C12 yard hydrocarbons, C14 yard hydrocarbons, C16 alkanes, C18 alkanes, C20 alkanes, C22 alkanes, C24 hydrocarbons, C26 soot, Any of a C28 alkane or a C30 alkane. In some embodiments in which the glycosidic related peptide is a Class 1, Class 2, or Class 3 glycosidic-related peptide, the 'long-chain hydrocarbons include C8 to C20 hydrocarbons, such as C14 hydrocarbons, C16 hydrocarbons, or C18. Alkanes In some embodiments, alkylation can be carried out between the Q and cholesterol moieties. For example, the hydroxyl group of cholesterol can displace the leaving group on the long chain alkane to form a cholesterol-glycanin peptide product. The alkylated peptide (Q) described herein can be further modified to comprise a hydrophilic moiety. In some particular embodiments, the hydrophilic moiety can comprise a polyethylene glycol (PEG) chain. Incorporation of the hydrophilic moiety can be achieved via any suitable method, such as any of the methods described herein. In some embodiments relating to a steroid class, class 2, class 3, class 4 or class 5 ghlylin-related peptide, the alkylated Q may comprise SEQ ID NO: 16 〇 1, or it comprises The one or more amino acid modified modified amino acid sequences, wherein the positions are 1 〇, 156004.doc -138·201143790 20, 24 and 29 (based on the amino acid number of the wild type glucosinolate) At least one of the amino acids comprises an alkyl group, and at least one of the amino acid or C-terminal amino acid at positions 16, 17, 21, 24 and 29, at the c-terminal extension is modified It is Cys, Lys, Orn, High-Cys or Ac-Phe, and the side chain of the amino acid is covalently bonded to a hydrophilic moiety (for example, PEG). In some embodiments relating to a class 1, class 2, class 3, class 4 or class 5 ghrelin-related peptide, the 'alkyl group is optionally via Cys, Lys, Orn, High-Cys or Ac The spacer of -φ Phe is attached to position 10 (numbered according to the amino acid of wild-type glycemic acid) and the hydrophilic moiety is incorporated at the Cys residue at position 24. Alternatively, the alkylated peptide Q may comprise a spacer wherein the spacer is alkylated and modified to comprise a hydrophilic moiety. Non-limiting examples of suitable spacers include spacers comprising one or more amino acids selected from the group consisting of Cys, Lys, Orn, high-Cys, and Ac-Phe. Stabilization of a helical structure In some embodiments, an intramolecular bridge φ bond is formed between two amino acid side chains to make a Class 1, Class 2, Class 3, Class 4, or Class 5 sucrose The three-dimensional structure of the slow-base portion of the prime-related peptide Q (for example, amino acid 12 to 29 (numbered according to the amino acid of wild-type glycoside)) is stable. The two amino acid side chains may be bonded to each other via hydrogen bonding, ionic interaction (such as formation of a salt bridge), or by covalent bonds. In some embodiments, the 'intramolecular bridge is formed between two amino acids separated by three amino acids, such as between the amino acid at position i and the amino acid at position i+4, where i is Any integer from 12 to 25 (eg 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25) (according to wild 156004.doc • 139·201143790 Amino acid number). More specifically, the amino acid pair is 12 and 16, 16 and 20, 20 and 24 or 24 and 28 (i = 12, 16, 20 or 24 amino acid pairs) (based on the amino group of wild type glycoside) The side chains of the acid numbering are bonded to each other and thereby stabilize the glycoside a helix. Alternatively, i can be 17». In some particular embodiments, wherein the amino acid at position i is linked to the amino acid at position i+4 by an intramolecular bridge, the size of the linker is about 8 atoms or about 7 Up to 9 atoms. In other embodiments, the intramolecular bridge is formed between two amino acids separated by two amino acids, such as between the amino acid at position j and the amino acid at position j+3, where j is Any integer from 12 to 26 (eg 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 and 26) (based on the amino acid number of wild-type glycoside ). In some particular embodiments, j is 17. In some particular embodiments, wherein the amino acid at position j is linked to the amino acid at position j + 3 by an intramolecular bridge, the size of the linker is about 6 atoms or about 5 to 7 atoms. In other embodiments, the intramolecular bridge is formed between two amino acids separated by six amino acids, such as between the amino acid at position k and the amino acid at position k+7, where & Any integer from 12 to 22 (e.g., 12, n, 14, 15, 16, 17, 18, 19, 20, 21, and 22) (numbered according to the amino acid of wild type glycoside). In some particular embodiments, k is 12, 13, or 17. In an exemplary embodiment, k is 17. Examples of amino acid pairs capable of covalently bonding to form a 6-atom bond bridge include Orn and Asp; Glu and an amino acid of formula I, wherein η is 2; and high bran 15604.doc 201143790 Amine acid and formula The amino acid of I, wherein η is 1, wherein Formula I is: Η

Η2Ν-C-COOH CH2)n

I nh2 wherein n=l to 4 [Formula I] Examples of amino acid pair capable of covalently bonding to form a 7-atom bond bridge include Orn-Glu (indole ring); Lys-Asp (indoleamine) ); or homoseramine-high glutamic acid (lactone). Examples of amino acid pairings which can form 8-atom linkers include Lys-Glu (internal amine); high lysine_Asp (indoleamine); 〇rn_ high face acid (indoleamine); 4-amine Phe-Asp (inactine); or Tyr-Asp (lactone). Examples of amino acid pairings which can form a 9-atom linker include high lysine-Glu (indoleamine); Lys-high glutamic acid (endoamine); 4-amino Phe-Glu (indoleamine) Or Tyr-Glu (lactone). Any of the side chains on these amino acids may be additionally substituted with other chemical groups as long as the three-dimensional structure of the alpha helix is not destroyed. Alternative artisans may envision alternative or alternative amino acid analogs, including chemically modified derivatives which form stable structures of similar size and desired effect. For example, the 'hypercysteine-hypercysteine disulfide bridge is 6 atoms in length and it can be further modified to provide the desired effect. Even in the absence of covalent bonds, the amino acid pairings described above or similar pairs that can be envisioned by one of ordinary skill can also provide an increase to the alpha helix via non-covalent bonds, such as via salt bridge or hydrogen bonding interactions. Stability. The size of the indoleamine ring may vary depending on the length of the amino acid side chain, and in some examples, 156004.doc • 141-201143790 In some embodiments, the indoleamine is linked to the glutamine by a side chain of the amino acid away from the amino acid. Formed by acid side chains. Other exemplary embodiments (based on the amino acid number of wild-type glycoside) include the following pairings (wherein the indoleamine bridge is selected): Glu at position 12 and Lys at position 16; native Lys at position 12 Glu at position 16; Glu at position 16 and Lys at position 20; Lys at position 16 and Glu at position 20; Glu at position 20 and Lys at position 24; Lys and position at position 20 • Glu on 24; Glu at position 24 and Lys at position 28; Lys at position 24 and Glu at position 28 » or the order of the indoleamine bond in the indoleamine ring can be reversed (eg guilty) The amine ring can be formed between Lys 12 and the side chain of Glu 16 or between Glu 12 and Lys 16). The alpha helix of Q can be stabilized using an intramolecular bridge other than the indoleamine bridge. In some embodiments, the intramolecular bridge is a hydrophobic bridge. In this case, the intramolecular bridge is optionally interposed between the side bonds of the two amino acids which are part of the hydrophobic surface of the alpha helix of Q. For example, one of the amino acids linked by a hydrophobic bridge can be an amino acid at positions 10, 14 and 18 (numbered according to the amino acid of wild type glucosinolate). In a particular aspect, one or two corners of the alpha helix of Q are crosslinked using an all-hydrocarbon crosslinking system using olefin metathesis. In this case, q may contain alpha-thiolated amino acids at i and i+4 or i + 7 positions, which have dilute side chains of different lengths and are configured to have type or stereochemistry . By way of example, the 'dilute hydrocarbon side bond' may comprise (CH2)n, where n is any integer from 1 to 6. In some embodiments, a suitable method for forming the intramolecular bridges for the cross-linking length of 8 atoms is described in the art. See, for example, Schafmeister et al., */· Jw. CAewi. Soc. 122: 5891-5892 156004.doc • 142· 201143790 (2000) and Walensky et al., Sdewcre 305: 1466-1470 (2004). Alternatively, Q may comprise a fluorenyl-allyl Ser residue at the adjacent helix corners which are bridged together via ring-shaped metathesis of ruthenium catalysis. Such cross-linking procedures are described, for example, in Blackwell et al, Chem., Int. Ed. 37: 3281-3284 (1998). In another specific aspect, a non-natural thiodialanine amino acid (ie, lanthionine, which has been widely adopted as a peptide mimetic of cysteine) is used to crosslink one corner of the alpha helix . Suitable methods based on cyclization of lanthionine are known in the art. See, for example, Matteucci et al, reira/iec/ri??? Leiierj 45: 1399-1401 (2004); Mayer et al, ·/. Corpse 51: 432-436 (1998); Polinsky et al, /·#^· C/ze/w. 35: 4185-4194 (1992); Osapay et al., 乂 C. / C/ie/n. 40: 2241-2251 (1997); Fukase et al., 5«//. (:/ ^Speaking.6<〇&1//7«· 65: 2227-2240 (1992); Harpp^A, J. Org. Chem. 36: 73-80 (1971); Goodman and Shao, Pure dpp/· C/ze/n. 68: 1303-1308 (1996); and Osapay and Goodman, J_Chem. Soc. Chew. Comwww. 1599-1600 (1993) o In some embodiments, position i and position i+7 are used An α,ω-diaminoalkane tether between the two Glu residues (for example, 1,4-diaminopropane and 1,5-diaminopentane) to make the alpha helix of Q Stable. These linkages are formed by a bridge of 9 atoms or more in length, depending on the length of the diamine-based hydrocarbon-based bond. A suitable method for preparing a peptide cross-linked with the tethers is This is described in the art. See, for example, Phelan et al., 丄c/iem. <Soc. 119: 455-460 (1997). 156004.doc -143· 201143790 In the present invention In one embodiment, one or two corners of the alpha helix of Q are crosslinked using a disulfide bridge. Alternatively, a modified disulfide bridge that causes an isobaric macrocyclization using one or two sulfur atoms via a methylene group substitution Stabilizing the alpha helix of Q. Suitable methods for modifying peptides based on disulfide bridges or sulfur-based cyclization are described, for example, in Jackson et al., /. CTzew. 5*oc. 113: 9391-9392 (1991); and Rudinger And Jost, 20: 570-571 (1964). In another embodiment, the alpha helix of Q is stabilized by the binding of a metal atom by two His residues at i and i+4 or a pair of His and Cys pairs. The metal atom can be, for example, Ru(III), Cu(II), Zn(II) or Cd(II). Such methods of metal-bound alpha helix stabilization are known in the art. See, for example, Andrews And Tabor, 55: 11711-11743 (1999);

Ghadiri et al., Jw. C/zem. Soc. 112: 1630-1632 (1990); and Ghadiri et al., /. <Soc. 1 19: 9063-9064 (1997). The alpha helix of Q may be stabilized by other peptide cyclization methods, as reviewed in Davies, «/. Toki " Heart. 5W. 9: 471-501 (2003). The a helix can be stabilized by the formation of a guanamine bridge, a thioether bridge, a thioester bridge 'gland bridge, an amino methacrylate bridge, a sulfonamide bridge, and the like. For example, a thioester bridge can be formed between the C-terminus and the side chain of the Cys residue. Alternatively, the thioester may be formed via a side chain of an amino acid having a thiol (Cys) and a side bond having an amino acid (e.g., Asp, Glu) having a carboxylic acid. In another method, a crosslinking agent such as a dicarboxylic acid (e.g., suberic acid/octanedioic acid) may have two functional groups in the side chain of the amino acid (such as a free amine group, a hydroxyl group, a thiol group). A bond is introduced between the base and its combination. According to some embodiments, the alpha helix of Q is stabilized by the incorporation of 156004.doc-144-201143790 hydrophobic amino acid at position 丨 and i+4. For example, i can be Tyr and i+4 can be Val or Leu; i can be Phe and i+4 can be Cys or Met; i can be Cys and i+4 can be Met; or i can be Phe and i+4 can be lie. It will be appreciated that for the purposes herein, the above amino acid pairings may be reversed such that the amino acid shown at position i may alternatively be on i+4 and the i+4 amino acid may be in the i position. According to another embodiment of the present invention, wherein Q is a glycosidin-related peptide, the alpha helix is numbered via a C-terminal portion of Q (approximately amino acid 12 to 29, according to the amino acid of wild-type glucosamine). Stabilized by incorporation (by amino acid substitution or insertion) of one or more alpha helix stabilized amino acids. In a particular embodiment, the alpha helix stabilized amino acid is an alpha, alpha disubstituted amino acid including, but not limited to, aminoisobutyric acid (Aib) selected from the group consisting of decyl, ethyl, and propyl. An amino acid which is disubstituted with the same or different groups of n-butyl groups, or an amino acid which is disubstituted with cyclooctane or cycloheptane (for example, 1-aminocyclooctanecarboxylic acid). In some embodiments, the position of the glycosidin-related peptide is 丨6, i7, 18, 19, 20, 21, 24 or 29, two, three, four or more of α, Alpha disubstituted amino acid substitution. In a particular embodiment, one, two, three or all of positions 16, 20, 21 and 24 are replaced by Aib. Conjugates In some embodiments, the peptide (Q) described herein is glycosylated, brewed aminated, carboxylated, phosphorylated, esterified, N-deuterated, cyclized via, for example, a disulfide bridge, or converted It is a salt (for example, an acid addition salt, a base addition salt), and/or optionally dimerized, polymerized, or polymerized, or combined. As described herein, Q may be a glycoside superfamily peptide or a glycoside related peptide (including class 1, class 2, class 3, 156004.doc 145·201143790 class 4 or class 5 sucrose A related peptide), or osteocalcin, calcitonin, amylopectin or an analogue, derivative or conjugate thereof. The invention also encompasses a combination of Q-L-Y Q further linked to a heterologous moiety. Covalent bonding and non-covalent bonding between Q and heterologous moieties (eg, electrostatic interactions, hydrogen bonding, van der Waals interactions, salt bridges, hydrophobic interactions, and Its analog) or a combination of these two types of bonds. A variety of non-covalent coupling systems can be used, including biotin-avidin, ligand/receptor, enzyme/substance, nucleic acid/nucleic acid binding protein, lipid/lipid binding protein, cell adhesion molecule conjugate; Any binding partner or fragment that has an affinity for each other. In some aspects, the covalent bond is a combination of a peptide bond and a heterologous moiety, which may be indirect or direct, the former may involve a linker or a spacer. Suitable linkers and spacers are known in the art and include, but are not limited to, in the section "Deuteration and Biosynthesis J and Bond # Difference" and in the subsection "ρ"

156004.doc White conjugate, in which the plasma protein is composed of fibrinogen and globulin, 201143790 group. In some embodiments, the plasma protein portion of the conjugate is albumin or transferrin. In some embodiments, the conjugate comprises Q and one or more of: a polypeptide, a nucleic acid molecule, an antibody or fragment thereof, a polymer, a quantum dot, a small molecule, a toxin, a diagnostic agent, a carbohydrate, an amino acid. C-terminal heterologous moiety In some embodiments, the heterologous moiety that binds to Q is a peptide other than Q and the conjugate is a fusion peptide or a chimeric peptide. In some embodiments, wherein Q is a glycoside superfamily peptide and the heterologous moiety is a peptide extension having from 1 to 21 amino acids. In a particular embodiment, wherein Q is a glycosidic related peptide (eg, a Class 1, Class 2, Class 3, Class 4, or Class 5 ghrelin-related peptide), the extension is linked to Q of C The end, for example, is attached to the amino acid at position 29. In some embodiments, the extension comprises the amino acid sequence SEQ ID NO: 1610 (GPSSGAPPPS), SEQ ID NO: 1611 (GGPSSGAPPPS-CONH2), SEQ ID NO: 1614 (KRNRNNIA), SEQ ID NO: 1643 (KRNR Or KGKKNDWKHNITQ (SEQ ID NO: 1613). In a particular aspect, the amino acid sequence is linked via a C-terminal amino acid of Q, such as an amino acid at position 29. In some embodiments, the amino acid sequences SEQ ID NO: 1610, 1611, 1613, 1614, and 1643 are bonded to the amino acid 29 of the peptide via a peptide bond. In some specific embodiments, the amino acid at position 29 of the glycosidin-related peptide (eg, class 1, class 2, class 3, class 4, or class 5 ghrelin-related peptide) is Gly, And Gly is fused to one of the amino acid sequences SEQ ID NOS: 1610, 1611, 1613, 1614 and 1643. Polymer Heterologous Portion In some embodiments, the heterologous moiety bound to Q is a polymer. In a number of examples, the polymer is selected from the group consisting of polyamines; polycarbonates; polyalkylenes and derivatives thereof, including polyalkylene glycols, poly Alkylene oxide, polyalkylene terephthalate; polymer of acrylate and methacrylate' including poly(decyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate) ), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly (decyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecyl acrylate); polyethylene polymer, including polyvinyl alcohol, polyvinyl ether, polyvinyl ester, poly Ethylene, poly(ethylene acetate) and polyethylene 吼 π each biting ketone; polyglycolide; polyoxyalkylene; polyurethane and its copolymer; cellulose, including alkyl Cellulose, hydroxyalkyl cellulose, cellulose ether, cellulose ester, nitrocellulose, Cellulose, ethyl cellulose, propyl cellulose, propyl-propyl decyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, phthalic acid Cellulose acetate, carboxyethyl cellulose, cellulose triacetate and sodium sulphate cellulose; polypropylene; polyethylene 'including poly(ethylene glycol), poly(ethylene oxide) and poly(p-benzoic acid) Ester); and polystyrene. In some aspects, 'polymers are biodegradable polymers, including synthetic biodegradable polymers (such as polymers of lactic acid and glycolic acid, polyanhydrides, poly(orthoacid) esters, polyurethanes, Poly(butyric acid), poly(valeric acid) and poly(lactide-co-caprolactone), and natural biodegradable polymers (such as alginate and other polysaccharides) including polydextrose and cellulose, collagen Protein, its chemical derivatives (chemical group (eg alkyl, alkyl) substitution, 156004.doc • 148- 201143790 plus 'passification, oxidation and other modifications routinely performed by those skilled in the art) , albumin and other hydrophilic proteins (such as zein and other pr〇lamine and hydrophobic proteins), and any copolymers or mixtures thereof. In general, such materials are degraded by surface or overall erosion by enzymatic hydrolysis or exposure to water in vivo. In some aspects, the polymer is a bioadhesive polymer such as the bioerodible hydrogel described by HS Sawhney, CP Pathak and JA Hubbell, Ma Cr〇m〇lecules, 1993, 26, 581-587, The teachings of this reference are incorporated herein; poly hyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, polyglucosamine 'poly(decyl methacrylate), poly(fluorenyl) Ethyl acrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate) ), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). In some embodiments, the polymer is a water soluble polymer or a hydrophilic polymer. Hydrophilic polymers are further described in the context of "Hypothesis". Suitable water soluble polymers are known in the art and include, for example, polyethylene groups, sigma, propylcellulose (HPC; Klucel), propylmethylcellulose (HPMC). Methocel), nitrocellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, methylcellulose, ethylcellulose (Ethocel), hydroxyethylcellulose Various alkyl celluloses and hydroxyalkyl celluloses; various cellulose ethers, cellulose acetate, carboxymethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, acetic acid 156004.doc • 149· 201143790 Vinyl ester/crotonic acid copolymer, poly-hydroxyalkyl methacrylate, hydroxydecyl methacrylate, methacrylic acid copolymer, poly(methacrylic acid), polymethyl methacrylate, maleic anhydride / Mercapto vinyl ether copolymer, polyvinyl alcohol, sodium polyacrylate and calcium polyacrylate, polyacrylic acid, acidic carboxyl polymer, carboxypolymethylene, carboxyvinyl polymer, polyoxyethylene polyoxypropylene copolymer, poly Methyl vinyl mystery-cis-succinic anhydride, rebel Amine, potassium methacrylate divinylbenzene copolymer, polyoxyethylene glycol, polyethylene oxide, and derivatives, salts and combinations thereof. In a particular embodiment, the polymer is a polyalkylene glycol, including, for example, polyethylene glycol (PEG). In some embodiments, the heterologous moiety is a carbohydrate. In some embodiments, the carbohydrate is a monosaccharide (eg, glucose, galactose, fructose), a disaccharide (eg, sucrose, lactose, maltose), an oligosaccharide (eg, raffinose, stachyose), a polysaccharide (starch, starch) Enzymes, gelatinous starch, cellulose, quercetin, tannins, kelp polysaccharides, xylan, mannan, fucoidan, galactomannan In some embodiments, the heterologous moiety is a lipid. In some embodiments, the lipid is a fatty acid, a decanoic acid, a prostaglandin, a leukotriene, a thromboxane, a N-mercaptoethanolamine, a glycerol lipid (eg, a monosubstituted, disubstituted, trisubstituted glycerol), a glycerophospholipid (eg phospholipid choline, phospholipid creatinine, phospholipid oxime ethanolamine, phospholipid lysine), sphingolipids (eg sphingosine, neuromannamine), sterol lipids (eg steroids, cholesterol), pregnenol Ketone lipid (pren〇1 lipid), bile lipid or polyketide, oil sputum, cholesterol, sterol, fat-soluble vitamin, monoglyceride, diglyceride, three 156004.doc _ 150· 201143790 glyceride Phospholipid

Fc fusion heterologous moiety As described above, in some embodiments, Q binds, eg, to an immunoglobulin or a portion thereof (eg, a variable region, a CDR or an Fc region). As described herein, Q can be a sucrose Super-family peptides, glycoside-related peptides (including diterpenoids, class 2, class 3, class 4, or class 5 ghrelin-related peptides), or osteocalcin, aspirin, and branches Starch or an analogue, derivative or combination thereof. Immunoglobulins (Ig) of the type that have been claimed include IgG, IgA, IgE, igD or IgM. The Fc region is the c-terminal region of the lg heavy chain that is responsible for binding to the receptor to perform such as recycling (prolonged half-life), antibody-dependent cell-mediated cytotoxicity (ADCC), and complement dependent cytotoxicity (CDC). active. For example, according to some definitions, the human IgG heavy chain Fc region is self-heavy.

Cys226 extends to the C-terminus. The "strand region" generally extends from Glu216 of human igGl to Pro230 (the hinge region of other IgG isoforms can be aligned with the IgG1 sequence by aligning cysteine involved in cysteine bonding). Fc of IgG The zone φ includes two constant domains CH2 and CH3. The CH2 domain of the human IgG Fc region typically extends from amino acid 231 to amino acid 341. The CH3 domain of the human IgG Fc region typically extends from amino acid 342 to 447. References to amino acid numbers of immunoglobulin or immunoglobulin fragments or regions are based entirely on Kabat et al., 1991, Sequences of Proteins of Immunological Interest, U.S. Department of Public Health, Bethesda, Md. In a related embodiment, the Fc region may comprise one or more native or modified constant regions other than CHI in the immunoglobulin heavy chain, such as the CH2 and CH3 regions of IgG and IgA, or the CH3 and CH4 regions of IgE. 136004.doc -151 - 201143790 Suitable binding moieties include portions of the immunoglobulin sequence that include the FcRn binding site. The rescue receptor FcRn negatively recycles the immunoglobulin and returns it to the blood circulation. The binding of the Fc portion of IgG to the region of the FcRn receptor has been described based on X-ray crystallography (Burmeister et al., 1994, Nature 372:379). The main contact region between Fc and FcRn is close to the junction of the CH2 domain and the CH3 domain. The Fc-FcRn contacts are all within a single Ig heavy chain. The main contact sites include the amino acid residues 248, 250-257, 272, 285, 288, 290-291, 308_311 and 314 of the CH2 domain, and the amino acid residues 385-387, 428 and 433 of the CH3 domain. 436. Some binding moieties may or may not include a FcyR binding site. FcyR is responsible for ADCC and CDC. Examples of positions in the Fc region that are in direct contact with FcyR are amino acid 234-239 (lower hinge region), amino acid 265-269 (B/C ring), and amino acid 297-299 (C'/E ring). And amino acid 327-332 (F/G ring) (Sondermann et al., iVaiwre 406: 267-273, 2000). The hinge region under the IgE also involves FcRI binding (Henry et al., 36, 15568-15578, 1997). Residues involved in IgA receptor binding are described in Lewis et al, μ 175:6694-701, 2005). Amino acid residues involved in IgE receptor binding are described in Sayers et al. (//〇/C/zem. 279(34): 35320-5, 2004) in which the Fc region of an immunoglobulin can be amined. Acidic modification. The variant Fc regions comprise at least one amino acid modification in the CH3 domain of the Fc region (residues 342 to 447) and/or at least one amine in the CH2 domain of the Fc region (residues 231 to 341) Acidic modification. Mutations conferring enhanced affinity for FcRn include T256A, T307A, E380A and N434A (Shields et al, 2001, 156 156004. doc-152-201143790 5/o/· CTiem 276:6591). Other mutations can reduce the binding of the Fc region to FcyRI, FcyRIIA, Fc7RIIB and/or FcyRIIIA without significantly reducing the affinity for FcRn. For example, substitution of Asn at position 297 of the Fc region with Ala or another amino acid can remove highly conserved N-glycosylation sites and reduce the immunogenicity of the Fc region while extending half-life and reducing Combined with it (Routledge et al., 1995, TVanw/artiaizo) 60:847; Friend et al., 1999, Transplantation 68:1632; Shields et al., 1995, Lu./. C/zem. 276:6591). In igGl Amino acid modification at positions 233 to 236 to reduce binding to FcyR (Ward and Ghetie 1995, TTzerapewiic /; «(10)〇/〇幻; 2:77; and Armour et al., 1999, five wr. ·/ 29:2613). Some exemplary amino acid substitutions are described in U.S. Patent Nos. 7,355,008 and 7,381,408, the disclosures of each of each of each of The Q is covalently bonded to the hydrophilic moiety φ. As described herein, Q may be a glycoside superfamily peptide or a glycoside related peptide (including the first class 'category 2, class 3, Class 4 or Category 5 ghrelin-related peptides)' or osteocalcin, calcitonin, amylopectin or analogues or derivatives thereof The conjugate. The hydrophilic moiety can be attached to Q under any conditions suitable for reacting the protein with the activated polymer molecule. Any means known in the art can be used, including via a reactive group on the PEG moiety (eg, aldehyde) , amine, ester, thiol, decyl, maleimide or fluorenyl) reactive groups on the target compound (eg aldehyde, amine, ester, thiol, alpha-dentate) Mercapto, maleimide or fluorenyl) 醯156004.doc -153· 201143790 chemistry, reductive ortho-ation, Michael addition, thiol alkylation or other chemical selectivity Binding/joining methods. Activating groups that can be used to bond a water soluble polymer to one or more proteins include, without limitation, cis, maleimide, sulfhydryl, thiol, trifluoromethanesulfonic acid Ester group, difluoroethyl acid S group, nitrogen propylene bite, ethylene bromide, 5-° ratio bite base and α-halogenated base (eg α-iodoacetic acid, α-bromoacetic acid, α-gas acetic acid) If the linker is attached to the peptide by reductive denaturation, the selected polymer should have a single reactive aldehyde. In order to control the degree of polymerization. See, for example, Kinstler et al., di/v. Dri/g. De/iverj; ^ev 54: 477-485 (2002); Roberts et al., 乂DrMg De/iver;; 54: 459-476 (2002); and Zalipsky et al., ddv. 16: 157-182 (1995). Other activating groups which can be used to bond the hydrophilic moiety (water soluble polymer) to the protein include alpha-halogenated sulfhydryl groups (e.g., alpha-iodoacetic acid, alpha-bromoacetic acid, alpha-gas acetic acid). In a particular aspect, the amino acid residue having a thiol is modified with a hydrophilic moiety such as PEG. In some embodiments, a thiol-containing amino acid on Q is modified with a maleic acid-activated PEG in a Michael addition reaction to produce a PEGylated peptide comprising a thioether linkage as follows:

In some embodiments, the thiol of the amino acid of Q is modified with a ketone-activated PEG in a nucleophilic substitution reaction to produce a PEGylated peptide comprising a sulfur linkage as shown below: 156004.doc • 154· 201143790 Peptide ο ° Suitable hydrophilic parts include polyethylene glycol (PEG), polypropylene glycol, polyoxyethylated polyols (such as POG), polyoxyethylated sorbitol, polyoxyethylated glucose, polyoxygen Ethylene glycerol (POG), polyoxygen oxide, polyethylene glycol propionaldehyde, copolymer of ethylene glycol/propylene glycol, monomethoxy-polyethylene glycol, mono-(C1-C10) alkoxy_polyethyl Di- or aryloxy-polyethylene glycol, carboxymethyl cellulose, polyacetal, polyvinyl alcohol (PVA), polyvinylpyrrolidone, poly-1,3-dioxolane, Poly-fluorene, 3,6-trioxane, ethylene/maleic anhydride copolymer, poly(β-amino acid) (homopolymer or random copolymer), poly(n_vinyl" Poly(ethylene glycol), polypropylene glycol homopolymer (ppG) and other polyoxyalkylenes, polyoxypropylene/ethylene oxide copolymers, colonic acid (c〇1〇nic acid) or other polysaccharides , Fei Keer (Ficoll) or polydextrose, and mixtures thereof. Polydextrose is a polysaccharide unit in which the glucose subunit is mainly bonded by α 1 -6 bonds. Polydextrose can be used in a variety of molecular weight ranges (e.g., from about 1 kD to about 100 kD' or from about 5, 10, 15 or 20 kD to about 20, 30, 40, 50, 60, 70, 80 or 90 kD). According to some embodiments, the hydrophilic moiety, such as a polyethylene glycol chain, has a molecular weight selected from the range of from about 500 to about 40,000 Daltons. In some embodiments, the polyethylene glycol chain has a molecular weight selected from the range of from about 5 Å to about 5, 〇〇〇 Daltons, or from about 1,000 to about 5,000 Daltons. In another embodiment, the hydrophilic moiety, such as a polyethylene glycol chain, has a molecular weight of from about 丨〇, 〇〇〇 to about 20,000 Daltons. In other exemplary embodiments, the hydrophilic moiety, such as a polyethylene glycol chain, has a molecular weight of from about 2 Torr to about 4 Torr. 156004.doc •155· 201143790 Covers linear or branched hydrophilic polymers. The resulting combination preparation is substantially monodisperse or polydisperse, and each peptide may have about 〇5, 〇7, i, 1.2, 1.5 or 2 polymer moieties. In some embodiments, the native amino acid of the peptide is substituted with an amino acid having a side chain suitable for crosslinking with the hydrophilic moiety to facilitate bonding of the hydrophilic moiety to the shape. Exemplary amino acids include Cys, Lys, 〇rn, high-Cys or acetyl-phenylalanine (Ac-Phe). In other embodiments, an amino acid modified to include a hydrophilic group is added to the peptide at the C-terminus. In some embodiments, the peptide of the conjugate is bonded to the hydrophilic moiety via a covalent bond between the side chain of the amino acid of the peptide and the hydrophilic moiety, such as pEG^, in some embodiments, wherein Q is the first class a Class 2, Class 3, Class 4 or Class 5 ghlylin-related peptide, the position of the peptide via position 丨6, i 7, 2 i, 24, 29, 40, C-terminal extension, or c The terminal amino acid, or the side chain of the amino acid on the combination of these positions, is bonded to the hydrophilic moiety. In some aspects, an amino acid covalently bonded to a hydrophilic moiety (eg, a side bond comprising a hydrophilic amine group Ssl is covalently bonded to a hydrophilic moiety (eg, peg). rPEG heterologous moiety in some embodiments In the present invention, the conjugate of the present invention comprises Q fused to a helper peptide (e.g., a recombinant pEG (rpEG) molecule) capable of forming a stretch similar to that of a chemical PEG, such as the International Patent Application Publication No. WO〇2〇09 The PEG molecule is not polyethylene glycol as described in U.S. Patent Application Publication No. 2,8/2,868,8. In some aspects, the rPEG knife contains glycine. , alanine, amylin, aspartic acid, c] 56004.doc -156- 201143790 A polypeptide of one or more of aminic acid or proline. In some aspects, rPEG is a homopolymer. For example, poly-glycine, poly-serine, poly-glutamic acid, poly-aspartic acid, poly-alanine or poly-proline. In other embodiments, rPEG contains two types of repeats. Amino acids, such as poly(Gly Ser), poly(Gly-Glu), poly(Gly_Ala), poly(Gly_Asp), poly(Gly_pr〇), poly(8^-011 1) Etc. In some aspects, rPEG contains three different types of amino acids, such as poly(Gly-Ser-Glu) » In a particular aspect, rpEG extends the half-life of q φ. In some cases, rPEG Containing a net positive or net negative charge. In some aspects, rPEG lacks a secondary structure. In some embodiments, the length of 'rPEG is greater than or equal to 1 胺 amino acid, and in some embodiments, the length is about 40 to about 50 amino acids. In some aspects, the helper is fused via a peptide bond or protease cleavage site to the N-terminus or c-terminus of the peptide of the invention or inserted into the loop of the peptide of the invention. In some aspects Wherein rPEG comprises an affinity tag or linkage to a PEG greater than 5 kDa. In some embodiments, rPEG confers a conjugate of the invention to increase hydrodynamic radius, serum half-life, protease resistance or solubility, and Some aspects give the conjugate a reduced immunogenicity. Q can be achieved by making the target amino acid residue of the peptide and the selected side chain or N-terminal residue or C-terminus of the target amino acid. The organic derivatizing agent of the residue reaction is linked via a direct covalent bond To the binding moiety. The reactive group on the peptide or binding moiety includes, for example, an aldehyde, an amine group, an ester, a thiol, an α-dentyl fluorenyl group, a maleenedimino group or a fluorenyl group. Derivatizing agents include, for example, cis. Butadiene diimide benzylidene hydrazinoyl succinimide (clustered via cysteine residues), hydrazine-hydroxybutanediamine (via lysine residues), glutaraldehyde - 156004.doc -157- 201143790 or other derivatizing agents known in the art. Alternatively, the binding moiety can be indirectly linked to the peptide via an intermediate carrier, such as a polysaccharide or polypeptide carrier. Examples of multi-biliary carriers include amine-based polydextrose. Examples of suitable polypeptide carriers include polylysine, polyglutamic acid, polyaspartic acid, copolymers thereof, and mixed polymers of such amino acids with other amino acids (e.g., serine) to impart The resulting supported support has the desired solubility characteristics. Multimers For class 1 'category 2 and class 3 ghrelin-related peptides, q can be a dimeric, dimer comprising at least two, three or more peptides linked via a linker A portion of a graded multimer' wherein at least one or two of the peptides are glycopeptide-related peptides. The dimer can be a homodimer or a heterodimer. In some embodiments, the linker is selected from the group consisting of a difunctional thiol crosslinker and a difunctional amine crosslinker. In certain embodiments, the linker is pEG, such as 5 kDa PEG, 20 kDa PEG. In some embodiments, the linker is a disulfide bond. For example, each monomer of the dimer may comprise a cys residue (e.g., a Cys located at the end or inside), and the sulfur atom of each Cys residue participates in disulfide bond formation. In some aspects of the invention, the monomer is via a terminal amino acid (eg, N-terminus or C-terminus), via an internal amino acid, or via at least one monomeric terminal amino acid and at least one other monomer Internal amino acid linkage. In a particular aspect, the monomers are not linked via an N-terminal amino acid. In some aspects, the monomers of the 'multimer are oriented in a "tail-to-tail" orientation in which the C-terminal amino acids of each monomer are linked together. The binding moiety can be covalently linked to any of the glycein-related peptides described herein, including dimers, trimers or higher polymers. 156004.doc -158· 201143790 The combination of the heterogeneous part and Q is based on the "Weng Teng Thirst" part and the "2 and /41"/6Peiyu#" sub-parts. The source moiety binds to the peptide (Q).

The peptide (Q) disclosed herein can be prepared by standard synthetic methods, recombinant DNA techniques, or any other method of preparing peptides and fusion proteins. While certain non-natural amino acids cannot be represented by standard recombinant DNA techniques, their preparation techniques are known in the art. Compounds of the invention encompassing non-peptide moieties can be synthesized by standard organic chemical reactions as well as standard peptide chemical reactions where appropriate. Peptides of the invention can be obtained by methods known in the art. Suitable methods for re-synthesizing peptides are described, for example, in Chan et al., Fwoc So/zW household/mje Peptide Synthesis, Oxford University Press, Oxford, United Kingdom, 2005; Peptide and Protein Drug Analysis, Reid, R. ed., Marcel Dekker, Inc., 2000; Μα/?〆, issued by Westwood et al., Oxford University Press, Oxford, United Kingdom, 2000; and U.S. Patent No. 5,449,752. Likewise, where the peptide of the present invention does not comprise any non-coding or non-natural amino acid, the peptide can be recombinantly produced using standard recombinant methods using nucleic acids encoding the amino acid sequence of the peptide. See, for example, Sambrook et al, Molecular Cloning: A Laboratory Manual. 3rd edition, Cold Spring Harbor Press, Cold Spring Harbor, NY 2001; and A\is\ibe\Special Rule, Current Protocols in Molecular Biology,

Greene Publishing Associates and John Wiley & Sons, NY, 1994. 156004.doc -159- 201143790 In some embodiments, the peptides of the invention are isolated. In some embodiments, the peptides of the invention are purified. It should be understood that "purity" is a relative term and does not necessarily have to be considered absolute or absolute or absolute. In some aspects, the purity is at least or about 50%, at least or about 60%, at least or about 70%, at least or about 80%, or at least or about 90% (eg, at least or about 91%, at least or about 92). %, at least or about 93%, at least or about 94%, at least or about 95%, at least or about 96°, at least or about 97°, at least or about 98%, at least or about 99%, or about 100. %). In some embodiments, the peptides described herein can be synthesized commercially from companies such as Synpep (Dublin, CA) 'Peptide Technologies Corp. (Gaithersburg, MD) and Multiple Peptide Systems (San Diego, CA). In this regard, the peptide can be a synthetic, recombinant, isolated, and/or purified peptide. The various glycosidin related peptides (Q) are described in detail below. For parts of the invention relating to class 1, class 2, class 3, class 4 and class 5 ghrelin-related peptides, 'on the glycoside associated with the Q_L-Y conjugate detailed above The peptide moiety (Q) describes the modification. Thus, for a class of ghrelin-related peptides, the structural element is a structural element of Q, which is then further modified to produce a Q-L-Y conjugate as described above. Class 1 Glycoglycan-Related Peptides In certain embodiments, the glycosidin-related peptide is a Class 1 glycoside-related genus, which is described herein and in International Patent Publication No. WO 2009/155257 (2009-12) Published on the 23rd of the month), International Patent Application Publication No. W〇2008/086086 (published on July 17, 2008) and International Patent Application Publication No. 156004.doc • 160·201143790 Case No. WO 2007/056362 ( The contents of these patents are hereby incorporated by reference in their entirety in their entireties. The biological sequences (SEQ ID NO: 801-915) mentioned in the following section for the class 1 glucosamine-related peptide correspond to SEQ ID NOS: 1-115 in International Patent Publication No. WO 2009/155257. Activity The first type of ghrelin peptide retains glycosidic receptor activity relative to the native glucagon peptide (SEQ ID NO: 801). For example, the activity retained by the glycoside peptide is at least 1%, 20%, 30%, 40%, 50%, 60°/ of the native glycemic activity. , 70°/. , 75°/. , 80%, 85% or 90% (calculated as the inverse ratio of ECso of the glycemic peptide to Ec5〇 of the glycein, for example as measured by cAMP production using the assay described generally in Example 2). In some embodiments, the activity of the first type of ghrelin-related peptide is the same as or greater than the activity of the glycoside (synonymously used herein with the term r-efficacy). In some embodiments, the glycoside peptides described herein exhibit an activity of up to about 100 of the activity of the native glycosidic peptide. /〇, 1〇〇〇%, 1〇〇〇〇%, 1〇〇〇〇〇% or 1,000,000% Any of the Class 1 glycosidin-related peptides described herein are overexpressed in, for example, the test using Example 2. The EC5Q exhibited by the human glucomannin receptor upon induction of cAMp in HEK293 cells of the glycosidic receptor may be about 1〇〇nM, 75 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 5 nM, 1 nM or i nM or less. In general, PEGylated peptides exhibit higher ec5〇 than peptides that are not pegylated. For example, the diterpene glycosidic traits described herein exhibit a glucosinoid-like activity on the glycoside receptor when PEGylated. 156004.doc -161 - 201143790 is a native glucosinolate (SEQ ID) NO·· 801) at least 20% of the activity of the glycemic receptor (eg, at least 30%, at least 4%, at least 5%, at least, at least 75%, at least 80%, at least 90%, at least 95°) /., at least 98. /, at least 99%, 1〇0%, 15〇%, 2〇〇%, 4〇〇%, 5〇〇% or more than 5〇〇). In certain embodiments, the diterpene-like glycosidic-related peptide described herein exhibits an activity on the glycosidic receptor in the absence of a hydrophilic moiety as indicated by the percentage of native glycemic activity, but in the presence of a hydrophilic The activity exhibited by the glycosidic receptor in the sexual moiety was reduced compared to the percentage of native glycemic activity. For example, a third glucoside-related peptide described herein exhibits at least 2% (eg, at least 3%) of the activity of a native glycein upon PEGylation. At least 4%, at least 5%, at least 6%, to /7/〇, at least 8%, at least 9%, or at least 1%). In some embodiments, the activity of the first type of ghrelin-related peptide described herein for a glycosidic receptor can be any of the activities shown above, but is at most 1000% of the native glycemic activity, 10,000%, 100,000% or 1%β In some embodiments, the activity of the diterpene glycosidic-related peptide on the GLP_丨 receptor is about 5% of the native GLP-1 activity, 4%, 3%, 2% or less and/or its selectivity to the glycoside receptor is about 5 times, 1 time or more than the selectivity to the GLP-1 receptor. For example, in some embodiments, the Class 1 ghlylin-related peptide exhibits a GLPd receptor exhibiting less than 5% of the native GLP-1 and exhibits selectivity for the Glycosin receptor to the GLP. The selectivity of the -1 receptor is more than 5 times. Improved Solubility Native Glycerin exhibits poor performance in aqueous solutions, especially at physiological pH. 136004.doc •162- 201143790 Solubility' tends to accumulate and precipitate over time. In contrast, in some embodiments, the solubility of the first type of glycosidin-related peptide at a pH of 6 to 8 or 6 to 9 (eg, pH 7) after 24 hours at 25 ° C is the solubility of the native glycein. At least 2 times, 5 times or even 5 times or more. Thus 'in some embodiments, the first type of ghrelin-related peptide has been relative to the wild-type peptide 1^-86]>0111-013/'-1'111>-?116-1'1111-8611-eight 8卩-丁丫1>-861·-

Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-

Trp-Leu-Met-Asn-Thr (SEQ ID NO: 801) is modified to improve the solubility of the peptide in an aqueous solution, especially at a pH in the range of from about 5.5 to about 8.0, while retaining the biological activity of the native peptide. For example, the solubility of any of the diterpene-like glycosidin-related peptides described herein can be further improved by attaching a hydrophilic moiety to the peptide. Introduction of such groups also extends the duration of action, e.g., as measured by the extended circulating half-life. Hydrophilic moieties are further described herein. Modification with Charged Residues In some embodiments the solubility is replaced by a charged amino acid selected from the group consisting of lysine, arginine, histidine, aspartic acid, and glutamic acid. The charged amino acid is improved by adding a charged amino acid to the amine or carboxyl terminal of the peptide to add a charge to the first type of glycosidin-related peptide. According to some embodiments, the first type of ghrelin-related peptide has been introduced into the C-terminal portion of the peptide by substitution and/or addition by an amino acid, and in some embodiments, The peptide is modified from the C-terminus to position 27 of SEQ ID NO: 801 to have improved solubility. can

156004.doc -163- S 201143790 Optionally, one m charged amino acid is introduced into the c-terminal portion, and in some embodiments, the c-terminus is introduced into position 27. According to some embodiments 'the primary amino acid at position 28 and/or 29 is substituted with a charged amino acid' and/or one to three charged amino acids are added to the c-terminus of the peptide, eg position 27 28 or 29 after that. In an exemplary embodiment, one, two, two or all of the charged amino acids are negatively charged. In other embodiments, one, two, three or all of the charged amino acids are positively charged. In a specific exemplary embodiment, the first type of ghrelin-related peptide may comprise either or both of the following modifications: substitution of N28 with E; substitution of N28 with D; substitution of T29 with D; substitution of T29 with E; Insert E after 27, 28 or 29; insert d after position 27 '28 or 29. For example, D28E29, E28E29, E29E30, E28E30, D28E30. According to an exemplary embodiment, the steroidal glycoside-related peptide comprises the amino acid sequence SEQ ID NO: 811 ' or it is contained relative to the native glycoside! Up to 3 analogs of other amino acid modifications (described herein with respect to the glycoside agonist), or their glycoside agonist analogs. SEq Π) NO: 811 represents a modified type 1 ghlylin-related peptide in which the aspartic acid residue at position 28 of the native protein has been substituted with aspartic acid. In another exemplary embodiment, the first type of ghrelin-related peptide comprises the amino acid sequence SEQ ID NO: 838, wherein the aspartame residue at position 28 of the native protein has been substituted with glutamic acid. Other exemplary embodiments include the first class of ghrelin-related peptides of SEQ ID NOs: 824, 825, 826, 833, 835, 836, and 837. Substituting a charged amino acid for the amino acid normally present at position 28 and/or 29 and/or adding one or two charged amino acids to the first type of glycosidic phase 156004.doc • 164-201143790 The carboxy terminus of the peptide enhances the solubility and stability of the glycopeptide peptide in the aqueous solution at physiologically relevant pH (i.e., a pH of from about 6.5 to about 7.5) to at least 5 fold and up to 3 fold. Thus, some of the i-type glycosidic peptides of some embodiments retain glycemic activity and are exhibited at a predetermined pH (eg, pH 7) of about 55 to 8 when measured 24 hours after 25 °C. The solubility is at least 2 times, 5 times, 1 time, 15 times, 25 times, 30 times or 30 times or more of the solubility of the native glycein. φ may perform other modifications to the type 1 ghlylin-related peptide (eg, conservative substitutions such modifications are further described herein) while still retaining glycosidic activity. Improved stability of any type 1 glucosin peptide Additional improved stability and/or reduced degradation may be exhibited, for example, retaining at least 95% of the original peptide after 24 hours at 25 °C. Any of the dioxins-like peptides disclosed herein may additionally exhibit improved stability at pH values in the range of 55 to 8, for example at 25. At least 75%, 80%, 90%/〇, 95%, 96%, 97%, 98% or 99% of the original peptide is retained after 24 hours of φ. In some embodiments, the i-type glycosidin-related peptides of the invention exhibit improved stability, thereby at least 2 Å. 〇 (eg 2rc, 22°C, 23°C, 24. (:, 25〇C, 26〇C, at least 27.5°C, at least 3 (TC, at least 35°C, at least 4 (TC, at least 50.〇) And at a temperature below 100t, below 85C, below 75C or below 70C in solution for about weeks or more (for example about 2 weeks, about 4 weeks, about 1 month, about 2 months, about At least 75% (eg, at least 8%) can be detected by ultraviolet (UV) detectors at 280 nm after 4 months, about 6 months, about 8 months, about 10 months, about 12 months. , 156004.doc -165- 201143790 at least 85%, at least 90%, at least 95%, 95% or more, up to 1% by weight of the peptide or about 25 ° /. (for example, 20% or less, 15 / 〇 Hereinafter, a degradation peptide of 1 〇 0 / 〇 or less, 5 〇 / 〇, 4 〇 / 〇, 3%, 2%, 1% or less, down to 〇 %). The first type of glucosamine related peptide may include a change thereof Medical properties, such as enhancing potency, prolonging circulating half-life, extending shelf life, reducing precipitation or aggregation, and/or reducing degradation, such as reducing other modifications that occur after storage or chemical modification. In other exemplary embodiments, any of the above Diterpene glycoside The peptide can be further modified to improve stability by modifying the amino acid at position 15 of SEQ ID NO: 801 to reduce degradation of the peptide, particularly in acidic or alkaline buffers over time. In an exemplary embodiment The Asp at position 15 is substituted with Glu, high-Glu, sulfoalanine or homosulfoalanine. Alternatively, any of the first type of ghrelin-related peptides described herein can be modified by SEQ ID NO: 801 The amino acid at position 16 is further modified to improve stability. In an exemplary embodiment, Ser at position 16 is substituted with Thr or Aib' or as described herein with respect to the first class of ghrelin-related peptides. Any amino acid substitution that enhances the potency of the glycoside receptor. These modifications reduce the cleavage of the peptide bond between Aspl5-Serl6. In some embodiments, any of the diterpene-like glycosidin-related peptides described herein can be Further modification at each amino acid position by modification of either, two, three, or all of positions 2, 21, 24, or 27 to reduce degradation. Exemplary embodiments include using Ser , Thr, Ala or Aib replaces Gin at position 20; replaces with Glu Asp at position 21; replace Gin at position 24 with Ala or Aib; replace Met at position 27 with Leu or Nle. Remove or J 56004.doc -166- 201143790 Substituting thiol amide to reduce methionine Degradation by acid oxidation. Removal or substitution of Gin or Asn can reduce the degradation caused by Gin or Asn deamination. The removal or substitution of Asp can reduce the formation of cyclic dimercaptoimine intermediates by the dehydration of Asp. Degradation of the formation of iso-aspartate. Enhanced Potency According to another embodiment, there is provided a Class 1 ghlylin-related peptide having enhanced potency to a glycoside receptor, wherein the peptide is at position 16 of the native glucosinolate (SEq out NO: 801) Contains amino acid modifications. In a non-limiting example, either by using glutamic acid or by using another negatively charged amino acid having a side chain of 4 atoms in length, or using branic acid, lysine or sulfopropylamine Any of the acids, or a substituted amino acid having a side chain having at least one hetero atom (eg, n, fluorene, S, P) and having a side chain length of about 4 (or 3 to 5) atoms The naturally occurring serine at position 16 provides this enhanced efficacy. Substitution of the leucine at position 16 with glutamic acid enhances the glycosidic activity of the glycosidic receptor by at least 2 fold, 4 fold, 5 fold and up to 1 fold. In some embodiments, the selectivity of the diterpene-like glycosidic-related peptide to the glycoside receptor is, for example, at least 5, 10 or 15 times greater than the selectivity to the GLPq receptor. DPP-1V Resistance In some embodiments, the Class 1 ghlylin peptides disclosed herein are in position 1 or 2 to a progressive repair to reduce the likelihood of dipeptidyl peptidase IV causing cleavage. More specifically, in some embodiments, position 1 and/or position 2 of the i-type glucosinoid-related peptide is substituted with a Dppqv-resistant amino acid as described herein. In some embodiments, position 2 of the analog-like peptide is taken from the aminoisobutyric acid 156004.doc-167-201143790 generation. In some embodiments, position 2 of a similar peptide is substituted with an amino acid selected from the group consisting of: D-serine D-alanine, glycine, N-methylserine, and ε-amine Butyric acid. In another embodiment, position 2 of the first type of ghrelin-related peptide is substituted with an amino acid selected from the group consisting of D-serine, glycine, and aminoisobutyric acid. In some embodiments, the amino acid at position 2 is not D-serine. The decrease in glycemic activity after modification of the amino acid at position 1 and/or position 2 of the glycemic peptide can be achieved by stabilizing the glycoside-like C-terminal portion (approximately amino acid 12 to 29) The alpha-helical structure is restored. The alpha helix structure can be formed, for example, by the formation of a covalent or non-covalent intramolecular bridge (e.g., a side chain of an amino acid at position "i" and an amino acid at position r i+4" as described further herein. An intrinsic amine bridge between the side chains, wherein i is an integer from 12 to 25), substituted with an alpha helix stabilized amino acid (eg, an alpha, alpha disubstituted amino acid) and/or inserted substantially at position 12 Stabilize by the amino acid up to 29. The modified glycosidic receptor activity at position 3 can be modified by amino acid at position 3 (numbered according to the amino acid of wild type glucosin), for example by acid, anionic or hydrophobic amino acid The naturally occurring branial acid at position 3 reduces β by way of example and s ' substitution at position 3 with glutamic acid, ornithine or noraltamine can substantially reduce or disrupt the glycosidic receptor activity.

The activity at the glycecan receptor can be maintained or enhanced by modifying the Gin at position 3 with a glutamate analog as described herein. For example, the glycoside agonist may comprise the amino acid sequence SEQ ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 870, SEQ ID NO: 871, SEQ ID 156004. doc-168 - 201143790 NO : 872, SEQ ID NO: 873 and SEQ ID NO: 874. The C-terminal guanamine and the ruthenium glp-1 activity enhance the activity of the GLP-1 receptor by replacing the C-terminal amino acid with a charge-neutral group such as a guanamine or an ester. Conversely, the native tracism at the c-terminus of the retained form maintains that the selectivity of the first type of glycosidin-related peptide to the glycoside receptor is relatively higher than that of the GLP4 receptor (eg, the former is about 5 of the latter). 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16

17, 18, 19 or 20 times or more). Other Modifications and Combinations Other modifications of the Class 1 ghlylin-related peptide can be made to further enhance solubility and/or stability and/or glycemic activity. The first class of ghrelin-related peptides may alternatively comprise other modifications that do not substantially affect solubility or stability and do not substantially reduce the activity of the glycoside. In an exemplary embodiment, the steroidal glycoside-related peptide may comprise a total of up to 11 or up to 12, or up to η, or up to 14 amino acid modifications. For example, it may be conservative or at any of positions 2, 5, 7, 10, u, 12, 13, 14, 17, 18, 19, 20, 21, 24, 27, 28 or 29. Non-conservative substitutions, additions or deletions. Exemplary modifications of the first class of ghrelin-related peptides include, but are not limited to: (4) non-conservative substitutions, conservative substitutions, additions or deletions while retaining at least a portion of the glycemic agonist activity, eg, at position 2 5,7,1〇,12,13,14,16,17,18,mm" (4) or more in the conservative substitution or in the position of the heart substitution Tyr' replaces Lys at position 12 with Arg. Substituting one or more of these 156004.doc 201143790 positions; (b) causing the amino acid at position 29 and/or 28' and optionally deleting the amino acid at position 27 while retaining at least a portion of the glycemic acid An agonist activity; (0) to modify aspartic acid at position 15 by substitution with glutamic acid, glutamic acid, sulfoalanine or homo-alanine to reduce degradation; or for example by Use threonine, Aib, glutamic acid or another negatively charged amino acid with a side chain of 4 atoms in length, or use branic acid, glutamic acid or high sulfoalanine Either one of them is substituted to modify the serine at position 16, so as to reduce the bond due to gossip 15 8^16 Degradation caused by; (d) adding a hydrophilic moiety (such as a water-soluble polymer polyethylene), for example, at position 16, I?, 2?, 21, 24, 29, 40 or a C-terminal amino acid as described herein; a diol) to enhance solubility and/or extend half-life; (e) to modify methionine at position 27 to reduce oxidative degradation, for example by substitution with leucine or ortho-amine; (f) Modification of Gin at position 20 or 24 by substitution with Ser, Thr, Ala or Aib to reduce degradation by removal of the guanamine group via Gin; (g) modification of position 21 by, for example, substitution with Glu Asp, to reduce degradation by the formation of cyclic succinimide intermediates via Asp dehydration and subsequent isomerization of isoaspartic acid; (h) Improved lpp_iv cleavage at position 1 or 2 as described herein The modification of the resistance 'as appropriate combines intramolecular bridges, such as the intrinsic amine bridge between positions ri" and "1+4", where i is an integer from 丨2 to 25, for example 12 ' 16 ' 20 &gt ; 24 ; 156004.doc -170- 201143790 (i) Deuterated or alkylated ghrelin peptide as described herein to enhance glycoside And/or activity of the GLP-1 receptor, prolonging the circulating half-life and/or prolonging the duration of action and/or delaying the onset of action; optionally adding a hydrophilic moiety; additionally or alternatively, optionally combining Modifications that reduce the activity of the GLP-1 peptide, such as modification of Thr at position 7, such as substitution of Thr at position 7 with an amino acid lacking a transradical (eg, Abu or ne); Deletion of the amino acid in the amino acid (eg, deletion of one or two amino acids at positions 28 and 29 to yield a peptide of 27 or 28 amino acids in length); (1) C-terminus as described herein Extending (k) homodimerization or heterodimerization as described herein; and combinations of (a) to (k). In some embodiments, exemplary modifications of the first type of ghrelin-related peptide comprise at least one amino acid modification selected from group A and one or more amino acids selected from group b and/or group C Modification, wherein group A is: substituting Asn at position 28 with a charged amino acid; replacing position 28 with a charged amino acid selected from the group consisting of

Asn: Lys, Arg, His, Asp, Glu, sulfoalanine and high sulfoalanine; substituted with Asn, Asp or Glu at position 28; substituted with Asp at position 28; used at position 28 Substituting Glu; substituting a charged amino acid for Thr at position 29; 156004.doc -171 - 201143790 Substituting Thr: Lys, Arg, His, at position 29 with a charged amino acid selected from the group consisting of: Asp, Glu, propyl aginate and homotyl alanine; substituted with Asp, Glu or Lys at position 29; substituted with Glu at position 29; 1 to 3 charged amino acids after position 29; Insert Glu or Lys after position 29; insert Gly-Lys or Lys-Lys after position 29; or a combination thereof; wherein group B is: replace Asp at position 15 with Glu; replace position 16 with Thr or Aib Ser ; and wherein group C is: Substituting His at position 1 with a non-primary amino acid that reduces the possibility of cleaving the glycosidic peptide by dipeptidyl peptidase IV (DPP-IV); using a reduced dipeptidyl peptidase IV (DPP-IV) substitution of the non-primary amino acid of the possibility of cleavage of the glycosidic peptide with Ser at position 2; substitution of position 12 with Arg Lys; replace Gin at position 20 with Ser, Thr, Ala or Aib; replace Asp at position 21 with Glu; replace Gin at position 24 with Ser, Thr, Ala or Aib; replace position 27 with Leu or Nle Met; deletion of the amino acid at positions 27 to 29; deletion of the amino acid at positions 28 to 29; 156004.doc -172-201143790 deletion of the amino acid at position 29; or a combination thereof. In an exemplary embodiment, Lys at position 12 is substituted with Arg. In other exemplary embodiments, the amino acid at position 29 and/or 28, and optionally at position 27, is deleted. In some particular embodiments, the glycoside peptide comprises (a) an amino acid modification at position 1 and/or 2 that confers DPP-IV resistance, such as substitution of DMIA at position 1, or substitution of Aib at position 2. (b) within positions 12 to 29, such as intramolecular bridges at positions 16 and 20, or one or more positions of amino acids at positions 16, 20, 21 and 24 via alpha, alpha disubstituted amino acids Substituting; as the case may be, for example, via a Cys on position 24, 29 or a Cys linkage on a C-terminal amino acid to a hydrophilic moiety such as PEG; optionally comprising (d) a Met at position 27 substituted by, for example, Nle Amino acid modification; optionally comprising (e) a reduced amino acid modification at positions 20, 21 and 24; and optionally (1) linked to SEQ ID NO: 820. When the glycosidic peptide is linked to SEQ ID NO: 820, in certain embodiments, the amino acid at position 29 is Thr or Gly. In other specific embodiments, the glycosidin peptide comprises (a) Asp28Glu29, or Glu28Glu29, or Glu29Glu30, or Glu28Glu30, or Asp28Glu30, and optionally comprises (b) an amino acid at position 16 where Ser is substituted with, for example, Thr or Aib. Modifications, and optionally, at position (c), Met is modified with, for example, Nle-substituted amino acid at position 27, and optionally with (d) amino acid modifications at positions 20, 21, and 24 that reduce degradation. In a particular embodiment, the glycosidin peptide is T16 > A20, E21, A24, Nle27, D28, E29. In some embodiments, the first type of ghrelin-related peptide comprises the following amino acid C; 156004.doc -173- 201143790 Sequence: X1 -X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr- Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Z (SEQ ID NO: 839) having 1 to 3 amines a base acid modification, wherein XI and/or X2 is a possibility of reducing the dipeptidyl peptidase IV (DPP-IV) cleavage of the glyce peptide (or enhancing the resistance of the glycopeptide to the cleavage caused by dipeptidyl peptidase IV) a non-native amino acid, wherein the Z is selected from the group consisting of _COOH (a naturally occurring C-terminal carboxylate group), -Asn-COOH, Asn-Thr-COOH, and Y-COOH, wherein Y is 1 to 2 amino acids, and wherein the intramolecular bridge, preferably covalently bonded to the side chain of the amino acid at position i and the side bond of the amino acid at position i+4, where i is 12, 16 20 or 24 = In some embodiments the 'intramolecular bridge is an intrinsic amine bridge. In some embodiments, the amino acid at position i of SEQ ID NO: 839 and the amino acid at position 丨 +4 It is Lys and Glu, such as Glul6 and Lys20. In some embodiments, the XI is selected from the group consisting of D-His, N-methyl-His, α-methyl-His, imidazoleacetic acid, de-amino-His, hydroxy-His, ethenyl _ His, high-His and α,α-dimethylimidazoliumacetic acid (DMIA). In other embodiments, the oxime 2 is selected from the group consisting of D-Ser, D-Ala, Gly, Ν-methyl-Ser, Val, and α-aminoisobutyric acid (Aib). In some embodiments, the glycosidic peptide is covalently linked at any of the amino acid positions 16, 17, 20, 21, 24, 29, 40, within the C-terminal extension, or at the C-terminal amino acid. To the hydrophilic part. In an exemplary embodiment, the hydrophilic moiety is covalently linked to Lys, Cys, 〇rn, homocysteine or acetyl group on any of the above positions 156004.doc • 174-201143790 Amphetamine residues "Exemplary hydrophilic moieties include, for example, polyethylene glycol having a molecular weight of from about 1,000 Daltons to about 40,000 Daltons, or from about 2 Daltons to about 40,000 Daltons ( Peg). In other embodiments, the Class I ghrelin-related peptide comprises the following amino acid sequence:

Xl-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-

Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-

Met-Z (SEQ ID NO: 839) > wherein XI and/or X2 is a reduced dipeptidyl peptidase ιγφρρ^ν) possibility of cleavage of the glycosidic peptide (or enhancement of the glycosidic peptide to dipeptidyl peptidase) a non-native amino acid of 1 caused by cleavage resistance, wherein one of the positions 16, 20, 21 and 24 of the glycosidic peptide, two, three, four or more of α, The α-disubstituted amino acid is substituted, and the lanthanide thereof is selected from the group consisting of _C00H (a naturally occurring c-terminal carboxylate group), -Asn-COOH, Asn-Thr-COOH, and Y-COOH, wherein Y Exemplary 1 to 2 amino acids. Exemplary other amino acid modifications to the above-described class 1 glucomannin-related peptides or analogs include the use of amino acids lacking hydroxyl groups (eg, aminobutyric acid (Abu), lie). Substituting Thr at position 7; optionally combined to be substituted or added with an amino acid comprising a covalent linkage (optionally via a spacer) to the sulfhydryl or alkyl side chain, which is naturally Substituted amino acid is non-native; replaces Lys at position 12 with Arg; replaces Asp at position 15 with Glu; replaces Ser at position 16 with Thr or Aib; uses Ser, Thr, Ala or 156004.doc •175· 201143790

Aib replaces Gin at position 20; replaces Asp at position 21 with Glu; replaces Gin at position 24 with Ser, Thr, Ala or Aib; replaces Met at position 27 with Leu or Nle; replaces with charged amino acid Substituting Asn at position 28; substituting Asn at position 28 with a charged amino acid selected from the group consisting of: Lys, Arg, His, Asp, Glu, sulfoalanine, and high sulfoalanine; using Asn, Asp or Glu is substituted at position 28; substitution at position 28 with Asp; substitution at position 28 with Glu; Thr at position 29 with charged amino acid; with band selected from the group consisting of Charged amino acid substituted for Thr at position 29: Lys, Arg, His, Asp, Glu, sulfoalanine, and high sulfoalanine; substituted with Asp, Glu or Lys at position 29; with Glu at position 29 Substituting; inserting 1 to 3 charged amino acids after position 29; inserting Glu or Lys at position 3 (i.e., after position 29); optionally with insertion at position 3 1

Lys, SEQ ID NO: 820 is added to the C-terminus, optionally wherein the amino acid at position 29 is Thr or Gly; substitution or addition is made with an amino acid covalently attached to the hydrophilic moiety; or a combination thereof. Any of the above-described modifications of the glycosidic receptor activity, retention of partial glycosidic receptor activity, improved solubility, increased stability, or reduced degradation described in relation to the Type 1 glycosidic agonist may be used individually or in combination. In the first class of glycosidic peptides. Thus, a first type of ghrelin-related peptide can be prepared which retains activity against the glycoside receptor of at least 2% of the activity of the native glycein and at a pH of 6 to 8 or 6 to 9 (eg, PH 7) is soluble at a concentration of at least 1 mg/mL and retains at least 95% of the original peptide (eg, 5% or less of the original peptide is degraded or cleaved) after 24 hours at 25t. . Alternatively, 156004.doc -176- 201143790 prepares a high performance class 1 glycosidic peptide exhibiting at least about 100%, 125%, 150% of the activity of the proglucagon receptor for the activity of the proglucagon receptor. , 175%, 200%, 250%, 300%, 350%, 400%, 450%, 500%, 600%, 700%, 800%, 900% or 10 times or more, and optionally 6 It is soluble at a concentration of 8 or 6 to 9 (for example, pH 7) at a concentration of at least 1 mg/mL, and at least 95% of the original peptide is retained after 24 hours at 25 ° C (for example, 5 ° / ◦) Or less than 5% of the original peptide is degraded or cleaved). In some embodiments, the activity of a type 1 ghlylin peptide described herein for a glycoside receptor can be at least any of the relative activities shown above, but its activity on a glycoside receptor Examples of Examples of Up to 1,000% '5,000% or 10,000% of the Class 1 Glycanin-Related Peptide Activity According to some embodiments, the native glucagon peptide of SEQ ID NO: 801 is Substituting a negatively charged amino acid (eg aspartic acid or glutamic acid) for the primary amino acid at position 28 and/or 29 and optionally a negatively charged amino acid (eg aspartic acid or glutamine) The acid) is added to the carboxy terminus of the peptide to be modified. In an alternate embodiment, the native glucagon peptide of SEQ ID NO: 801 replaces the native amine group at position 29 with a positively charged amino acid (eg, an amine acid, arginine, or histidine) The acid is optionally modified by the addition of one or two positively charged amino acids (for example, an amine acid, arginine or histidine) to the carboxy terminus of the peptide. According to some embodiments, a glycoside analog having improved solubility and stability is provided, wherein the analog comprises the amino acid sequence SEQ ID NO: 834, with the restriction that at least one amino acid at position 28 or 29 is Acidic amino acid substitution and/or addition of 156004.doc • 177·201143790 additional acidic amino acid on the carboxy terminus of SEQ ID NO: 834. In some embodiments, the acidic amino acid is independently selected from the group consisting of Asp, Glu, sulfoalanine, and high sulfoalanine. According to some embodiments, a glycosidic agonist is provided having improved solubility and stability, wherein the agonist comprises the amino acid sequence SEQ ID NO: 833, wherein the amino acid at position 27, 28 or 29 is At least one of which is substituted with a non-primary amino acid residue (ie, at least one amino acid present at position 27, 28 or 29 of the analog is different from the corresponding position in SEQ ID NO: 801) An acidic amino acid of an amino acid, according to some embodiments, provides a glycosidic agonist comprising the sequence of SEQ ID NO: 833, with the proviso that when the amino acid at position 28 is aspartame and When the amino acid at position 29 is sulphonic acid, the peptide further comprises one to two amino acids independently added to the base of the glycosidic peptide, independently selected from the group consisting of Lys, Arg, His, Asp or Glu. . It has been reported that certain positions of the native glucagon peptide can be modified while retaining at least some of the activity of the parent peptide. Therefore, the applicant of the present invention expects the peptide of SEq ID NO: 811 to be located at positions 2, 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28 Or one or more of the amino acids on 29 may be substituted with an amino acid different from the amino acid present in the native glucagon peptide and still retain the enhanced potency, physiological pH of the parent glycoside Stability and biological activity under the value. For example, according to some embodiments, the methionine residue present at position 27 of the native form is changed to leucine or ortho-amine to prevent oxidative degradation. In some embodiments, a glycoside analog of SEQ ID N: 833 is provided, wherein the analog is selected from the group consisting of positions j, 2, 5, 7, i 〇, 1 ji 2, 136004.doc -178· 201143790 13 1 to 6 amino acids of 14, 16, 17, 18, 19, 20, 21 or 24 are different from the corresponding amino acids of SEQ ID NO. According to another embodiment, a glycoside analog of SEQ ID NO: 833 is provided, wherein the analog is selected from the group consisting of positions 1, 2, 5, 7, 10, 11, 12, 13, 14, 16, 17, 18 One to three amino acids of 19, 20, 21 or 24 are different from the corresponding amino acids of SEQ ID NO: 801. In another embodiment, a glycosidic analog of SEQ ID NO: 807, SEQ ID NO: 808 or SEQ ID NO: 834 is provided, wherein the analog is selected from the group consisting of positions 1, 2, 5, 7, 10, 11 1, 12, 13, 14, 16, 17, 18, 19, 20, 21 or 24 of 1 to 2 amino acids are different from the corresponding amino acids of SEQ ID NO: 8 01 and in another embodiment, The 1 to 2 different amino acids represent a conservative amino acid substitution relative to the amino acid present in the native sequence (SEQ ID NO: 801). In some embodiments, a glycoside peptide of SEQ ID NO: 811 or SEQ ID NO: 813 is provided, wherein the glycosidin peptide is further selected from the group consisting of positions 2, 5, 7, 10, 11, 12, 13, 14 At the position of 16, 17, 18, 19, 20, 21, 24, 27 or 29, one, two or three amino acid substitutions are included. In some embodiments, the substitution at position 2, 5, 7, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 27 or 29 is a conservative amino acid substitution. In some embodiments, a glycosidic agonist comprising a similar peptide of SEq ID NO: 801, wherein the analog differs from SEQ ID NO: 801 in that it has a different position than position in position 2 Amino acid of the amino acid and having an acidic amino acid at position 28 or 29 in place of the native amino acid, or an acidic amino acid having a carboxy terminus added to the peptide of SEQ ID NO: 801. In some embodiments, the acidic amino acid is aspartic acid or glutamic acid. In some 156004.doc • 179·201143790 embodiments, a glycoside analog of SEQ ID NO: 809, SEQ ID NO: 812, SEQ ID NO: 813 or SEQ ID NO: 832 is provided, wherein the analog and the parent The difference between molecules is the substitution at position 2. More specifically, position 2 of the like peptide is substituted with an amino acid selected from the group consisting of D-serine, alanine, D-alanine, glycine, N-methylserine and amine Isobutyric acid. In another embodiment, a glycosidic agonist comprising a similar peptide of SEQ ID NO: 801, wherein the analog differs from SEQ ID NO: 801 in that it differs from position 1 An amino acid of histidine and having an acidic amino acid substituted for the native amino acid at position 28 or 29, or an acidic amino acid having a carboxy terminus added to the peptide of SEQ ID NO: 801. In some embodiments, the acidic amino acid is aspartic acid or glutamic acid. In some embodiments, a glycoside analog of SEQ ID NO: 809, SEQ ID NO: 812, SEQ ID NO: 813, or SEQ ID NO: 832 is provided, wherein the analog differs from the parent molecule in position Replaced on the 1st. More specifically, position 1 of the analog-like peptide is substituted with an amino acid selected from the group consisting of DMIA, D-histamine, deaminoglycolic acid, hydroxy-histamine, acetyl-histamine Acid and high-histidine. According to some embodiments, the modified glucagon peptide comprises a sequence selected from the group consisting of SEQ ID NO: 809, SEQ ID NO: 812, SEQ ID NO: 813, and SEQ ID NO: 832. In another embodiment, a glycosidin peptide comprising the sequence of SEQ ID NO: 809, SEQ ID NO: 812, SEQ ID NO: 813 or SEQ ID NO: 832, further comprising added to SEQ ID NO: 809, SEQ ID NO: 812, SEQ ID NO: 156004. doc-180-201143790 8 13 or one to two amino acids at the C-terminus of SEQ ID NO: 832, wherein the additional amino acids are independently selected from the group consisting of Group of constituents: Lys, Arg, His, Asp, Glu, sulfoalanine or high sulfoalanine. In some embodiments, the additional amino acid added to the carboxy terminus is selected from the group consisting of Lys, Arg, His, Asp, or Glu, or in another embodiment, the additional amino acid is Asp or Glu. In another embodiment, the glycoside peptide comprises the sequence SEq ID NO: 807 or a glycoside agonist analog thereof. In some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 808, SEQ ID NO: 810, SEQ ID NO: 811, SEQ ID NO: 812, and SEQ ID NO: 813. In another embodiment, the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 808, SEQ ID NO: 810, and SEQ ID NO: 8 11 » In some embodiments, the glycoside peptide comprises the sequence SEq Id N〇: 808, SEQ ID NO: 810 and SEQ ID NO: 811, further comprising an additional amino acid selected from the group consisting of Asp and Glu added to the C-terminus of the glycemic peptide. In some embodiments the 'glycosidin peptide comprises the sequence SEq ID NO: 8 11 or SEQ ID NO: 813, and in another embodiment, the glycosidin peptide comprises the sequence SEQ ID NO: 811. According to some embodiments, a glycoside agonist comprising a modified glycosidic peptide selected from the group consisting of: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr is provided. -Ser-Lys-

Tyr-Leu-Xaa-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- ID NO· 834); NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser- A sp-Tyr-S er-Ly ξ -181 - ι 56〇〇4.d〇c 201143790

Ty rL eu-Asp-Ser-Arg-Arg-Ala-Gin-A sp-Phe-Val-Gln-Trp-Leu-Met-Asp-Thr-R (SEQ ID NO: 811); and NH2-His-Ser -Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Xaa-Ty rL eu-Glu-Ser-Arg-Arg-A la-Gin-Asp-Phe-Val-Gin-Trp-Leu_Met- Asp-Thr-R (SEQ ID NO: 813), wherein Xaa at position 15 is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine, and Xaa at position 28 is Asn or an acid amine The base acid ' and the Xaa at position 29 is Thr or an acidic amino acid, and R is an acidic amino acid, COOH or CONH2, with the limitation that the acidic amino acid residue is present at one of positions 28, 29 or 30. on. In some embodiments, R is COOH, and in another embodiment, R is CONH2. The present invention also encompasses a glycoside fusion peptide in which a second peptide has been fused to the C-terminus of the glycein peptide to enhance the stability and solubility of the glycoside peptide. More specifically, the fusion glycosidin peptide may comprise: a glycoside agonist analog comprising

S er-Ly s-Ty r-Leu-Xaa-Ser-Arg-Arg-A la-Gin-A sp-Phe-Val-Gln-Trp-Leu-Xaa-Xaa-Xaa-R (SEQ ID NO: 834 Wherein R is an acidic amino acid or a bond; and the amino acid sequence linked to the carboxy terminal amino acid of the glycosidic peptide is SEQ ID NO: 820 (GPSSGAPPPS), SEQ ID NO: 821 (KRNRNNIA) or SEQ ID NO: 822 (KRNR)» In some embodiments, the glycosidic peptide is selected from the group consisting of SEQ ID NO: 833, SEQ ID NO: 807 or SEQ ID NO: 808, further comprising a linkage to liter The amino acid sequence of the carboxy terminal amino acid of the glycopeptide SEQ ID NO: 820 (GPSSGAPPPS), SEQ ID NO: 821 (KRNRNNIA) or SEQ ID 156004.doc • 182·201143790 NO: 822 (KRNR) » in some In an embodiment, the glycosidin fusion peptide comprises SEQ ID NO: 802 'SEQ ID NO: 803 ' SEQ ID NO: 804 ' SEQ ID NO. 805 and SEQ ID NO: 806 or a glycoside agonist analog thereof And further comprising an amino acid sequence SEQ ID NO: 820 (GPSSGAPPPS), SEQ ID NO: 821 (KRNRNNIA) or SEQ ID NO: 822 (KRNR) linked to the amino acid 29 of the glycemic peptide. According to some embodiments, the fusion peptide further comprises a PEG chain linked to an amino acid at positions 16, 17, 21, 24, 29, an amino acid in the C-terminal extension or a C-terminal amino acid, wherein the PEG The chain is selected from the range of 500 Daltons to 40,000 Daltons. In some embodiments, the amino acid sequence SEQ ID NO: 820 (GPSSGAPPPS), SEQ ID NO: 821 (KRNRNNIA), or SEQ ID NO: 822 (KRNR) is linked to the amino acid of the glycemic peptide via a peptide bond. . In some embodiments, the glycoside peptide portion of the glycoside fusion peptide comprises a sequence selected from the group consisting of SEQ ID NO: 810, SEQ ID NO: 811, and SEQ ID NO: 813. In some embodiments, the glycoside peptide portion of the glycoside fusion peptide comprises the sequence of SEQ ID NO: 811 or SEQ ID NO: 813, wherein the PEG chains are linked to positions 21, 24, 29, respectively, and the C-terminal extension Internal or C-terminal amino acid. In another embodiment, the glycopeptide peptide sequence of the fusion peptide comprises the sequence SEQ ID NO: 811, which further comprises an amino acid sequence SEQ ID NO: 820 (GPSSGAPPPS) linked to the amino acid 29 of the glycemic peptide ), SEQ ID NO: 821 (KRNRNNIA) or SEQ ID NO: 822 (KRNR). In some embodiments, the glycoside fusion peptide comprises a sequence selected from the group consisting of: SEQ ID NO: 824, SEQ ID NO: 825, and SEQ ID NO: 826. 156004.doc -183- 201143790 The fusion peptide of the present invention has a c-terminal amino acid containing a standard carboxylic acid group. However, analogs of the c-terminal amino acid having the sequence of the substituted carboxylic acid guanamine are also contemplated as examples. According to some embodiments, the fusion glycosidin peptide comprises a glycoside agonist analog selected from the group consisting of SEQ ID NO: 810, SEQ ID NO: 811, and SEQ id NO: 813, further comprising a linkage to liter The amino acid sequence of the amino acid 29 of the glycosidic peptide is SEQ ID NO: 823 (GPSSGAPPPS-CONH2). The glycosidic agonist of the present invention can be further modified to improve the solubility and stability of the peptide in an aqueous solution while retaining the biological activity of the glycoside peptide. According to some embodiments, the introduction of a hydrophilic group at one or more positions selected from positions 16, 17, 20, 21, 24, and 29 of the peptide of SEQ ID NO: 811 or its glycosidic agonist analog is expected The solubility and stability of the pH-stabilized glycoside analog can be improved. More particularly, in some embodiments, the glycoside peptide of SEQ ID NO: 810, SEQ ID NO: 811, SEQ ID NO: 813, or SEQ ID NO: 832 is modified to comprise a covalent linkage to the presence One or more hydrophilic groups of the amino acid side chain at positions 21 and 24 of the glycosidic peptide. The glycosidic peptide of SEQ ID NO: 811 is modified according to some embodiments at positions 16, 17, 20 And 21, 24, and/or 29 contain one or more amino acid substitutions wherein the primary amino acid is substituted with an amino acid having a side chain suitable for crosslinking with a hydrophilic moiety, including, for example, PEG. The native peptide may be substituted with a naturally occurring amino acid or a synthetic (non-naturally occurring) amino acid. The synthetic or non-naturally occurring amino acid means not naturally occurring in vivo, but may be incorporated into the peptide structure described herein. Amino acid. 156004.doc -184- 201143790 In some embodiments, a glycoside agonist of SEQ ID NO: 810, SEQ ID NO: 811 or SEQ ID NO: 813 is provided, wherein the native glycosidic sequence has been modified to The position of the native sequence is at least one of 6, 17, 2, 24, 29, a C-terminal amino acid or a C-terminal amino acid containing a naturally occurring or synthetic amino acid where the amino acid is substituted The substance further comprises a hydrophilic moiety. In some embodiments, the substitution is at position 2 or 24 and in another embodiment, the hydrophilic moiety is a PEG chain. In some embodiments φ 'the glycoside peptide of SEQ ID NO: 811 is substituted with at least one cysteine residue' wherein the side chain of the cysteine residue is thiol-reactive (including, for example, The enediminoimine group, vinyl sulfone, 2-pyridinethio group, haloalkyl group and dentate group are further modified. Such thiol-reactive reagents may contain carboxy, thiol, thiol and ether groups as well as other hydrophilic moieties such as polyethylene glycol units. In an alternate embodiment, the native glucagon peptide is substituted with an amine acid and uses an amine reactive reagent such as an active ester of a carboxylic acid (butyl iodide, anhydride, etc.), or a hydrophilic moiety (such as a poly The aldehyde of ethylene glycol) further φ modifies the side chain of the substituted lysine residue. In some embodiments, the glycoside is selected from the group consisting of SEq ID NO: 814, SEQ ID NO: 815, SEQ ID NO: 816, SEQ ID NO: 817, SEQ ID NO: 818, and SEQ ID NO: 819. According to some embodiments, a PEGylated glucagon peptide comprises two or more polyethylene glycol chains covalently bound to a glycemic peptide, wherein the total molecular weight of the glycosidic chain is about 1, 〇 to about 5, 〇〇〇 Dalton. In some embodiments, the 'pegylated glycosidic agonist package $SEq ID NO: 806' wherein the PEG chain is covalently bonded to the amino acid residue at position 21 and position 24, 156004.doc - 185-201143790 base, and the combined molecular weight of two of the PEG chains is from about looo to about 5 〇〇〇 Daltons. In another embodiment, the PEGylated glycosidic agonist comprises a peptide of SEQ ID NO: 806, wherein the PEG chain is covalently linked to an amino acid residue at positions 21 and 24, and wherein The combined molecular weight of the two pEG chains is from about 5,000 to about 20,000 Daltons. The polyethylene glycol chain can be in a linear form or it can be branched. According to some embodiments, the average molecular weight of the polyethylene glycol chain is selected from the range of from about 5 Torr to about 40,000 Daltons. In some embodiments, the polyethylene glycol chain has a molecular weight selected from the range of from about 500 to about 5,000 Daltons. In another embodiment, the polyethylene glycol linkage has a molecular weight of from about 20,000 to about 40, 〇〇〇Dalton. Any of the glycosidic peptides described above may be further modified to include a covalent or non-covalent intramolecular bridge or an alpha helix stabilized amine within the C-terminal portion of the glycemic peptide (amino acid positions 12 to 29). Base acid. According to some embodiments, in addition to the amino acid substitution of the alpha, alpha disubstituted amino acid (eg, Aib) at position 16, 20, 21 or 24 (or a combination thereof), the glycoside peptide also comprises the above Any one or more of the modifications discussed. According to another embodiment, in addition to the intramolecular bridge (eg, indoleamine) between the side chain of the amino acid at position ί6 of the glycemic peptide and the side chain of the amino acid at position 20, the sucrose The peptide also includes any one or more of the modifications discussed above. According to some embodiments, the glycoside peptide comprises the amino acid sequence SEQ ID NO: 877, wherein Xaa at position 3 is an amino acid comprising a side chain of structure I, Π or III: i_R2

Such as r1-ch2-x structure I 156004.doc -186 - 201143790 !-r1-ch2』-y structure II ο l-^-CHs-S-CHa-R4 structure III,

Wherein R1 is C〇-3 alkyl or C〇-3 heteroalkyl; R2 is NHR4*^.3 alkyl; R3 is C!_3 alkyl; R4 is hydrazine or Cw alkyl; X is hydrazine, hydrazine or S ; and Y is NHR4, SR3 or OR3. In some embodiments, X is ΝΗ or Υ is NHR4. In some embodiments, R1 is C0.2 alkyl or C! heteroalkyl. In some embodiments, R2 is NHR4*^alkyl. In some embodiments, R4 is deuterium or C1 alkyl. In an exemplary embodiment, an amino acid comprising a side chain of structure I, wherein R1 is CH2-S, X is hydrazine, and R2 is CH3 (acetamidomethyl-cysteine, C (Acm) )); R1 is CH2, X is NH, and R2 is CH3 (acetamidodiaminebutyric acid, Dab(Ac)); R1 is C〇alkyl, X is NH, R2 is NHR4, and R4 is Η( Aminomethylmercaptopropionic acid, Dap (urea)); or R1 is CH2-CH2, X is NH, and R2 is CH3 (ethinylguanine, Orn (Ac)). In an exemplary embodiment, an amino acid comprising a side chain of structure π wherein R1 is CH2, Y is NHR4, and R4 is CH3 (methyl glutamic acid 'Q(Me)) is provided; in an exemplary implementation In one embodiment, an amino acid comprising a side chain of the structure π , is provided, wherein R 1 is CH 2 and R 4 is hydrazine (methionine-arylene, hydrazine); in a particular embodiment, the amine group at position 3 The acid is replaced by Dab (Ac). For example, the glycoside agonist can comprise the amino acid sequence SEq ID NO: 863, SEQ ID NO: 869, SEQ ID NO: 871, SEQ ID NO: 872, SEQ ID NO: 873, and SEQ ID NO: 874. 156004.doc -187- 201143790 In certain embodiments, the glycemic peptide is a glycoside peptide analog of SEQ ID NO: 877. In a particular aspect, the analog comprises any of the amino acid modifications described herein, including, but not limited to, substituting a charged amino acid for Asn at position 28; with a charge selected from the group consisting of Amino acid substitution of Asn at position 28: Lys, Arg, His, Asp, Glu, cis-propylamine oxime and homo-propanine; substitution at position 28 with Asn, Asp or Glu; position at position 28 with Asp Substituting; substitution at position 28 with Glu; replacement of Thr at position 29 with a charged amino acid; substitution of Thr: Lys, Arg, His at position 29 with a charged amino acid selected from the group consisting of: Asp, Glu, sulfoalanine and high-performance propylalanine; substitution at position 29 with Asp, Glu or Lys; substitution at position 29 with Glu; insertion of 1 to 3 charged amino acids at position 29; Insert Glu or Lys after position 29; insert Gly-Lys or Lys-Lys after position 29; and combinations thereof. In certain embodiments, the glycoside peptide analog of SEQ ID NO: 877 comprises an alpha, alpha disubstituted amine group on one, two, three or all of positions 16, 20, 21 and 24. Acid, such as Aib. In certain embodiments, the glycoside peptide analog of SEQ ID NO: 877 comprises one or more of the following modifications: His at position 1 is cleaved by a dipeptidyl peptidase IV (DPP_IV) cleavage ghrelin peptide a possibility of substitution by a non-native amino acid; a position 2 is substituted with a non-native amino acid which reduces the possibility of dipeptidyl peptidase IV (DPP-IV) cleavage of the glycosidic peptide; Thr at position 7 Substituted by amino acid lacking hydroxyl group (for example, Abu or lie); Tyr at position 10 is substituted by Phe or Val; Lys at position 12 is substituted by Arg; Asp at position 15 is 156004.doc • 188 · 201143790

Glu substitution; Ser at position 16 is replaced by Thr or Aib; Gin at position 20 is substituted by Ala or Aib; Asp at position 21 is replaced by Glu; Gin at position 24 is replaced by Ala or Aib; Met at position 27 Substituted by Leu or Nle; amino acid at positions 27 to 29 is deleted; amino acid at positions 28 to 29 is deleted; amino acid at position 29 is deleted; amino acid sequence SEq id NO: 820 is added to c The terminal, wherein the amino acid at position 29 is Thr or Gly; or a combination thereof. According to a particular embodiment, the glycosidic peptide comprises any one of the amino acid sequences SEq ID N〇: 862-867 and 869-874. In certain embodiments, the glycoside peptide analog comprising SEq ID NO: 877 comprises an amino acid or C covalently bonded to any of positions 16, 17, 20, 21, 24, and 29. A hydrophilic moiety of an amino acid, such as pEG.

In certain embodiments, a glycoside peptide analog comprising SEq ID NO: 877 comprises an amino acid comprising a side chain covalently attached via a spacer to a brewing or alkyl group, as appropriate Sulfhydryl or alkyl is non-native to naturally occurring amino acids. In some embodiments, the thiol group is from €4 to €3. In other embodiments, the alkyl group is an alkyl group. In a particular aspect, the 'branched or danic group is covalently attached to the side chain of the amino acid at position 1 . In some embodiments, the amino acid at position 7 is Ile or Abu. The glycoside agonist may be a peptide comprising any one of the amino acid sequences SEQ ID NO: 801-919, optionally having up to 1, 2, 3, 4 or 5 retained glycosidic agonist Other modifications of activity. In certain embodiments, the glycosidic agonist comprises an amino acid of any one of SEQ ID NOs: 859-919. Class 2 Glucagon related peptide 156004.doc • 189. 201143790 In certain embodiments In the case, the glycoside-related peptide is a type 2 glycoside-related trait, which is described in this document and in International Patent Publication No. W〇2010/011439 and US Application No. 61/187,578 (June 16, 2009) The contents of these patents are incorporated herein by reference in their entirety. The biological sequence (SEQ ID NO: 1001-1262) referred to in the following section for the second type of ghrelin-related peptide corresponds to SEq ID NO: 1-262 in International Patent Publication No. 2010/011439. SEQ ID NOs: 1263 to 1275 for Class 2 glucosamine related peptides correspond to 3 ugly (1) and 0: 657 to 669 in U.S. Application Serial No. 61/187,578. The active proglucagon does not activate the GIP receptor' and typically, its activity on the GLP-1 receptor is about 1% of the activity of native GLP-1. Modification of the native glucagon sequence described herein produces an effective glycemic activity that exhibits activity equal to or superior to native glucosinolate (SEQ ID NO: 1001), equal to or superior to native GIP (SEQ ID NO: 1004) A potent GIP activity of activity, and/or a Class 2 glycosidin-related peptide that is equal or superior to the potent GLP-1 activity of native GLP-1 activity. In this regard, the second type of glycosidin-related peptide may be a glycoside/GIP co-activator, a glycoside/GIP/GLP-1 triple agonist, a GIP/GLP-1 co-activator or a GIP. One of the effector glycosaminoglycans, as further described herein. In some embodiments, the Class 2 ghlylin-related peptides described herein exhibit an EC5 对于 of about 100 nM or less, or about 75 nM, 50 nM, 25 nM, 10 for GIP receptor activation activity. nM, 8 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM or 1 nM or less. In some embodiments, 156004.doc -190. 201143790, the second class of ghrelin-related peptide exhibits an EC50 of about 100 nM or less, or about 75 nM, 50 nM, 25 for glycosidic receptor activation. nM, 10 nM, 8 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM or 1 nM or less. In some embodiments, the second class of ghrelin-related peptide exhibits an EC5 对 of about 100 nM or less, or about 75 nM, 50 nM, 25 nM, 10 nM, 8 for GLP-1 receptor activation. nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM or 1 nM or less. Receptor activation can be measured by measuring CAMP-induced activity in HEK293 cells overexpressing the receptor

In vitro assays, for example, as described in Example 2, were assayed using HEK293 cells co-transfected with the DNA encoding the receptor and the luciferase gene linked to the cAMP response element. In some embodiments, the activity exhibited by the Glycerin-related peptide of the second class of GIP receptors relative to the native GIP is at least about 0.1%, 0.2°/〇, 0.3% '0.4% '0.5%' 0.6% ' 0.7% ' 0.8% ' 0.9% ' 1% > 5% ' 10% ' 20% ' 30% ' 40% ' 50% ' 60% ' 75% ' 100% ' 125% , 150% , 175° / . Or 200% or more (GIP performance). In some embodiments, the glycosaminoglycan peptide described herein exhibits an activity against the GIP receptor of up to 1000%, 10,000%, 100,000% or 1,000,000°/〇 relative to the native GIP. In some embodiments, the activity of the second type of ghrelin-related peptide for the glycosidic receptor is at least about 1%, 5%, 10%, 20%, 30% relative to the activity of the native glycemic glycoside, 40%, 50%, 60% ' 75% ' 100% ' 125% ' 150% ' 175% > 200% ' 250% > 300%, 350%, 400°/〇, 450% or 500% or 500 More than % (glycoside potency). In some embodiments, the glycosidic peptide described herein is at least 1000°/〇, 10,000%, 100,000 for the activity exhibited by the glycoside by the 156004.doc •191·201143790 body relative to the native glucagon. % or 1,000,000%. In some embodiments, the activity exhibited by the Glycerin-related peptide of class 2 to the GLP-1 receptor is at least about 0.1%, 0.2%, 0.3%, 0.4%, 0-5%, relative to the activity of native GLP-1. 0.6%, 0.7%, 0.8%, 0.9%, 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 75%, 100%, 125%, 150%, 175% Or 200% or more (GLP-1 efficacy). In some embodiments, the glycosaminoglycan peptides described herein exhibit up to 1000%, 10,000%, 100,000% or 1,000,000% of the activity exhibited by the GLP-1 receptor relative to native GLP-1. The activity of the second type of glucosamine related peptide on the receptor relative to the native ligand of the receptor is calculated as the inverse ratio of the EC50 of the second type of glucosinoid related peptide to the ec5 原 of the native ligand. In some embodiments, the second type of glycosidin-related peptide exhibits activity on the glycoside receptor and the GIP receptor ("glycoside/GIP co-activator"). These class 2 ghrelin-related peptides have lost the selectivity of native glycosides to the glycoside receptor compared to the GIP receptor. In some embodiments, the second type of ghrelin-related peptide is about 50-fold, 40-fold, 30-fold or less than the EC5Q of the GIP receptor (higher or lower) than the EC5Q of the glycosidic receptor. . In some embodiments, the GIP potency of the second type of ghrelin-related peptide differs (higher or lower) than the glycemic potency by about 500 times, 450 times, 400 times, 350 times, 300 times, 250 times, 200 times. Multiple, 150 times, 100 times, 75 times, 50 times, 25 times, 20 times, 15 times, 10 times or less. In some embodiments, the ratio of the EC5 of the Glyceglycan-related peptide to the GIP receptor divided by the EC5 of the Glycoside-related peptide to the Glucagon Receptor is about 100, 75, 60. , 50, 40, 30, 156004.doc -192- 201143790 20, 15, 10 or less. In some embodiments, the EC50 of the GIP receptor divided by the EC5G of the glycemic receptor is about 1 or less (eg, about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067). , 0.1, 0.2). In some embodiments, the GIP potency of the second type of glycosidin-related peptide is about 500, 450, 400, 350, 300, 250 compared to the glycemic potency of the second type of glycosidin-related peptide. 200, 150, 100, 75, 60, 50, 40, 30, 20, 15, 10 or less. In some embodiments, the ratio of potency of the GIP receptor divided by potency of the glycemic receptor is about 1 or less (eg, about 0.01, 〇·〇 13, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067, 0.1, 0.2) » In some embodiments, the GLP-1 activity has been modified, for example, by an amino acid at position 7, and the amino acid in the amino acid at the C-terminus to position 27 or 28 is deleted. A peptide having 27 or 28 amino acids, or a combination thereof, is produced which is significantly reduced or destroyed. In another aspect, the second type of ghrelin-related peptide exhibits activity against the glycosidic receptor, the GIP receptor, and the GLP-1 receptor ("glycoside triple agonist"). These class 2 ghrelin-related peptides have lost the selectivity of native glucosin to the glucosamine receptor over the GLP-1 receptor and GIP receptor. In some embodiments, the second type of glycosidin-related peptide is about 50 times greater than the Ec5〇 of the GIP receptor and its individual ec^ for the glycoside receptor and the GLP-1 receptor (above or below) 40 times, 30 times or 20 times or less. In some embodiments, the GIP potency of the first type of glycosidin-related peptide differs from the glycemic potency and GLp_丨 potency by a factor of about 500, 450, 400, and 350. 〇 times, 250 times, 200 times, 15 times, 1 times, 75 times, 5 times, times, 15 times, 1G times or less. In some embodiments, the ratio of the ECm of the GIP receptor divided by the triple agonist to the EC50 of the GLP-1 receptor is about 100, 75, 60, 50, 40. , 30, 20, 15, 1 or 5 or less. In some embodiments 'eg to the Gip receptor: 5. The ratio obtained by dividing the ECw of the glp]* body is about 1 or less (for example, about 〇1, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067, 0.1, 0.2). In some embodiments, the ratio of GIP potency of the triple agonist to GLP-1 potency of the triple agonist is about 10 〇, 75, 6 〇, 5 〇, 40, 30, 20, 15, 10 Or 5 or less. In some embodiments, the ratio of the potency of the GIp receptor divided by the potency of the GLP-1 receptor is about! Or about j (for example, about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05, 0.067, 0.1, 0.2). In a related embodiment, the ratio of the ECw of the triple agonist to the GIP receptor divided by the agonist of the agonist to the ec5q of the glycosidic receptor is about 100, 75, 60, 50, 40, 30, 20, 15, 1 or 5 or less. In some embodiments, the ratio of the ECw of the GIP receptor divided by the ECso of the glycemic receptor is about 1 or less (eg, about 〇〇1, 0.013, 0.0167, 0.02, 0.025, 0.03, 0.05). , 0.067, 〇.1, 0.2). In some embodiments, the ratio of the gip potency of the triple agonist to the glycemic potency of the triple agonist is about 5, 450, 400, 350, 300, 250, 200, 150, 100, 75, 60, 50, 40, 30, 20, 15, 10 or less. In some embodiments, the ratio of potency of the GIP receptor divided by potency of the glycemic receptor is about 1 or less (eg, about 0.01, 0.013, 0.0167, 0.02, 0.025, 0.03, 〇05, 0.067, 0.1, 0.2). In some embodiments, the ratio of the triplet agonist to the Glp_i receptor EC" divided by the triple agonist to the glycoside receptor EC5Q is 156004.doc •194·201143790 is about 100, 75, 60, 50, 40, 30, 20, 15, 10 or less. In some embodiments, the ratio of EC5Q to the GLP-1 receptor divided by the EC of the glycemic receptor is about! Or about 1 or less (for example, about 〇 〇 1, 〇. 〇丨 3, 0.0167, 〇.〇2, 0.025, 0_03, 〇.〇5, 0.067, 0.1, 0.2). In some embodiments, the ratio of GLPd potency of the triple agonist to the glycemic potency of the triple agonist is about 1 〇〇, 75, 60, 5 〇, 4 〇, 30 '20, 15, 1〇 or below. In some embodiments, the ratio of the potency of the GLp_i receptor Φ divided by the potency of the glycemic receptor is about 1 or less (eg, about 0.01, 0.013, 〇.〇167, 0 02, 〇). 〇25, 〇〇3, 0.05, 0.067, 0.1, 〇.2). In another aspect, the second type of ghrelin-related peptide exhibits activity against the GLP·1 receptor and the GIP steroid, but wherein the glycosidic activity has been significantly reduced, for example, by modification of the amino acid at position 3 or Destruction ("Gip/GLp" co-activator"). For example, substitution with an acidic, basic or hydrophobic amino acid (glutamic acid, ornithine, orthraenic acid) at this position reduces the glycemic φ activity. In some embodiments, the glycoside peptide differs (above or below) the EC5Q of the GIP receptor from its ECw to the GLP-1 receptor by about 5, 々, 3, or 20 times. In some embodiments, the GIP potency of the Type 2 ghlylin-related peptide differs (higher or lower) than the GLP-1 potency by about 25 fold, 2 fold, 15 fold, 10 fold or less. In some embodiments, the activity of the second type of ghrelin-related peptide to the glycosidic receptor is about 10% or less, such as about 1% to 10%, or about about 1% to 10%, of the activity of the native glycosidin. 〇1% to 1%, or about 0.1% or more but about 10% or less. In some embodiments, the ratio of the galvanin-related peptide of the second type of glucosinolate-related peptide to the ec^ of the GIP receptor divided by the EC5 受体 of the GLp 156004.doc-195-201143790 1 receptor of the second type of glucosinoid-related peptide It is about 1 〇〇, 75, 60, 50, 40, 30, 20, 15, 10 or less and not less than i. In some embodiments, the GIP potency of the second type of ghrelin-related peptide is about 1 〇〇, 75, 6, 50, 50, 40 compared to the GLP-1 potency of the second type of glucosinoid-related peptide. , 30, 20, 15, 10 or less and not less than 1. In another aspect, 'the second type of ghrelin-related peptide exhibits activity on the gip receptor' wherein the glycosidic and GLP-1 activities have been modified with Glu at position 3, for example, and at position 7 The amide was modified with ile to significantly reduce or destroy ("GIP agonist glycosidic peptide"). In some embodiments, 'the activity of the second type of ghrelin-related peptide to the glycosidic receptor is about 1% or less, such as about 1% to 1%, of the activity of the native glycein, Or about 0.1% to 10%, or about 0.1%, 05% or more, but about 5% or less. In some embodiments, the activity of the second type of ghrelin-related peptide to the GLP-1 receptor is also about 1% or less, such as about 1% to 10%, of the activity of the native glP-1. , or about 1% to 10%, or about 1%, 〇5〇/〇 or more than 1% but about 1%, 5% or less. In some embodiments, when the catechin-related peptide of the second type is not PEGylated, the EC5 活化 of the Glycerin-activated peptide of the second type of glycosin-related peptide is about 4 nM, 2 nM, 1 nM or Below 1 iiM, or the activity of the analog to the GIP receptor is at least about 1%, 2%, 3%, 4% or 5% of the native GIP activity. In a related embodiment, the 'glycosylation-related peptide that is not pegylated, the EC5〇 that activates the GLP-1 receptor is about 4 nM, 2 nM, 1 nM or less, or The activity of the -1 receptor is at least about 1%, 2%, 3%, 4% or 5% of the activity of native GLP-1. In other related embodiments, the EC5〇 activated by the glycoside receptor of the second type of glycosidin-related peptide that is not pegylated by -196-1 S6004.doc 201143790 is about 4 nM, 2 nM, 1 nM. Or less than 1 nM, or its activity on the glycosidic receptor is at least about 5%, 1%, 15% or 20% of the activity of the native glycein. In some embodiments, the activity of the non-pegylated type 2 glycosidin-related peptide to the glycosidic receptor is less than about 1% of the activity of the native glycein. In other embodiments, the activity of the non-pegylated Type 2 glycosidin-related peptide to the GLP-1 receptor is about 10%, 5% or less of the activity of the native GLP-i. In embodiments in which a type 2 ghlylin-related peptide is linked to a hydrophilic moiety such as pEG, the relative EGO to one or more receptors can be higher, e.g., increased to about ίο. For example, the PEGylation analog has an ECm of about 1〇11 blue or less than 1〇nM for activation of the GIp receptor, or the activity of the second type of glycosidin-related peptide to the GIP receptor is active for the native GIP. At least about 1%, 〇2〇/. , 0.3%, 〇.4% or 〇.5%. In a related embodiment, the ECw of the PEGylated Category 2 ghlylin-related peptide has a ECw of about 1 〇 11 or less, or a pair of (}1 _1 receptors) for GLP-丨 receptor activation. The activity is at least about 0.1%, 〇.2%, 〇.3%, 〇.4% or 〇5% of the activity of the native GLp-丨. In other related embodiments, the PEGylation of the second type liter The glycoside-related ECS(s) for glycosidic receptor activation is less than about 10 nM 410 nM, or its activity on the glycosidic receptor is at least about 0.5%, 1%, or 5% of the activity of the native glycein or In some embodiments, the second type of ghrelin-related peptide is less than about 1% of the activity of the glycoside receptor steeply to native glucosin. In other embodiments, the second type of ghrelin-related peptide to QLp "The activity of the receptor is about 1%, 5% or less of the activity of the native GIp." 156004.doc • 197. 201143790 Modifications The modification disclosed herein with respect to the type 2 glycan-related peptide allows for the sucrose The nucleoside (SEQ ID NO: 1001) is manipulated to form a glycosidin peptide exhibiting enhanced sputum activity, glycosidic activity, and/or GLP-1 activity. Others disclosed herein with respect to the second class of ghrelin-related peptides repair The decoration prolongs the half-life of the resulting peptide, increases its solubility, or enhances its stability. Other modifications disclosed herein with respect to the second type of glycosidin-related peptide have no effect on activity, or may be performed without destroying the desired activity. Any combination of ghrelin-related peptides for the same purpose (eg, enhanced GIP activity) may be used individually or in combination. Any single combination or combination of properties conferring enhanced properties with a class 2 ghlylin-related peptide may be Individual or combined applications, such as GIP and/or glp-1 activity enhancement may be combined with extended half-life. In related embodiments, amines at 1, 2, 3, 4, 5, 6, or 6 or more The acid modification may be a non-conservative substitution, addition or deletion. In some embodiments, the amino acid modification at 1, 2, 3, 4, 5, 6, or 6 may be conservative. The modification affecting G1P activity provides enhanced activity to the GIP receptor by performing amino acid modification at position 1. For example, the position of His is substituted with a large aromatic amino acid, which is a large aromatic amine. The base acid is Tyr, Phe, Trp, depending on the situation. Base-Phe, nitro-Phe, gas-Phe, sulfo-Phe, 4-pyridyl-Ala, fluorenyl-Tyr or 3-amino group 1*. Tyr at position 1 corresponds to amino acid 12 A stable combination of alpha helices in the region to 29 provides a Glycerin-related peptide that activates the GIP receptor as well as the GLP-1 receptor and the Glucagon receptor. The alpha helix structure can be obtained by the example 156004.doc 201143790 If a covalent or non-covalent intramolecular bridge is formed, or an alpha helix stabilized amino acid (eg, an alpha, alpha disubstituted amino acid) is substituted and/or an amino acid substantially at positions 12 to 29 is inserted. Stabilization also provides enhanced activity against GIP receptors by amino acid modification at position 27 and/or 28, as appropriate, at position 29. For example, substituting a large aliphatic amino acid (as appropriate as Leu) for Met at position 27, substituting a small aliphatic amino acid (as appropriate for Ala) for Asn at position 28, and using a small aliphatic amine The base acid (as appropriate Gly) replaces Thr at position 29. Substitution with LAG at positions 27 to 29 provides enhanced GIP activity to the native MNT sequence relative to each other. Enhancement of the GIP receptor is also provided by amino acid modification at position 12. For example, position 12 is replaced with a large aliphatic non-polar amino acid (optionally lie). The GIP receptor enhanced activity is also provided by amino acid modification at positions 17 and/or 18. For example, the position 17 ' is replaced with a polar residue (optionally Gln) and the position 丨8 is replaced with a small aliphatic amino acid (as appropriate, Ala). Substitution with QA at positions 17 and 18 provides enhanced Gip activity to the native RR sequence relative to each other. Modification of the GIP receptor is provided by a modification that allows for the formation of an intramolecular bridge between the amino acid side chains at positions 12 to 29. For example, an intramolecular bridge can be formed by a covalent bond at position i and position i+4, or at position j and at position j + 3 or at position k and at position k+7. Between the side chains. In an exemplary embodiment, the bridge is between positions 12 and 16, between positions 16 and 20 'between positions 2 and 24, between positions 24 and 28 156004.doc -199- 201143790 Between, or between positions 17 and 20. In other embodiments, a non-covalent interaction, such as a salt bridge, can be formed between the positively charged amino acid and the negatively charged amino acid at such positions. Any of the modifications described above for enhancing GIP receptor activity can be used individually or in combination. Combinations of modifications that enhance GIP receptor activity provide Gip activity generally higher than the GIp activity provided by either of these modifications alone. Modification of Claudin Activity In some embodiments, enhanced glycosidic potency is provided by amino acid modification at position 16 of the native glucagon (SEQ ID N: 1). By way of non-limiting example, either by using glutamic acid or by using another negatively charged amino acid having a side chain of 4 atoms in length, or by using branic acid, glutamic acid or high sulfopropylamine Any of the acids, or a substituted amino acid having a side bond having at least one hetero atom (e.g., N, 0, S, P) and having a side chain length of about 4 (or 3 to 5) atoms The naturally occurring serine acid at position 丨6 provides this enhanced efficacy. In some embodiments, the glycoside peptide retains its original selectivity for the ghrelin receptor relative to the GLP-1 receptor. Glycoglycan receptor activity can be reduced by amino acid modification at position 3, for example by replacing the naturally occurring glutamic acid at position 3 with an acidic, basic or hydrophobic amino acid. Substitution with glutamic acid, ornithine or ortho-amine at position 3 substantially reduces or disrupts glycosidic receptor activity. The activity at the glycecan receptor can be maintained or enhanced by modifying the Gin at position 3 with a glutamate analog as described herein. For example, the glycoside 156004.doc -200- 201143790 agonist may comprise any of the amino acid sequences SEQ ID NOs: 1243-1248, 1250, 1251 and 1253-1256. Restoring glycosidic activity that has been reduced by amino acid modification at positions 1 and 2 by stabilizing the alpha helix structure of the C-terminal portion of the glycoside peptide or analog thereof (amino acid 12 to 29) . For example, an intramolecular bridge can be formed by a covalent bond at position i and position i + 4, or at position j and position j+3, or at position k and at position k+7 by two amino acids. Between the side keys. In other embodiments φ, a non-covalent interaction, such as a salt bridge, can be formed between the positively charged amino acid and the negatively charged amino acid at such positions. In other embodiments, one or more alpha, alpha disubstituted amino acids are inserted or substituted at positions in the C-terminal moiety (amino acids 12 to 29) that retain the desired activity. For example, one, two, three or all of positions 16, 2, 21 or 24 are replaced with an alpha, alpha disubstituted amino acid (e.g., Aib). Modifications affecting GLP-1 activity The activity of enhancing the GLP-1 receptor is provided by replacing the C-terminal amino acid with a charge-neutral group such as a guanamine or an ester. Alternatively, as further described herein, for example, via the formation of an intramolecular bridge in the side chain of two amino acids, or the substitution of an alpha helix stabilized amino acid (eg, an α'α disubstituted amino acid) / or inserting an amino acid substantially at positions a to 29 to stabilize the alpha helix structure in the c-terminal portion of the glycemic glycoside (approximately the amino acid in _) to provide enhanced activity against the GLp i receptor. In the example of the embodiment, the amino acid pairs 12 and 16, η and Η, 16 and 2 〇, 17 and 20 and 24 or 24 and 28 (i = 12, 16, 20 or 24 amino acids) The side chains of the pair are bonded to each other and thereby stabilize the glycoside to a helix. In some embodiments 156004.doc • 201· 201143790, especially when the bridge is between position 丨 and 丨+4, the length of the bridge or linker is about 8 (or about 7 to 9) atoms. In some embodiments, especially when the bridge is between position j and j+3, the length of the bridge or linker is about 6 (or about 5 to 7) atoms. In some embodiments, the intramolecular bridge is formed by (a) using glutamic acid or another negatively charged amino acid having a side chain of 4 atoms in length or using branic acid, high Any of a face acid or a high-performance propylamine, or a side chain having at least one hetero atom (eg, N, 〇, S, p) having a side chain length of about 4 (or 3 to 5) atoms a charged amino acid substituted for the naturally occurring serine at position 16; and (b) with another side chain having a charge or hydrogen bonding ability and having a length of at least about 5 (or about 4 to 6) atoms A hydrophilic amino acid (e.g., aminic acid, citrulline, arginine or ornithine) replaces the naturally occurring hammer g5 amine at position 20. The side chain of the amino acid at position 16 and the side chain of the amino acid at position 20 may form a salt bridge or may be covalently bonded. In some embodiments, the two amino acids combine to form an indoleamine ring. In some embodiments, the alpha helix structure in the C-terminal portion of the glycemic peptide is stabilized via the formation of intramolecular bridges other than the indoleamine bridge. For example, a suitable covalent bonding method includes any one or more of the following: olefin metathesis, melamine-based cyclization, disulfide bridge or modified sulfur-containing bridge formation, using α, ω_ The diaminoalkane tethers form a metal-atomic bridge and the other peptides are cyclized to stabilize the alpha helix. In other embodiments, one or more alpha, alpha disubstituted amino acids are inserted or substituted in the C-terminal moiety (amino acids 12 to 29) to retain the desired activity. 156004.doc -202 - 201143790 Set it up. For example, one, two, three or all of positions 16, 20, 21 or 24 are replaced with an alpha, alpha disubstituted amino acid (e.g., Aib). The enhanced activity against the GLP-1 receptor is provided by amino acid modification at position 20 as described herein. The GLP-1 receptor-enhancing activity is provided by the addition of GPSSGAPPPS (SEQ ID NO: 1095) or XGPSSGAPPPS (SEQ ID NO.. 1096) to the C-terminus. The GLP-1 activity of the analogs can be further enhanced by modifying the amino acid at position 18, 28 or 29 or at positions 18 and 29 as described herein. GLP-1 potency is further moderately enhanced by modifying the amino acid at position 10 to a large aromatic amino acid residue, optionally Trp. The reduced activity against the GLP-1 receptor is provided, for example, by performing amino acid modification at position 7 as described herein. The potency of the GLP-1 receptor can be further enhanced by alanine substitution of the native arginine at position 18. Any of the modifications described above for the enhanced GLP-1 receptor activity described in the Type 2 glycanin-related peptide may be applied individually or in combination. A modified combination that enhances GLP-1 receptor activity provides GLP-1 activity generally higher than that provided by either of these modifications alone. For example, the present invention provides for the inclusion of a modification at position 16, position 20, and C-terminal carboxylic acid groups, optionally having a covalent bond between the amino acid at position 16 and the amino acid at position 20. a glycopeptide; a modified glycosidic peptide at position 16 and C-terminal carboxylic acid groups; a modification at positions 16 and 20, optionally with amino acid at position 16 and position 20 a glycosidic peptide covalently bonded between amino acids; and a modified glycosidic acid at position 20 and C-terminal carboxylic acid groups 156004.doc -203 - 201143790 peptide 0 modified DPP-1V resistance Modifications at positions 1 and/or 2 may enhance peptide-to-dipeptidyl peptidase IV (DPP IV) cleavage m. For example, the position 丨 and / may be replaced with a _ IV-resistant amino acid as described herein. Or position 2. In some embodiments, the amino acid at position 2 is substituted with N. methyl alanine. It has been observed that modification at position 2 (eg, occlusion at position 2) and modification at position 1 under two conditions (eg, DMIA at position 1) can reduce glycemic activity, sometimes significantly Glucagon activity; surprisingly, this decrease in glycemic activity can stabilize the c-terminal portion of the glycemic glycoside by forming a covalent bond between the side chains of the two amino acids as described herein ( It is restored by the alpha helix structure of the amino acid 12 to 29). In some embodiments, the covalent bond is between position ri" and position "i+4", or position "j" and position "j+3"' such as positions 12 and 16, positions 16 and 20, positions 20 and 24 'Between positions 24 and 28 or amino acids at positions 17 and 20. In the exemplary embodiment, this covalent bond is the intrinsic amine bridge between the glutamic acid at position 16 and the perion acid at position 20. In some embodiments, as described herein, the covalent bond is an intramolecular bridge other than an indoleamine bridge. Modifications to Reduce Degradation In other exemplary embodiments, any of the Type 2 ghlylin-related peptides may be further modified to improve stability by modifying the amino acid at positions 15 and/or 16 of SEQ ID NO: 1001. This reduces the degradation of the peptide over time, especially in acidic or alkaline buffers. These modifications reduce the cleavage of the Asp 15-Ser 16 peptide bond. In an exemplary embodiment, the amino acid at position 15 is modified to 156004.doc •204·201143790

Asp is deleted or substituted with glutamic acid, glutamate, sulfoalanine or high sulfoalanine. In other exemplary embodiments, the amino acid at position 丨6 is modified to be Ser-substituted or substituted with Thr or Aib. In other exemplary embodiments 'with glutamic acid or another negatively charged amino acid having a side chain of 4 atoms in length' or with branamide, glutamic acid or high sulfoalanine Either replace the Ser at position 16. In some embodiments, the guanidine thio acid residue present at position 27 of the native peptide is modified, for example, by deletion or substitution. These modifications prevent oxidative degradation of the peptide. In some embodiments, the Met at position 27 is replaced with leucine, isoleucine or norleucine. In some specific embodiments, the Met at position 27 is replaced with leucine or normic acid. In some embodiments, Gin at positions 2〇 and/or 24 is modified, for example, by deletion or substitution. These modifications reduce the degradation that occurs upon removal of the guanamine group via Gin. In some embodiments, the Gin at positions 20 and/or 24 is replaced with Ser, Thr, Ala or Aib. In some embodiments, Gin at positions 20 and/or 24 is replaced with Lys, Arg, 〇rn or citrulline. In some embodiments, Asp at position 21 is modified, for example, by deletion or substitution. Such modifications may reduce degradation by the formation of a cyclic succinimide intermediate formed by dehydration of ASp, which in turn constitutes isoaspartate. In some embodiments, position 21 is replaced with Glu, high face acid or high sulfoalanine. In some particular embodiments, position 21 is replaced with Glu. Stabilization of the a-helical structure The c-terminal portion of the glucosinoid-related peptide of the second type (approximately amino acid 12 to 29) _ the alpha helix structure provides enhanced glp-1 and/or GIP activity and is 156,004. Doc •205· 201143790 Glycerin activity that has been reduced by amino acid modification at position 1 and/or 2. The alpha helix structure can be substituted, for example, by the formation of a covalent or non-covalent intramolecular bridge, or by an alpha helix stabilized amino acid (e.g., an alpha, alpha disubstituted amino acid) and/or inserted substantially at positions 12-29. The amino acid is stabilized. The alpha helix structure of the GIP agonist can be stabilized as described herein. Brewing and Alkylation According to some embodiments, the glycoside peptides disclosed herein are modified to comprise a thiol or alkyl group, such as a non-native thiol or alkane as described herein for a naturally occurring amino acid. base. Deuteration or alkylation can extend the half-life of the glycoside peptide in the cycle. Deuteration or alkylation may advantageously delay the onset of action and/or prolong the duration of action on the glycoside receptor and/or GLP-1 receptor and/or improve resistance to proteases such as DPP-IV. And / or improve solubility. The activity of the glycoside peptide to the glycemic receptor and/or the receptor and/or the GIP receptor can be maintained after the brewing. In some embodiments, the efficacy of the glycosylated peptide can be enhanced. Compatible with the undeuterated form of the glycemic peptide. As described herein, the second type of ghrelin-related peptide can be deuterated at the same amino acid position of the bonded hydrophilic moiety or at a different amino acid position. Or alkylation. In some embodiments, the invention provides a glycosidic peptide modified to comprise a sulfhydryl or alkyl group of an amino acid covalently bonded to the position of the glycosidic peptide. The glycoside peptide may further comprise a spacer between the amino acid at the position of the glyce peptide and the thiol or alkyl group. In some embodiments, the thiol group is a fatty acid or a bile acid or a salt thereof. , for example, to a fatty acid, or even a fatty acid, a bile acid, or even a (four) alkyl group, a C8^24 alkyl group, or a steroid-containing portion of a steroid group. The spacer is suitable for the connection of 156004.doc 201143790 Or any portion of a reactive group of an alkyl group. In an exemplary embodiment, the spacer comprises an amino acid, a dipeptide, a peptide, a hydrophilic bifunctional spacer or a hydrophobic bifunctional spacer. In some embodiments, the spacer is selected from the group consisting of Trp, Glu, Asp, Cys, and comprising NH2(CH2CH20)n(CH2)mC00H a spacer, wherein m is any integer from 1 to 6 and η is any integer from 2 to 12. The halogenated or alkylated glycosidic peptide may further comprise a hydrophilic moiety (as the case may be polyethylene) Alcohol) Any of the above glycosidic peptides may comprise two thiol groups or two alkyl groups or a combination thereof. The conjugate and fusion GIP agonist may optionally be linked via a linker via a covalent bond and optionally via a linker. The binding moiety described herein. In other embodiments, the second peptide is XGPSSGAPPPS (SEQ ID NO: 1096), wherein the X is selected from one of the 20 common amino acids, such as glutamic acid, aspartame Acid or glycine. In some embodiments, X represents an amino acid such as Cys, which further comprises a hydrophilic moiety covalently bonded to the side chain of the p-amino acid. The C-terminal extensions improve solubility and It can also improve GIP or GLP-1 activity. The glycoside peptide further comprises a carboxyl terminal extension. In some embodiments, the carboxy terminal amino acid of the extension ends with a guanamine or ester group rather than a carboxylic acid. In some embodiments, for example, in a glycoside peptide comprising a C-terminal extension, native liter The threonine at position 29 of the glycosidic peptide is replaced by glycine. For example, the threonine at position 29 is substituted with glycine and comprises the C-terminal extension GPSSGAPPPS (SEQ ID NO: 1095). The potency of the peptide to the GLP-1 receptor is four times that of the 156004.doc-207-201143790 modified to contain the native C-glycan of the same C-terminal extension. This T29G substitution can be used in conjunction with other modifications disclosed herein to enhance The affinity of the glycoside peptide for the GLP-1 receptor. For example, the T29G substitution can be combined with the S16E and N20K amino acid substitutions, optionally with the intrinsic amine bridge linkage between the amino acids 16 and 20, and optionally with the addition of a PEG chain as described herein. In some embodiments, an amino acid is added to the C-terminus, and the additional amino acid is selected from the group consisting of glutamic acid, aspartic acid, and glycine. Modification to enhance solubility In another embodiment, an amine group preferably introduced at the C-terminus of SEQ ID NO: 1001 to position 27 can be introduced into the C-terminal portion of the peptide by introducing a charged amino acid into the peptide. Acid substitution and/or addition to improve the solubility of any glycoside peptide. One, two or three charged amino acids may optionally be introduced into the c-terminal moiety' preferably introduced into the C-terminus to position 27. In some embodiments, one or two charged amino acids are substituted for the native amino acid at positions 28 and/or 29, and/or in another embodiment, the three charged amino groups are also Acid addition to the C-terminus of the peptide. In an exemplary embodiment, one, two or all of the charged amino acids are negatively charged. In some embodiments, the negatively charged (acidic) amino acid is aspartic acid or glutamic acid. Other modifications (e. g., conservative substitutions) can be made to the glycoside peptide while still retaining GIP activity (and optionally retaining GLP-1 activity and/or glycemic activity). Other Modifications for Enhancing or Decreasing Gip Activity, Strengthening or Decreasing Glucagon Receptor Activity, and Enhancing GLP-丨 Receptor Activity, as described in the second class of peptides, may be 156004.doc •208· 201143790 Ground or combination application. Any of the modifications described above for the Type 2 ghlylin-related peptide may also confer other desirable properties, such as enhanced solubility and/or stability, as described herein with respect to the Type 2 glycanin-related peptide. Or other combination of modifications that extend the duration of action. Alternatively, any of the modifications described above for the Type 2 ghrelin-related peptide may be combined with other modifications described herein with respect to the Type 2 glycanin-related peptide that do not substantially affect solubility or stability or activity. Modifications include, but are not limited to: _ (A), for example, by introducing one, two, three or more charged amino acids into the end portion of the native glycein, preferably introduced at the c-terminus The position in position 27 is used to improve solubility. The charged amino acid can be introduced by replacing the primary amino acid with a charged amino acid, for example, at position 28 or 29, or by, for example, adding a charged amino acid after position 27, 28 or 29. In the exemplary embodiment, one, two, three or all of the charged amino acids are negatively charged. In other embodiments, one, two, three or all charged amino acids are positively charged. These modifications enhance solubility, for example, • so that the solubility is at 25<> (after 24 hours, the solubility of the native glycemic is at least 2 at a given pH of about 5.5 to 8 (e.g., pH 7).倍, 5倍, 1〇, 15, 25, 30 or 30 times. (B) By as described herein, for example, at the position of the peptide 丨 6, 17, 2, 21, 24 or 29 Adding a hydrophilic moiety such as a polyethylene glycol chain to the upper, C-terminal extension or "terminal amino acid" to enhance solubility and prolong the duration of action or circulating half-life. (C) by deuteration or alkane as described herein Glycosyl peptide to enhance solubility and/or prolongation duration or circulatory half-life and/or delay initiation 156004.doc • 209-201143790. Time (D) by position 1 or 2 as described herein The amino acid is modified to introduce resistance to cleavage of dipeptidyl peptidase IV (DPP IV) to prolong the duration of action or circulating half-life. » (E) by, for example, by deletion or with glutamic acid, glutamine Substitution of acid, sulfoalanine or high sulfoalanine to modify Asp at position 丨5 to enhance stability. The decoration can reduce degradation or cracking at a pH in the range of 5.5 to 8, for example, retaining at least 75%, 80%, 90%/〇, 95%, 96%, 97% after 24 hours at 25 °C, 98% or 99%, up to 100% of the original peptide. These treatments reduce the cleavage of the peptide bond between Aspl 5-Serl 6. (F) Modify the Ser at position 16 by, for example, substitution with Thr or Aib Enhances stability. These modifications also reduce the cleavage of peptide bonds between Aspl5-Serl6. (G) Enhance stability by modifying methionine at position 27, for example, by substitution with leucine or ortho-amine. Such modifications may reduce oxidative degradation. Gin at position 20 or 24 may also be modified, for example, by substitution with Ser, Thr, Ala or Aib to enhance stability.

Degradation of Gin to the guanamine group. The Asp at position 21 can be modified, for example, by substitution with Glu to enhance stability. These modifications can be reduced via

Dehydration of Asp forms a cyclic butyl quinone imine intermediate which in turn constitutes degradation of the isoaspartate. 'Sufficient substitution, addition, 丄 2, 13, 14, 28 or 29 or (H) does not substantially affect the non-conservative or preserved or absent activity, eg at positions 2, 5, 9, 1 〇, 1 i 15 , 16 , 17 , 18 , 19 , 20 , 21 , 24 , 27 , 156004.doc 210- 201143790 conservative substitutions on many; replacing one or more of these positions with Ala, position 27, Deletion of the amino acid on one or more of 28 or 29; or deletion of the amino acid 29, optionally as a combination of a hydrazine or an ester instead of a c-terminal carboxylic acid group; Lys; replaces Tyr at position 1 with (10) or phe. Maintains activity after PEGylation by adding GPSSGAPPPS (SEQ ID NO: 1095) to the C-terminus. Some modifications can be made to the position of the native glucagon peptide. While retaining at least some activity of the parent peptide. Therefore, applicants of the present invention are expected to be located at positions 2, 5, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, 24, 27, 28 or 29 One or more of the amino acids may be substituted with an amino acid different from the amino acid present in the native glucagon peptide, The activity on the glycoside receptor is still retained. In some embodiments, the position 18 is replaced with an amino acid selected from the group consisting of Ala, Ser or Thr. In some embodiments, Ser, Thr, φ Lys, Arg, Om, citrulline or Aib replaces the amino acid at position 2. In some embodiments, position 21 is replaced with Glu, glutamic acid or high-performance propylamine. In some embodiments, 'glycanin peptide An amino acid modification comprising one to one oxime selected from the group consisting of positions 16, 17, 18, 20, 21, 23, 24, 27, 28 and 29. In an exemplary embodiment, the modification is selected from the group consisting of One or more amino acid substitutions: Glnl7, Alal8, Glu21, Ile23, Ala24, Val27, and Gly29. In some embodiments, one to two amino acids selected from positions 17 to 26 are different from the parent peptide. In one embodiment, one to two amino acids selected from positions 17 to 22 are different from the parent peptide. In other examples 156004.doc -211 · 201143790 'modified to Glnl7, Alal8, Glu21, Ile23 and AU24. In some implementations In one embodiment, one or more amino acids are added to the carboxy terminus of the glycosidic peptide. The amino acid is usually selected. One of the 20 common amino acids, and in some embodiments, the amino acid has a guanamine group in place of the carboxylic acid of the native amino acid. In an exemplary embodiment, the added amino acid is selected Free glutamic acid and a group of aspartic acid and glycine.

Other modifications that do not disrupt activity include W1Q or R2Q. In some embodiments, the second class of ghlylin-related peptides disclosed herein are modified by truncating the C-terminus by one or two amino acid residues. Similar activity and potency are still retained for the glycoside receptor, GLP-1 receptor and/or GIP receptor. In this regard, the amino acid at positions 29 and/or 28 can be deleted. EXEMPLARY EMBODIMENT According to some embodiments of the invention, the analog of Glycosin (SEq ID N〇: 1〇〇1) having GIP agonist activity comprises SEq id no: 1〇〇丨, which has (a a modification of the amino acid that confers gip agonist activity at position 1, (b) a modification of the alpha helix structure that stabilizes the C-terminal portion of the analog (amino acid 12 to 29) and (c) as appropriate,丨 to 1〇 (for example, 〖, 2, 3, 4, $, 6, 7, 8, 9 '1〇) other amino acid modification. In some embodiments, the activity exhibited by the analog to the GIP receptor is at least about the activity of the native GIp, or any other activity of the GIP receptor described herein. In certain embodiments, the modification of the stabilized alpha helix structure provides for the introduction or introduction of intramolecular bridge bonds, including, for example, covalent intramolecular bridge bonds, such as modifications of any of the intramolecular bridges described herein. In some embodiments, the covalent intramolecular bridge is an intrinsic amine bridge. The internal amine bridges of the analogs of these embodiments can be 156004.doc 201143790 for the indoleamine bridge as described herein. See, for example, the "Stabilization of the alpha helix structure" for the teaching of the intrinsic amine bridge. . For example, the indoleamine bridge can be the amino acid side chain and position between the amino acid side bond at position i and the amino acid side chain at position 丨+4 or at position j. An intrinsic amine bridge between the amino acid side bonds on j+3, where i is 12, 13, 16, 17, 20 or 24, and wherein j is 17. In certain embodiments, the indoleamine bridge can be between the amino acid at position 16 and the amino acid at position 20, one of the amino acids at positions 16 and 20 via Glu. The other of the amino acids substituted and at positions 16 and 20 is substituted with Lys. In an alternate embodiment, the modification of the stabilized alpha helix structure is the introduction of one, two, three or four alpha, alpha disubstituted amino acids at positions 16, 20, 21 and 24 of the analog. In some embodiments, the alpha, alpha disubstituted amino acid is Aib. In certain aspects, the alpha, alpha disubstituted amino acid (eg, Aib) is at position 20' and the amino acid at position 16 is via a positively charged amino acid (such as an amine group of formula IV as described herein). Acid) substitution. The amino acid of formula IV can be high Lys, Lys, Orn or 2,4-diaminobutyric acid (Dab). In a particular aspect of the invention, the amino acid at position 1 is modified to replace His with an amino acid lacking the side chain of the imidazole (e.g., a large aromatic amino acid (e.g., Tyr)). In some aspects, the glycoside analog comprises an amino acid modification at one, both or all of positions 27, 28 and 29. For example, a large aliphatic amino acid (as appropriate as Leu) can be substituted for the Met at position 27, and a small aliphatic amino acid (as appropriate) can be substituted for Asn at position 28, and a small aliphatic amine group can be used. The acid (as appropriate Gly) replaces Thr at position 29, or the above two 156004.doc-213-201143790 or a combination of the three. . In a particular embodiment, the glycoside analog comprises Leu' at position 27 comprising Ala at position 28 and Gly or Thr at position 29. In certain embodiments of the invention, the glycoside analog comprises an extension having from 1 to 21 amino acids on the amino acid from the C-terminus to the position 29. The extension may comprise, for example, the amino acid sequence SEQ ID NO: 1095 or 1096. Additionally or alternatively, the glycoside analog can comprise an extension wherein one to six amino acids of the extension are positively charged amino acids. The positively charged amino acid can be an amino acid of formula IV 'including, but not limited to, LyS, high Lys, Orn, and Dab. In some embodiments, the 'glycan analogs are deuterated or alkane as described herein. Basic. For example, a tallow or an alkyl group can be attached to the glycoside analog in the presence or absence of a spacer, attached to the position of the analog at 1 or 4, as further described herein. The analog may additionally or alternatively be modified to comprise a hydrophilic moiety' as further described herein. Furthermore, in some embodiments the 'analogs comprise any one or combination of the following modifications: (a) Ser at position 2 via D-Ser, Ala, D-Ala, Gly, N-methyl-Ser, Aib , Val or α-amino-N-butyric acid substitution; (b) Tyr at position 10 is substituted with Trp, Lys, Orn, Glu, Phe or Val; (c) Stimulated to Lys at position 10; (d) Lys at position 12 is substituted by Arg or lie; (e) Ser at position 16 is replaced by Glu, Gin, glutamic acid, homosulfoylamine, Thr, Gly or Aib; 156004.doc •214 · 201143790 (f) Arg at position 17 is replaced by Gin; (g) Arg at position 18 is replaced by Ala, Ser, Thr or Gly; (h) Gin at position 20 via Ser, Thr, Ala, Lys, Melon Substituted by aminic acid, Arg, Orn or Aib; (i) Asp at position 21 is substituted with Glu, glutamic acid, or high sulfoalanine; (j) Val at position 23 is replaced by lie; (k) position 24 Gin is replaced by Asn, Ser, Thr, Ala or Aib; Lu (1) and position 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 8, 19, 20, 21, 24, 27 Conservative substitutions on any of 28, 29 and 29. In an exemplary embodiment, the analog of Glycosin (SEQ ID NO: 1001) having GIP agonist activity comprises the following modifications: (a) Amino acid modification at position 1 that confers GIP agonist activity, ( b) the amino acid side chain between position i and the amino acid side chain at position i+4 or the amino acid side chain at position j and the amino acid side at position j+3 An intrinsic amine bridge between the chains, wherein i is 12, 13, 16, 17, 20 or 24, and wherein j is 17, (c) one, two or all of positions 27, 28 and 29 Performing an amino acid modification on-such as amino acid modification at positions 27 and/or 28, and (d) l to 9 or 1 to 6 other amino acid modifications, such as 1, 2, 3' 4, Other amino acid modifications at 5, 6, 7, 8 or 9 and the EC5Q for activation of the GIP receptor is about 10 nM or less. 156004.doc -215 · 201143790 The internal guanamine bridge of the analogs of these embodiments can be an internal guanamine bridge as described herein. See, for example, the teaching of the intrinsic amine bridge under the "Stabilization of the alpha helix structure". For example, the indoleamine bridge can be between the amino acid at position 16 and the amino acid at position 20, wherein one of the amino acids at positions 16 and 20 is replaced by Glu and position 16 The other of the amino acids of 20 and 20 is substituted with Lys. According to such embodiments, the analog may comprise, for example, any of the amino acid sequences SEQ ID NO: 1005-1094. In other exemplary embodiments, the analog of Glycosin (SEQ ID NO: 1〇〇1) having GIP agonist activity comprises the following modifications: (a) Amino group that confers GIP agonist activity at position 1. Acid modified, (b) one of the amino acids at positions 16, 20, 21 and 24 of the analogue, two, or all of which are substituted by an alpha, alpha disubstituted amino acid, (c) Amino acid modification is performed on one, both or all of positions 27, 28 and 29, such as amino acid modification at positions 27 and/or 28, and (d) l to 9 or 1 to 6 Other amino acid modifications, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 other amino acid modifications, and the analogs have an EC5 活化 of about 10 nM or 1 对 for GIP receptor activation. Below nM. The alpha, alpha disubstituted amino acids of the analogs of these examples may be any alpha, alpha disubstituted amino acids including, but not limited to, aminoisobutyric acid (Aib) selected from sulfhydryl groups. An amino acid which is disubstituted by the same or different groups of ethyl, propyl and n-butyl groups or an amino acid which is disubstituted by cyclooctane or cycloheptane (for example, aminocyclooctane-1-decanoic acid ). In certain embodiments, the alpha, alpha disubstituted amino acid is I56004.doc • 216·201143790

Aib. In certain embodiments, the amino acid at position 2 is substituted with a disubstituted amino acid (e.g., Aib). The analogs according to these examples may comprise, for example, any of the amino acid sequences SEQ id NO: 1099-1141, 1144-1164, 1166-1169 and 1173-1178. In other exemplary embodiments, the analog of Glycosin (SEQ ID NO: 1001) having GIP agonist activity comprises the following modifications: Amino acid modification conferring GIP agonist activity at position (a) (b) Amino acid substitution of Ser at position 16 with an amino acid of formula IV: h2n-c-COOH (CH2)n

I

[Formula IV], wherein n is 1 to 16, or 1 to 10, or 1 to 7, or 1 to 6, or 2 to 6, and φ R1 and R2 are each independently selected from the group consisting of H, C1 - C18 alkyl, (C1-C18 alkyl) fluorene H, (C1-C18 alkyl) NH2, (C1-C18 alkyl) SH, (C0-C4 alkyl) (C3-C6) cycloalkyl, (C0 -C4 alkyl)(C2-C5 heterocyclyl), (C0-C4 alkyl)(C6-C10 aryl)R7 and (C1-C4 alkyl)(C3-C9heteroaryl), wherein R7 is hydrazine Or OH, and the side chain of the amino acid of formula IV comprises a free amine group, (c) an amino acid substitution of Gin at position 20 with an alpha, alpha disubstituted amino acid, (d) at positions 27, 28 And one or both of the amines are subjected to amine 156004.doc • 217·201143790 base acid modification, for example, amino acid modification at positions 27 and/or 28, and (e) 1 to 9 or 1 Up to 6 other amino acid modifications, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 other amino acid modifications, and the EC5〇 of the analog for GIP receptor activation is about 10 nM Or below 10 nM. The amino acid of formula IV of the analogs of these embodiments may be any amino acid such as η 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 , 15 or 16 of the amino acid of formula IV. In certain embodiments, η is 2, 3, 4, or 5, in which case the amino acids are Dab, Orn, Lys, or high Lys, respectively. The alpha, alpha double substituted of the analogs of these embodiments The amino acid can be any alpha, alpha disubstituted amino acid 'including but not limited to, aminoisobutyric acid (Aib), the same or different selected from the group consisting of methyl, ethyl, propyl and n-butyl A group of a disubstituted amino acid, or an amino acid which is disubstituted with cyclooctane or cycloheptane (for example, hydrazine-aminocyclooctane-1-carboxylic acid). In certain embodiments, the alpha, alpha disubstituted amino acid is Aib. The analogs according to these embodiments may comprise, for example, any of the amino acid sequences SEq ID NO: 1099-1165. In other exemplary embodiments, the analog of Glycosin (SEQ ID NO: 1001) having GIP agonist activity comprises: (a) an amino acid modification that confers GIP agonist activity at position 1, and b) an extension of from about 1 to about 21 amino acids on the amino acid at the C-terminus to position 29 wherein at least one of the amino acids of the extension is deuterated or alkylated, 156004.doc • 218* 201143790 wherein the analog has an EC5G for GIP receptor activation of about 10 nM or less. In some embodiments, the deuterated or alkylated amino acid is an amino acid of formula I, II or III. In a more specific embodiment, the amino acid of formula I is Dab, Orn, Lys or high Lys. Also in some embodiments, the extension having from about 1 to about 21 amino acids comprises the amino acid sequence GPSSGAPPPS (SEQ. ID NO: 1095) or XGPSSGAPPPS (SEQ ID NO: 1096), wherein X is any amino acid; or comprises the amino acid sequence GPSSGAPPPK (SEQ ID NO: 1170) or XGPSSGAPPPK (SEQ ID NO: 1171) or XGPSSGAPPPSK (SEQ) ID NO: 1172) wherein X is Gly or a small aliphatic or a non-polar or slightly polar amino acid. In some embodiments, from about 1 to about 21 amino acids can comprise a sequence that contains one or more conservative substitutions relative to SEQ ID NO: 1095, 1096, 1170, 1171, or 1172. In some embodiments, the deuterated or alkylated amino acid is located at position 37, 38, 39, 40, 41, 42 or 43 of the C-terminally extending analog. In certain embodiments, the deuterated or alkylated amino acid is located at position 40 of the C-terminally extended analog. In some embodiments, the analog having GIP agonist activity further comprises an amino acid modification at one, both or all of positions 27, 28, and 29, such as an amine at position 27 and/or 28 Acidic modification. In any of the above exemplary embodiments, the amino acid modification imparting GIP agonist activity at position 1 may be the substitution of His with an amino acid lacking the imidazole side chain. The amino acid modification at position 1 can, for example, be the replacement of His with a large aromatic amino acid. In some embodiments, the large aromatic amino acid is any of the 156004.doc-219-201143790 large aromatic amino acids described herein, such as Tyr. In some aspects, the analog does not contain an amino acid modification at position 1, which imparts GIP agonist activity. In some aspects, the amino acid at position is not a large aromatic amino acid, such as Tyr. In some embodiments, the amino acid at position 1 is an amino acid comprising an imidazole ring, such as a His, His analog. In certain embodiments, the analog is not any of the compounds disclosed in International Patent Application Publication No. WO 201〇/(m439. In certain aspects, the analog comprises the amino acid sequence SEQ ID N〇: 1263 1275 Similarly, for the above exemplary embodiments, the amino acid modification on one, both or all of positions 27, 28, and 29 can be any of the positions described herein. Modifications. For example, a large aliphatic amino acid (as appropriate) may be substituted for Met at position 27, and a small aliphatic amino acid (as appropriate) may be substituted for Asn at position 28, and/or may be used. The small aliphatic amino acid (optionally Gly) replaces Thre at position 29 or the analog may comprise such amino acid modifications at positions 27 and/or 28. The analogs of the above exemplary embodiments may further comprise丨 to 9 or 丨 to 6 other additional amino acid modifications, such as 1, 2, 3, 4, 5, 6, 7, 8 or 9 other amino acid modifications, such as enhancements or reductions as described herein Activity, improved solubility of any of the Gip receptor, GLP-1 receptor and glycein receptor Any modification that alters the duration of action or circulating half-life, delays the onset of action, or enhances stability. The analog may further comprise, for example, an amino acid modification at position 12, optionally as a substitution; and/or position Amino acid modification at 17 and 18, optionally at position 17 with 卩I56004.doc •220-201143790 and with position 18 at position 18; and/or GPSSGAPPPS (SEQ ID NO: 1095) Or XGPSSGAPPPS (SEQ ID NO: 1096), or a sequence containing one or more conservative substitutions relative to SEQ ID NO: 1095 or 1096, is added to the C-terminus. The analog may comprise one or more of the following modifications: (1) The Ser at position 2 is substituted with D-Ser, Ala, D-Ala, Gly, N-mercapto-Ser, Aib, Val or α-amino-N-butyric acid; (ii) Tyr at position 10 via Trp , Lys, Orn, Glu, Phe or Val; (iii) thiol linkage to Lys at position 10; (iv) Lys at position 12 is substituted by Arg; (v) Ser via position 16 , Gin, high-facial acid, high-performance propylalanine, Thr, Gly or Aib substitution; (vi) Arg at position 17 is replaced by Gin; (vii) Arg at the 18 by Ala, Ser, Thr or Gly substituted; Gin on the 20 • (viii) position by Ala, Ser, Thr, Lys, citrulline,

Arg, Orn or Aib substituted; (ix) Asp at position 21 is substituted with Glu, glutamic acid, high sulfoalanine; (X) Val at position 23 is replaced by lie; (xi) Gin at position 24 Substituted by Asn, Ala, Ser, Thr or Aib; and (xii) positions 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 27 , 156004.doc -221 - 201143790 on either of 28 and 29. In some embodiments, the analog comprises a combination of modifications (1) to (xii). Alternatively or additionally, the analog may comprise an amino acid modification at position 3 (e.g., amino acid substitution of Gin with Glu), wherein the activity of the analog to the glycosidic receptor is a glycosidic activity 1 %the following. Alternatively or additionally, the analog may comprise an amino acid modification at position 7 (e.g., an amino acid substitution of Thr with a transbasic amino acid (e.g., Abu or lie)), wherein the analog is for GLP-1 The activity of the receptor is about 1% or less of the activity of GLP-1. For the exemplary embodiment, the analog can be covalently bonded to the hydrophilic moiety. In some embodiments the ' analog is covalently bonded to the hydrophilic moiety at any of the amino acid positions 16, 17, 20, 21, 24, 29, 40 or C-terminus. In certain embodiments the 'analog comprises a C-terminal extension (eg, amino acid sequence SEQ ID NO: 1095) and is added with an amino acid comprising a hydrophilic moiety, such that the hydrophilic moiety can be covalently bonded at position 40. Linked to the analog. In some embodiments the 'hydrophilic moiety is covalently linked to the analog of Lys, Cys, Orn, homocysteine or ethionyl phenylalanine. Lys, Cys, Orn, homocysteine or ethionyl-phenylalanine may be a native amino acid for the glycosidic sequence (SEQ ID NO: 1001), or it may be a substitution of SEQ ID NO: 1001 The amino acid of the native amino acid. In some embodiments, wherein the hydrophilic moiety is attached to Cys, the linkage to the hydrophilic moiety can comprise the following structure:

156004.doc -222- 201143790 Peptide I η ks-*YNN^〇V-〇)^nCH3 ο 〇 For analogs comprising a hydrophilic moiety, the hydrophilic moiety can be any of the hydrophilic moieties described herein. See, for example, the teachings under the section "Key Connections of Hydrophilic Parts". In some embodiments, the hydrophilic moiety is polyethylene glycol (PEG). In certain embodiments, the molecular weight of the PEG is from about 1,000 Daltons to about 40,000 Daltons, such as from about 20,000 Daltons to about 40,000 Daltons.

For an exemplary embodiment, the analog may comprise a modified amino acid in which the side chain is covalently bonded to a thiol or alkyl group (eg, a non-native thiol or alkyl group for a naturally occurring amino acid) . The deuterated or alkylated analogs can be subjected to the deuterated or alkylated peptides described in the section "Deuteration and Alkylation". In some embodiments, the thiol group is a C4 to C30 fatty sulfhydryl group, such as a C10 fatty decyl or alkyl group, a C12 fatty decyl or alkyl group, a C14 fatty decyl or alkyl group, a C16 fatty decyl group or an alkyl group, C18 Fat thiol or alkyl, C20 decyl or alkyl or C22 decyl or alkyl. The thiol or alkyl group can be covalently attached to any of the amino acids of the analog, including, but not limited to, an amino acid or a C-terminal amino acid at position 10 or 40. In certain embodiments the 'analog comprises a C-terminal extension (eg, the amino acid sequence SEQ ID NO: 1095) and is added with an amino acid comprising a thiol or alkyl group, such that the aryl or the pendant can be in position 40. The covalent bond is attached to the analog. In some embodiments, a fluorenyl or alkyl group is covalently bonded to a side chain of an amino acid of formula I, π or hydrazine (e.g., a Lys residue). The thiol or alkyl group can be covalently linked to the amino acid native to the glycosidic sequence (SEQ ID NO: 1001), or can be linked to the addition to the sequence SEQ ID NO: 1001 or to the SEQ ID 156004.doc • 223· 201143790 NO: 1001 followed by an amino acid in the sequence of SEQ ID NO: 1095 (on the N-terminus or C-terminus), or may be linked to a native amino group that replaces SEQ ID NO: 1001 An amino acid of an acid (e.g., Tyr at position 10). In the above exemplary embodiments, wherein the analog comprises a thiol or alkyl group, the analog can be attached to a thiol or alkyl group via a spacer as described herein. The spacer may be, for example, 3 to 10 atoms in length, and the spacer may be, for example, an amino acid (e.g., 6-aminohexanoic acid, any of the amino acids described herein), a dipeptide (e.g., Ala-Ala, pAla) -pAla, Leu-Leu, Pro-Pro, γ-〇1ιι-γ-

Glu), a tripeptide, or a hydrophilic or hydrophobic bifunctional spacer. In some aspects, the total length of the spacer and the thiol or alkyl group is from about 4 to about 28 atoms. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments the 'didentate spacer is not Y-Glu-y-Glu. In other exemplary embodiments, the glycosidic analog having GIP agonist activity comprises any one of the amino acid sequences SEQ ID NO: 1227, 1228, 1229 or 1230' which further comprises the following modifications: An amino acid modification imparting GIP agonist activity at position 1 as appropriate, (b) an extension of from about 1 to about 21 amino acids at the C-terminus to the amino acid at position 29 ' wherein at least one amino acid of the extension is deuterated or alkylated, and (d) up to 6 other amino acid modifications, wherein the analog has an EC5q for activation of the GIP receptor of about 1 〇 nM or 10 Below nM. In some aspects, the deuterated or alkylated amino acid is 156004.doc of the formula I, hydrazine or III. 224-201143790 Amino acid. In a more specific embodiment, the amino acid of formula I is Dab, Orn, Lys or high Lys. Also in some embodiments, from about 1 to about 21 amino acids comprise the amino acid sequence GPSSGAPPPS (SEQ ID NO: 1095) or XGPSSGAPPPS (SEQ ID NO: 1096), wherein X is any amino acid; or comprises Amino acid sequence 〇? 88〇 gossip? ? Ruler (3 £ (^1〇)^〇: 1170) or XGPSSGAPPPK (SEQ ID NO: 1171) or XGPSSGAPPPSK (SEQ ID NO: 1172), where X is Gly or a small aliphatic or non-polar or slightly polar amine In some embodiments, from about 1 to about 21 amino acids may comprise a sequence containing one or more conservative substitutions relative to SEQ ID NO: 1095, 1096, 1170, 1171 or 1172. In some embodiments The deuterated or alkylated amino acid is located at position 37, 38, 39, 40, 41, 42 or 43 of the C-terminally extended analog. In certain embodiments, deuterated or alkylated The amino acid is located at position 40 of the C-terminally extended analog. In any of the above exemplary embodiments, the amino acid that imparts GIP agonist activity at position 1 can be an amino acid lacking the imidazole side chain. The above amino acid can be, for example, a large aromatic amino acid. In some embodiments, the large aromatic amino acid is any of the large aromatic amino acids described herein, such as Tyr. Similar to the above exemplary embodiments The substance may further comprise from 1 to 6 other amino acid modifications, such as enhancing or reducing the GIP receptor, GLP-1 receptor and Any modification of the activity of the glycoside receptor, improved solubility, duration of modification or circulating half-life, delayed onset time, or enhanced stability. In some aspects, in the above exemplary embodiments The glycoside analogs include other amines 156004.doc -225 - 201143790 base acid modifications in one, both or all of positions 27, 28 and 29. Modifications at these positions may be described herein for such Any modification described in the position. For example, for SEQ ID NO: 1227, 1228, 1229 or 1230, position 27 can be substituted with a large aliphatic amino acid (eg, Leu, ne or orthanoic acid) or Met, position 28 may be substituted with another small aliphatic amino acid (e.g., Gly or Ala) or Asn, and/or position 29 may be substituted with another small aliphatic amino acid (e.g., Ala or Gly) or Thr. Alternatively, the analog The amino acid modifications may be included at positions 27 and/or 28. The analog may further comprise one or more of the following other modifications: (1) The amino acid at position 2 is D-Ser, Ala, D- Any of Ala, Gly, N-methyl-Ser, Aib, Val or α-amino-N-butyric acid (Π) The amino acid at position 10 is Tyr, Trp, Lys, Orn, Glu, Phe or Val; (iii) the thiol linkage to Lys at position 10; (iv) the amino acid at position 12 Is lie, Lys or Arg; (v) the amino acid at position 16 is any of Ser, Glu, Gin, glutamic acid, homoreactivic acid, Thr, Gly or Aib; (vi) at position 17 The amino acid is Gin or Arg; (vii) the amino acid at position 18 is any one of Ala, Arg, Ser, Thr or Gly; (viii) the amino acid at position 20 is Ala, Ser Any one of Thr, Lys, citrulline, Arg, Orn or Aib or another alpha, alpha disubstituted amino acid; (ix) the amino acid at position 21 is Glu, Asp, glutamine Any of acid, high recurring alanine; 156004.doc -226- 201143790 (X) The amino acid at position 23 is Val or lie; (xi) The amino acid at position 24 is Gin, Asn, Ala' Any of Ser, Thr or Aib; and (xii) positions 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 ' 19, 20, 21, 24, 27, One or more conservative substitutions on either of 28 and 29. In some embodiments the 'analogs comprise a combination of modifications (1) to (xii). Alternatively or additionally, the analog may comprise an amino acid modification at position 3 (e.g., amino acid substitution of Gin with Glu), wherein the activity of the analog to the glycosidic receptor is a glycosidic activity 1 %the following. Alternatively or additionally the analog may comprise an amino acid modification at position 7 (e.g., amino acid substitution of Thr with an amino acid lacking a hydroxyl group (e.g., Abu or lie)), wherein the analog is directed to the GLP-1 receptor The activity is less than about 1% of the activity of glp-1. For an exemplary embodiment, the analog can be covalently bonded to the hydrophilic moiety. In some embodiments the ' analog is covalently bonded to the hydrophilic moiety at any of the amino acid positions 16, 17, 20, 21, 24, 29, 40 or C-terminus. In certain embodiments, the analog comprises a hydrophilic moiety covalently bonded to the analog at position 24. In some embodiments the 'hydrophilic moiety is covalently linked to the analog of Lys, Cys, 〇rn, homocysteine or acetyl-phenylalanine. Lys, Cys, 〇rn, homocysteine or acetyl-alkalonic acid may be a native amino acid for ID NO: 1001, 1227, 1228, 1229 or 123 ,, or it may be substituted Amino acid, in some embodiments, wherein the hydrophilic moiety is bonded to CyS, the linkage may comprise the following structure: 156004.doc -227- 201143790

o For an analog comprising a hydrophilic moiety, the hydrophilic moiety can be any of the hydrophilic moieties described herein. See, for example, the teachings under the section "Links of hydrophilic moieties". In some embodiments, the hydrophilic moiety is polyethylene glycol (PEG). In certain embodiments, the pEG has a molecular weight of from about 1 Dalton to about 40, a Dalton, for example about 2, and a Dalton to about 4 Daoer. pause. For exemplary embodiments, the analog may comprise a modified amino acid covalently bonded to the thiol or alkyl group in the C-terminal extension. The deuterated or alkylated analog may be a deuterated or alkylated peptide as described in the section "Deuteration and Alkylation". In some embodiments, the thiol group is a C4 to C30 fatty sulfhydryl group, such as a C10 fatty decyl or alkyl 'C12 fatty decyl or alkyl group, a C14 fatty decyl or alkyl group, a C16 fatty decyl group or an alkyl group, C18 Fat thiol or alkyl, C20 decyl or alkyl, or C22 aryl or alkyl. Any amino acid that can be covalently attached to the analog, such as, but not limited to, an amino acid or a C-terminal amino acid at position 10 or 40. In some embodiments, a thiol or alkyl group is covalently bonded to the side chain of an amino acid of Formula I, II or III (eg, a Lys residue). The thiol or alkyl group is covalently bonded to SEQ ID NO. : 1001, 1227, 1228, 1229 or 1230 for a native amino acid, or it may be bonded to a substituted amine 156004.doc -228·201143790 acid. A mercapto or alkyl group is covalently bonded to an amino acid native to SEQ ID NO: 1095, 1096, 1171 or 1172, or which may be bonded to a substituted amino acid, in the above exemplary embodiments, Wherein the analog comprises a thiol or alkyl group, the analog being attachable to a thiol or alkyl group via a spacer as described herein. The spacer may be, for example, 3 to 1 inch in length, and the spacer may be, for example, an amino acid (eg, 6-aminohexanoic acid, any of the amino acids described herein) 'dipeptide (eg, Ala-Ala, pAla-pAla ' Leu-Leu > Pro-Pro ' y-Glu-γ-

Glu), a tripeptide, or a hydrophilic or hydrophobic bifunctional spacer. In some aspects, the total length of the spacer and the brewing or glare is from about 14 to about 28 atoms. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments, the dipeptide spacer is not y-G1u-y-G1u. In some very specific embodiments, the analog of the invention comprises a population selected from the group consisting of SEQ ID NOs: 1099-1141, 1144-1164, 1166, 1192-1207, 1209-1221, and 1223 or selected from SEQ ID NO: 1167 - Amino acid sequence of the group consisting of 1169, 1173-1 178 and 1225. Furthermore, specific examples of analogs of the invention include, but are not limited to, any of the analogs mentioned in Tables 1 to 3. In other exemplary embodiments, the glycoside analog having GIP agonist activity comprises a thiol or alkyl group (eg, a non-native sulfhydryl or alkyl group for a naturally occurring amino acid), wherein the thiol group Or an alkyl group attached to a spacer, wherein (1) the spacer is attached to the side chain of the amino acid at position 10 of the analog; or (ii) the analog comprises at the C-terminus to the amino acid at position 29 An extension of from 1 to 21 amino acids and the spacer is attached to a side chain of an amino acid corresponding to one of positions 37 to 43 of SEQ ID NO: 1001 of 156004.doc 229. 201143790, wherein the The EC5() of the GIP receptor activation is about 10 nM or less. In such embodiments, the analog may comprise the amino acid sequence SEQ ID NO: 1001, wherein (i) the amino acid modification '(Π) imparting GIP agonist activity at position 1 is at positions 27, 28 And (a) at least one of the following: (A) an amino acid side chain of the analog at position i and an amine at position 丨 +4 The intrinsic amine bridge is contained between the amino acid side bond or the amino acid side bond at position j and the amino acid side chain at position j+3, wherein the oxime is 12, 13, 16, 17, 20 Or 24, and wherein j is 17; (B) one of the amino acids at positions 16, 2, 21, and 24 of the analog, two, or all of the amines substituted by α,α Substituted by a base acid; or (c) the analog comprises an amino acid substitution of the amino acid of the formula IV to the Ser at position 丨6: H2N—C—COOH (CH 2 ) n

I

Wherein n is from 1 to 7, wherein ri and R2 are each independently selected from the group consisting of hydrazine, C丨-Cl8, (Cl_Ci8 alkyl) 〇H, yl) nh2, (Cl_Cl8) Base) SH, (CVC4 alkyl) (C3_c^cycloalkyl, (C〇_C4 fluorenyl) (C2_c5 heterocyclic), (CVC4 alkyl) (C6_Ci. aryl) II and 156004.doc • 230- 201143790 (Ci-C4 alkyl) (C3-C9 heteroaryl), wherein R7gH or OH, and the side chain of the amino acid of formula IV comprises a free amine group; and (Η) α,α disubstituted amino acid pair Substituting the amino acid of Gin at position 20; and (iv) performing up to 6 other amino acid modifications. The alpha, alpha disubstituted amino acid of the analogs of these embodiments may be any alpha, alpha disubstituted Amino acids including, but not limited to, aminoisobutyric acid (Aib), an amino acid that is disubstituted with the same or different groups selected from methyl, ethyl, propyl and n-butyl groups a cyclooctane or cycloheptane disubstituted amino acid (e.g., hydrazine-aminocyclooctane-1 -carboxylic acid). In certain embodiments, the alpha, alpha disubstituted amino acid is Aib. An analog of the formula IV amino acid can be Any amino acid such as the amino acid of formula IV wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12' 13, 14, 15 or 16. In the examples, ^ is 2, 3, 4 or 5, in which case the amino acids are Dab, 〇rn, Lys or high Lys, respectively. In any of the above exemplary embodiments, GIP is imparted at position 1. The active amino acid modification may be the substitution of His with an amino acid lacking an imidazole side bond. The amino acid modification at position 1 may, for example, be replaced by a large aromatic amino acid.

His ^ In some embodiments, the large aromatic amino acid is any of the large aromatic amino acids described herein, such as Tyr. Likewise, for the above exemplary embodiments, the amino acid modification on either or both of positions 27, 28, and 29 can be any modification at these positions as described herein. For example, a large aliphatic amino acid (optionally Leu) can be substituted for Met at position 27, and a small aliphatic amino acid (Ala, 156004.doc • 231 - 201143790, as appropriate) can be substituted for Asn at position 28. And/or a small aliphatic amino acid (as appropriate Gly) may be substituted for Thr at position 29. Alternatively, the analog may comprise such amino acid modifications at positions 27 and/or 28. The analogs of the above exemplary embodiments may further comprise from 丨 to 9 or from 丨 to 6 other additional amino acid modifications, for example! '2, 3, 4, 5, 6, 7, 8 or 9 other amino acid modifications, such as those described herein, enhance or reduce the presence of o's, GLP-1 receptors and glycoside receptors Any modification of activity, improvement/gluten degree, duration of modification or circulating half-life, delayed onset time, or enhanced stability. The analog may further comprise, for example, an amino acid modification at position 12, In the case of substitution with ne; and/or amino acid modification at positions 17 and 18, as appropriate, substitution with q at position 17 and substitution with A at position 18; and/or GPSSGAPPPS (SEQ ID) NO: 1095) or XGPSSGAPPPS (SEQ ID NO: 1096), or a sequence containing one or more conservative substitutions relative to SEQ ID NO: 1095 or 1096, added to the C-terminus. The analog may comprise one of the following modifications or Many: (1) The Ser at position 2 is substituted by D-Ser, Ala, D-Ala, Gly, N-mercapto-Ser, Aib, Val or α-amino-N-butyric acid; (ii) Position 10 Tyr is substituted by Trp, Lys, Orn, Glu, Phe or Val; (iii) thiol linkage to Lys at position l; (iv) Lys at position 12 is taken by Arg (v) Ser at position 16 is replaced by Glu, Gln, glutamate, sulfoalanine, Thr, Gly, Lys or Aib; 156004.doc • 232· 201143790 (vi) Arg at position 17 Substituted by Gin; (vii) Arg at position 18 is substituted with Ala, Ser, Thr or Gly; (viii) Gin at position 20 is substituted with Ala, Ser, Thr, Lys, citrulline, Arg, Orn or Aib; (ix) Asp at position 21 is substituted with Glu, glutamic acid, or high sulfoalanine; (X) Val at position 23 is replaced by lie; (xi) Gin at position 24 is passed through Asn, Ala, Ser, Thr or Aib substitution; and (xii) position 2, 5, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 27, 28, and 29 Conservative substitutions on one. In some embodiments, the analogs comprise a combination of modifications (1) to (xii). Alternatively or additionally, the analog may comprise an amino acid modification at position 3 (eg, Gin for Gin) An amino acid substituted), wherein the activity of the analog to the glycosidic receptor is less than 1% of the activity of the glycosidic acid. Alternatively or additionally, the analog may comprise: an amine group at position 7 Acid modification (eg, amino acid substitution of Thr with an amino acid lacking a hydroxyl group (eg, Abu or lie)), deletion of an amino acid from the c-terminus to the amino acid at position 27 or 28 yields 27 or 28 A peptide of an amino acid, or a combination thereof, wherein the activity of the analog to the GLP-1 receptor is about 10% or less of the activity of GLP-1. For exemplary embodiments, the analog can be covalently bonded to the hydrophilic moiety. In some embodiments, the analog is covalently bonded to the hydrophilic moiety at any of the amino acid positions 16, 17, 20, 21, 24, 29, 40 or C-terminus. In certain embodiments the 'analog comprises a C-terminal extension (eg, amino acid sequence 156004.doc • 233 · 201143790 SEQ ID NO: 1095) and is added with an amino acid comprising a hydrophilic moiety, such that the hydrophilic moiety can Covalently bonded to the analog at position 40. In some embodiments the 'hydrophilic moiety is covalently bonded to the analog of Lys, Cys, Orn, homocysteine or acetyl-phenylalanine. Lys, Cys, Orn, homocysteine or acetyl-phenylalanine may be a native amino acid for the glycoside sequence (SEQ ID NO: 1〇〇1), or it may be a replacement SEQ ID NO: The amino acid of the native amino acid of 1001. In some embodiments, wherein the hydrophilic moiety is attached to Cys, the linkage to the hydrophilic moiety can comprise the following structure:

Peptide I Η For an analog comprising a hydrophilic moiety, the hydrophilic moiety can be any of the hydrophilic moieties described herein. See, for example, the teachings under the section "Key Connections of Hydrophilic Parts". In some embodiments, the hydrophilic moiety is polyethylene glycol (PEG). In certain embodiments, the pEG has a molecular weight of from about 1 Dalton to about 40,000 Daltons, such as from about 2 Torr Daltons to about 4 Torr Daltons. In an exemplary embodiment, wherein the analog comprises a thiol or alkyl group attached to the analog via a spacer, the spacer can be any spacer as described herein. The length of the spacer can be, for example, from 3 to 1 原 original I56004.doc • 234-201143790, and the spacer can be, for example, an amino acid (eg, 6-aminohexanoic acid, any of the amino acids described herein), Dipeptides (eg, Ala-Ala, PAla-pAla, Leu-Leu, Pro-Pro, y-Glu-Y-Glu), tri-, or hydrophilic or hydrophobic bifunctional spacers. In some aspects, the total length of the spacer and the thiol or alkyl group is from about 14 to about 28 atoms. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments, the dipeptide spacer is not γ-ϋΐιι-γ-Glu fluorenyl or the alkyl group is any sulfhydryl or alkyl group as described herein, such as non-native to a naturally occurring amino acid. Mercapto or alkyl. In some embodiments, the thiol or alkyl group is a C4 to C30 fatty sulfhydryl group, such as a C10 fatty decyl or alkyl group, a C12 fatty decyl or alkyl group, a C14 fatty decyl group or an alkyl group, a C16 fatty decyl group or an alkyl group. Base, C18 fatty decyl or alkyl, C20 decyl or alkyl, or C22 decyl or alkyl, or C4 to C30 alkyl. In a particular embodiment, the thiol group is a C12 to C18 fatty sulfhydryl group (e.g., a C14 or C16 fatty sulfhydryl group). In some embodiments, the extension of the 'end of the analog to the amino acid at position 29 having from about 1 to about 21 amino acids comprises an amino acid sequence

GPSSGAPPPS (SEQ ID NO: 1095) or XGPSSGAPPPS (SEQ ID NO: 1096), wherein X is any amino acid; or comprises the amino acid sequence GPSSGAPPPK (SEQ ID NO: 1170) or XGPSSGAPPPK (SEQ ID NO: 1171) or XGPSSGAPPPSK (SEQ ID NO: 1172), wherein X is Gly or a small aliphatic or non-polar or slightly polar amino acid. In some embodiments, from about 1 to about 21 amino acids may comprise a sequence comprising one or more conservative substitutions 156004.doc - 235 · 201143790 relative to SEQ ID NO: 1095, 1096, 1170, 1171 or 1172. In some embodiments, the deuterated or alkylated amino acid is at position 37, 38, 39' 40, 41, 42 or 43 of the c-terminally extended analog. In certain embodiments, the deuterated or alkylated amino acid is located at position 40 of the C-terminally extended analog. The GIP agonist can be an amino acid sequence comprising an amino acid sequence such as SEq id NO: 1005-1094 and optionally has up to 2, 3, 4 or 5 retention of GIP agonist activity Other modified peptides. In certain embodiments, the GIP agonist comprises an amino acid of any one of SEQ ID NO: 1 〇 99. 1275. Class 3 Glucagon Related Peptides In certain embodiments, the 'glycoglycan-related peptide is a Class 3 ghlylin-related peptide, which is described herein and in International Patent Application Publication No. WO 2 〇〇 9/155258 The contents of such patents are hereby incorporated by reference in their entirety in their entireties in the entire disclosure of the the the the the the the the the the Some of the biological sequences (SEQ ID NO: Μ%) mentioned in the following section for the third class of ghrelin-related peptides correspond to SEQ m N〇: 1656 in International Patent Application Publication No. 2009/155258. Activity Class 3 glycosidic susceptibility may be a peptide exhibiting enhanced activity to the glucagon receptor' and in other embodiments' exhibit enhanced biophysical stability and/or water solubility. In addition, 一些 In some embodiments, the third type of ghrelin-related peptide loses the native glycemic glycoside, and the selectivity to the GUM receptor, and thus represents the total An agonist. Class 3 sucrose 156004.doc 201143790 The selected amino acid modification within the prime-related peptide controls the relative activity of the peptide to the GLP-1 receptor relative to the glycoside receptor. Therefore, the third type of glycosidin-related peptide may be a glycoside/GLP-1 co-activator which is more active against the glycoside receptor than the GLP-1 receptor; An equivalent activity of a glycoside/GLP-1 co-activator; a glycoside/GLP-1 co-promoting agent beta that is more active at the GLP-1 receptor than a glycosidic receptor The co-activator can be engineered to exhibit little or no activity on the glycosidic receptor while still retaining the ability to activate the GLP-1 receptor with the same or superior potency of native GLP-1. . Any of these co-activators may also include modifications that confer enhanced biophysical stability and/or water solubility. The third class of ghrelin-related peptides can be modified to produce a glycosidic peptide having an activity against the GLP-1 receptor of at least about 1° against the activity of the native GLP-1. (including at least about 1.5%, 2%, 5%, 7%, 10% ' 20% ' 30% ' 40% ' 50% ' 60% ' 75% ' 100% ' 125%, 150%, 175%) to About 200% or more, and its activity on the glycosidic receptor is at least about 1% relative to the activity of the native glycein (including about 1.5%, 2%, 5%, 7%, 10%, 20) %, 30%, 40%, 50〇/〇, 60% ' 75% ' 100% ' 125% ' 150% ' 175% ' 200% ' 250% ' 300%, 350%, 400°/., 450% ) to about 500% or more. The amino acid sequence of the native glucagon is SEQ ID NO: 1, the amino acid sequence of GLP-1 (7-36) guanamine is SEQ ID NO: 52, and the amine of GLP-1 (7-37) acid The base acid sequence is SEQ ID NO:50. In an exemplary embodiment, the activity of the third type of ghrelin-related peptide on the glycoside receptor can be at least 10% of the activity of the native glycein, and the activity exhibited by the GLP-1 receptor can be It is at least 50% of the activity of native GLP-1 156004.doc • 237-201143790; or the activity exhibited by the glycoside receptor can be at least 40 of the activity of the native glycein. /. And the activity exhibited by the GLp i receptor may be at least Na of the activity of the original SGLP-1; or the activity exhibited by the glycoside receptor may be at least 6% of the activity of the native glycein, and The activity exhibited by the GLp.1 receptor may be at least 6% of the activity of the original SGLP1. ^ The selectivity of the third type of glycosidin-related peptide to the glucosin receptor relative to the GLp-丨 receptor may be described as relative Glucagon/GLP" activity ratio (the activity of the peptide relative to the native glycein to the glycosidic receptor divided by the activity of the peptide relative to the native GLP-1 receptor), for example, for glycosides The third class of glycosidin-related peptides exhibited by the receptor exhibiting activity of 6% by weight of the native glycemic activity and exhibiting 60% of the activity of the native GLP-1 activity to the GLpq receptor have ι:ι glucosin /GLP-1 activity ratio. An exemplary glycosidin/GLp i activity ratio includes about 1.5:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 1 〇: 1, or about 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2 or 1:1.5. For example, a 1 〇:1 glucosin/GLP1 activity ratio indicates that the selectivity to the glucosamine receptor is 1 〇 more selective for the GLP-1 receptor. Similarly, a 10:1 GLP-1/glycosidin activity ratio indicates that the selectivity to the (}1^_1 receptor is 1% greater than the selectivity to the glycemic receptor. In some embodiments, the third The activity of the glucagon-related peptide on the glycosidic receptor is about 1% or less of the activity of the native glycein, for example, about ι〇/〇 to 1%% or about 1·1% to 1 〇%, or about 0 μ% or more but less than about 丨〇%, and its activity for the GLP-1 receptor is at least 2% of the activity of GLP-1. For example, the examples described herein The activity of the galactin-related peptide of the third type is about 5%, about 1% or about 7% of the activity of the native glucosamine, and 156004.doc • 238-201143790, the activity exhibited by the GLP_1 receptor is At least 20% of the activity of GUM. The glyphos-related peptide may be a glycoside having an activity that enhances or decreases the activity of the glycoside receptor or the glp_i receptor or both. The third type of glycosidin-related peptide It may be a glycosidic peptide that changes the selectivity of the glycoside morpheme relative to the GLP 丨 receptor. Thus, as disclosed herein, a high performance is provided that also exhibits improved solubility and/or stability. Class rise Peptide-related peptides. Exemplary high potency class 3 levulin glycoside-related activity exhibited by the glycoside receptor is at least about 200% of the native glycemic activity, and optionally 6 to 8' or 6 to 9, or a pH of 7 to 9 (eg pH 7) is soluble at a concentration of at least 丨mg/mL, and optionally retains at least 95% of the original peptide after 24 hours at 25 ° C (eg 5% or 5% or less of the original peptide is degraded or cleaved.) As another example, an exemplary third type of glycosidin-related peptide exhibits an activity of about 4% or more or more than about 60% to the glycospergic receptor and the GLpq receptor ( Between about 1:3 and 3:1, or about ij to 2:1, depending on the case, at a pH of 6 to 8, or 6 to 9, or 7 to 9 (for example, PH 7) Soluble at a concentration of 1 mg/mL, and optionally at 25. (: at least 95% of the original peptide is retained after the next 24 hours. Another exemplary type 3 glucosinoid-related peptide is expressed by the glycoside receptor The activity is about 175% or more of the activity of the native glucagon and the activity exhibited by the GLP-1 receptor is about 20°/. or less than 20% of the native GLPJi activity, optionally 6 to 8 , or 6 to 9, or 7 to 9 pH (eg pH 7) Soluble at a concentration of at least 1 mg/mL, and optionally retain at least 95% of the original peptide after 24 hours at 25 ° C. Another exemplary class 3 glucosinoid-related peptide to the glycoside receptor The activity exhibited is about 10% or less of the activity of the native glycein and the 156004.doc-239·201143790 activity exhibited by the GLP-1 receptor is at least about 2% of the activity of the native GLP-1, Depending on the pH of 6 to 8, or 6 to 9, or 7 to 9 (for example, pH 7), it is soluble at a concentration of at least 丨mg/mL, and is retained at least at 25 ° C for 24 hours. 95% of the original peptide. Another exemplary class 3 ghrelin-related peptide exhibits an activity on the glycoside receptor that is less than about 丨〇% or 丨〇% of the activity of the native glucosamine but above 0.1%, 0.5% or 1°. /. And the activity exhibited by the GLP-1 receptor is at least about 50%, 60%, 70〇/〇, 80〇/〇, 90% or 100 of the activity of the native GLP-1. /. Or more than 100%, as appropriate at a pH of 6 to 8, or 6 to 9, or 7 to 9 (eg pH 7) at a concentration of at least 1 mg/mL, and optionally at 25 ° C At least 95% of the original peptide is retained after 24 hours. In some embodiments, the Class 3 astaxanthin-related peptide retains at least 22, 23, 24, 25, 26, 27 or 28 naturally occurring positions in the corresponding positions in the native glucagon Amino acid (for example, having 1 to 7, 1 to 5 or 1 to 3 modifications relative to a naturally occurring glycoside). Modification of the effect of glycosidic activity by the native glucosin (SEQ ID NO) The amino acid modification is carried out at position 16 of 1) to provide enhanced activity against the glycemic receptor. In some embodiments, the third type of ghrelin-related peptide is already relative to the wild-type peptide 沁3-861*-0111-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu -Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr (SEQ ID NO: 1) modified to enhance peptide potency against glycemic receptors Glycan agonist. The usual presence of serine acid at position 16 of the native glucosinolate (SEQ ID NO: 1) can be substituted with the selected acidic amino acid to stimulate cAMP synthesis in established in vitro model assays (see Example 2). In terms of enhancement 156004.doc • 240· 201143790 Glucagon efficacy. More specifically, this substitution enhances the potency of the analog to the glycemic receptor by at least 2 fold, 4 fold, 5 fold and up to 1 fold. This substitution also enhances the activity of the analog to the gum receptor by at least 5 fold, 1 fold or 15 fold relative to the native glucagon, but maintains selectivity for the glycoside receptor over the GLP-1 receptor. By way of non-limiting example, either by using glutamic acid or by using another negatively charged amino acid having a side chain of 4 atoms in length, or by using branic acid, glutamic acid or high sulfopropylamine Any of the acids, or a substituted amino acid having a side chain having at least one hetero atom (e.g., N, 0, S, P) and having a side chain length of about 4 (or 3 to 5) atoms The naturally occurring serine acid at position 16 provides this enhanced efficacy. According to some embodiments, the position of the native glycein is replaced with an amino acid selected from the group consisting of glutamic acid, glutamic acid, glutamic acid, high sulfoalanine, threonine or glycine. a serine residue. According to some embodiments, the serine residue at position 16 of the native glycoside is replaced with an amino acid selected from the group consisting of glutamic acid, acetophenric acid, facial acid and arginine. And in some embodiments, the serine residue is substituted with glutamic acid. In some embodiments, a third class of ghrelin-related peptides with enhanced potency

a glycoside comprising SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, or SEQ ID NO: Agent analog. According to some embodiments, a third class of ghrelin-related peptides having enhanced potency against a glycoside receptor relative to wild-type glycoside, wherein the peptide comprises the sequence of SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 or SEQ ID NO: 10, wherein the glycosidin peptide 156004.doc • 241·201143790 retains its selectivity for the glycoside receptor relative to the GLP-1 receptor. In some embodiments, a third type of glycosidin-related peptide having enhanced specificity for a glycoside receptor comprises the peptide of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 or a sucrose thereof A agonist analog whose carboxy terminal amino acid retains its primary carboxylic acid group. According to some embodiments, the third class of ghrelin-related peptides comprises the sequence >1112-1^-86Bu 0111-01; /-1[111*-?116-7'111>-861>-八3卩-

Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-COOH (SEQ ID NO: 10), wherein The potency exhibited by the peptide for the glycoside receptor was increased by about five-fold relative to the potency of the native glycein as measured by the in vitro cAMP assay of Example 2. The glycosidic receptor activity can be reduced, maintained or enhanced by amino acid modification at position 3, e.g., by replacing the naturally occurring glutamic acid at position 3. In some embodiments, substituting an acidic, basic or hydrophobic amino acid (glutamic acid, ornithine, orthraenic acid) for the amino acid at position 3 has been shown to substantially reduce or destroy the glycoside Receptor activity. The activity of the analog substituted with, for example, glutamic acid, ornithic acid or orthanoic acid to the glycosidic receptor is about 10% or less than the activity of the native glycemic glycanin, for example, about 1% to i. , or about 1.1°/. To 10. /. 'or about 1% or more but about 10% or less, and the activity exhibited by the 〇1^_1 receptor is at least 20% of the activity of GLP-1. For example, the activity of the exemplary analogs described herein is about 0.5%, about 1%, or about 7% of the activity of the native glucagon, and its activity on the GUM receptor is GLP-1 activity. At least 20% » In particular, any of the Category 3 glycosidin-related peptides described herein (including glycosidic analogs, glycosidic agonist analogs, 156004.doc • 242-201143790 glycosides) And the glycoside/GLp-1 coactivator molecule) can be modified to contain a modification at position 3, for example, Gln is substituted by Glu to produce a GLP compared to the selectivity to the glycoside receptor. 1 A peptide having a high selectivity (e.g., ten-fold selectivity).

In another embodiment, the naturally occurring branamine at position 3 of any of the third class of glycosidic peptides can be substituted with a glutamate analog as described herein without substantial loss of the glycoside receptor Active and in some cases, enhances glycosidic receptor activity. In a particular embodiment, the amino acid at position 3 is substituted with Dab(Ac). For example, the glycoside agonist can comprise the amino acid sequence SEQ 〇 NO: 595, SEQ ID NO: 601, SEQ ID NO: 603, SEQ ID NO: 604, SEQ ID NO: 605, and SEQ ID NO : 606. It can be observed that the modification at position 2 (e.g., Aib at position 2) and the modification at position 1 in some cases can reduce glycemic activity. This decrease in glycemic activity can be achieved, for example, via the methods described herein, for example, via amines at positions "1" and "i+4" (eg, 12 and 16, 16 and 2, or 2 and 24). The covalent bond between the acid side chains is restored by stabilizing the helix in the c-terminal portion of the glycemic glycoside. In some embodiments, the covalent bond is an intrinsic amine bridge between the glutamic acid at position (iv) and the amine acid at position 20. In some embodiments, the covalent bond is an intramolecular bridge other than an indoleamine bridge. For example, a suitable covalent bonding method includes any one or more of the following: olefin metathesis, melamine based cyclization, disulfide bridge or modified sulfur-containing bridge formation, using α, ω- Diaminoalkane chain bonds, and other peptide cyclization methods. Modification of GLP-1 activity to form a metal atom bridge 156004.doc -243- 201143790 Provides GLP-1 receptor by replacing the carboxylic acid of the c-terminal amino acid with a charge-neutral group such as a guanamine or ester Body-enhancing activity, in some embodiments, such a class 3 ghlylin-related peptide comprises the sequence seq id NO: 20, wherein the thiol-terminated amino acid has a carboxylic acid group substituted for the native amino acid Amidoxime. This 4th class 3 glycoside correlate has potent activity on the glycoside receptor and glp-1 receptor and thus acts as a co-activator for both receptors. According to some embodiments, the third type of ghrelin-related peptide is a co-activator of a glycoside receptor and a glp-1 receptor, wherein the peptide comprises the sequence of SEQ ID NO: 20, wherein the amino acid at position 28 is Asn or Lys ' and the amino acid at position 29 is Thr-guanamine. The GLP-1 receptor enhanced activity is provided by performing a clock that stabilizes the ct helix in the C-terminal portion of the glycemic glycoprotein (e.g., substantially residues 12 to 29). In some embodiments, the modifications result in the separation of the two amino acids of the amino acid (ie, the amino acid at position "i" and the amino acid at position "i+4"). Where i is any integer from 12 to 25), two amino acids separated by two amino acids (ie, the amino acid at position "j" and the amino acid at position "j+3", "" is any integer from 12 to 27), or two amino acids separated by an amino acid (ie, the amino acid at position "k" and the amino acid at position "k+7") An intramolecular bridge is formed between the side chains of , wherein ^ is any integer from 12 to 22. In an exemplary embodiment, the bridge or linker is about 8 (or about 7 to 9) atoms in length and is formed at positions 12 and 16, or positions 16 and 20, or positions 20 and 24, or positions. Between 24 and 28 on the amino acid side bond. The two amino acid side bonds can be linked via a non-covalent bond (e.g., hydrogen bonding), an ionic interaction (such as forming a salt bridge), or by a covalent bond to each other 156004.doc • 244·201143790. According to some embodiments, the third class of ghrelin-related peptide exhibits a glycoside receptor/GLP-1 receptor co-activator activity and comprises a population selected from the group consisting of SEQ ID NOs: 11, 47, 48, and 49. Amino acid sequence. In some embodiments, the side chains are covalently bonded to each other, and in some embodiments, the two amino acids are combined with each other to form a decylamine ring.

According to some embodiments, the third class of ghrelin-related peptides comprises SEQ 45, wherein at least one internal guanamine ring is formed between the side chains of the amino acid selected from the group consisting of the following amino acid pairs: amino acids For 12 and 16, 16 and 20, 20 and 24 or 24 and 28. And X. Intramolecular indoleamine bridge between 2〇. In some embodiments, the third type of ghrelin-related peptide comprises the sequence of SEQ ID NO: 20, wherein the intramolecular indoleamine bridge is formed between amino acid positions 12 and 16, and the amino acid positions 16 and 20 are Between, or between amino acid positions 20 and 24, and the amino acid at position 29 is glycine, wherein the sequence SEQ ID NO: 29 is linked to the C-terminal amino acid of SEQ ID NO. In another embodiment, the amino acid at position 28 is aspartic acid. In some specific embodiments, the helical structure is stabilized in the c-terminal portion of the third type of glycosidin-related peptide via the formation of an intramolecular bridge other than the indoleamine bridge. For example, suitable covalent bonding methods include any of the following: olefin metathesis, sulfonamide-based cyclization, disulfide bridge or sulphur-containing bridge formation, use of alpha, The ω-diamine-based hydrocarbon-based bond forms a metal-atomic bridge and is cyclized using other peptides to stabilize 156004.doc • 245·201143790. In addition, one or more α,α disubstituted amino acids can be intentionally introduced at a position to retain the desired activity to stabilize the c-terminal portion of the glycemic peptide (approximately amino acid 12 to 29). The a-helical structure to achieve enhanced activity against the glp-1 receptor. Such peptides can be considered herein to be peptides lacking intramolecular bridges. In some aspects, the alpha helix can be stabilized in this manner without introducing intramolecular bridges, such as salt bridges or covalent bonds. In some embodiments, one of the positions 16, 17, 18, 19, 20, 21, 24, or 29 of the glycemic peptide is 'two, three, four, or more, substituted by α,α, Substituted by an amino acid. For example, substituting amino acid isobutyric acid (Aib) for position 16 of a third type of glycosidin-related peptide enhances glP-1 activity in the absence of a salt bridge or indoleamine. In some embodiments, one, two, three or more of 'positions 16, 20, 21 or 24 are replaced by Aib. The GLP-1 receptor-enhancing activity can be achieved by amino acid modification at position 20. In some embodiments, another hydrophilic amino acid having a charge or hydrogen bonding ability and having a side chain of at least about 5 (or about 4 to 6) atoms in length (eg, an amine acid, a melon) is used. Aminic acid, arginine or ornithine) replaces the glutamic acid at position 20. The third class ghrelin-related peptide comprising a C-terminal extension of SEQ ID NO: 26 exhibits enhanced activity against the GLP-1 receptor. The GLP-1 activity of the third type of glycosidin-related peptide comprising SEQ ID NO: 26 can be further enhanced by modifying the amino acid at position 18, 28 or 29 or at positions 18 and 29 as described herein. . The GLP-1 potency can be further moderately enhanced by modifying the amino acid at position 10 to Trp. 156004.doc -246- 201143790 The GLp-1 activity provided by a combination of modifications that enhance GLP-1 receptor activity may be singly provided with GLp_丨 activity provided by either of these modifications. For example, a Category 3 ghlylin-related peptide may comprise a modification at position 16, position 20, and a c-terminal acid group, optionally having an amino acid at position 16 and an amino acid at position 20, as appropriate. Covalent bond between; may include modifications at position 16 and C-terminal acid-fastening groups; may include repairs at positions 16 and 20, optionally with amino acid at position 16 and position 2〇 a covalent bond between the amino acids; or a lion may be included at the position 2〇&c terminal carboxylic acid group; optionally, the amino acid at position 12 is not Arg; or, as appropriate 'The restriction is that the amino acid at position 9 is not Giu. Modification of the solubility of Jingdongsheng Adding a hydrophilic moiety The third type of glycosidin-related peptide can be further modified to improve the solubility and stability of the peptide in an aqueous solution at physiological pH, while retaining high relative to native glycosides. Biological activity. The hydrophilic moiety as discussed herein can be linked to a Category 3 ghlylin-related peptide as discussed further herein. According to some embodiments, the introduction of a hydrophilic group at positions 17, 21 and 24 of a third type of ghrelin-related peptide comprising SEQ ID NO: 9 or SEQ ID NO: 1 is expected to improve the high-potency glycosidic analog Is it physiological? Solubility and stability in a solution of 1^ value. The introduction of such groups also extends the duration of action, e.g., as measured by the extended circulating half-life. In some embodiments t, the third class of ghrelin-related peptides comprises selected from the group consisting of

Sequence of the consisting group: SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEq ID 156004.doc • 247·201143790 NO: 16, SEQ ID NO: 17, SEQ ID NO: 18 and SEQ ID NO: 19, wherein the amino acid residue side chain on one of positions 16, 17, 21 or 24 of the third type of glycosidin-related peptide is further A polyethylene glycol linkage comprising a molecular weight selected from the range of from about 5 Å to about 40,000 Daltons is included. In some embodiments, the molecular weight of the polyethylene glycol chain is selected from the range of from about 500 to about 5,000 Daltons. In another embodiment, the polyethylene glycol chain has a molecular weight of from about 1 Torr to about 20,000 Daltons. In other exemplary embodiments, the polyethylene glycol linkage has a molecular weight of from about 20,000 to about 40,000 Daltons. Suitable hydrophilic moieties include any water soluble polymer 'known in the art' including the hydrophilic moieties described herein, homopolymers or copolymers of PEG' and PEG polymers (mPEG) substituted with monodecyl groups. According to some embodiments, the hydrophilic group comprises a polyethylene glycol (PEG) chain. More particularly, in some embodiments the 'category 3 ghlylin-related peptide comprises the sequence SEq id NO: 6 or SEQ ID NO: 7 ' wherein the PEG chain is covalently linked to the presence of a glycoside present in the third class The amino acid side chain at positions 21 and 24 of the peptide and the tetamine amino acid of the third type of glucosamine related peptide have a tickotropic group. According to some embodiments, the average molecular weight of the polyethylene glycol linkage is selected from the range of from about 500 to about 1 Torr, 〇〇〇Dalton. According to some embodiments, a PEGylated third-class ghrelin-related peptide comprises two or more polyethylene glycol bonds covalently bound to a third-type glycosidin-related peptide, wherein the glycosidic bond is The total molecular weight is from about 1, 〇〇〇 to about 5, 〇〇〇 Dalton. In some embodiments, the pegylated glycosidic agonist comprises a peptide consisting of SEQ ID NO: 5 or a glycosidic agonist analog of SEQ ID NO: 5 wherein the PEG chain is covalently linked Amino groups 156004.doc • 248 - 201143790 acid residues at positions 21 and 24, and wherein the combined molecular weight of the two PEG chains is from about 1 Torr to about 5,000 Daltons. The solubility of a charged C-terminus comprising a third type of ghrelin-related peptide of SEQ ID NO. 20 can be introduced, for example, by introducing one, two, three or more charged amino acids to SEQ ID NO: The c-terminal portion of the glycoside peptide is preferably further introduced from the c-terminus to the position in position 27. The charged amino acid can be introduced by replacing the primary amino acid with a charged amino acid, for example at position 28 or 29, or by, for example, adding a charged amino acid after position 27, 28 or 29. In an exemplary embodiment, one, two, three or all of the charged amino acids are negatively charged. Other modifications (e.g., conservative substitutions) can be made to the third class of ghrelin-related peptides while still retaining the glycemic activity. In some embodiments, an analog of a third type of ghrelin-related peptide of SEQ ID NO: 20 is provided, wherein the analog differs from SEQ ID NO. 20 in positions 1 to 2 of positions 17 to 26. The amino acid is substituted, and in some embodiments, the analog is different from the peptide of SEQ ID NO: 20 by the amino acid substitution at position 2〇. Deuteration/Alkylation According to some embodiments, the glycosidic peptide is modified to comprise a mercapto or alkyl group, such as a C4 to C30 or a alkyl group. In some aspects, a mercapto or alkyl group is not naturally occurring. On the amino acid. In a particular aspect, the thiol or alkyl group is non-native to any naturally occurring amino acid. Deuteration or alkylation may increase the cyclic half-life and/or delay the onset of action and/or prolong the duration of action and/or improve resistance to proteases such as DPP-IV. After deuteration, the activity of the glycoside receptor-related peptides on the glycoside receptor and the GLP_丨 receptor was maintained even if it was not enhanced by the third 156004.doc • 249·201143790. In addition, the efficacy of the deuterated analog can compete with the undeuterated form of the third type of glycoside-related peptide, even if it is not substantially enhanced. In some embodiments, the invention provides a third class of glycosidic associates that are modified to comprise a sulfhydryl or alkyl group of an amino acid covalently bonded to the position of the glycosidic peptide. The glycoside peptide may further comprise a spacer between the amino acid at position 10 of the third type of ghrelin-related peptide and the thiol or alkyl group. Any of the above third class of ghrelin-related peptides may comprise two thiol groups or two alkyl groups or a combination thereof. In a particular aspect of the invention, the deuterated class 3 ghrelin-related peptide comprises any one of the amino acid sequences SEQ ID NO: 534-544 and 546-549. C-terminal truncation In some embodiments, a third type of ghrelin-related peptide described herein can be truncated or deleted by one of the C-termini of the glycopeptide or two amino acids (ie, position 29) And/or 28) further modified without affecting its activity and/or potency to the glycemic receptor and GLP-1 receptor. In this regard, the third class of glycosidic peptides can comprise the amino acid 1 to 27 or 1 to 28 of the native glucagon peptide (SEQ ID NO: 1), optionally having one or more of the Modification. In some embodiments, the truncated type 3 ghlylin-related peptide comprises SEQ ID NO: 550 or SEQ ID NO: 551. In another embodiment, the truncated glycosidin agonist peptide comprises SEQ ID NO: 552 or SEQ ID NO: 553. C-terminal extension According to some embodiments, the third type of glycosidin-related peptide system disclosed herein is 156004.doc • 250· 201143790

Modified by adding a second peptide (eg, SEQ ID NO: 26, SEQ ID NO: 27, or SEQ ID NO: 28) to the carboxy terminus of the glycemic peptide, in some embodiments, having a The third type of ghlylin-related peptide of the sequence of the composition is covalently bound to the second peptide via a peptide bond: SEQ ID NO: u, SEq ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ Id NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO. 18, SEQ ID NO: 19, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68 and SEQ ID NO 69, wherein the second peptide comprises a sequence selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 28. In another embodiment, in the third type of ghrelin-related peptide comprising a C-terminal extension, the threonine at position 29 of the native glucagon peptide is replaced with glycine. The third class of ghlylin-related peptides of the third class of ghlylin-related peptides of col SEQ ID NO: 26 substituted with sulphate at position 29 and comprising glycosylation extensions SEQ ID NO: 26 are modified to comprise a carboxy terminal extension Four times the native glucagon of SEQ ID NO: 26. The potency of the GLP-1 receptor can be further enhanced by alanine substitution of the native arginine at position 18. Thus, a Class 3 ghrelin-related peptide can have a carboxy terminal extension of SEQ ID NO: 27 (KRNRNNIA) or SEQ ID NO: 28. According to some embodiments, the third type of ghrelin-related peptide comprising SEQ ID NO: 33 or SEQ ID NO. 20 further comprises an amino acid sequence of amino acid 29 linked to a glycosidic peptide SEQ ID NO: 27 (KRNRNNIA) or SEQ ID NO: 28. More specifically, the third class ghrelin-related peptide comprises a sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO : 15, which further comprises the linkage amino acid 156004.doc • 251 · 201143790 to the amino acid sequence of the amino acid 29 of the glycosidic peptide SEQ ID NO: 27 (KRNRNNIA) or SEQ ID NO: 28. More specifically, the glycoside peptide comprises a sequence selected from the group consisting of SEQ ID NO. 10, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15. SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 55, and SEQ ID NO: 56, which further comprises the amino acid sequence SEQ ID NO: 26 (GPSSGAPPPS) or SEQ ID NO: 29 linked to the amino acid 29 of the third type of glycosidin-related peptide. In some embodiments, the third class of ghrelin-related peptide comprises the sequence of SEQ ID NO: 64 °. Other Modifications for enhancing or decreasing glycosidic receptor activity and enhancing GLP as described above for the third type of glycosidic peptide Any modification of the -1 receptor activity can be applied individually or in combination. Combinations of modifications that enhance GLP-1 receptor activity provide GLP-1 activity generally higher than that provided by either of these modifications alone. Any of the modifications described above may also be combined with other modifications described herein with respect to the third class of glycosidic peptides to confer other desirable properties, such as enhanced solubility and/or stability and/or prolonged duration of action. . Alternatively, any of the modifications described above can be combined with other modifications described herein with respect to the third class of ghrelin-related peptides that do not substantially affect solubility or stability or activity. Exemplary modifications include, but are not limited to: (A) being introduced, for example, by introducing one, two, three or more charged amino acids into the C-terminal portion of the native glycein, preferably End to 156004.doc -252- 201143790

Position in position 27 to improve solubility. The charged amino acid can be introduced by replacing the primary amino acid with a charged amino acid, for example, at position 28 or 29, or by, for example, adding a charged amino acid after position 27, 28 or 29. In an exemplary embodiment, one, two, three or all charged amino acids are negatively charged. In other embodiments, one, two, three or all of the charged amino acids are positively charged. The modifications enhance solubility, for example, when the solubility is measured at 25 C after 24 hours, at about 5 5 to 8 At a predetermined value (for example, pH 7), it is at least 2 times, $ times, 10 times, 15 times, 25 times, 30 times or 30 times or more of the solubility of the native glycosidic acid. (B) enhancing solubility by, for example, adding a hydrophilic moiety such as a polyethylene glycol chain to the peptide at position 16, 17, 2, 21, 24 or 29 or the C-terminal amine acid as described herein. Prolong the duration of action or the half-life of circulation. (C) The aspartic acid at position 15 is modified to enhance stability, for example, by deletion or substitution with glutamic acid, homoglycine, methionine or high-performance propylamine. Such modifications may reduce degradation or cleavage in the range of from 5 5 to (4), especially in acidic or assay buffers, such as retention of at least 75%, (four), 9{) after 24 hours at 25 °C. %, _, _, 97°/. , 98% or 99% of the original peptide. ° (D) Modification of methionine at position 27 to enhance stability, for example, by substitution with leucine or ortho-amine, which reduces oxidative degradation. The Gln at position 20 or 24 can also be modified to increase (4) qualitatively, for example, by substitution with Ser, Thr, A1?» 弋 δ 或 or Alb. Such modifications may reduce the degradation of the lean-deaminamine group. The Asp at position 21 may be modified, for example, by substitution with (10) U to enhance inertness. These modifications can be reduced (4) 156004.doc •253· 201143790

Dehydration of Asp forms a cyclic butyl quinone imine intermediate which in turn constitutes degradation of the isoaspartate. (E) by modifying the amino acid at position 1 or 2 with a dipeptidyl peptidase IV (Dpp-resistant amino acid described herein) (and including modifying the amine at position 2 with N-methyl-alanine) Base acid) to enhance resistance to DPP-IV cleavage. (F) Conservative or non-conservative substitutions, additions or deletions that do not affect activity' eg position 2, 5, 7, 10, 11, 12, 13, 14 a conservative substitution on one or more of 16, 17, 18, 19, 20, 21, 24, 27, 28 or 29; a deletion in one or more of positions 27, 28 or 29; or an amine The base acid 29 is deleted, optionally in place of the c-terminal carboxylic acid group, with a c-terminal amide or ester. (G) Add a c-terminal extension as described herein. (H) For example, via a hydrazine or an alkane as described herein. Glycosylation of peptides to increase circulating half-life and/or prolonged duration of action and/or delayed onset of action. (I) Performing homodimerization or heterodimerization as described herein. Other modifications include the use of large aromatic amines. The base acid (eg Tyr, phe, Trp or amino-Phe) substitutes His at position i; replaces Ser at position 2 with Ala; Tyr at position 1 with Val or Phe; replaces position 12 with Arg Lys; replaces Asp at position 15 with Glu; replaces Ser at position 16 with Thr or Aib. His-position of His with non-conservative substitution of large aromatic amino acids (eg Tyr) with GLP-1 activity Class 3 ghlylin-related peptides may retain glu activity 'with the proviso that the alpha helix is stabilized via an intramolecular bridge (eg, any of the 156004.doc-254-201143790 intramolecular bridges described herein). Conjugates and fusions 3 The ghrelin-related peptide may be linked to the binding moiety via a covalent bond and optionally via a linker. The third type of ghrelin-related peptide may also be part of a fusion peptide or a fusion protein, wherein the second peptide or polypeptide Has been fused to the end of a third type of glycosidic related peptide, such as a slow base.

More specifically, the fusion class 3 ghlylin-related peptide may comprise a glycosidic agonist of SEQ ID NO: 55, SEQ ID NO: 9 or SEQ ID NO: 10, further comprising a linkage to the sucrose The amino acid sequence of the amino acid 29 of the peptide is SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) or SEQ ID NO: 28 (KRNR). In some embodiments, the amino acid sequence SEQ ID NO: 26 (GPSSGAPPPS), SEQ ID NO: 27 (KRNRNNIA) or SEQ ID NO: 28 (KRNR) is linked via a peptide bond to a third type of glycosidin-related peptide Amino acid 29. Applicants of the present invention have found that in a third type of glycosidin-related peptide fusion peptide comprising a C-terminal extension peptide of incretin analog-4 (e.g., SEQ ID NOCh 26 or SEQ ID NO: 29), position 29 The substitution of the primary sulphate residue with glycine acid significantly enhanced the GLP-1 receptor activity. This amino acid substitution can be used to enhance the affinity of the glycoside analog for the GLP-1 receptor along with other modifications disclosed herein for the third class of ghrelin related peptides. For example, the T29G substitution can be combined with the S16E and N20K amino acid substitutions, optionally with an intrinsic amine bridge linkage between the amino acids 16 and 20, and optionally with the addition of a PEG chain as described herein. In some embodiments, the third type of ghrelin-related peptide comprises the sequence of SEQ ID 156004.doc -255 - 201143790

NO: 64. In some embodiments, the third type of glycosidin-related peptide portion of the glycemic fusion peptide is selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 2. SEQ ID NO: 3, SEQ ID NO 4 and SEQ ID NO: 5 ' wherein the PEG chain is present at position 17, 21, 24 or C-terminal amino acid, or is present on both 21 and 24 from 5 to 4, 〇 The range of Dalton. More specifically, in some embodiments, the third type of glycosidin-related peptide is selected from the group consisting of SEq ID NO: 7, SEQ ID NO: 8 and SEQ ID NO: 63 'where the peg chain From 500 to 5, the range of 〇〇〇Dalton. In some embodiments, the third type of ghrelin-related peptide is an inclusive sequence

The fusion peptide of SEQ ID NO: 55 and SEQ ID NO: 65, wherein the peptide of SEQ ID NO: 65 is linked to the carboxy terminus of SEq ID NCh 55. Other chemical modifications to the third type of ghrelin-related peptide of SEQ ID N〇: 1〇 according to some embodiments can enhance the potency of the GLP-1 receptor to the relative activity of the glycoside receptor and to the GLP-i The relative activities of the receptors are nearly identical. Thus, in some embodiments, the third class of ghrelin-related peptides comprises a terminal amino acid comprising a guanamine group in place of the carboxylic acid group present on the native amino acid. The relative activity of the third type of glycosidin-related peptide to the respective glycosidic receptor & GLp_i receptor can be modulated by further modification of the third type of glycosidin-related peptide, thereby producing the following analogs, such The analogue exhibits an activity of about 0.5% or more of the activity of the native glycein expressed by the glycoside receptor, and the activity exhibited by the GLpq receptor is the native tongue f About 20% to about 2%. or more than 200%, for example, it increases the normal activity of glp-1 receptor activity relative to glycosides to 5 times, ^(9) times or 1 〇〇. In some embodiments, the glycosidic peptide described herein exhibits an activity of up to about 100%, 1000%, 1% of the activity of the glycoside 156004.doc 201143790 receptor. 〇〇〇%, 1〇〇, 〇〇〇% or 1,000,000%. In some embodiments, the activity exhibited by the glycoside peptide described herein for the GLP-1 receptor is the activity of native GLP-1. Up to about 1〇〇〇/0, 1〇〇〇〇/., 10, 〇〇〇〇/0, 100,000% or 1, 〇〇〇, 〇〇〇〇/0 〇 exemplified embodiments according to some For example, a glycosidin analog comprising the sequence SEQ ID NO: 55 is provided, wherein the analog differs from SEQ ID NO: 55 in that it is selected from positions 1, 2, 3, 5, 7, 10, 11, 13, 1 to 3 amino acids of 14, 17, 18, 19, 21, 24, 27, 28 and 29, wherein the activity exhibited by the glycoside peptide to the GLP-1 receptor is the activity of native GLP-1 At least 20%. According to some embodiments, a glycosidin receptor/GLP-1 receptor co-agonist is provided comprising the sequence: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp -Tyr-Ser-Lys-Tyr-Leu-Xaa-Xaa-Arg-Arg-Ala-Xaa-Asp-Phe-Val-Xaa-Trp-Leu-Met_Xaa-Xaa-R (SEQ ID NO: 33), wherein position The Xaa on 15 is selected from the group consisting of amino acid consisting of Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine, and the Xaa at position 16 is selected from Ser, Glu, Gin, and high bran. A group of amino acids consisting of aminic acid and high sulfoalanine, Xaa at position 20 is Gin or Lys, Xaa at position 24 is Gin or Glu, and Xaa at position 28 is Asn, Lys or acid amino acid , Xaa at position 29 is Thr, Gly or acidic amino acid, and R is COOH or CONH2, limiting conditions When position 16 is serine, position 20 is Lys, or when the position of 156004.doc -257- 201143790 16 is serine, position 24 and position 20 is Glu or position 28 is Lys. In some embodiments, the glycosidin receptor/GLP-1 receptor co-agonist comprises the sequence of SEQ ID NO: 33, wherein the amino acid at position 28 is aspartic acid and the amino acid at position 29 For glutamic acid. In another embodiment, the amino acid at position 28 is native aspartame, the amino acid at position 29 is glycine, and the amino acid sequence is SEQ ID NO: 29 or SEQ ID NO: 65. The valency is linked to the carboxy terminus of SEQ ID NO:33.

In some embodiments, a co-activator comprising the sequence of SEQ ID NO: 33 is provided, wherein an additional acidic amino acid is added to the carboxy terminus of the peptide. In another embodiment, the carboxy terminal amino acid of the "glycoside analog has a guanamine that replaces the guanylating group of the natural amino acid. In some embodiments, the glycoside analog comprises a sequence selected from the group consisting of SEQ ID NO: 40, SEQ

ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43 and SEQ ID NO: 44 提供 provides a glycoside peptide analogue of SEQ ID NO: 33 according to some embodiments, wherein the analog is SEQ ID NO : 33 differs in that one to three amino acids selected from positions 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, and 27 are restricted in position. Where the amino acid at 16 is a serine, position 20 is between the amino acid at position 'or acid' at position 24 and the amino acid at position 2 or the amino acid at position 28. Bridge key. According to some embodiments, the analog differs from SEQ ID NO: 33 by one to three amino acids selected from positions 1, 2, 3, 21 and 27. In some embodiments, the glycosidin peptide analog of SEQ ID NO: 33 differs from the sequence in that it is selected from the group consisting of positions 1, 2, 3, 5, 7, 1 , 11, 13, 14, 17, 156,004 .doc • 258· 201143790 18, 19, 21 and 27 of 1 to 2 amino acids, or in some embodiments, differing in a single amino acid selected from the above positions, with the restriction being at position 16 Where the amino acid is serine, the position 20 is from the amine acid, or the amino acid at position 24 forms an amino acid bridge with the amino acid at position 20 or the amino acid at position 28. According to another embodiment, a relatively selective GLP-1 receptor agonist is provided,

Tyr-Ser-Lys-Tyr-Leu-Xaa-Xaa-Arg-Arg-Ala-Xaa-Asp-Phe-Val-Xaa-Trp-Leu-Met-Xaa-Xaa-R (SEQ ID NO: 53), wherein The Xaa at position 3 is selected from the group of amino acids consisting of Glu, Orn or Nle, and the Xaa at position 15 is selected from the group consisting of Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine. Group of amino acids, Xaa at position 16 is selected from the group consisting of Ser, Glu, Gin, glutamic acid and high sulfoalanine, and Xaa at position 20 is Gin or Lys, position Xaa on 24 is Gin or Glu, Xaa at position 28 is Asn, Lys or acidic amino acid, Xaa at position 29 is Thr, Gly or acidic amino acid, and R is COOH, CONH2, SEQ ID NO: 26 or SEQ ID NO: 29, with the proviso that when position 16 is a serine, position 20 is Lys, or when position 16 is a serine, position 24 is Glu and position 20 or position 28 is Lys. In some embodiments, the amino acid at position 3 is glutamic acid. In some embodiments, the acidic amino acid substituted at positions 28 and/or 29 is aspartic acid or glutamic acid. In some embodiments, the glycosidin peptide comprising a co-activator peptide comprises the sequence SEQ ID NO: 33, which further comprises an additional acidic amino acid added to the carboxy terminus of the peptide. In another embodiment, the carboxyl group of the glycoside analog 156004.doc • 259·201143790 terminal amino acid has a guanamine that replaces the carboxylic acid group of the native amino acid. According to some embodiments, a glycosidic receptor/GLP-1 receptor co-agonist comprising a modified glycosidic peptide selected from the group consisting of: NH2-His-Ser-Gln-Gly-Thr- is provided Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Xaa-Xaa-Arg-Arg-Ala-Xaa-Asp-Phe-Val-Xaa-Trp-Leu-Met-Xaa-Xaa-R ( SEQ ID NO: 34), wherein Xaa at position 15 is selected from the group consisting of amino acid consisting of Asp, Glu, sulfoalanine, glutamate, and high sulfoalanine, and Xaa is selected at position 16. Group of amino acids consisting of free Ser, Glu, Gin, glutamic acid and high sulfoalanine, Xaa at position 20 is Gin or Lys, Xaa at position 24 is Gin or Glu and Xaa at position 28 Is Asn, Asp or Lys, R is COOH or CONH2, Xaa at position 29 is Thr or Gly, and R is COOH, CONH2, SEQ ID NO: 26 or SEQ ID NO: 29, with the constraint that when position 16 is silk In the case of aminic acid, position 20 is Lys, or when position 16 is serine, position 24 is Glu and position 20 or position 28 is Lys. In some embodiments, R is CONH2, Xaa at position 15 is Asp, and Xaa at position 16 is selected from the group consisting of Glu, Gin, glutamic acid, and high sulfoalanine, position 20 Xaa on Xaa and position 24 are each Gin, Xaa at position 28 is Asn or Asp, and Xaa at position 29 is Thr. In some embodiments, Xaa at position 15 and Xaa at position 16 are each Glu, Xaa at position 20 and Xaa at position 24 are each Gin, and Xaa at position 28 is Asn or Asp, at position 29 Xaa is Thr and R is CONH2. It has been reported that certain positions of the native glucagon peptide can be modified while retaining at least some of the activity of the parent peptide. Therefore, the applicant of the present invention expects that the peptides of SEQ ID NO: 156004.doc - 260 - 201143790 位于 are located at positions 2, 5, 7, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, One or more of the amino acids on 24, 27, 28 or 29 may be substituted with an amino acid different from the amino acid present in the native glucagon peptide and still retain the glycoside receptor active. In some embodiments, the methionine residue present at position 27 of the native peptide is changed to leucine or norleucine to prevent oxidative degradation of the peptide. In another embodiment, the amino acid at position 2 is substituted with Lys, Arg, Orn or citrulline and/or the amino acid at position 21 is replaced with Glu, lysine or homo-propyl alanine. In some embodiments, a glycoside analog of SEQ ID NO. 20 is provided, wherein the analog is selected from the group consisting of positions 1, 2, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21 a 27, 28 or 29 to 1 amino acid different from the corresponding amino acid of SEQ ID NO: 1, with the proviso that when the amino acid at position 16 is a serine, position 20 is Lys, or When position 16 is a serine acid, 'position 24 is Glu and position 20 or position 28 is Lys. According to another embodiment, a glycoside analog of SEQ ID NO: 20 is provided, wherein the analog is selected from position 1. 1, 3, 7, 10, 11, 13, 14, 17, 18, 19, 20, 21, 27, 28 or 29 of 1 to 3 amino acids are different from the corresponding amino acids of SEQ ID NO: 1. In another embodiment, a glycoside analog of SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 11 is provided, wherein the analog is selected from the group consisting of positions 1, 2, 5, 7, 1 1 to 2 amino acids of 11, 11, 3, 14, 17, 18, 19, 20 or 21 are different from the corresponding amino acids of SEQ ID NO: 1, and in another embodiment, 1 to 2 The different amino acid represents a conservative amino acid substitution relative to the amino acid present in the native glucagon sequence (SEQ ID NO: 1). In some embodiments, the SEq ID N0 is provided: 156004.doc -261 - 201143790 12. The glycoside peptide of SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15, wherein the glycosidic peptide is further selected from the group consisting of positions 2, 5, 7, 10, 11, 13, The position of 14, 17, 18, 19, 20, 21, 27 or 29 contains one, two or three amino acid substitutions. In some embodiments, the substitution at position 2, 5, 7, 10, 11, 13, 14, 16, 17, 18, 19, 20, 21, 27 or 29 is a conservative amino acid substitution. According to some embodiments, a glycosidin receptor/GLP-1 receptor co-agonist comprising a variant of the sequence of SEQ ID NO 33, wherein the variant is selected from the group consisting of positions 16, 17, 18, 20, 21 is provided 1, 1 to 10 of the amino acids of 23, 24, 27, 28 and 29 are respectively different from the corresponding amino acids of SEQ ID NO: 1. According to some embodiments, a variant of the sequence SEQ ID NO 33 is provided, wherein the variant differs from SEQ ID NO: 33 by one or more amino acid substitutions selected from the group consisting of: Glnl7, Alal8, Glu21 , Ile23, Ala24, Val27 and Gly29. According to some embodiments, a glycosidin receptor/GLP-1 receptor co-agonist comprising a variant of the sequence of SEQ ID NO 33, wherein the variant is selected from the group consisting of positions 17 to 26 of 1 to 2 amines The base acid is different from the corresponding amino acid of SEQ ID NO: 1. According to some embodiments, a variant of the sequence SEQ ID NO 33 is provided, wherein the variant differs from SEQ ID NO: 33 by an amino acid selected from the group consisting of Glnl7, Alal8, Glu21, Ile23 and AU24 . According to some embodiments, a variant of the sequence SEQ ID NO 33 is provided, wherein the variant differs from SEQ ID NO: 33 by an amino acid substitution at position 18, wherein the substituted amino acid is selected from the group consisting of Ala, Ser , a group of Thr and Gly. According to some embodiments, a variant of the sequence SEQ ID NO 33 is provided, wherein 156004.doc-262-201143790 the variant differs from SEQ ID NO: 33 in that amino acid substitution at position 18 via Ala. These changes are covered by SEQ ID NO: 55. In another embodiment, a glycosidin receptor/GLP-1 receptor co-agonist is provided comprising a variant of SEQ ID NO: 33, wherein the variant is selected from positions 17 to 22 of 1 to 2 The amino acid is different from the corresponding amino acid of SEQ ID NO: 1, and in another embodiment, a variant of SEQ ID NO: 33 is provided, wherein the variant differs from SEQ ID NO: 33 in position 20 And 1 or 2 of the amino acid substitutions on 21. According to some embodiments, a glycosidic receptor/GLP-1 receptor co-agonist comprising the following sequence is provided: NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser -Lys-Tyr-Leu-Xaa-Xaa-Arg-Arg-Ala-Xaa-Xaa-Phe-Val-Xaa-Trp-Leu-Met-Xaa-Xaa-R (SEQ ID NO: 5 1), wherein position 1 Xaa on 5 is Asp, Glu, primate, homoprolin, or homo-alanine, Xaa at position 16 is Ser, Glu, Gin, glutamic acid or homo-alanine, and Xaa at position 20 is Gin, Lys, Arg, Orn or citrulline, Xaa at position 21 is Asp, Glu, succinic acid or syl-alanine, Xaa at position 24 is Gin or Glu, and Xaa at position 28 is Asn, Lys or acidic amino acid, Xaa at position 29 is Thr or acidic amino acid, and R is COOH or CONH2. In some embodiments, the ruler is CONH2. According to some embodiments, a hirudin receptor/GLP-1 receptor co-agonist is provided comprising SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15. A variant of SEQ ID NO: 47, SEQ ID NO: 48 or SEQ ID NO: 49, wherein the variant differs from the sequence by an amino acid substitution at position 2〇. In some embodiments 156004.doc • 263-201143790, the amino acid substitution at position 20 is selected from the group consisting of Lys, Arg, 〇rn or citrulline. In some embodiments, a glycosidic agonist comprising a similar peptide of SEQ ID NO: 34, wherein the analog differs from SEQ m N〇: 34 in that it has a different position than serine at position 2 Amino acid. In some embodiments the 'silanic acid residue is substituted with an amine isobutyric acid, D-alanine, and in some embodiments, the serine residue is substituted with an aminoisobutyric acid. Such modifications inhibit cleavage by dipeptidyl peptidase IV while retaining the intrinsic potency of the parent compound (eg, at least 75%, 8%, 85%, 90%, 95%, 95% or more of the potency of the parent compound) In some embodiments, for example, by introducing one, two, three or more charged amino acids into the c-terminal portion of the native glycein, preferably introduced from the c-terminus to the position 27 The position in the enhances the solubility of the analog. In an exemplary embodiment, one, two, three or all of the charged amino acids are negatively charged. In another embodiment, the analog further comprises an acidic amino acid substituted for the native amino acid at position 28 or 29 or an acidic amino acid added to the carboxy terminus of the peptide of SEQ ID NO: 34. In some embodiments The glycosidic analog disclosed herein is further modified at position 丄 or 2 to reduce the possibility of cleavage caused by dipeptidyl peptidase iv. In some embodiments, SEQ ID NO: 9, SEQ ID NO is provided. A glucagon analog of SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15, wherein the analog differs from the parent molecule by a substitution at position 2, And the possibility of cleavage by dipeptidyl peptidase IV is reduced (i.e., resistance is more specific, in some embodiments 156004.doc • 264. 201143790, position 2 of the like peptide is selected from an amine selected from the group consisting of Base acid substitution: D-serine, D-alanine, valine, amine n-butyric acid, glycine, N-methylserine, and aminoisobutyric acid. In some embodiments, similar Position 2 of the peptide is substituted with an amino acid selected from the group consisting of D-serine, D-alanine, glycine, N-A Baseline acid and aminoisobutyric acid. In another embodiment, position 2 of the like peptide is substituted with an amino acid selected from the group consisting of D-serine, glycine, N-methyl Serine and aminoisobutyric acid. In some embodiments, the amino acid at position 2 is not D-serine. In some embodiments, the glycoside peptide comprises the sequence of SEQ ID NO: 21 or SEQ ID NO: 22. In some embodiments, a sucrose of SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14 or SEQ ID NO: 15 is provided A analog, wherein the analog differs from the parent molecule in substitution at position 1, and is less likely to be cleaved by the dipeptidyl peptidase IV (ie, resistance). More specifically, the position of the peptide-like 1 is substituted with an amino acid selected from the group consisting of D-histamine, α,α-dimethylimidazoliumacetic acid (DMIA), fluorenyl-mercapto histidine, α-methylhistamine, imidazole Acetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histidine, and high-histamine. In another embodiment, a glycosidic agonist comprising SEQ ID NO: Similar to 34 Wherein the analog differs from SEq ID Ν〇: 34 in that it has an amino acid different from histamic acid at position 1 in some embodiments 'eg by one, two, three or three More than one charged amino acid is introduced into the C-terminal portion of the native glycein, preferably introduced at the C-terminus to position 27 to enhance the solubility of the analog. Example 156004.doc -265-201143790 In the example, one, two, three or all charged amino acids are negatively charged. In another consistent embodiment, the analog further comprises an acidic amino acid substituted for the native amino acid at position 28 or 29 or an acidic amino acid added to the tickend of SEQ ID NO: 34. In some embodiments, the acidic amino acid is aspartic acid or glutamic acid. In some embodiments, the glycosidin receptor/GLP-1 receptor co-agonist comprises the sequence of SEQ ID NO: 20, further comprising an amino acid or selected from SEQ ID NO: 26, SEQ ID NO: An additional reciprocal extension of the peptide of the group consisting of 27 and SEQ ID NO: 28. In an embodiment where a single amino acid is added to the rebel end of SEQ ID NO: 20, the amino acid is typically selected from one of the 20 common amino acids, and in some embodiments, an additional slow base The amino acid has a guanamine group in place of the carboxylic acid of the native amino acid. In some embodiments, the additional amino acid is selected from the group consisting of glutamic acid, aspartic acid, and glycine. In an alternate embodiment, a glycosidic receptor/GLP-1 receptor co-activator is provided wherein the peptide comprises at least one side chain formed on the side chain of the glutamic acid residue and the side chain of the lysine residue An intrinsic amine ring wherein the glutamic acid residue is separated from the lysine residue by three amino acids. In some embodiments, the carboxy terminal amino acid of the glycoside peptide having a decylamine has a guanamine group in place of the carboxylic acid of the native amino acid. More particularly, in some embodiments, a glycoside and GLP-1 co-agonist is provided comprising a modified glycosidic peptide selected from the group consisting of: NH2-His-Ser-Gln-Gly- Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-

Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp- 156004.doc -266- 201143790

Leu-Met-Xaa-Xaa-R (SEQ ID NO: 66); NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu -Arg-Arg-Ala-Lys-Asp-Phe-Val-Gln-Trp-Leu-Met-Xaa-Xaa-R (SEQ ID NO: 67); NH2-His-Ser-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-Xaa-Xaa-R (SEQ ID NO: 68);

NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Ty r-Leu-Asp-Ser-Arg-Arg-Ala-Gin-Asp-Phe-Val-Glu -Trp-Leu-Met-Lys-Xaa-R (SEQ ID NO: 69); NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu- Asp-Glu-Arg-Arg-Ala-Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-Asn-Thr-R (SEQ ID NO: 16); NH2-His-Ser-Gln-Gly-Thr -Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Glu-Trp-Leu-Met-Lys-Thr-R (SEQ ID NO: 17); NH2-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Ty r-Leu-Asp-Glu-Arg-Arg-Al a- Lys-Asp-Phe-Val-Glu-Trp-Leu-Met-Lys-Thr-R (SEQ ID NO: 18),

Wherein Xaa at position 28 is Asp or Asn, Xaa at position 29 is Thr or Gly, and R is selected from the group consisting of COOH, CONH2, glutamic acid, aspartic acid, glycine, SEQ ID NO 26, SEQ ID NO: 27 and SEQ ID NO: 28, and the indoleamine bridge is formed for SEQ ID NO: 66 between Lys at position 12 and Glu at position 16, for SEQ ID 156004. Doc-267-201143790 NO: 67 is formed between Glu at position 16 and Lys at position 20, for SEQ ID NO: 68 formed between Lys at position 20 and Glu at position 24, For SEQ ID NO: 69, between Glu at position 24 and Lys at position 28, for SEQ ID NO: 16 between Lys at position 12 and Glu at position 16 and at position 20 Between the upper Lys and the Glu at position 24, between SEQ ID NO. 17 is formed between Lys at position 12 and Glu at position 16 and between Glu at position 24 and Lys at position 28. And for SEQ ID NO: 18, formed between Glu at position 16 and Lys at position 20 and between Glu at position 24 and Lys at position 28. In some embodiments, the R is selected from the group consisting of COOH, CONH2, glutamic acid, aspartic acid, and glycine, the amino acid at position 28 is Asn, and the amino acid at position 29 is S Amino acid. In some embodiments, the ruler is CONH2, the amino acid at position 28 is Asn and the amino acid at position 29 is sulphate. In another embodiment, the R line is selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 29, and SEQ ID NO: 65, and the amino acid at position 29 is glycine. In another embodiment, the glycoside receptor/GLP-1 receptor co-agonist is selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, wherein the peptide further comprises an amino acid or is selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: : 27 and an additional carboxy terminal extension of the peptide of the group consisting of SEQ ID NO: 28. In some embodiments, the terminal stretch comprises the sequence of SEQ ID NO: 26, SEQ ID NO: 29 or SEQ ID NO: 65, and the glycoside peptide comprises the sequence 156004.doc • 268 - 201143790, SEQ ID NO: 55. In some embodiments, the glycosidin receptor/GLP-1 receptor co-activator comprises the sequence of SEQ ID NO: 33, wherein the amino acid at position 16 is glutamic acid and the amino acid at position 20 is The lysine, the amino acid at position 28 is aspartame, and the amino acid sequence SEQ ID No: 26 or SEQ ID NO: 29 is linked to the carboxy terminus of SEQ ID NO: 33.

In an embodiment where a single amino acid is added to the carboxy terminus of SEQ ID NO: 20, the amino acid is typically selected from one of the 20 common amino acids, and in some embodiments, the amino acid has An amidino group which replaces the carboxylic acid of the native amino acid. In some embodiments, the additional amino acid is selected from the group consisting of glutamic acid and aspartic acid and glycine. In embodiments where the glycoside agonist analog further comprises a carboxy terminal extension, the carboxy terminal amino acid of the extension ends in some embodiments with a guanamine or ester group rather than a carboxylic acid. In another embodiment, the glycosidin receptor/GLP-1 receptor co-agonist comprises

Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Asn-Thr-Xaa-CONH2 (SEQ ID NO: 19), wherein Xaa at position 30 represents any amino acid. In some embodiments, Xaa is selected from one of the 20 common amino acids, and in some embodiments, the amino acid is glutamic acid, aspartic acid, or glycine. The solubility of the peptide can be further improved by covalently linking the PEG chain to the side chain of the amino acid at position 17, 21, 24 or 30 of SEQ ID NO: 19. In another embodiment, the peptide comprises an additional carboxy terminal extension having a peptide selected from the group consisting of SEQ ID NO: 26, SEQ ID NO: 27, and SEQ ID NO: 28. According to some embodiments, the glycoside receptor/GLP-1 receptor co-agonist package 156004.doc -269- 201143790 comprises the sequences SEQ ID NO: 30, SEQ ID NO: 31 and SEQ ID NO: 32 Glycosin sequence SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18. Other site-specific modifications within SEQ ID NO: 19 and SEQ ID NO: 64 to produce a collection of glycoside agonists with variable GLP-1 agonism. Thus, peptides having virtually identical in vitro potency to each receptor have been prepared and characterized. Similarly, a peptide having a potency selectivity to any of the two receptors up to ten-fold has been identified and characterized. As described above, substituting glutamic acid for the serine residue at position 16 enhances the potency of native glycein to the glycoside receptor and GLP-1 receptor, but maintains about ten for the glycosidic receptor. Multiple selectivity. In addition, a glycoside analog exhibiting about ten-fold selectivity for the GLP-1 receptor was produced by substituting glutamic acid for the native bran amino acid at position 3 (SEQ ID NO: 22).

The glycoside can be added by introducing a hydrophilic group at positions 16, 17, 21 and 24 of the peptide, or by adding a single modified amino acid (i.e., an amino acid modified to include a hydrophilic group) The carboxyl end of the GLP-1 co-activator peptide further enhances the solubility of the glycoside/GLP-1 co-activator peptide in aqueous solution at physiological pH while preserving it relative to native glycosides High biological activity. According to some embodiments, the hydrophilic group comprises a polyethylene glycol (PEG) chain. More specifically, in some embodiments, the glycoside peptide comprises the sequence of SEQ ID NO: 10 'SEQ ID NO: 11 > SEQ ID NO: 12 ' SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID 156004.doc -270- 201143790 NO: 16, SEQ ID NO: 17 or SEQ ID NO: 18, wherein the PEG chain is covalently linked to positions 16, 17, 21 of the glyce peptide a side chain of an amino acid or a C-terminal amino acid at 24, 29, with the proviso that when the peptide comprises SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12 or SEQ ID NO: 3, The polyethylene glycol chain is covalently bound to an amino acid residue at position 17, 21 or 24, and when the peptide comprises SEQ ID NO: 14 or SEQ ID NO: 15, the polyethylene glycol chain is covalently bound to the position An amino acid residue at 16, 17 or 21, and when the peptide comprises SEQ ID NO: 16, SEQ ID NO: 17 or SEQ ID NO: 18, the polyethylene glycol chain is covalently bound to position 17 or 21 Amino acid residues. In some embodiments, the glycoside peptide comprises the sequence of SEQ ID NO: 11, SEQ ID NO: 12 or SEQ ID NO: 13, wherein the PEG chain is covalently linked to positions 17, 21, 24 of the glyce peptide A side chain of the amino acid or a C-terminal amino acid, and the carboxy terminal amino acid of the peptide has a guanamine group in place of the carboxylic acid group of the native amino acid. In some embodiments, the glycosidin receptor/GLP-1 receptor coactivator peptide comprises a sequence selected from the group consisting of: SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO: 19, wherein the PEG chain is covalently linked to SEQ ID NO: 12 of the glycemic peptide, a side chain of an amino acid at positions 17, 21 or 24 of SEQ ID NO: 13 and SEQ ID NO: 19, or covalently linked to positions 16, 17 of SEQ ID NO: 14 and SEQ ID NO: 15 or The side chain of the amino acid on 21, or the side chain of the amino acid covalently linked to positions 17 or 21 of SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18. In another embodiment, the glycoside 156004.doc •271 - 201143790 receptor/GLP-1 receptor co-agonist peptide comprises the sequence SEQ ID NO: 11 or SEQ ID NO: 19, wherein the PEG chain is covalently bonded Linked to the side chain of the amino acid or C-terminal amino acid at position 17, 21 or 24 of the glycemic peptide. According to some embodiments and subject to the limitations described in the preceding paragraph, the glycosidic co-activator peptide is modified to contain one or more positions at position 16, 17, 21, 24 or 29 or a C-terminal amino acid. Amino acid substitution wherein the native amino acid is substituted with an amino acid suitable for side chains which are crosslinked with a hydrophilic moiety comprising, for example, PEG. The native peptide can be substituted with a naturally occurring amino acid or a synthetic (non-naturally occurring) amino acid. A synthetic or non-naturally occurring amino acid refers to an amino acid that does not naturally occur in vivo but can be incorporated into the peptide structures described herein. Alternatively, an amino acid having a side chain suitable for crosslinking with a hydrophilic moiety comprising, for example, PEG can be added to the carboxy terminus of any of the glycoside analogs disclosed herein. According to some embodiments, the amino acid substitution is selected from the group consisting of 16, 17, 21, 24 or 29 in the glycosidic receptor/GLp-1 receptor coactivator peptide to be selected from the group consisting of amines The amino acid of the group consisting of acid, cysteine, ornithine, cysteine, and acetophenone replaces the native amino acid, wherein the substituted amino acid further comprises covalently bonded to the amino acid side Chain of PEG chains. In some embodiments, the glycoside peptide selected from the group consisting of: is further modified to comprise a pEG strand covalently linked to the amino acid side chain at position 17 or 21 of the glycemic peptide: SEq ID 12.

SEQ ID NO: 13, SEQ ID NO: 14 'SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, and SEQ ID NO. 19 In some embodiments, Polyethylene II The alcoholated ghrelin receptor/GLP-1 receptor co-agonist further comprises the sequence 卩 n〇: %, I56004.doc -272- 201143790 ID NO: 27 or SEQ ID NO: 29. In another embodiment, the glycoside peptide comprises the sequence of SEQ ID NO: 55 or SEQ ID NO: 56, further comprising a C-terminal amino acid linked to SEQ ID NO: 5 5 or SEQ ID NO: 56 C-terminal extension SEQ ID NO: 26, SEQ ID NO: 29 or SEQ ID NO: 65, and optionally further comprises an amine group covalently bonded to position 17, 18 ' 21 ' 24 or 29 of the peptide The PEG chain of the side chain of the acid or C-terminal amino acid. In another embodiment, the glycoside peptide comprises the sequence SEQ ID NO: 55 or SEQ ID NO: 56, wherein the PEG chain is covalently linked to the sucrose The amino acid side chain at position 21 or 24 of the prime peptide, and the peptide further comprises a C-terminal extension SEQ ID NO: 26 or SEQ ID NO: 29 °. In another embodiment, the glycoside peptide comprises the sequence SEQ ID NO: 55 or SEQ ID NO: 33 or SEQ ID NO: 34, wherein an additional amino acid is added to the carboxy terminus of SEQ ID NO: 33 or SEQ ID NO: 34, and the PEG chain is covalently linked to the addition The side chain of the amino acid. In another embodiment, the PEGylated glycosidic analog further comprises a C-terminal extension SEQ ID NO: 26 linked to the C-terminal amino acid of SEQ ID NO: 33 or SEQ ID NO: 34 Or SEQ ID NO: 29. In another embodiment, the glycoside peptide comprises the sequence of SEQ ID NO: 19, wherein the PEG chain is covalently linked to the amino acid side chain at position 30 of the glycemic peptide, and the peptide further comprises a linkage The C-terminal extension of the C-terminal amino acid of SEQ ID NO: 19 is SEQ ID NO: 26 or SEQ ID NO: 19. The polyethylene glycol chain can be in a linear form or it can be branched. According to some embodiments, the average molecular weight of the polyethylene glycol chain is selected from the range of from about 500 to about 10,000 Dao 156004.doc -273 - 201143790. In some embodiments, the average molecular weight of the polyethylene glycol linkage is selected from the range of from about 1,000 to about 5,000. In an alternate embodiment, the average molecular weight of the polyethylene glycol chain is selected from the range of from about 10,000 to about 20, in the range of 〇〇〇Dalton. According to some embodiments, the pegylated glycoside peptide comprises two or more polyethylene glycol chains covalently bound to a glycemic peptide, wherein the total molecular weight of the glycosidic chain is from about 1,000 to about 5,000 Dalton. In some embodiments, a 'pegylated glycosidic agonist comprises a peptide consisting of SEQ ID NO: 5 or a glycosidic agonist analog of SEQ ID NO: 5, wherein the peg linkage is covalently linked To the amino acid residues at positions 21 and 24, and the combined molecular weight of the twelve PEG chains is from about 1 to about 5,000 Daltons. In certain exemplary embodiments, the glycoside peptide comprises an amino acid sequence SEq ID NO: 1 'having an amino acid modification of at most 1 , and comprising an amine which is deuterated or alkylated at position 1 Base acid. In some embodiments, the amino acid at position 1 is deuterated or alkylated with a C4 to C3 hydrazine fatty acid. In some aspects, the amino acid at position 10 comprises a non-native sulfhydryl or alkyl group for a naturally occurring amino acid. In certain embodiments, the glycoside peptide comprising an amino acid that has been deuterated or alkylated at position 10 comprises a stabilized alpha helix. Thus, in certain aspects, the glycoside peptide comprises a thiol or alkyl group as described herein, and an amino acid side chain at position i and an amino acid side chain at position i+4. Intramolecular bridges, such as covalent intramolecular bridges (eg, endoamine bridges), where i is 12, 16, 20, or 24. Alternatively or additionally, the glycoside peptide comprises a brewing group or an alkyl group as described herein, and one of the positions 16, 2, 21 and/or 24 of the glycemic peptide, two, three or three The above is substituted with a 1,1 double substituted amino acid (for example, 156004.doc • 274. 201143790 such as Aib). In some cases, the non-native glucagon peptide comprises a Glu at position 16 and a Lys at position 20, wherein, depending on the case, the intrinsic amine bridges link Glu to Lys, and optionally, the glycemic peptide further comprises One or more modifications of the group consisting of: Gin at position 17, Ala at position 18, Glu at position 21, ne at position 23, and Ala at position 24 are also in any embodiment, Wherein the glycoside peptide comprises an amino acid which is deuterated or deuterated at position 10, and the glycosidic peptide may further comprise a C-terminal guanamine which replaces the C-terminal alpha carboxylate. In some embodiments, the glycoside peptide comprising a thiol or alkyl group as described herein further comprises an amino acid substitution at position 1, position 2 or position 1 and 2 wherein the or the amino acid is substituted DPP-IV protease resistance was achieved. For example, the 'His at position 1 can be substituted with an amino acid selected from the group consisting of D-histamine, α,α-dimercaptoimidazoleacetic acid (dmia), N-mercapto histidine, Α-mercapto histidine, imidazoleacetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histamic acid and high-histamine. Alternatively or additionally, Ser at position 2 may be substituted with an amino acid selected from the group consisting of D-serine, alanine, D-alanine, valine, glycine, N-methyl Amine acid, N-methyl alanine and aminoisobutyric acid. In some embodiments, the amino acid at position 2 is not D-serine.

A glycoside peptide comprising an amino acid which has been deuterated or alkylated as described herein at position 10 can comprise any of the amino acid sequences substantially associated with SEQ ID NO: 1. For example, a glycopeptide comprises SEQ 156004.doc having up to 1 胺 amino acid modification (eg, 0, 1, 2, 3, 4, 5, ό, 7, 8, 9, 10 modifications). 275- 201143790 ID NO: 1. In certain embodiments, the amino acid sequence of the deuterated or alkylated ghrelin peptide is 25°/SEQ ID NO: 1. The above is consistent (for example, with SEQ ID NO: 1 30% ' 35% ' 40% > 50% ' 60% ' 70% ' 75% ' 80% ' 85% , 90% , 95% , 96 % , 97 % , 98%, 99% or more or close to 100%. In certain particular embodiments, the glycoside peptide is a peptide comprising SEQ ID NO: 55 (wherein the amino acid at position 10 is deuterated or alkylated as described herein). The glycosidin peptide can be SEQ ID NO: 55, SEQ ID NO: 55 with 1 or 2 amino acid modifications, SEQ ID NO: 2-4, 9-18, 20, 23-25, 33, 40- Any of 44, 53, 56, 61, 62, 64, 66-514, and 534. The thiol or alkyl groups of such embodiments can be any of the fluorenyl or alkyl groups described herein. For example, the thiol group can be a C4 to C30 (e.g., C8 to C24) fatty sulfhydryl group, and the alkyl group can be a C4 to C30 (e.g., C8 to C24) alkyl group. The amino acid to which the thiol or alkyl group is attached may be any of the amino acids described herein, such as the amino acid of Formula 1 (e.g., Lys), Formula II, and Formula III. In some embodiments, the aryl or alkyl group is attached directly to the amino acid at position 10. In some embodiments, a thiol or alkyl group is attached to the amino acid at position 10 via a spacer such as a spacer having a length of from 3 to 10 atoms, such as an amino acid or a dipeptide. Described herein are spacers suitable for linking a thiol or alkyl group. According to some embodiments, the Category 3 ghlylin-related peptide can be an analog of any of the above-described Class 3 ghlylin-related peptides as described herein, the analog exhibiting agonist activity at the GIP receptor. The activity of the analog on the glycoside receptor, GLP-1, 156004.doc •276·201143790 and GIP receptors, the potency of each of these receptors, and among these receptors The selectivity of each can be in accordance with the teachings described herein with respect to class 2 glycosidic related peptides. See the teachings under the sub-section entitled "Activity" in the second class of glycosidin-related peptides. In some embodiments of the invention, an analog of a glycoside peptide is provided that exhibits agonist activity at the GIP receptor. In certain embodiments, the analog comprises the amino acid sequence SEQ ID NO: 1, which has at least one amino acid modification (optionally, up to 15 amino acid modifications) and the c-terminal to position of the analog The amino acid on 29 has an extension of from 1 to 21 amino acids. In some aspects, the analogs comprise at least one amino acid modification and up to 15 amino acid modifications (eg, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15 at the amino acid modification, at most 1 胺 amino acid modification). In certain embodiments, the analogs comprise at least one amino acid modification and up to 10 amino acid modifications as well as other conservative amino acid modifications. Conservative amino acid modifications are described herein. In some aspects, at least one amino acid modification imparts a stabilized alpha helix structure in the C-terminal portion of the analog. Modifications to achieve a stabilized alpha helix structure are described herein. See, for example, the teaching under the section entitled Stabilization of the alpha helix / intramolecular bridge. In some aspects, the analog comprises an intramolecular bridge (e.g., a covalent intramolecular bridge, a non-covalent intramolecular bridge) between the two amino acid side chains of the analog. In some aspects, the intramolecular bridge bond is linked to the amino acid side chain at position i and the amino acid side chain at position i+4 where i is 12, 13, 16, 17, 20 or 24. In other aspects, the intramolecular bridge is linked to the amino acid side chain at position j and the amine group at position j+3 is 156004.doc -277·201143790 acid side bond 'where j is 17; or at position k The amino acid side bond and the amino acid side bond at position k+7", wherein k is any integer from 12 to 22. In some embodiments the 'intramolecular bridge is a covalent intramolecular bridge' such as an intrinsic amine bridge. In a particular aspect, the indoleamine bridge linkages to the amino acid side chain at position 16 and the amino acid side chain at position 20. In a particular aspect, one of the amino acid at position 16 and the amino acid at position 20 is a positively charged amino acid and the other is a negatively charged amino acid. For example, the analog can comprise an intrinsic amine bridge linking the Glu side bond at position 16 to the Lys side chain at position 20. In other aspects, a negatively charged amino acid forms a salt bridge with a positively charged amino acid. In this case, the intramolecular bridge is a non-covalent intramolecular bridge. In a particular aspect, the stabilizing enthalpy is imparted [the helical amino acid is modified to insert the alpha, alpha disubstituted amino acid into SEQ id NO: 1 or to replace SEQ ID with an alpha, alpha disubstituted amino acid. NO: 1 Amino Acids The alpha, alpha disubstituted amino acids suitable for stabilizing helices are described herein and include, for example. In some aspects, one, two, three or more of the amino acids at positions 16, 20, 21 and 24 of SEQ ID NO: 1 are subjected to an alpha, alpha disubstituted amino acid ( For example, Aib) is substituted. In a particular embodiment, the amino acid at position 丨6 is Aib. Analogs that exhibit agonist activity on the GIP receptor may comprise additional modifications, such as any of the modifications described herein. For example, such amino acid modifications enhance or decrease the activity against one or both of the GLP-1 receptor and the glycemic receptor. Such amino acid modifications enhance the stability of the peptide, e.g., increase resistance to degradation of the DPP-IV protease, and stabilize the bond between the amino acids 15 and 16. Such amino acid modifications may enhance the solubility of the peptide and/or alter the duration of action of the analog 156004.doc-278-201143790 on any of the GIP receptor, the glycoside receptor, and (^^-丨 receptor) A combination of any of these types of modifications may be present in an analog that exhibits agonist activity on a GIP receptor. Thus, 'in some aspects, the analog comprises an amine group having one or more of the following Acid sequence SEQ ID NO: 1 : Gin at position 17, Ala at position 18, Glu at position 21, lie at position 23, and Ala or Cys at position 24, or its conservative amino acid substitution. In some aspects, the analog comprises a C-terminal guanamine that replaces the C-terminal alpha carboxylate. In certain embodiments, the analog comprises an amino acid substitution at position 1, position 2 or positions 1 and 2, or These substitutions achieve DPP-IV protease resistance. Suitable amino acid substitutions are described herein. For example, position 1 is DM1 Α and/or position 2 is d-Ser or Aib. In some embodiments The amino acid in position 'in position 2 is not d-serine. Alternatively or alternatively the 'analog may comprise one or a combination of the following: ( a) Ser at position 2 is substituted with Ala; (b) Gin at position 3 is substituted with Glu or glutamic acid analog; (c) Thr at position 7 is replaced by lie; (d) Tyr at position 10 Substituted by Trp or an amino acid containing a non-native sulfhydryl or alkyl group for the naturally occurring amino acid; (e) Lys at position 12 is substituted by lie; (f) Asp at position 15 is replaced by Glu (g) Ser at position 16 is replaced by Glu; (h) Gin at position 20 is replaced by Ser, Thr, Ala, Aib; (i) Gin at position 24 is replaced by Ser, Thr, Ala, Aib; j) Met at position 27 is replaced by Leu or Nle; (k) Asn at position 29 is substituted with a charged amino acid (as appropriate, Asp or Glu); and (1) Thr at position 29 via Gly or band Substituted by a charged amino acid (as appropriate, Asp or Glu) 156004.doc -279· 201143790 For analogs that exhibit agonist activity on the GIP receptor, the analog comprises from 1 to 21 amino acids (eg 5 to An extension of 19, 7 to 15, 9 to 12 amino acids. The extension of the analog may comprise any amino acid sequence' with the proviso that the extension is from 1 to 21 amino acids. state Wherein the extension is from 7 to 15 amino acids, and in other aspects, the extension is from 9 to 12 amino acids. In some embodiments, the extension comprises (1) the amino acid sequence SEQ ID NO: 26 or 674, (Π) and the amino acid sequence SEQ ID NO: 26 or 674 have a degree of sequence identity (eg, at least, 85%, 90%, 95%, 98%, 99%) of the amino acid A sequence, or (iH) an amino acid sequence (1) or (丨丨) having one or more conservative amino acid modifications. In some embodiments, at least one of the amino acids of the extension is deuterated or alkylated. The amino acid comprising a brewing group or a burnt group can be located at any position of the extension of the analog. In certain embodiments, the deuterated or alkylated amino acid of the extension is at one of positions 37, 38, 39, 40, 41 or 42 (numbering according to SEQ ID NO: 1) of the analog. on. In certain embodiments, the deuterated or alkylated amino acid is at position 4 of the analog. In an exemplary embodiment, the thiol or alkyl group is a non-native sulfhydryl or alkyl group for a naturally occurring amino acid. For example, the thiol or alkyl group can be a C4 to C30 (e.g., C12 to C18) fatty sulfhydryl group or a C4 to C30 (e.g., C12 to C18) alkyl group. The thiol or alkyl group can be any of the fluorenyl or alkyl groups discussed herein. In some embodiments, the thiol or alkyl group is attached directly to the amino acid, for example, via a side chain of an amino acid. In other embodiments, the sulfhydryl or alkyl group is attached to the amine via a spacer (eg, an amino acid, a dipeptide, a tripeptide, a hydrophilic bifunctional spacer, 156004.doc • 280-201143790 aqueous bifunctional spacer) Base acid. In some aspects, the spacer has a length of from 3 to 10 atoms. In some embodiments, the amino acid spacer is not γ-Glu. In some embodiments, the dipeptide spacer is not γ-ϋΐιι-γ-Glu 〇. In an exemplary embodiment, the amino group attached to the thiol or alkyl group can be any of the amino acids described herein, including For example, the amino acid of formula I, II or hydrazine. The deuterated or alkylated amino acid can be, for example, Lys. Suitable amino acids containing mercapto or alkyl groups, as well as suitable mercapto and alkyl groups, are described herein. See, for example, the teachings under the section entitled Deuteration and Alkylation. In other embodiments, from 1 to 6 amino acids (eg, 1 to 2, 1 to 3, 1 to 4, 1 to 5 amino acids) of the extension are positively charged amino acids, eg, An amino acid of formula IV, such as Lys. The term "positively charged amino acid" as used herein refers to any naturally occurring or non-naturally occurring amino acid that contains a positive charge at the atom of the side chain at physiological pH. In some aspects the 'positively charged amino acid is located at any of positions 37, 38, 39, 40, 41, 42 and 43. In a particular embodiment, the positively charged amino acid is at position 40. In other instances, the extension is deuterated or alkylated as described herein and comprises from 1 to 6 positively charged amino acids as described herein. In other embodiments, the analog exhibiting agonist activity to a GIP receptor comprises (1) an amino group having a at least one amino acid modification of SEQ ID NO: 1, (ii) an analog C-terminus to a position 29 An extension of 1 to 21 amino acids (eg, 5 to 18, 7 to 15, 9 to 12 amino acids) on the acid, and (Hi) located outside the C-terminal extension (eg, at position 1 to Any of the above 29) package 156004.doc -281- 201143790 contains an amino acid which is a non-native sulfhydryl or alkyl group for naturally occurring amino acids. In some embodiments, the analog comprises a deuterated or alkylated amino acid at position 1 . In a particular aspect, the thiol or alkyl group is a C4 to C30 fatty sulfhydryl group or a C4 to C30 alkyl group. In some embodiments, the thiol or alkyl group is attached via a spacer (e.g., an amino acid, a dipeptide, a tripeptide, a hydrophilic bifunctional spacer, a hydrophobic bifunctional spacer). In some aspects, the analog comprises an amino acid modification of a stabilized alpha helix, such as a salt bridge between Glu at position 16 and Lys at position 20, or any of positions 16, 20, 21, and 24 One, two, three or more of α,α disubstituted amino acids. In a particular aspect, the analog additionally comprises an amino acid modification that confers resistance to the DPP-IV protease, such as DMIA at position 1, Aib at position 2. Analogs containing other amino acid modifications are contemplated herein. In certain embodiments, the analog having GIP receptor activity exhibits at least 0.1% of the activity of the GIP receptor (eg, at least 0.5%, 1%, 2%, 5%, 10%, 15% or 20%). In some embodiments, the activity exhibited by the analogs to the GIP receptor is greater than 20% of the activity of the native GIP (eg, 50% or more, 75% or more, 100% or more, 200% or more, 300% or more, 500) %the above). In some embodiments, the analog exhibits significant agonist activity on one or both of the GLP-1 receptor and the glycemic receptor. In some aspects, the selectivity of these receptors (GIP receptor and GLP-1 receptor and/or glucosamine receptor) is within 1000 fold. For example, the selectivity of the GIP receptor-active analog to the GLP-1 receptor may be 500-fold, 100-fold or less, 50-fold less than the selectivity to the GIP receptor and/or the glycosidic receptor, Within 25 times, within 15 times, within 10 times. 156004.doc -282- 201143790 According to some embodiments, the third class of ghrelin-related peptides comprises an amino acid sequence (SEQ ID NO: 1) comprising the following modified native glucosin: Aib at position 2, position 3 Glu on top, Lys on position 10, Glu on position 16, Gin at position 17, Ala at position 18, Lys at position 20, Glu at position 21, lie at position 23, position 24 Ala; wherein the Lys is deuterated by C14 or C16 fatty acid, and wherein the C-terminal carboxylic acid vinegar is replaced by decylamine. In a specific embodiment, the third type of ghrelin-related peptide is linked to the NHR ligand (Y) via a linker (L). According to some embodiments, the third class of ghrelin-related peptides comprises, consists essentially of, or consists of any of the amino acid sequences SEQ ID NO: 70-514, 517-534 or 554, The situation has up to 1, 2, 3, 4 or 5 other modifications that retain the activity of the GLP-1 agonist and/or glycosidic agonist. In certain embodiments, the third type of ghrelin-related peptide comprises the amino acid of any one of SEQ ID NO: 562-760. In some embodiments, the third type of ghrelin-related peptide comprises an amino acid. Sequence SEQ ID NO: 1301-1421. Class 4 Glucagon Related Peptides In certain embodiments, 'Q is a Class 4 ghlylin-related peptide (see, for example, International (PCT) Patent Application Publication No. WO 2009/058662, which is incorporated by reference in its entirety herein. All of the biological sequences (SEQ ID NO: 1301-1371) referred to in the following sections incorporated herein correspond to SEQ ID NO: 1-71 in WO 2009/058662. Activity provides a fourth class of liter according to some embodiments Glycogen-related peptide (hereinafter referred to as 156004.doc -283-201143790 Class 4 peptide). In some aspects, a peptide having a glycoside antagonist activity, a type 4 peptide, a glycoside antagonist is provided. It is used in any context that requires inhibition of glycosidic agonism. The most relevant and obvious use is for the treatment of diabetes. The glycosidic antagonism has been shown to lower blood glucose in preclinical models of hyperglycemia. Glycoglycan Antagonism The agent may be further modified to improve the biophysical stability and/or water solubility of the compound while maintaining the antagonist activity of the parent compound. In some aspects, the 'type 4 peptide' is defined as a pure glycemic antagonist. "Glucagon antagonist" means offset A glycosidic activity or a compound that inhibits glycosidic function. For example, a 'glycoglycan antagonist exhibits at least a 6% inhibition of the maximum response achieved by a glycoside to a glycoside receptor (eg, at least 70%) Inhibition) and preferably, at least 8% inhibition. In some embodiments, the glycoside antagonist exhibits at least a 90% inhibition of the maximum response achieved by the glycoside to the glycoside receptor. In a particular embodiment, the glycoside antagonist exhibits a loo% inhibition of the maximum response achieved by the glycemic receptor to the glycemic receptor. Additionally, the glycoside antagonist exhibits a concentration of about 丨μΜ Glucagon is less than about 20% of the maximum agonist activity achieved by the glycosidic receptor. In some embodiments, the glycosidic antagonist exhibits the greatest contribution to glycosidic receptors by glycosides. The agent activity is less than about 1%. In a particular embodiment, the 'glycoglycan antagonist exhibits less than about 5% of the maximum agonist activity achieved by the glycoside to the glycosidic receptor. In a specific example, the glycemic antagonist exhibits a glycoside to a glycoside. 0% of the maximum agonist activity achieved by the body. "Puremic Glucagon Antagonist" is cAMP produced by the in vitro model test established by the use of 156004.doc •284-201143790 (see for example, w〇2009/058662) A glycoside antagonist that does not produce any stimulatory effects of glycosidic or GLP-1 receptor activity. For example, a pure glycemic antagonist exhibits a glycoside to a glycoside. About 5% or less of the maximum agonist activity achieved by the receptor (for example, about 4% or less, about 3% or less 'about 2% or less, about 1% or less, about 〇%), and exhibits GLP-1 to GLP The maximum agonist activity achieved by the -1 receptor is about 5% or less (e.g., about 4% or less, about 3% or less, about 2% or less, about 1% or less, and about 0%). Thus, in some aspects, a Class 4 peptide exhibiting the activity of a pure glycemic antagonist is provided. According to some embodiments, the glycosidic antagonist exhibits an activity of: in an in vitro assay, when the glycosidic receptor is simultaneously contacted with 〇.8 nM glucosin and a glycoside buckling agent, such as by CAMP production The glycoside inhibitor measures up to a maximum of at least 50% of the ascending hormone-induced camp of the glycosidic receptor. In some embodiments, the glycemic antagonist increases the glycemic receptor. Glycogen-induced CAMP is reduced by at least 80%. The salt G class 4 peptide is suitable for any of the uses previously described for the glycoside antagonist. Thus, the Class 4 peptides described herein can be used to treat hyperglycemia or to treat other metabolic diseases caused by high blood glucose levels or high blood sugar levels. According to some embodiments, the patient treated with the Class 4 peptide disclosed herein is a domestic animal, and in another embodiment, the patient treated is a human. Studies have shown that in the absence of glycosidic inhibition in diabetic patients, it partially accelerates glycogen breakdown, leading to postprandial hyperglycemia. Individuals with higher 156004.doc •285 - 201143790 glycoside content have been shown during oral glucose tolerance test (OGTT) and analyzed for blood glucose in the presence or absence of somatostatin-induced glucagon inhibition. The internal blood glucose is significantly increased. Thus, class 4 peptides of the invention are useful in the treatment of hyperglycemia and are contemplated for use in the treatment of various types of insulin-dependent or non-insulin-dependent diabetes, including type I diabetes, type II diabetes, or diabetes. And reduce the complications of diabetes, including kidney disease, retinopathy and vascular disease.

In some embodiments, the terminal 10 amino acids of the incretin analog-4 (i.e., the sequence SEQ ID NO: 1319 (GPSSGAPPPS)) are linked to the carboxy terminus of the type 4 peptide. Such fusion proteins are expected to have pharmacological activity that inhibits appetite and induces weight loss/maintenance. According to some embodiments, the Class 4 peptide disclosed herein can be further modified to include the amino acid sequence of the amino acid 24 linked to the peptide of class 4 of SEQ ID NO: 1342 SEQ ID NO: 1319 (GPSSGAPPPS) And the individual is administered to induce weight loss or to contribute to weight maintenance. More specifically, the class 4 peptide comprises a sequence selected from the group consisting of: and further comprising an amino acid sequence SEQ ID NO: 1319 (GPSSGAPPPS) linked to the amino acid 24 of the class 4 peptide, which is used for Appetite suppressant and induces weight loss/weight maintenance: SEQ ID NO: 1302, SEQ ID NO: 1303, SEQ ID NO: 1304, SEQ ID NO: 1305, SEQ ID

NO: 1306, SEQ ID NO: 1307, SEQ ID NO: 1308, SEQ ID

NO: 1336, SEQ ID NO: 1339, SEQ ID NO: 1340, SEQ ID

NO: 1341, SEQ ID NO: 1342, SEQ ID NO: 1343 and SEQ ID NO: 1344. In some embodiments, the Class 4 peptide administered comprises the sequence SEQ ID NO: 1346 or SEQ ID NO: 1347. These methods for suppressing appetite or promoting weight loss are expected to be suitable for weight loss, prevention of weight gain or treatment of obesity caused by various causes, including 156004.doc -286· 201143790 including drug-induced obesity' and mitigation and obesity Symptoms related to the disease include vascular disease (coronary artery disease, stroke, peripheral vascular disease, ischemia-reperfusion, etc.), local blood pressure, type II diabetes, hyperlipidemia, and musculoskeletal disorders.

The class 4 peptide of the present invention can be administered alone or in combination with other anti-diabetic agents or anti-obesity agents. Anti-diabetic agents known or under investigation in the art include insulin; sulfonylureas such as tolbutamide (Onnase), acetoxime hexamide ) (Dymelor), tolazamide (Tolinase), chi-rpr〇pamide (Diabinese) , gHpizide (Gluc〇tr〇1), glyburide (Diabeta), glibenclamide (Micronase), glibenclamide (Glynase) )), glimepiride (Amaryl) or gliclazide (Diamicron); meglitinide, such as repaglinide ( Repaglinide) (Prandin) or nategiinide (Starlix); biguanide, such as metformin (Glucophage) or benzene Phenomorphin; thiazolidinedione, such as rosiglitazone (Avandia), beta gliglitazone (Actos) or troglitazone (troglitazone) (Rezulin), or other ΡΡΑίΙγ inhibitors; alpha-glucosidase inhibitors that inhibit carbohydrate digestion, such as miglitol (Glyset), acarbose ) (Precose / Glucobay); exenatide (Byetta) or praminintide; 156004.doc -287- 201143790 dipeptide Peptidase-4 (DPP-4) inhibitors, such as vildagliptin or sitagliptin; SGLT (nano-dependent glucose transporter 1) inhibitor; or FBPase (fructose 1, 6-bisphosphatase) inhibitor. Anti-obesity agents known or under investigation in the art include appetite suppressants, including phenethylamine-type irritants, phentermine (as appropriate, together with fenfluramine or dexfenfluramine) ), diethylpr〇pion (Tenuate®), phendimetrazine (Prelu-2®, Bontril®), benzphetamine (Didrex®), Nomex Pavilion (sibutramine) (Meridia®, Reductil®); rimonabant (Acomplia®), other cannabinoid receptor antagonists; acid regulator; fluoxetine hydrochloride Prozac); Qnexa (topiramate and phentermine), Excalia (bupropion) and zonisamide ) or Contrave (butazone and naltrexone); or lipase inhibitors, similar to xenical (Orlistat) or celestatin (Cetilistat) ) (also known as ATL-962), or GT 389-255. The fourth type of peptide of the present invention can also be administered to a patient suffering from a catabolic depletion disease. It is estimated that more than half of cancer patients experience catabolic depletion, which is characterized by unplanned and progressive mass loss, weakness, and less body fat and muscle. This syndrome is also common in AIDS patients and can also be found in bacterial and parasitic diseases, rheumatoid arthritis, and chronic intestinal, liver, lung, and heart diseases. It is usually associated with anorexia and can be reported as 156004.doc •288- 201143790 is a condition that is aging or caused by physical trauma. A catabolic consuming disease is a symptom that lowers the quality of life, worsens the underlying condition, and is the leading cause of death. The present inventors expect that the class 4 peptides disclosed herein can be administered to a patient to treat a catabolic depletion disorder. Pharmaceutical compositions comprising a Class 4 peptide disclosed herein can be formulated and administered to a patient using standard pharmaceutically acceptable carriers and routes of administration known to those skilled in the art. Accordingly, the invention also encompasses pharmaceutical compositions comprising one or more of the Class 4 peptides disclosed herein and a pharmaceutically acceptable carrier. The pharmaceutical compositions may comprise a Class 4 peptide as a separate pharmaceutically active component, or a Class 4 peptide may be combined with one or more other active agents. According to some embodiments, there is provided a potting composition comprising a fourth class peptide of the invention and a compound that activates the GLP-1 receptor (such as GLP-1, GLP-1 analog, intestinal membrane analog-4) Analogs, or derivatives thereof, according to some embodiments, provide a composition comprising a Class 4 peptide of the invention and an insulin or insulin analog. Alternatively, a composition for inducing weight loss or preventing weight gain can be provided comprising: the sequence SEq ID NO: 1342, the sequence further comprising an amino acid sequence linked to the amino acid 24 of SEQ ID NO: 1342 SEQ ID NO: 1319 (GPSSGAPPPS); and an anti-obesity peptide. Suitable anti-obesity peptides include those disclosed in U.S. Patent Nos. 5,691, 3, 9, 6, 436, 435, or U.S. Patent Application No. 200501 76643, and include, but are not limited to, GLP-1, GIP (suppressive polypeptide), MP1, PYY, MC-4, leptin. Class 4 Peptide Structures In some embodiments, a Class 4 Glycosin-related peptide is provided, wherein aspartic acid is typically present at position 9 of the glycoside 156004.doc • 289·201143790 (SEQ ID NO: 1301) It has been substituted with glutamic acid or a derivative based on sulfoalanine. More specifically, in some aspects, the first amino acid is deleted (de-His) and the aspartic acid at position 9 is substituted with a face acid to produce a Class 4 peptide. A type 4 ghlylin-related peptide having a sulfonic acid substituent substituted at position 9 of an amino acid of a glycosidic acid behaves similarly to a carboxylic acid-based amino acid' but is somewhat critical in physical properties such as solubility difference. The high-retentive alanine (hCysS03) retains the class 4 peptide as a partial antagonist and a weak agonist when it is substituted for the iso- glutamate at position 9 of the His-His Glu9 Class 4 peptide. In some embodiments, a Class 4 peptide is provided wherein the first 2 to 5 amino acids are removed and position 9 (numbered according to SEQ ID NO: 1301) is via hCys (S03), glutamic acid, Replacement of β-high glutamic acid or an alkylcarboxylate derivative of cysteine having the following structure:

H2C\, s COOH, wherein X5 is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group, which is used as a hormone antagonist having high specificity, effectiveness and no agonist properties. Compound. According to some embodiments, a class 4 peptide is provided which comprises the deletion of 2 to 5 amino acid residues at 1<>> and glutamic acid, glutamic acid, lysine, cysteamine Acid sulfonic acid derivative or cysteine 156004.doc • 290· 201143790 of the following structure to replace the aspartic acid residue at position 9 of the native protein relative to the wild type sequence SEq ID NO: 1301 modified glycosidin peptide:

H2C\ X5\ COOH > ® where X5 is a C1_C4 yard, a C2-C4 base or a C2-C4 block. In a particular embodiment, the 2 to 5 amino acid residues at the N-terminus of the native glucagon are deleted and the Asp-substituted class 4 peptide at position 9 is further modified by up to three amino acid modifications. . For example, a Class 4 peptide can comprise one, two or three conservative amino acid modifications. Alternatively or additionally, the class 4 peptide may comprise one or more amino acid modifications selected from the group consisting of: A. Group 4 peptide positions 1 〇, 2 〇 and 24 (according to SEq ID Ν〇 13 〇 One or two amino acids or a C-terminal amino acid on the amino acid of 1 is covalently bonded to a thiol group via a tethered bond, a scaly bond, a sulfur bond, a guanamine bond or an alkylamine bond. Or alkyl amino acid substitution; B. Class 4 peptide at positions 16, 17, 2, 21 and 24 (according to the amino acid number of SEQ m N〇: 1301) or two amino acids Or a ν-terminal or c-terminal amino acid substituted with an amino acid selected from the group consisting of Cys, Lys, ursolic acid, tfj cysteine, and ethionyl-phenylalanine (Ac_phe), wherein The amino acid in the group is covalently bonded to the hydrophilic moiety;

C. Adding an amino acid covalently bonded to the hydrophilic moiety to the N-type peptide of the fourth type 156004.doc •291·201143790 end or c-terminus; D. position 15 (according to the numbering of SEQ ID NO: 1301) Asp is substituted with sulfoalanine, glutamic acid, glutamic acid and high sulfoalanine; E. Ser at position 16 (numbering according to SEQ ID NO: 1301) via sulfoalanine, glutamic acid High glutamic acid and high sulfoalanine substitution; F. substituted with Aib in one or more of positions 16, 20, 21 and 24 (amino acid numbering according to SEQ ID NO: 1301); Amino acid at position 29 or amino acid at positions 28 and 29 (numbered according to SEQ ID NO: 1301) is deleted; H. Asn at position 28 and Thr at position 29 (amine according to SEQ ID NO: 1301) Each or both of the base acid numbers are substituted with a charged amino acid; and/or one or two charged amino acids are added to the C-terminus of SEQ ID NO: 1301; I. position 27 (according to Met on SEQ ID NO: 1301 is substituted with Leu or orthanoic acid; J. Adds a peptide having any of amino acid sequences SEQ ID NOs: 19-21 and 53 to SEQ ID NO: 1301 C-end, where The Thr at position 29 (based on the numbering of SEQ ID NO: 1301) is Thr or Gly; and the K·C terminal carboxylate is replaced with a decylamine. In a particular embodiment, the Class 4 peptide comprises an amino acid modification of A, B or C as described above or a combination thereof. In another specific embodiment, the class 4 peptide further comprises, in addition to the amino acid modification of A, B and/or C, an amino acid modification of any of D to K as described above, or combination. In some embodiments, the Class 4 peptide comprises a glycosidic peptide wherein the first 5 amines 156004.doc -292- 201143790 base acid has been removed from the N-terminus and the remaining N-terminal amine group has been hydroxyl substituted ("PLA6 similar The peptide of SEQ ID NO: 1339 was produced. The applicant of the present invention found that the substitution of phenyl-lactic acid for the first five amino acids has been deleted and that the phenylalanine in the class 4 peptide analog substituted with glutamic acid at position 9 (relative to native astaxanthin) can be further Enhance the potency of their class 4 peptide analogs.

In some embodiments, the Class 4 peptide of SEQ ID NO: 1339 is substituted with an aspartic acid residue at position 4 (position 9 of the native glycein) with an amino acid having the following general structure; Further modified:

Χ6, wherein X6 is C1-C3 alkyl, C2-C3 olefin or C2-C3 alkynyl, and in some embodiments 'Χό is C1-C3 alkyl, and in another embodiment, x6*C2 alkyl . In some embodiments, the Class 4 peptide comprises a glycosidic peptide wherein the first 5 amino acids have been removed from the N-terminus and the aspartic acid residue at position 4 (position 9 of the native glycein) It has been substituted with sulfoalanine or high sulfoalanine. In some embodiments, the Class 4 peptide comprises a Glycosin peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1339, SEQ ID NO: 1307, and SEQ ID NO: 13 08. In some embodiments, the Class 4 peptide comprises an amino acid sequence selected from the group consisting of SEQ id NO: 1308, wherein the amino acid at position 4 is a high sulfoalanine. In another embodiment, the class 4 peptide of SEQ ID NO: 1339 is obtained by using a face acid, a glutamic acid, a β-glutamic acid or an alkyl carboxylic acid having the following structure: The ester derivative is substituted at position 4 (position 9 of the native glycein) on the aspartic acid residue of 156004.doc -293- 201143790 and passed through the step. H2N^C〇〇n H2C\ xs x5 \ COOH Wherein X5 is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2_C4 alkynyl group. In a particular embodiment, X5 is Cl or C2 alkyl. However, applicants of the present invention have found that in the case of a 5-glycosin analog (i.e., a glycosidic analog in which the first five amino acids are deleted), it is not necessary to further replace the phenylalanine with pLA. Substituting the native aspartate residue at position 4 (position 9 of the native glycein) produces an analog that exhibits pure antagonism. This result is surprising considering the following prior art teachings: the native aspartate residue at position 4 must be substituted to produce a high affinity and potent glycoside antagonist analog (2-29). Substitution with PLA improved the relative potency of Asp9 analogs to a point comparable to Glu9 and hCys(S03H)9 analogs. Substituting amphetamine residues with other amphetamine analogs below is less effective than PLA substitution: 3,4-2F-phenylalanine (3,4-2F-Phe), 2-naphthylamine (2-Nal) , N-arginyl-phenylalanine (Ac-Phe), α-methylhydrocinnamic acid (MCA) and benzylmalonic acid (ΒΜΑ) » in addition to position 6 (based on the amino acid of the native glycosidic acid number Substitution with PLA at sites other than (including positions 4 and 5) has revealed that the PLA6 analog is significantly more potent than the glycoside analog with a slightly extended N-terminus 156004.doc • 294-201143790 agent. The invention also includes analogs of the "terminal" peptide substitution of the N-terminal amine group by deuteration and alkylation. Furthermore, the 'PL6 substitution' not only enhances the potency of the antagonist but also plays a key role in the polyethylene glycolation. The PLA6 analog can be selectively PEGylated without activating the glycosidic effect. In the absence of PLA substitution, PEGylation of analogs can surprisingly induce glycosidic agonism. This glycosidic effect was not observed in the polyethylene glycolated PLA6 analog. Several PEGylation sites were studied' including positions 3, 6 and 19 (positions 8, 11 and 19 of the native glycein) and terminal amino acid residues. In some embodiments, PEGylation is carried out at position 19 (position 24 of the native glucagon) as this site exhibits the most potent and selective glycosidic antagonism. In some embodiments, the Class 4 peptide comprises a general structure ABC, wherein the A is selected from the group consisting of: (i) phenyl lactic acid (PLA); (ii) an oxy derivative of PLA; (iii) a peptide of 2 to 6 amino acids, wherein two consecutive amino acids of the peptide are linked via an ester bond or an ether bond; B represents the amino acids i to 26 of SEQ ID NO: 1301, wherein i is 3, 4 , 5, 6 or 7, optionally comprising one or more amino acid modifications selected from the group consisting of: (iv) Asp at position 9 (amino acid number according to SEQ ID NO: 1301) via Glu , Cys sulfonic acid derivative, high glutamic acid, β-high glutamic acid, or an alkyl carboxylate derivative of cysteine having the following structure: 156004.doc •295- 201143790

H2C\COO Η s X5\ COOH > wherein X5 is a C1-C4 alkyl group, a C2-C4 alkenyl group or a C2-C4 alkynyl group. (v) one of the positions 1〇, 20 and 24 (based on the amino acid number of SEQ ID NO: 1301) or two amino acids via an ester bond, an ether bond, a sulfur bond, a guanamine bond or an alkylamine The bond is covalently attached to a mercapto or alkyl amino acid substitution; (vi) one of the positions 16, 17, 20, 21 and 24 (based on the amino acid numbering of SEQ ID NO: 1301) or two amine groups The acid is substituted with an amino acid selected from the group consisting of Cys, Lys, auramine, homocysteine, and acetyl-phenylalanine (Ac-Phe), wherein the amino acids in the group are The valency is linked to the hydrophilic moiety; (vii) the Asp at position 15 (according to the numbering of SEQ ID NO: 1301) is substituted with sulfoalanine, a face acid, glutamic acid and a high sulfoalanine; (viii) The position 16 (based on the numbering according to SEQ ID NO: 1301) is substituted with sulfoalanine, glutamic acid, homoelandic acid and high sulfoalanine; (ix) at positions 16, 20, 21 and 24 ( Substituting Aib according to one or more of the amino acid numbers of SEQ ID NO: 1301; and C is selected from the group consisting of: (X) X; (xi) XY; (xii) XYZ; Xiii) XYZ-R10, 15600 4.doc •296· 201143790 where X is Met, Leu or Nle; Y is Asn or a charged amino acid; z is Thr, Gly, Cys, Lys, ornithine (〇rn), homocysteine, Acetyl phenylalanine (Ac-Phe) or a charged amino acid; wherein r1 lanthanide is selected from the group consisting of SEq ID NO: 1319-1321 and 1353; and (xiv) (X) to (xiii) In one case, the c-terminal carboxylic acid ester is replaced by decylamine. In a particular aspect, the Class 4 peptide comprises an oxy derivative of PLA. As used herein, "oxyl derivative of PLA" refers to a compound comprising a modified pla structure in which the radical has been replaced by O-R, wherein Rii is a chemical moiety. In this regard, the oxy derivative of PLA may be, for example, an ester of PLA or an ether of PLA. Methods of preparing oxy derivatives of PL A are known in the art. For example, when the oxy derivative is an ester of PLA, the ester can be formed by reacting a pla group with a nucleophile having a carbonyl group. The nucleophile can be any suitable nucleophile including, but not limited to, an amine or a hydroxyl group. Therefore, the ester of PLA may comprise the structure of formula IV:

Wherein R7 is a 156004.doc • 297·201143790 ester formed when a hydroxyl group of PLA reacts with a nucleophile having a carbonyl group. A nucleophile having a carbonyl group (which reacts with a hydroxyl group of PLA to form an ester) may be, for example, a tickic acid, a tickic acid derivative, or an activated acid. The tickic acid derivative can be, but is not limited to, a mercapto vapor, an acid needle, a guanamine, a g or a nitrile. The acidified ester of the acid can be, for example, N-hydroxybutylenimide (NHS), toluenesulfonate (Tos), carbodiimide or hexafluorophosphate. In some embodiments, the carbodiimide is 1,3-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), 1-ethyl-3-(3-dimethyl Aminopropyl)carbodiimide hydrochloride (EDC) or 1,3-diisopropylcarbodiimide (DICD). In some embodiments, the 'hexafluorophosphate salt is selected from the group consisting of benzotriazol hexafluoro-oxy-xyl (dimethylamino) scale (BOP), hexafluorophosphate Triazol-1-yl-oxytrifluoropyridyl scale (PyBOP), 2-(1Η-7-azabenzotriazol-1-yl)-hexafluorophosphate-1,1,3,3· Tetrakidinopurine (HATU) and hexafluorophosphate 0-benzotriazole-N,N,N',N'-raf*-^ (HBTU). Methods for producing ethers by reaction with a hydroxyl group (e.g., a hydroxyl group of PLA) are also known in the art. For example, the hydroxyl group of the PLA can be reacted with a halogenated alkyl alcohol or a decyl benzoate to form a hydrazone bond. In general, the R" chemical moiety is a chemical moiety that does not degrade the activity of the Class 4 peptide. In some embodiments, the chemical moiety enhances the activity, stability, and/or solubility of the Class 4 peptide. In a particular embodiment, the chemical moiety that is bonded to the PLA via an oxygen-containing bond (eg, via an ester bond or an ether bond) is a polymer (eg, a polyalkylene glycol), a carbohydrate, an amino acid, a peptide, or a lipid, for example, Fatty acids or steroids. In a particular embodiment, the chemical moiety is an amino acid, which is optionally part of the peptide 156004.doc • 298. 201143790, such that Formula IV is a peptide. In this regard, pl A may be at a position other than the N-terminal amino acid residue of the class 4 peptide, and thus the class 4 peptide comprises one or more between the n-terminus and the PLA residue (for example, 1, 2) , 3, 4, 5, 6 or more) amino acids. For example, a Class 4 peptide can comprise PLA at position η of the Class 4 peptide, wherein η is 2, 3, 4, 5 or 6. The amino acid between the terminal and the PLA residue may be a synthetic or naturally occurring amino acid. In a particular embodiment, the amino acid between the terminal and the PLA is the naturally occurring amino acid. In some embodiments, the amino acid between the terminal and the PLA is the terminal amino acid of the native glycoside. For example, a Class 4 peptide can comprise, at the terminus, any of the amino acid sequence SEQ ID NO: 1354-1358, wherein the PLA is linked to the threonine via an ester linkage: SEQ ID NO: 1354 His- Ser-Gln-Gly-Thr-PLA SEQ ID NO: 1355 Ser-Gln-Gly-Thr-PLA SEQ ID NO: 1356 Gln-Gly-Thr-PLA SEQ ID NO: 1357 Gly-Thr-PLA SEQ ID NO: 1358 Thr-PLA. In an alternate embodiment, one or more N-terminal amino acids may be substituted with an amino acid other than the amino acid of the native glycosidic acid. For example, when the class 4 peptide comprises PLA as the amino acid at position 5 or 6, the amino acid at position 1 and/or position 2 may be a decrease in the likelihood of dipeptidyl peptidase IV causing cleavage. Amino acid. More specifically, 'in some embodiments, position 1 of the class 4 peptide is an amino acid selected from the group consisting of D-histamine, alpha, alpha.-dimethylimipropetic acid (DMIA). , Ν-mercapto histidine, α-mercapto histidine, imidazoleacetic acid, deaminoglycolic acid, trans-histamine, ethyl-histidine and high-histamine 156004.doc - 299· 201143790 Acid. More specifically, in some embodiments the position 2 of the 'antagonist peptide is an amino acid selected from the group consisting of D-serine, D-alanine, lysine, glycine, N- Methyl serine, N-methylalanine and aminoisobutyric acid (Aib). Similarly, by way of example, when a class 4 peptide comprises pLA as the amino acid at position 4, 5 or 6, the amino acid at position 3 of the class 4 peptide may be glutamic acid rather than native glucosinolate. Native glutamic acid residues. In an exemplary embodiment of the invention, the class 4 peptide comprises at the N-terminus any of the amino acid sequences SEQ ID NO: 1359-1361. For a class 4 peptide comprising a compound of formula IV, the polymer can be any polymer, with the proviso that it can react with the hydroxyl groups of the PLA. The polymer can be a natural or generally a polymer comprising a nucleophile having a carbonyl group. Alternatively, the polymer can be a polymer that has been derivatized to comprise a nucleophile having a carbonyl group. The polymer may be a derivatized polymer of any of: polydecylamine; polycarbonate; polyalkylene and derivatives thereof, including polyalkylene glycol, polyoxyalkylene, polyalkylene terephthalate Acrylate and methacrylate polymers, including poly(decyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate) ), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(acrylic acid) Propyl ester), poly(isobutyl acrylate) and poly(octadecanoacetate); polyethylene polymer, including polyvinyl alcohol, polyvinyl ether, polyvinyl ester, poly-ethylene, poly(acetic acid) Vinyl ester) and polyvinylpyrrolidone; polyglycolide; polyoxyalkylene; polyamino phthalate and its copolymer; cellulose, including alkyl cellulose, hydroxyalkyl cellulose, cellulose ether , cellulose ester, nitrocellulose, methyl fiber 156004.doc •300· 201143790 Cellulose, m-propyl cellulose, trans-propyl propyl ketone, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate , post-ethyl cellulose, cellulose triacetate and cellulose and cellulose sodium sulfate; polypropylene; polyethylene, including poly (ethylene glycol), poly (ethylene oxide) and poly (for stupid acid Ethyl ester); and polystyrene. The polymer may be a biodegradable polymer 'including synthetic biodegradable polycondensates (eg, polymers of lactic acid and glycolic acid, polyacid fields, poly (ortho acid) vinegar, polyamino phthalates, poly(butyl) Acid), poly(valeric acid) and poly(lactide-co-endrolone), and natural biodegradable polymers (such as alginate and z other polysaccharides, including polydextrose and cellulose, collagen, Chemical derivatives (substitution, addition, hydroxylation, oxidation, and other modifications conventionally performed by those skilled in the art), albumin and other hydrophilic proteins (such as corn) Proteins and other prolamin and hydrophobic proteins), as well as any copolymers or mixtures thereof. In general, Φ such substances are degraded by surface or overall erosion by enzymatic hydrolysis or exposure to water in vivo. The polymer may be a bioadhesive polymer such as the bioerodible hydrogel described by H. s. Sawhney, CP Pathak and J. A. Hubbell, Macromolecules, 1993, 26, 581-587, this reference The teachings of the literature are incorporated herein; poly hyaluronic acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, polyglucamine, poly(methyl methacrylate), poly(methacrylic acid B) Ester), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(mercaptopropyl 156004.doc -301 - 201143790 isodecyl enoate ), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate) ). In some embodiments, the polymer is a water soluble polymer. Suitable water soluble polymers are known in the art and include, for example, polyvinylpyrrolidone, hydroxypropylcellulose (HPC; Klucel), hydroxypropylmethylcellulose (HPMC; Methocel), nitro Cellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, decylcellulose, ethylcellulose (Ethocel), ethylcellulose, various calcined fibers And burnt-base cellulose, various cellulose ethers, cellulose acetate, carboxymethyl cellulose, sodium thioglycolate, calcium carboxymethyl cellulose, vinyl acetate / butenoic acid copolymer, poly- Hydroxymethyl methacrylate, methacrylic acid via methyl ester, methacrylic acid copolymer, polymethacrylic acid, polymethyl methacrylate, maleic anhydride / mercapto vinyl ether copolymer, polyvinyl alcohol , sodium polyacrylate and calcium polyacrylate, polyacrylic acid, acidic carboxyl polymer, carboxyl polyalkylene group, carboxyvinyl polymer, polyoxyethylene polyoxypropylene copolymer, polydecyl vinyl ether co-maleic anhydride Carboxymethylamine, potassium methacrylate Benzene copolymer, polyoxyethylene glycol, polyethylene oxide, and derivatives, salts and combinations thereof. In a particular embodiment, the polymer is a polyalkylene glycol, including, for example, polyethylene glycol (PEG). The carbohydrate may be any carbohydrate, with the proviso that it comprises or is prepared to comprise a carbonyl group having an alpha leaving group. The carbohydrate may, for example, be a carbohydrate that is derivatized to comprise a carbonyl group having an alpha leaving group. In the case of 156004.doc • 302· 201143790, carbohydrates may be derived from, for example, glucose, galactose, fructose, and second brews (eg, sugar; milk:,: (: sugar), oligosaccharides (such as cotton). Sugar, stachyose), multi-enzyme (Gentamic starch, 'cellulose, chitin, sputum, sucrose, xylan, mannan, fucoidan, galactomannan

For a class 4 peptide comprising a compound of formula w, the lipid can be any lipid comprising a carbonyl group having an alpha leaving group. The lipid may, for example, be a lipid that has been derivatized to contain a few groups. In this regard, the lipid may be a derivative of a fatty acid (eg, a C4 to C30 fatty acid, a stannic acid, a prostaglandin, a leucotriene, a thromboxane, a guanidine-mercaptoethanolamine), a glycerol lipid (eg, Monosubstituted, disubstituted, trisubstituted glycerol), glycerophospholipids (eg phospholipid choline phosphatidylinositol, linoleum ethanolamine, carbon ester tyrosine), sphingolipids (eg sphingosine, neural crest) Amine), sterol lipids (eg steroids, cholesterol), pregnenolone lipids, glycolipids or polyketides. In some embodiments, the lipid is oil, wax, cholesterol, sterol, fat soluble vitamin, monoglyceride, diglyceride, triglyceride, phospholipid. In some embodiments, the molecular weight of R7 is about 1 〇〇 kDa or less than 1 〇〇 kDa 'eg, about 90 kDa or less, about 80 kDa or less, about 70 kDa or less, about 60 kDa, about 60 kDa. Or below 60 kDa, below 50 kDa or below 50 kDa, below 40 kDa or below 40 kDa. Thus, r7 may have a molecular weight of about 35 kDa or less, about 30 kDa or less, about 25 kDa or less, about 20 kDa or less, about 20 kDa or less, about 15 kDa or less, about 10 kDa, about 10 kDa. Or below 10 kDa, below 5 kDa or below 5 kDa, or about 1 kDa. 156004.doc -303- 201143790 In an alternative embodiment, the class 4 peptide comprises as a 2 to 6 amino acids as A' wherein the two consecutive amino acids are via a self-primary or ether linkage Union. The ester bond or ether bond can be, for example, between the amino acids 2 and 3, 3 and 4, 4 and 5, or 5 and hydrazine. Optionally, the peptide may be further modified by covalent attachment to another chemical moiety, including linkage to a polymer (e.g., a hydrophilic polymer), alkylation, or deuteration. For a class 4 peptide comprising the general structure ABC, Β represents the amino acid of the native glucosinus such as i to 26 of SEQ ID NO: 1301, wherein i is 3, 4, 5, 6 or 7' as appropriate Contains one or more amino acid modifications. In a particular embodiment, B represents the amino acids 7 to 26 of SEQ ID NO: 1301, which are optionally further modified. In some embodiments, B is modified by up to three amino acid modifications. For example, a modification of the primary amino acid sequence SEQ ID NO: 1301 is modified by one or more conservative amino acid modifications. In another embodiment 'B' comprises one or more amino acid modifications selected from the group consisting of (iv) to (jjx) as described herein. In a particular embodiment, B comprises one or both of the amino acid modifications (v) and (vi). In another specific embodiment, B further comprises, in addition to (v) and (vi), an amino acid modification or amine selected from the group consisting of (iv), (vii), (viu) and (ix) A combination of base acid modifications. In another specific embodiment, the Class 4 peptide comprises one or more charged amino acids at the C-terminus. For example, Y and/or Z may be a charged amino acid, such as Lys, Arg, His. , Asp and Glu. In another embodiment, the Class 4 peptide comprises one to two charged amino acids (e.g., Lys, Arg, His, Asp, and Glu) at the C-terminus to Z. In a particular aspect, one or two of the following are charged. 156004.doc -304- 201143790 The Z of the amino acid does not contain R1〇. In some embodiments, as described herein, the Class 4 peptide comprises a hydrophilic moiety covalently bound to the amino acid residue of the Class 4 peptide. For example, a Class 4 peptide can comprise a hydrophilic moiety covalently linked to an amino acid at position 1, 16, 20, 21 or 24 (numbered according to SEQ ID NO: 1301). In another embodiment, the 'hydrophilic moiety' is attached to the C-terminal amino acid of the Class 4 peptide, which in some cases is 1 or 11 amino acids between C-terminus and Z. In another embodiment, when A is PLA, PLA-Phe or PLA-Thr-Phe, the hydrophilic moiety is attached to the PLA, wherein the PLA is modified to comprise a hydrophilic moiety. In another embodiment, an amino acid comprising a hydrophilic moiety is added to the N-terminus or C-terminus of the Class 4 peptide. In another embodiment, the Class 4 peptide comprises a thiol or alkyl group as described herein. For example, the oximation or alkylation can be carried out on the amino acid side chain at position 1, 〇, 2 or 24 (numbered according to SEQ ID NO: 1301). In an alternate embodiment, the deuteration or alkylation is carried out on the side chain of the c-terminal amino acid of the class 4 peptide, which in some cases is between C-terminal to Z- or 11 amino acids. In another embodiment, when a is PLA, PLA-Phe or PLA-Thr-Phe, the PLA is modified to comprise a thiol or alkyl group. Illustrative Examples The Class 4 peptides can comprise any synthetic or naturally occurring amino acid, with the restriction that at least two consecutive amino acids of the peptide are linked via an ester or ether linkage. In a particular embodiment, the peptide comprises an amino acid of native glucosin. For example, the peptide may comprise native glucosin (SEq ID N〇: 13〇1) to 6, wherein j is 1, 2, 3, 4 or 5. Alternatively, the peptide may comprise an amino acid sequence having one or more amino acid modifications based on the N-terminus of SEQ 156004.doc • 305-201143790 1301. The amino acid at position 1 and/or position 2 can be an amino acid which reduces the likelihood of dipeptidyl peptidase IV causing a cleavage. For example, the peptide may comprise an amino acid selected from the group consisting of D. histidine, alpha, alpha-dimercaptoimidazoleacetic acid (DMIA), guanidine-methyl at position i of the class 4 peptide. Histamine, α-methylhistamine, imidazoleacetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histidine and histidine. More specifically, 'in some embodiments, position 2 of the antagonist peptide is an amino acid selected from the group consisting of D-serine, D-alanine, valine, glycine, Ν- Methylserine, Ν-methylalanine, and aminoisobutyric acid (Aib)» Also, for example, the amino acid at position 3 of the class 4 peptide may be glutamic acid rather than native glucosin. Native glutamic acid residues. Thus, a Class 4 peptide can comprise the following amino acid sequence:

Xaal-Xaa2-Xaa3-Thr-Gly-Phe (SEQ ID NO: 1368); Xaa2-Xaa3-Thr-Gly-Phe (SEQ ID NO: 1369); or Xaa3-Thr-Gly-Phe (SEQ ID NO: 1370) Wherein Xaal is selected from the group consisting of: His, D-histamine, α,α-dimercaptoimidazoleacetic acid (DMIA), Ν-mercapto histidine, α-methylhistamine, imidazole Acetic acid, deaminoglycolic acid, hydroxy-histidine acid, acetyl-histidine acid and high-histamine; Xaa2 is selected from the group consisting of Ser, D-serine, D-alanine , proline, glycine, N-methyl serine, N-mercaptoalanine and aminoisobutyric acid (Aib); and Xaa3 is Gin or Glu. The invention also encompasses embodiments in which the C-terminal amino acid of the Class 4 peptide has a guanamine group substituted for the carboxylic acid group present on the native amino acid. In some embodiments, wherein the type 4 peptide is pegylated, the fourth class 156004.doc-306·201143790 comprises a truncated glycoside peptide, particularly comprising 6-29, wherein the "N-terminal" amine The base acid is PL A (phenyl-lactic acid). These glycoside derivatives exhibit unique properties. It is a peptide which is more effective than a peptide having a native N-terminal phenylalanine, and it inhibits any glycosidic agonism caused by pegylation, and this glycosidic effect is not observed under phenylalanine. Finally, although the current literature demonstrates that substitution of the native aspartic acid at position 9 is required for antagonist activity, the applicants of the present invention have found the following surprising results: not in the PLA6-(6-29) literose analogue This kind of substitution is needed again. In some embodiments, the amino acid of the class 4 peptide is substituted with at least one cysteine residue wherein the side chain of the cysteine residue is thiol-reactive (including, for example, maleic acid) The imine group, the vinyl anthracene, the 2-pyridinethio group, the dentate group and the tooth 8 blue group are further modified. These thiol reactive reagents may contain an entic, keto, hydroxy and ether group, as well as other hydrophilic moieties such as polyethylene glycol units. In an alternate embodiment, the amino acid of the fourth type of peptide is substituted with an amine acid and an amine reactive reagent such as an active ester of a carboxylic acid (butyl phthalimide, anhydride, etc.) or such as polyethylene The aldehyde of the hydrophilic portion of the diol is further modified to replace the side chain of the amine acid residue. According to some embodiments, the lytic acid residue corresponding to position 丨2 of the native peptide is substituted with arginine and for the amine group corresponding to position 1, 16, 17, 2, 21, 24 or 29 of the native peptide One of the acids is inserted into a single lysine substitution, or the lysine is added to the N-terminus or the c-terminus of the class 4 peptide. In a further embodiment, the methionine residue corresponding to position 27 of the native peptide is changed to leucine or norleucine to prevent oxidative degradation of the peptide. In some embodiments, the Class 4 peptides described herein are truncated or deleted by exchanging one or two amino acids at the c-terminus of the glycoside 156004.doc • 307·201143790 peptide (ie, truncating native The position of the glycoside 29 or the amino acid at positions 28 and 29 is further modified without affecting the activity and/or potency of the glycemic receptor. In this regard, the Class 4 peptides described herein can, for example, consist essentially of the amino acids 1-27, 1-28, 2-27, 2-28, 3-27 of the native glucosinolate peptide (seq id NO: 1301). Composition of, 3-28, 4-27, 4-28, 5-27, 5-28, 0-27 or 6-28, or consisting of the above-described amino acid, which has one or more Modification of class 4 peptide activity. The Class 4 peptides disclosed herein also encompass amino acid substitutions where it is known that is not critical to the function of the glycemic peptide. In some embodiments, the substitutions are selected from the group consisting of position 2, 5, 6, 7, 8, 9 ' 12, 13, 14, 15, 16, 19, 22, 23 or 24 of SEQ ID NO: 1339 Substituting a conservative amino acid at one, two or three positions of the group. In some embodiments, the 'type 4 peptide comprises a derivative peptide of SEQ ID NO: 1342, wherein the glycoside peptide is selected from positions 2, 5, 6, 8, 9 12, 13 relative to SEQ ID NO: 13 42 And 14 to 3 amino acid positions contain other amino acid substitutions. In some embodiments, the substitution at positions 2, 5, 6, 8, 9, 12, 13 and 14 of SEQ ID NO: 1342 is a conservative amino acid substitution. In some embodiments, the amino acid corresponding to position 16, n, 2, 21, 24 or 29 of the native peptide, and more particularly, the amino acid at position 21 and/or 24 via cysteamine Acid or lysine substitution wherein the PEG chain is covalently attached to a substituted cysteine or lysine residue. According to some embodiments, the modified Class 4 peptide comprises two or more polyethylene glycol chains covalently bound to the peptide, wherein the total molecule of the glycosidic chain is 156004.doc -308·201143790 is about 1,000 to about 5,000 Daltons. In some embodiments, the PEGylated Class 4 peptide comprises a peptide selected from the group consisting of SEQ ID NO: 13 12 and SEQ ID NO: 1322, wherein the peptide comprises an amine bonded to positions 11 and 19 A polyethylene glycol chain of a base acid, and the combined molecular weight of the two PEG chains is from about 1,000 to about 5,000 Daltons. According to some embodiments, a Class 4 peptide is provided comprising a modified glycosaminoglycan peptide selected from the group consisting of:

Ri - Phe-Thr-Ser-Xaa-Tyr-Ser-Xaa-Tyr-Leu-Xaa-Xaa-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Xaa-Asn-Thr- Ri (SEQ ID NO: 1309);

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Xaa-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Xaa-Phe-Val-Gln-Trp-Leu-Xaa-Asn-Thr- R2 (SEQ ID NO: 1310);

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Xaa-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Xaa-Trp-Leu-Xaa-Asn-Thr- R2 (SEQ ID NO: 1311); and

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Xaa-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-Gln-Xaa-Phe-Val-Xaa-Trp-Leu-Xaa-Asn-Thr- R2 (SEQ ID NO: 1312), wherein Xaa at position 4 is aspartic acid, glutamic acid, sulfoalanine or homo-propyl alanine, Xaa at position 7 is Lys or Arg, and Xaa at position 10 is Aspartic acid, sulfoalanine, glutamic acid, glutamic acid and high sulfoalanine; Xaa at position 11 is Ser, Lys, Cys, Orn 'Homocysteine or Ethyl phenylamine Acid, Xaa at position 16 is Asp, Lys, Cys, 156004.doc 309· 201143790 〇rn, homocysteine or acetamino albinoic acid, and Xaa at position 19 is Gin, Lys, Cys, Orn , homocysteine and acetopheniric acid, Xaa at position 22 is Met, Leu or Nle, R丨 is OH or NH2, and ruler 2 is (:0011 or <:0&0>1112, wherein for 8 The peptide is PEGylated at position 11 for 〇10 1 < 0:13 09; for SEQ ID NO: 1310, the peptide is PEGylated at position 16; for SEQ ID NO: '1311' the peptide is PEGylated at position 19; and for SEQ ID NO: 13 12 The peptide is pegylated at positions 16 and 19; with the proviso that when Xaa at position 4 is aspartic acid, the heart is 〇H. According to some embodiments, the peptide comprises the sequence SEQ ID NO: 1309, SEQ ID NO: 13 10 or SEQ ID NO: 1311 ' wherein 1 is 〇H and R2 is CONH2. In some embodiments, the peptide comprises the sequence SEQ ID NO: 1309, SEQ ID NO: 1310 or SEQ ID NO: 1311 'wherein R丨 is 〇H, 尺2 is CONH2 and the amino acid at position 4 is aspartic acid, and in another embodiment, the peptide comprises a carboxy terminal extension comprising the sequence SEQ ID NO: 1319 According to some embodiments, the peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO: 1313, SEQ ID NO: 1314, and SEQ ID NO: 1316, wherein SEQ ID NO: 13 09 and SEQ ID NO: 1313, the peptide is PEGylated at position 11; for SEQ ID NO: 1310, the peptide is PEGylated at position 16; For SEQ ID NO: 1310 and SEQ ID NO: 1314, the peptide was pegylated at position 19. In some embodiments, the glycoside agonist comprises a peptide of SEQ ID NO: 13 13 or SEQ ID NO: 1314. In some embodiments, the c-terminal amino acid of class 4 peptide 156004.doc • 310· 201143790 disclosed herein has a guanamine group in place of the carboxylic acid group present on the native amino acid. According to some embodiments, the Class 4 peptide comprises the sequence of SEQ ID NO: 1318. A class 4 peptide is provided according to some embodiments, wherein the plasma protein has been covalently linked to the amino acid side chain of the peptide to improve the solubility, stability and/or pharmacokinetics of the glycemic peptide. For example, serum albumin can be covalently bound to the fourth type presented herein. In some embodiments, the protein is covalently bound to an amino acid corresponding to position 16, 17, 20, 21, 24 or 29 of the native glucagon peptide. More particularly, in some embodiments, the plasma protein binds to an amino acid corresponding to position 16 or 24 of the native glucagon peptide, wherein the class 4 peptide comprises the sequence of SEQ ID NO: 1303, SEQ ID NO : 1304, SEQ ID NO: 1305, SEQ ID NO: 1306, SEQ ID NO: 1307, SEQ ID NO: 1308, SEQ ID NO: 1309, SEQ ID NO: 1311, SEQ ID NO: 1312, SEQ ID NO: 1322 SEQ ID NO: 1323, SEQ ID NO: 1324, SEQ ID NO: 1325, SEQ ID NO:

1326 'SEQ ID NO: 1327 'SEQ ID NO: 1328 ' SEQ ID NO: 1336 and SEQ ID NO: 1339. In some embodiments, the Class 4 peptide comprises a peptide selected from the group consisting of SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO: 13 11 and SEQ ID NO: 1312.

According to some embodiments, a Class 4 peptide is provided wherein the linear amino acid sequence representing the Fc portion of the immunoglobulin molecule has been covalently linked to the amino acid side chain of the fourth type disclosed herein to improve the glycemic acid Solubility, stability and/or pharmacokinetics of the peptide. For example, an amino acid sequence representing the Fc portion of an immunoglobulin molecule can be covalently bound to SEq no: 1307, SEQ 156004.doc -311 · 201143790 ID NO: 1339, a hemolysin peptide or a glycoside thereof The position of the object is 11, 12, 15, 16, 19, 21 or 24. In some embodiments, the Fc peptide is covalently joined to position 11 or 19 of the class 4 peptide of SEQ ID NO: 1306, SEQ ID NO: 1307, SEQ ID NO: 1308, or SEQ ID NO: 1336. The Fc portion is usually isolated from IgG, but Fc peptide fragments from any immunoglobulin should function equivalently. In some embodiments, the glycosidic peptide is selected from the group consisting of SEQ ID NO: 1303, SEQ ID NO: 1304, SEQ ID NO: 1305, SEQ ID NO: 1307, SEQ ID NO: 1308, and SEQ ID NO··1339' wherein the Fc portion is linked to the corresponding position of 16, 17, 2, 21, 24 or 29 of the native glucagon peptide. In some embodiments, the Class 4 peptide comprises a glycopeptide peptide selected from the group consisting of: 〇1〇1^0: 1309, SEQ ID NO: 1310, SEQ ID NO: 1311, and SEQ ID NO: 1312 'wherein the Fc peptide binds to the amino acid side chain at position ii, 16 or 19 of SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO: 13 11 , respectively, and binds to the SEq ID N〇: The position of 1312 is u&19 on both sides of the amino acid side chain. In certain embodiments of the invention, the Class 4 peptide comprises any one of the amino acid sequences SEQ ID NO: 1362, 1364-1367, and 1371. Modified solubility modification One-step modification to improve the peptide at physiological pH: value in water

The type 4 peptide can be subjected to solubility in a solution, activity. In the anti-agent activity of / 156004.doc 201143790. Thus, in some embodiments, the Class 4 peptides disclosed herein are further modified to comprise covalent linkages to amino acid positions 1, 16, 17, 20, 21, 24 corresponding to the native glycosidic peptide. And one or more hydrophilic groups of the amino acid side chain of 29 or the N-terminal or C-terminal amino acid side chain. In another embodiment, the amino acid side chain corresponding to amino acid positions 16 and 24 of the native glucagon peptide is covalently bonded to the hydrophilic group, and in some embodiments, the hydrophilic group is polyethylene. Alcohol (PEG) » Applicants have also discovered that native glucagon can be modified by introducing a charge on its carboxy terminus to enhance the solubility of the peptide while retaining the agonist properties of the peptide. Enhanced solubility allows for the preparation and storage of a glycemic solution at near neutral pH. The long-term stability of the class 4 peptide can be improved by formulating a glycemic solution at a relatively neutral pH (e.g., a pH of from about 6.0 to about 8.0). The Applicant again expects that the Class 4 peptides disclosed herein can likewise be modified to enhance their solubility in aqueous solutions at relatively neutral pH values (e.g., from about 6.0 to about 8.0 pH) while retaining the parent. Antagonistic properties of the protein. Thus, 'some embodiments of the invention pertain to a class 4 peptide of SEq ID NO: 1339, which has been substituted by a charged amino acid to replace a native uncharged amino acid' or to add a charged amino acid to a rebel The basal end is further modified with respect to the native amino acid present at positions 6 to 29 of wild-type glycoside (SEQ ID NO: 1301) to add a charge to the peptide. According to some embodiments, one to three uncharged peptides of class 4 of SEQ ID NO: 1339 are replaced with a charged amino acid by a charged amino acid. In some embodiments, the charged amidine acid is selected from the group consisting of lysine, arginine, histidine, aspartic acid, and face acid. More specifically, applicants of the present invention have discovered that the amino acid normally present on the corresponding position 28 and/or 29 of the native glycosin is substituted with a charged amino acid of 156004.doc 313-201143790 and/or The addition of 1 to 2 charged amino acids to the carboxy terminus of the class 4 peptide enhances the physiologically relevant 第]^ value (ie, a pH of from about 6.5 to about 7.5) in the aqueous solution. Solubility and Stability. Accordingly, such modifications to the Class 4 peptides disclosed herein are expected to have a similar effect on the solubility in aqueous solutions, especially at pH values in the range of from about 5.5 to about 8.0, while retaining the parent peptide. Biological activity. According to some embodiments, the class 4 peptide of SEQ ID NO: 1339 is substituted with a negatively charged amino acid (eg, aspartic acid or a face acid) for the corresponding position 28 of the native glycein and/or The primary amino acid on 29 and optionally a negatively charged amino acid (such as aspartic acid or glutamic acid) is added to the carboxy terminus of the peptide to be modified. In an alternate embodiment, the peptide of class 4 of SEQ ID NO: 1339 is substituted by a positively charged amino acid (eg, lysine, arginine or histidine) relative to the native glycoside The primary amino acid at position 29 and optionally one or two positively charged amino acids (e.g., an amine acid, arginine or histidine) are added to the carboxy terminus of the peptide to be modified. A Class 4 peptide having improved solubility and stability is provided according to some embodiments, wherein the peptide comprises the amino acid sequence SEQ ID NO: 1341, with the restriction being at least one of positions 23 or 24 of SEQ ID NO: 1341 The amino acid is substituted with an acidic amino acid and/or an additional acidic amino acid is added to the carboxy terminus of SEQ ID NO: 1341. In some embodiments, the acidic amino acid is independently selected from the group consisting of Asp, Glu, primate, and homo-alanine. According to some embodiments, there is provided a 15406.doc • 314· 201143790 4 class peptide having improved solubility and stability, wherein the antagonist comprises the amino acid sequence SEQ ID NO: 1341, SEQ ID NO: 1342, SEQ ID NO : 1343 or SEQ ID NO: 1344, wherein at least one of the amino acids at position 23 or 24 is substituted with a non-native amino acid residue (ie, at least at position 23 or 24 of the analog) An amino acid is an acidic amino acid different from the amino acid present at the corresponding position in SEQ ID NO: 1307. According to some embodiments, a glycosidin agonist is provided comprising the sequence of SEQ ID NO: 1341 or 1342, with the proviso that when the amino acid at position 23 is aspartame and the amino acid at position 24 is sulphate In the case of aminic acid, the peptide further comprises from 1 to 2 amino acids independently added to the group consisting of: Lys, Arg, His, Asp or Glu. In another embodiment, the solubility of the peptide of class 4 of SEQ ID NO: 1342 can be by covalently bonding a hydrophilic moiety to an amino acid residue at position 11, 12, 15, 16, 19 or 24. Improved, and in some embodiments, the hydrophilic moiety is bonded to the amino acid at position 11, 16 or 19, and in another embodiment, the hydrophilic moiety is bonded to the amino acid 19. In some embodiments, the hydrophilic moiety is a hemulin or immunoglobulin Fc portion, and in an alternate embodiment, the hydrophilic moiety is a hydrophilic hydrocarbon chain. In some embodiments the 'hydrophilic moiety' is a polyethylene glycol having a molecular weight selected from the range of from about 1,000 to about 5,000 Daltons. In another embodiment, the hydrophilic moiety is a polyethylene glycol having a molecular weight of at least about 20,000 Daltons. In some embodiments, the polyethylene glycol modified Class 4 peptide comprises the amino acid sequence SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO: 1311, SEQ ID NO: 1312, SEQ ID NO: 1343, SEQ ID NO: 1344 or SEQ ID NO: 156004. doc-315-201143790 1345. Modification of improved stability The Asp-Ser sequence at positions 15 to 16 of native glucosinol has been identified as a unique unstable dipeptide that causes premature chemical cleavage of primary hormones in aqueous buffer. For example, when maintained at 0.01 °C for 1 week at 37 °C, more than 50% of the native glycosides can be cleaved into fragments. The two cleavage peptides 1 to 15 and 16 to 29 released are deficient in glycosidic-like biological activity and thus constitute a limitation on the aqueous pre-mixing of glucosamine and its related analogs. Replacing the Asp of position 15 of the native glucagon peptide with Glu selective chemistry has been observed to actually eliminate the chemical cleavage of the 15-16 peptide bond.

Thus, it is contemplated that the Class 4 peptides of the invention may likewise be modified to reduce the likelihood of premature chemical cleavage in aqueous buffers. According to some embodiments, the native position at position 15 of the native glucosinolate peptide can be replaced by an amino acid selected from the group consisting of sulfoalanine, glutamic acid, glutamic acid, and high sulfoalanine. Aspartic acid amino acid to further modify the Class 4 peptides described herein to enhance its stability in aqueous solutions. According to some embodiments, the aspartic acid residue at position 10 of the peptide of class 4 of SEQ ID NO: 1339 can be selected from the group consisting of sulfoalanine, glutamic acid, glutamic acid, and high sulfoalanine. The group is substituted with an amino acid, and in some embodiments, the native aspartic acid at position 10 of SEq ID NO: 1339 is replaced with glutamic acid. A class 4 peptide having improved stability in an aqueous solution, wherein the antagonist comprises a sequence selected from the group consisting of SEQ ID NO: 1336, SEQ ID NO: 1340, and SEQ ID, according to some embodiments. NO: 1342. In another embodiment, the Class 4 peptide is amylated. 156004.doc -316· 201143790 According to some embodiments, position 16 (according to the number of native glycosides) may also be substituted by glutamic acid, sulfoalanine, glutamate or homosulfoalanine. Serine enhances its stability in a manner that reduces the degradation of the Class 4 peptides described herein. In a particular embodiment, the serine acid at position 16 (numbered according to the native glycosidic sequence number) is replaced with glutamic acid. In a more specific aspect, the Class 4 peptide comprising the modification comprises a C-terminal carboxylate group and is not amylated. According to some embodiments, a class 4 peptide comprising a glycopeptide peptide selected from the group consisting of SEQ ID NO: 13 07, SEQ ID NO: 1336, SEQ ID NO: 1339, SEQ ID NO: 1340 is provided. SEQ ID NO: 1341, SEQ ID NO: 1342, SEQ ID NO: 1343, and SEQ ID NO:

1344, which is further modified by substitution of one or more other amino acids at positions u, 12, 15, 16, 19 and/or 24 of the native glucagon peptide, wherein the amine groups Acid substitution involves substitution with an amino acid having a side chain suitable for crosslinking with a hydrophilic moiety, including, for example, peg. This form can be substituted with a naturally occurring amino acid or a synthetic (non-naturally occurring) amino acid. A synthetic or non-naturally occurring amino acid refers to an amino acid that does not naturally occur in vivo, but which can be incorporated into the peptide structures described herein. In some embodiments, 'providing a class 4 peptide' wherein the peptide comprises the sequence SEQ ID

NO: 1307, SEQ ID NO: 1336, SEQ ID NO: 1339, SEQ ID NO: 1340, SEQ ID NO: 1341, SEQ ID NO: 1342, SEQ ID NO: 1343, and SEQ ID NO 1·1344, and further comprising A polyethylene glycol chain that binds to the corresponding position 21 or 24 of the native glucagon peptide. In another embodiment, the C-terminus of the Class 4 peptide is modified to replace the carboxylic acid group with a guanamine group. 156004.doc -317· 201143790 Fusion peptides and conjugates The invention also contemplates a type 4 peptide fusion peptide in which the second peptide has been fused to the C-terminus of the class 4 peptide. More specifically, the fusion peptide may comprise a peptide of class 4 of SEQ ID NO: 1344, further comprising an amino acid sequence SEQ ID NO: 1319 (GPSSGAPPPS) linked to the C-terminal amino acid of the peptide of class 4, SEQ ID NO: 1320 (Lys Arg Asn Arg Asn Asn Alie Ala) or SEQ ID NO: 1321 (Lys Arg Asn Arg). In some embodiments, the amino acid sequence SEQ ID NO: 1319 (GPSSGAPPPS) binds to the amino acid 24 of the fourth class of peptide of SEQ ID NO: 1342 via a peptide bond. And SEQ ID NO: And further comprising the amino acid sequence SEQ ID NO: 1319 (GPSSGAPPPS) linked to the amino acid 24 of the class 4 peptide. And SEQ ID NO: 1339, SEQ ID A peptide of class 4343, which further comprises an amino acid sequence SEQ ID NO: 1320, SEQ ID NO: 1321 or SEQ ID NO: 1353 linked to the amino acid 24 of the class 4 peptide. In some embodiments, the Class 4 peptide fusion peptide comprises a sequence selected from the group consisting of SEQ ID NO: 1346 and SEQ ID NO 1347. In another embodiment, the C-terminus of the fusion peptide is modified to replace the carboxylic acid group with a guanamine group. In some embodiments, a Class 4 peptide fusion peptide is provided, wherein the peptide portion of the fourth peptide of the fusion peptide is selected from the group consisting of: SEQ ID NO: 156004. doc. 318. 201143790 1303, SEQ ID NO: 1304 SEQ ID NO: 1305, SEQ ID NO: 1306, SEQ ID NO: 1307, SEQ ID NO: 1308, SEQ ID NO: 1309, SEQ ID NO: 1311, SEQ ID NO: 1312, SEQ ID NO: 1313, SEQ ID NO: 1314, SEQ ID NO: 1315, SEQ ID NO: 1310, SEQ ID NO: 1316, SEQ ID NO: 1317, SEQ ID NO: 1318 and SEQ ID NO: 1339, and SEQ ID NO: 1319 fused to The carboxy terminus of the peptide moiety of class 4, and wherein the PEG chain, when present, is selected from the range of from 0 500 Daltons to 40,000 Daltons. More particularly, in some embodiments, the Class 4 peptide is selected from the group consisting of: SEQ m

NO: 1313, SEQ ID NO: 1314, SEQ ID NO: 1315, SEQ ID NO: 1316, SEQ ID NO: 1346, and SEQ ID NO: 1347, wherein the PEG chain is selected from about 500 Daltons to about 5, 〇 The range of 〇〇Dalton, and more specifically 'in some embodiments' the peg chain is about ι, 〇〇〇 Dalton. In another embodiment, the C-terminus is modified to replace the carboxylic acid group with a guanamine group. The class 4 peptide may further comprise hydrazine to two charged amine groups added to the carboxy terminus. In some embodiments, wherein 1 to 2 charged amino acids are added to the carboxy terminus of SEQ ID NO: 1344, the amino acids are negatively charged amino acids including, for example, glutamic acid and aspartame acid. And X. Group of amino acids, and wherein SEQ ID N: 1342 is optionally modified to include additional hydrazine added to the carboxy terminus to 2 negatively charged amino acids. In some embodiments, the negatively charged amino acid is a face acid or aspartic acid. 156004.doc -319- 201143790 The Class 4 peptides disclosed herein can be combined with other active agents, including, for example, insulin, to treat diseases or conditions characterized by excessive glycemic activity. In some embodiments, a Class 4 peptide that has been modified to covalently bind to a PEG chain having a molecular weight of greater than 1 〇〇〇 Dalton can be administered in conjunction with insulin to help maintain stable blood glucose levels in diabetic patients. The class 4 peptide of the present invention may be co-administered together with insulin as a single composition, administered simultaneously in the form of separate solutions, or the insulin and the class 4 peptide may be administered at different times with respect to each other. In some embodiments, the composition comprising insulin and the composition comprising the peptide of class 4 are administered within 12 hours of each other. The exact ratio of the class 4 peptide to the insulin administered will depend, in part, on the glycemic content of the patient and can be determined by routine experimentation. Dimerization The present invention also encompasses multimers of the modified Class 4 peptides disclosed herein. Two or more modified Class 4 peptides can be linked together using standard linkage agents and procedures known to those skilled in the art. For example, via the use of a bifunctional thiol crosslinker and a difunctional amine crosslinker, between two modified Class 4 peptides, especially in two (eg, in position 丨丨, 丨6 or i 9) a class 4 peptide substituted with a semi-deaminating acid, an lysine, an alanine, a homocysteine or an acetopheniric acid residue (eg, SEQ ID NO: 1309, SEQ ID NO: 1310, A dimer is formed between SEQ ID NO. 1311 and SEQ ID NO: 1312). The dimer can be a homodimer or can be a heterodimer. In some embodiments, the dimer is formed between two Class 4 peptides independently selected from the group consisting of SEQ ID NO: 1308, SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO · 1311, SEQ ID NO: 156004.doc • 320· 201143790 1312, SEQ ID NO: 1345, SEQ ID NO: 1346 or SEQ ID NO: 1347 'where the two peptides are linked to the position of each peptide via a linkage n, The linkers at position 16 of each peptide or at position 19 of each peptide or any combination thereof are linked to each other. In some embodiments, the linkage is a disulfide bond between a Cysl 1 residue and a Cysll residue' or a Cysl9 residue and a Cysl9 residue, or a Cysll residue and a Cys 19 residue of a respective Class 4 peptide. Union. Likewise, a dimer can be formed between two Class 4 peptides independently selected from the group consisting of SEQ ID NO: 1303, SEQ ID NO: 1304, SEQ ID NO: 1305, SEQ ID NO: 1306, SEQ ID NO: 1307, SEQ ID NO: 1308, SEQ ID NO: 1309, SEQ ID NO: 1310, SEQ ID NO: 1311, SEQ ID NO: 1312, SEQ ID NO: 1336, SEQ ID NO: 1337, SEQ ID NO: 1338, SEQ ID NO: 1339 and SEQ ID NO: 1342, wherein a linkage is formed between amino acid positions independently selected from positions 16, 21 and 24 relative to the native glucagon peptide. According to some embodiments, there is provided a Class 4 peptide dimer comprising two Class 4 peptides each comprising the sequence of SEQ ID NO: 1346, wherein the two antagonists are bonded to each other by a disulfide bond via an amino acid position 25 Union. In another embodiment, a Class 4 peptide dimer is provided comprising two Class 4 peptides each comprising the sequence of SEQ ID NO: 1347, wherein the two antagonists are linked to a sulfur bond via an amino acid position 35 Bond to each other. In some embodiments, the dimer is formed from a peptide of class 4 of SEQ ID NO. 1346 and a peptide of class 4 of SEQ ID NO: 1347, wherein the amino acid at position 10 is glutamic acid. In some embodiments, the dimer comprises a group selected from the group consisting of

A homodimer of a class 4 peptide fusion peptide: SEQ ID NO: 1307, SEQ ID 156004. doc-321-201143790 NO: 1308, SEQ ID NO: 1336, SEQ ID NO: 1337, SEQ ID NO: 1340 > SEQ ID NO: 1339 'SEQ ID NO: 1340' SEQ ID NO: 1341, SEQ ID NO: 1342 and pharmaceutically acceptable salts of the Class 4 peptides. According to some embodiments, a dimer comprising a first class 4 peptide that binds to a second class 4 peptide via a linker, wherein the first peptide and the second peptide of the dimer are independently selected from the group consisting of SEQ ID NO: 1308 'SEQ ID NO: 1336 ' SEQ ID NO: 1337, SEQ ID NO: 1339, SEQ ID NO: 1340, SEQ ID NO: 1341, and SEQ ID NO: 1342, and a pharmaceutically acceptable salt of the above-described glycosidic polypeptide. In another embodiment, the first class 4 peptide and the second class 4 peptide of the dimer are independently selected from the group consisting of SEQ ID NO: 1307, SEQ ID NO: 1308, SEQ ID NO: 1336, and SEQ ID NO: 1339 The group consisting of. In another embodiment, the dimer comprises a homodimer of a Class 4 peptide selected from the group consisting of SEQ ID NO: 1323, SEQ ID NO: 1324 ' SEQ ID NO: 1325 ' SEQ ID NO : 1326 > SEQ ID NO: 1327, SEQ ID NO: 1328, SEQ ID NO: 1329, SEQ ID NO: 1330, SEQ ID NO: 1331. In another embodiment, a Class 4 peptide dimer is provided, wherein the first peptide and the second peptide of the dimer comprise an amino acid sequence independently selected from the group consisting of SEQ ID NO: 1323, SEQ ID NO: 1324, SEQ ID NO: 1325, SEQ ID NO: 1326, SEQ ID NO: 1327, and SEQ ID NO: 1328. In another embodiment, the dimer comprises a homodimer of a class 4 peptide selected from the group consisting of: SEQ ID NO: 1309, SEQ ID NO: 1311, and SEQ ID NO: 156004.doc • 322 · 201143790 312 wherein the *Hail further comprises a polyethylene glycol chain covalently bound to the glycoside-like position 11 or 19. The fourth type of ghrelin-related peptide may comprise any one of the amino acid sequence SEQ ID N: 13〇1_1371, which optionally has up to 1, 2, 3, 4 or 5 retained glycosidic antagonist activity Other modifications. Class 5 Glycosin-Related Peptides In certain embodiments, the glycosidin-related peptide is a Category 5 ghlylin-related peptide (see, for example, International (PCT) Patent Application Publication No. w〇2〇〇9/〇58734 The letter 'is incorporated herein by reference in its entirety. the following. All of the biological sequences mentioned in the quinones (SEQ ID NO: 1518) correspond to SEQ ID NO: 1·ι 8 in International Patent Application Publication No. 2〇〇9/〇58734. ~ Activity In some aspects, a Category 5 ghlylin-related peptide (hereinafter referred to as "Category 5 peptide") may be a glycoside antagonist/GUM agonist. The glucoside inhibitor/φ GUM agonist is used in any context where it is desirable to inhibit glycosidic agonism while also stimulating GUM activity. For example, glycoside antagonist activity, along with GUM stimulation, can be used to treat diabetes, where glycoside antagonism has been shown to reduce glycogen in preclinical models of hyperglycemia, and GUM activity is associated with geranium production. . Compounds which exhibit GLIM activity are also known to be useful in the treatment of obesity and in preventing weight gain. In some aspects, the class 5 peptide is suitable for any of the uses previously described for other (tetra) antagonist/GUM agonists. These two activities have been shown separately for the treatment of metabolic syndrome, especially for the treatment of diabetes and obesity, which is required for 156004.doc -323 - 201143790 degrees. The glycemic antagonist activity is suitable for use in any context where it is desired to inhibit glycosidic agonism. The presence of GLP-1 agonism further inhibits the endogenous secretion of glycoside from the pancreas while stimulating insulin synthesis and secretion. These two pharmacological effects are used in a synergistic manner to normalize metabolic abnormalities. Class 5 peptides are therefore useful in the treatment of hyperglycemia or in the treatment of other metabolic diseases caused by hyperglycemia blood levels or high blood sugar levels. A patient treated with a glycoside inhibitor/GLP-1 agonist (such as a class 5 peptide disclosed herein) is a domesticated animal, and in another embodiment, the patient being treated is a human. . Studies have shown that the lack of glycosidic inhibition in diabetic patients is accelerated in part by postprandial hyperglycemia. During the oral glucose tolerance test (〇GTT), and in the presence or absence of somatostatin-induced glycosidin inhibition, T analysis of blood glucose has shown a significant increase in sugar in individuals with higher glycemic content. Thus, a glycoside antagonist/GUM agonist or a fifth type described herein can be used to treat hyperglycemia and is expected to be useful in the treatment of various types of insulin-dependent or non-insulin-dependent diabetes, including (iv) Diabetes, first-grade diabetes, or genital diabetes, and alleviate complications of diabetes, including kidney disease, retinopathy, and vascular disease. These methods for suppressing appetite or promoting weight loss are expected to be suitable for weight loss, weight loss, or treatment. Obesity caused by various causes, including drug-induced obesity, and alleviation of obesity-related complications, including vascular disease (coronary artery disease, stroke, peripheral vascular disease, ischemia-reperfusion, etc.), high gold pressure, The first type of diabetes onset, hyperlipidemia, and musculoskeletal disorders 156004.doc -324- 201143790 can be formulated and administered to patients using standard pharmaceutically acceptable carriers and routes of administration known to those skilled in the art. A pharmaceutical composition comprising a Class 5 peptide is administered. Accordingly, the present invention also encompasses a pharmaceutical composition comprising one of the disclosures disclosed herein a plurality of Class 5 peptides and a pharmaceutically acceptable carrier. The pharmaceutical compositions may comprise a Class 5 peptide as a separate pharmaceutically active ingredient, or a Class 5 peptide may be combined with one or more other active agents. By way of example, a composition comprising a class 5 peptide and an insulin or insulin analog. Or a composition for inducing weight loss or preventing weight gain comprising: the sequence of SEQ ID NO: 1415 or SEQ is provided. ID NO: 1451 'This sequence further comprises the amino acid sequence SEQ ID NO: 1421 (GPSSGAPPPS) or SEQ ID NO: 1450 linked to SEQ ID. NO: 141 5 or amino acid 24 of SEQ ID NO: 1451; And anti-obesity. Suitable anti-obesity peptides include those disclosed in U.S. Patent Nos. 5,691,309, 6, 436, 435, or U.S. Patent Application No. 20050176643. Class 5 Peptide Structures According to some embodiments, a Class 5 peptide is provided, The following modified glycosidic peptide: the first i to 5 amino acid residues (eg, the first amino acid, the first two amino acids, the first three amino acids, the first four amino acids, The first 5 amino acids are deleted from the N-terminus, and for example by The side chains of amino acids from positions 12 and 16, 16 and 20, 20 and 24' and 24 and 28 (relative to the native glucagon peptide sequence) are via hydrogen bonding or ionic interactions (such as the formation of a salt bridge) Or stabilizing the alpha helix structure in the terminal portion of the compound (approximately amino acid sites 12 to 29, according to the amino acid number of wild-type glycoside SEQ ID NO: 1401) by covalent bonding to each other. Stabilizing the alpha helix substantially at residues 12 to 29 by introducing one or more alpha, alpha disubstituted amino acids at a position that retains the desired activity 156004.doc -325 - 201143790. In some embodiments Wherein the position of the class 5 peptide or analog thereof is 16, 17, 18, 19, 20, 21, 24 or 29 (based on the amino acid number of the wild type glucosinolate), both, and three Four or more are substituted with an α,α disubstituted amino acid. For example, substitution of amino acid isobutyric acid (Aib) for position 5 of a class 5 peptide or analog thereof (numbered according to the amino acid of wild type glucosinolate) may be provided in the absence of a salt bridge or indoleamine Stabilized alpha helix. In some embodiments, one, two, three or more of the positions 丨6, 2〇, 21 or 24 (based on the amino acid number of wild-type glucosinolate) are substituted with Aib. According to some embodiments, a class 5 peptide is provided, wherein the peptide exhibits at least 80% of the greatest agonistic effect achieved by the native GLP-1 on the GLP-1 receptor and exhibits glycosidic antagonist activity, as in The in vitro assay is measured by the amount of cAMP production that reduces the maximum cAMP production induced by the glycoside receptor to the glycemic receptor by at least about 50% ^ in some embodiments, the fifth The activity exhibited by the peptoid to the GLP-1 receptor is at least 90% of the activity of native GLP-1, and it exhibits a glycosidic antagonist activity that causes the glycemic glycoside to be subjected to glycoside The maximum cAMP production induced by the body is reduced by at least about 80%. According to some embodiments, the Class 5 peptide comprises the derivative peptide of SEQ ID NO: 1402 wherein the peptide is selected from positions 1, 2, 4, 5, 6, 7, 8, 9, 10 relative to SEQ ID NO: 1402 1, 10, 12, 13, 14, 15, 16, 19, 22, and 24 1 to 3 amino acid positions contain other amino acid substitutions, and their activity on the GLP-1 receptor is native GLP At least 156004.doc • 326· 201143790 90% of the activity of -1, and it exhibits glycosidic antagonist activity, the maximum cAMp production induced by the glycemic receptor to the glycemic receptor Reduce by at least about 80%. In some embodiments, 'substituting and/or inserting, for example, by forming a covalent or non-covalent intramolecular bridge, or by stabilizing an amino acid (eg, an alpha, alpha disubstituted amino acid) with an alpha spiro The amino acid at positions 12 to 29 stabilizes the alpha helix structure of the C-terminal portion of the fifth type (approximately amino acid 12 to 29 'based according to the amino acid of wild-type glycoside). In some embodiments, one of the positions 16, 17, 18, 19, 20, 21, 24, or 29 (based on the amino acid of wild-type glycemic acid) of the Class 5 peptide or analog thereof, two The three, four or more are substituted with an α,α disubstituted amino acid such as aminoisobutyric acid (Aib). For example, the substitution of amino acid isobutyric acid (Aib) for position 5 of a class 5 peptide or analog thereof (based on the amino acid number of wild type glucosinolate) can be provided in the absence of a salt bridge or an indoleamine. Stabilized alpha helix. In some embodiments, the Class 5 peptide comprises SEQ ID NO: 141 5 or SEQ ID NO: 1451, and more specifically, comprises a sequence selected from the group consisting of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, SEQ ID NO: 1408, SEQ ID NO: 1409, SEQ ID NO: 1416, SEQ ID NO: 1417, SEQ ID NO: 1418, SEQ ID NO: 1419, SEQ ID NO: 1422, SEQ ID NO: 1423, SEQ ID NO: 1424 and SEQ ID NO: 1425. In other embodiments, the fifth type comprises a derivative peptide of SEQ ID NO: 1415 or SEQ ID NO: 1451, wherein the peptide is selected from positions 1, 2 relative to SEQ ID NO: 1415 or SEQ ID NO: 1451 5, 6, 8, 9, 12, 13 and 14 1 to 3 amino acid positions -327-156004.doc 201143790 Contains other amino acid substitutions. In some embodiments, the substitutions at positions 1, 2, 5, 6, 8, 9, 12, 13 and 14 are conservative amino acid substitutions. In some embodiments, the threonine at position 24 of SEQ ID NO: 1405 or SEQ ID NO: 1406 is substituted with glycine. According to some embodiments, the Class 5 peptide represents an additional modification to the peptide wherein, except for the N-terminal deletion, the amphetamine at position 6 of the native glucagon peptide is modified, for example, to include a trans-substituent that replaces the N-terminal amine group. In another embodiment, the natural tetamine of the c-terminal amino acid is replaced by a charge-neutral group such as a guanamine or ester. According to some embodiments, a type 5 peptide has been prepared in which 3 to 5 amino acids have been deleted before the native glucagon, and the amino acid at position 9 relative to the native glucagon peptide has been selected from the following Group of amino acid substitutions: a face acid, a high face acid, a β-high face acid, a cyclic acid derivative of cysteine, or an alkyl carboxylate derivative of cysteine having the following structure :

Χ5\COOH, where X5 is a C1-C4 alkyl group, a C2-C4 dilute group or a C2-C4 alkynyl group, and the C-terminal portion of the glycoside (approximately amino acid 12 to 29' is based on the amine of the wild type glycoside The alpha helix structure in the base acid numbering) forms, for example, via an internal amine linkage between the side chains of the amino acids 12 and 16 relative to the native glycemic peptide or the side chains of the amino acids 16 and 20. Stabilized. Examples of amino acid pairings capable of covalently bonding to form a bond bridge having 7 atoms 156004.doc - 328 - 201143790 are described in detail herein. In some embodiments, the sulfamic acid derivative of cysteine is sulfoalanine or homo-alanine. In some embodiments, a Class 5 peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, or SEQ ID NO: 1408 is provided. Wherein, for SEQ ID NO: 1405, the peptide comprises a indoleamine ring formed between the side chains of amino acids 7 and 11; for SEQ ID NO: 1406, the peptide comprises an amino acid formed a mesalamine ring between the side chains of 11 and 15; for SEQ ID NO: 1407, the peptide comprises an indoleamine ring formed between the amino acid side chains at positions 15 and 19; SEQ ID NO: 1408 'The peptide comprises an intrinsic amine ring formed between the amino acid side chains at positions 19 and 24, each of which is further modified to comprise hydrophilicity covalently bound to the peptide section. More specifically, in some embodiments, each of the Class 5 peptides having an indoleamine is modified by covalent attachment of a polyethylene glycol chain. For example, for a peptide of class 5 comprising SEQ ID NO: 1405, the peptide is PEGylated at a position selected from the group consisting of 12, 15, 16, 19 and 24; for inclusion of SEQ ID NO : In the case of a peptide of class 5406, the peptide is pegylated at a position selected from the group consisting of 12, 16, 19 and 24; for a peptide of the fifth type comprising SEQ ID NO: 1407, The peptide is PEGylated at a position selected from the group consisting of 11, 12, 16 and 24; for a peptide of the fifth type comprising SEQ ID NO: 1408, the peptide is selected from the group consisting of 11, 12, 15 and 16 The position of the group is PEGylated. According to some embodiments, there is provided a Class 5 peptide comprising SEQ ID NO: 1447 or SEQ ID NO: 1448 156004. doc-329-201143790, wherein the peptide is selected in a sequence relative to SEQ ID NO: 1447 or SEQ ID NO: 1448 The group consisting of free radicals 12, 16, 19 and 24 is PEGylated. In another embodiment, the peptide of SEQ ID NO: 1447 or SEQ ID NO: 1448 is further modified by adding the sequence SEQ ID NO: 1421 to the tickend of the peptide. As detailed above, in certain aspects, a Class 5 peptide is provided in which the five amino acids prior to the native glucagon have been deleted and the amine group of the N-terminal amino acid (phenylalanine) has been replaced by a hydroxyl group ( That is, the first amino acid is phenyl-lactic acid, and is selected from the group consisting of positions 12 and 16, 16 and 20, 20 and 24, and 24 and 28 of one or more amino acid pairs. Together, the class 5 peptide alpha helix is stabilized. According to some embodiments, there is provided a Class 5 peptide comprising the sequence of SEQ ID NO: 1402 'by substituting a position 11 of SEQ ID NO. 1402 with an amino acid selected from the group consisting of: The amino acid number of the glycoside, modified for the serine residue at position 16): glutamic acid, glutamic acid, tromethionine, high sulfoalanine, threonine or glycine . According to some embodiments, the serine residue at position 11 of SEQ ID NO: 1402 is substituted with an amino acid selected from the group consisting of glutamic acid, glutamic acid, glutamic acid, and high sulfoalanine. And in some embodiments, the serine residue is substituted with glutamic acid. According to some embodiments, the Class 5 peptide comprises the sequence SEQ ID NO: 1438. In some embodiments, a Class 5 peptide is provided wherein an intramolecular bridge is formed between the two amino acid side chains to stabilize the three dimensional structure of the carboxy terminus of the peptide of SEQ ID NO: 1402. More specifically, SEQ ID NO: 1402 156004.doc • 330· 201143790 a side chain selected from the group consisting of amino acid pairs 7 and 11, 11 and 15, 15 and 19 or 19 and 23 one or more amino acids Bonding to each other stabilizes the alpha helix in the C-terminal portion. The two side chains can be bonded to each other via hydrogen bonding, ionic interactions (such as forming a salt bridge), or by covalent bonds. According to some embodiments, the linker is 7 to 9 atoms in size, and in some embodiments, the linker is 8 atoms in size. In some embodiments, the Class 5 peptide is selected from the group consisting of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, and SEQ ID NO: 1408. In some embodiments, the c-terminal amino acid of the Class 5 peptide has a substituted amine group that replaces the tick-acid group present on the native amino acid. According to some embodiments, a Class 5 peptide is provided, wherein the analog comprises the amino acid sequence SEQ ID NO: 14〇9. In some embodiments, the three-dimensional structure of the carboxy terminus of the peptide of SEQ ID NO: 1409 is stabilized by the formation of a covalent bond between the side bonds of the peptide. In some embodiments, the two amino acid side chains combine to form an indoleamine ring. The size of the indoleamine ring may vary depending on the length of the amino acid side chain. In some embodiments, the indoleamine is separated. The side chain of the amino acid amino acid is bonded to the glutamic acid side chain. In some embodiments, the C-terminal amino acid of the Class 5 peptide has an amine-based group that replaces the tick-acid group present on the native amino acid. The order of the amine bond in the endo-amine can be reversed (for example, the internal amine ring can be formed between the Lysl2 side chain and the Glul6 side chain or between the Glul2 side chain and the Lysl6 side chain). According to some embodiments, a glycosidin analog of SEQ ID NO: 1409 is provided wherein at least one intrinsic amine ring is formed in SEQ ID NO: 1409 selected from the group consisting of amino acid pairs 7 and 11, 11 and 15, 15 and 19 Or 19 and 23 156004.doc -331 - 201143790 The group consisting of amino acids between the side chains. In some embodiments, a Class 5 peptide is provided, wherein the peptide comprises the sequence of SEQ ID NO: 1410, the sequence further comprising between amino acids 7 and 11 formed at SEQ ID NO: 1410 ' or an amino acid Intramolecular guanamine bridge between positions 11 and 15, or between amino acid positions 15 and 19. In some embodiments, a Class 5 peptide is provided, wherein the peptide comprises the sequence of SEQ ID NO: 1411, the sequence further comprising between amino acids 7 and 11 formed at SEQ ID NO: 1411, or an amino acid Intramolecular intracellular amine bridge between positions 11 and 15. In some embodiments, the Class 5 peptide comprises the sequence of SEQ ID NO: 1417. An additional class 5 peptide comprising a derivative of SEQ ID NO: 1405, wherein the aspartic acid on site 1 SEQ ID NO: 1405 (position 15 of the native glucagon) has glutamic acid, has the following Amino acid substitution of the general structure:

So3-wherein X6 is a C1-C3 alkyl group, a C2-C3 olefin or a C2-C3 alkynyl group, and in some embodiments 'X6 is a C1-C3 alkyl group, and in another embodiment, χ6 is a C2 alkyl group . In some embodiments, a peptide derivative of SEQ ID NO: 1409, wherein position 10 of SEQ ID NO: 1409 (position 15 of the native glucagon) is selected from the group consisting of glutamic acid, sulfoalanine, Amino acid substitution of a group consisting of high sulfoalanine and high glutamic acid. In another embodiment, position 10 of SEQ ID NO: 1409 is substituted with an amino acid selected from the group consisting of sulfoalanine or high sulfoalanine. In some embodiments, a peptide of SEQ ID NO: 1406, SEQ ID NO: 1407, or SEQ ID NO: 1408 is provided as a peptide of 156004.doc-332-201143790, wherein SEQ ID NO: 1406, SEQ ID NO: Position 1407 or SEQ ID NO: 1408 is substituted with an amino acid selected from the group consisting of glutamic acid, sulfoalanine, high sulfoalanine, and high face acid. In some embodiments, the C-terminal amino acid of the Class 5 peptide has a guanamine group substituted for the carboxylic acid group present on the native amino acid. In some embodiments, the amino acid of the fifth class of peptides is substituted with at least one cysteine residue, wherein the side chain of the cysteine residue is subjected to a thiol-reactive test agent (including, for example, maleic acid) The diquinone imine group, the vinyl anthracene, the 2-pyridylthio group, the haloalkyl group and the dentate group are further modified. These thiol reactive reagents may contain a suspending group, a keto group, a hydroxyl group and an ether group as well as other hydrophilic moieties such as polyethylene glycol units. In an alternate embodiment, the amino acid of the fifth class of peptides is substituted with an amine acid and uses an amine reactive reagent such as an active ester of a carboxylic acid (butyl iodide, anhydride, etc.) or a hydrophilic moiety ( An aldehyde such as polyethylene glycol) further modifies the side chain of the substituted lysine residue. According to some embodiments, the lytic acid residue corresponding to position 7 of the peptide of SEQ ID NO: 1405 is substituted with arginine φ, and for positions 12, 15, 16, 19 and 24 corresponding to SEQ ID NO: 1405 One of the amino acids is inserted into a single amine acid substitution. In another embodiment, the methionine residue corresponding to position 22 of the Class 5 peptide disclosed herein is changed to leucine or norleucine to prevent oxidative degradation of the peptide. Moreover, in some aspects, the Class 5 peptide also encompasses amino acid substitutions at positions that are not known to be critical for the function of the glycoside analog. In some embodiments, the substitutions are one or two selected from the group consisting of positions 2, 5, 6, 7, 8, 9, Η, U, 14, 15, 16, 19, 22, 23, or 24. 156004.doc • 333 - 201143790 or two positions of the insulgent amino acid substituted β. In some embodiments, the amino acid corresponding to the native glycosidic position 16, 17, 20, 21, 24 or 29, And more particularly with respect to the amino acid at position 21 and/or 24 of the native glycein substituted with cysteine or lysine, wherein the PEG bond is covalently attached to the substituted cysteine or lysine residue base. According to some embodiments, a class 5 peptide comprising a sequence consisting of SEQ ID NO: 1409 is provided by position corresponding to positions 12, 12, 15, 16, 19 and/or 24 of the peptide. Further modified by one or more other amino acid substitutions, including, for example, by cysteine substitution, wherein the amino acid substitution comprises an amine having a side bond suitable for crosslinking with a hydrophilic moiety, including, for example, PEG Base acid. The native glucagon can be substituted with a naturally occurring amino acid or a synthetic (non-naturally occurring) amino acid. A synthetic or non-naturally occurring amino acid refers to an amino acid that is not naturally occurring in vivo, but which may be incorporated into the peptide structures described herein. In some embodiments, a Class 5 peptide is provided, wherein the peptide comprises the sequence of SEQ ID NO: 1409 and further comprises a polyethylene glycol chain that binds to position 16 or 19 of the peptide. In another embodiment, the C-terminus of the glycoside analog is modified to replace the carboxylic acid group with a guanamine group. According to some embodiments, a Class 5 peptide is provided comprising a glycoside analog selected from the group consisting of:

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Lys-Tyr-Leu-Xaa-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Xaa-Asn-Thr- R2 (SEQ ID NO: 1439);

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-

Arg-Ala-Gln-Xaa-Phe-Val-Gln-Trp-Leu-Xaa-Asn-Thr-R2 156004.doc -334- 201143790 (SEQ ID NO: 1413);

Ri-Phe-Thr-Ser-Xaa-Tyr-Ser-Lys-Tyr-Leu-Asp-Glu-Arg-Arg-Ala-Gln-Asp-Phe-Val-Xaa-Trp-Leu-Xaa-Asn-Thr- R2 (SEQ ID NO: 1414); and R i-Phe-Thr-S er-Xaa-Tyr-S er-Lys-Tyr-L eu-Asp-Glu-Arg-Arg-Ala-Gln-Xaa-Phe- Val-Xaa-Trp-Leu-Xaa-Asn-Thr-R2 (SEQ ID NO: 1412), wherein Xaa at position 4 is aspartic acid, glutamic acid, sulfoalanine or homodiazepine alanine, Xaa at position 10 is Asp, Glu, resveryl alanine, high glutamic acid and high sulfoalanine, and Xaa at position 16 is Asp, Cys, Orn, homocysteine or acetaminophen, And Xaa at position 19 is Gin, Cys, Orn, homocysteine and acetyl phenylalanine, Xaa at position 22 is Met, Leu or Nle, the size is OH or NH2, and R2 is Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser (SEQ ID NO: 1421); Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Xaa (SEQ ID NO: 1450; wherein Xaa is Cys, Orn, homocysteine or acetopheniramine Acid; COOH; or CONH2, wherein the peptide is PEGylated at position 16 of SEQ ID NO: 1413 and PEGylated at position 19 of SEQ ID NO: 1414, as appropriate And in SEQ ID NO: 16 and position 1412 of the pegylated 19. In some embodiments, Thr at position 24 of SEQ ID NOs: 1412-1414 and 1439 is replaced by Gly. According to some embodiments, the peptide comprises the sequence SEQ ID NO: 13 or SEQ ID NO: 1414, wherein I is OH. According to some embodiments, the peptide comprises the sequence SEQ ID NO: 1413 or 8 ugly 10 1^0: 1414, wherein the ruler 1 is (^ and the ruler 2 is (: 01 ^ out. Root 156004.doc - 335 - 201143790 In some embodiments, the peptide comprises the sequence of SEQ ID NO: 1413 or SEQ ID NO: 1414' wherein R! is OH 'R2 is C〇NH2, and the threonine at position 24 is substituted with glycine. In some embodiments The 'type 5 peptide' is further modified to include one or more amino acids of native Glp-1 by substituting a native glycosidic residue at the corresponding amino acid position, for example, 'type 5 peptide One or more amino acid substitutions may be included at any of positions 2, 3, 17, 18, 21, 23, and 24 (based on the amino acid number of the native glucagon). In a particular embodiment The fifth type of peptide is modified by one or more of the following amino acid substitutions. Ser2 is replaced by Ala, Gln3 is replaced by Glu 'Argl7 is replaced by Gin, and Arg at position 18 is replaced by Ala'. By Glu substitution, Val at position 23 is replaced by lie' and Gin at position 24 is replaced by Ala (amino acid position is based on the native glycosidic sequence). In a case, the class 5 peptide is modified by replacing Ser2 with Ala and replacing Gln3 with Glu (numbering the amino acid according to the native glycosidic acid). In another specific embodiment, the class 5 peptide is composed of the following Modification by amino acid substitution: Argl 7 is replaced by Gin, Arg at position 18 is replaced by Ala's Asp at position 21 by Glu, Val at position 23 is replaced by lie, and Gln at position 24 is replaced by AU ( According to the amino acid of the native glucosin number.) In another specific embodiment, the class 5 peptide is modified to comprise Glu only at position 21 (numbering according to SEQ ID NO: 1401). Thus 'Category 5 The peptide may comprise any of the amino acid sequences 8]^1〇\〇: 1460-1470, 1473-1478, 1480-1488, 1490-1496, 1503, 1504, 1506 and 1514-1518. a class 5 peptide or a combination thereof comprising (丨) via the means described in 156004.doc-336-201143790 (for example via an intramolecular bridge or incorporation of one or more alpha, alpha disubstituted amino acids' Or in the position 16 (in accordance with the numbering of SEQ ID ΝΟ: 1401) to incorporate an acidic amino acid, or a combination thereof, stabilized & (2) a C-terminal amide or ester substituted with a c-terminal citric acid, and a general structure a_B-C, wherein the lanthanide is selected from the group consisting of: (i) phenyl lactic acid (PLA); (ii) An oxy derivative of PLA; and (iii) a peptide having 2 to 6 amino acids wherein the two consecutive amino acids of the peptide are linked via an ester bond or an ether bond; wherein B represents SEQ ID NO: 1401 Amino acids p to 26, wherein p is 3, 4, 5, 6 or 7, and B optionally comprises one or more amino acid modifications as described herein, including, for example, any modifications described for the class 5 peptide . For example, one or more modifications may be selected from the group consisting of: (iv) Asp at position 9 (based on the amino acid number of SEQ ID NO: 1401), a sulfonic acid derivative of Glu, Cys, high bran Substituted by an amine acid, β-high glutamic acid, or an alkyl carboxylate derivative of cysteine having the following structure:

H2C\x5 \ COOH, wherein X5 is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl; (v) positions 10, 20 and 24 (based on the amino acid numbering of SEQ ID NO: 1401) One or two amino acids are substituted by an amino acid covalently bonded to a mercapto or alkyl group via an ester bond, an ether bond, a thioether bond, an oxime 156004.doc-337-201143790 amine bond or an alkylamine bond; Vi) one of the positions 16, 17, 20, 21 and 24 (based on the amino acid number of SEQ ID NO: 1401) or two amino acids substituted with an amino acid selected from the group consisting of Cys, Lys , alanine, homocysteine, and ethionyl-Acetylamine (Ac-Phe)' wherein the amino acid in the group is covalently linked to the hydrophilic moiety; (vii) position 15 (according to SEQ ID NO: No. 1401 is substituted with sulfoalanine, glutamic acid, glutamic acid and high sulfoalanine; (viii) Ser at position 16 (number according to SEQ ID NO: 1401) Substituting sulfoalanine, glutamic acid, glutamic acid and high sulfoalanine; (ix) Arg at position 17 is replaced by Gin, Arg at position 18 is replaced by Ala, and Asp at position 21 is replaced by Glu , Val on position 23 Replaced by lie, and Gin at position 24 is replaced by Ala (according to the amino acid number of SEQ ID NO: 1401); (X) Ser at position 16 is replaced by Glu, Gin at position 20 is replaced by Glu, or position Gin on 24 is replaced by Glu (based on the amino acid number of SEQ ID NO: 1401); wherein the C line (of the general structure ABC) is selected from the group consisting of: (vii) X; (viii) XY; (ix (x) XYZ-R10; wherein X is Met, Leu or Nle; Y is Asn or a charged amino acid; z is Thr, Gly, Cys, Lys, ornithine (Orn), High cysteine, acetamyl 156004.doc - 338 - 201143790 phenylalanine (Ac-Phe) or a charged amino acid; wherein R10 is selected from the group consisting of SEQ ID NOS: 1421, 1426, 1427 and 1450. In a particular aspect, the peptide comprises an oxy derivative of PLA. As used herein, "oxyl derivative of PLA" refers to a compound comprising a modified PLA structure in which the hydroxyl group has been replaced by O-Rn, wherein Rn is a chemical moiety. In this regard, the oxy derivative of PLA may be, for example, a pendant of PLA or an ether of PLA. Methods of preparing oxy derivatives of PLA are known in the art. For example, when the oxy derivative is an ester of PLA, the ester can be formed by reacting a hydroxyl group of PLA with a nucleophile having a carbonyl group. The nucleophile can be any suitable nucleophile including, but not limited to, an amine or a hydroxyl group. Therefore, the ester of PLA may comprise the structure of formula IV: 0

Wherein R7 is formed when a hydroxyl group of PLA is reacted with a nucleophile having a carbonyl group. A nucleophile having a carbonyl group which reacts with a hydroxyl group of PLA to form an ester may be, for example, a carboxylic acid, a carboxylic acid derivative, or an activated ester of a carboxylic acid. The carboxylic acid derivative can be, but is not limited to, a mercapto vapor, an anhydride, a guanamine, an ester or a nitrile. The activated ester of the carboxylic acid may be, for example, N-hydroxybutylimine (NHS), tosylate 156004.doc-339-201143790 (Tos), carbodiimide or hexafluorophosphate. In some embodiments, the carbodiimide is 1,3·dicyclohexylcarbodiimide (Dcc), 1,1'-carbonyl dipmi beta (CDI), 1-ethyl-3-(3) -Dimethylaminopropyl)carbodiimide hydrochloride (EDC) or 1,3-diisopropylcarbodiimide (DICD). In some embodiments, the hexafluorophosphate salt is selected from the group consisting of benzotriazol hexafluoro-yl-oxy-parade (dimethylamino) squama (BOP), benzohexafluorophosphate Triazole-1-yl-oxytripyrrolidinyl scale (PyBOP), 2-(1Η-7-azabenzotriazol-1-yl)-1,1,3,3-tetradecyl hexafluorophosphate Based on (HATU) and bismuth hexafluorophosphate-benzotriazole-oxime, hydrazine, hydrazine, hydrazine--tetramethyl-hydrazine (HBTU). Methods for producing ethers by reaction with a hydroxyl group (e.g., a hydroxyl group of PLA) are also known in the art. For example, the hydroxyl group of the PLA can be reacted with a halogenated or anthraquinone acid to form an ether linkage. In a particular embodiment, the chemical moiety bonded to the PLA via an oxygen-containing bond (eg, via an ester bond or an ether bond) is a polymer (eg, a polyalkylene glycol), a carbohydrate, an amino acid, a peptide, or a lipid, for example, Fatty acids or steroids. In a particular embodiment, the chemical moiety is an amino acid, which is optionally part of a peptide such that Formula IV is a depsipeptide. In this regard, the PLA may be at a position other than the amino acid residue of the peptide, so that the peptide contains one or more (for example, 1, 2, 3) between the ν end and the PL Α residue. , 4, 5, 6 or more) amino acids. For example, the peptide may comprise PLA at position η of the peptide, wherein n is 2, 3, 4, 5 or 6. The amino acid between the terminal and the PLA residue may be a synthetic or naturally occurring amino acid. In a particular embodiment, the amino acid between the terminal and the PLA is the naturally occurring amino acid. In some embodiments, the amine between the terminal and the PLA 156004.doc • 340- 201143790 base acid is the N-terminal amino acid of the native glycein. For example, the peptide may comprise on the N-terminus any of the amino acid sequence SEQ ID NO: 1452-1456, wherein the PLA is linked to the threonine via an ester linkage: SEQ ID NO: 1452 His-Ser- Gln-Gly-Thr-PLA SEQ ID NO: 1453 Ser-Gln-Gly-Thr-PLA SEQ ID NO: 1454 Gln-Gly-Thr-PLA SEQ ID NO: 1455 Gly-Thr-PLA SEQ ID NO: 1456 Thr- PLA. In an alternate embodiment, one or more N-terminal amino acids may be substituted with an amino acid other than the amino acid of the native glycosidic acid. For example, when the peptide comprises PLA as the amino acid at position 5 or 6, the amino acid at position 1 and/or position 2 can be an amine group which reduces the likelihood of dipeptidyl peptidase IV causing cleavage. acid. More specifically, in some embodiments, position 1 of the peptide is an amino acid selected from the group consisting of D-histamine, alpha, alpha-dimercaptoimidazoleacetic acid (DMIA), guanidine-A Histamine, α-mercapto histidine, imidazoleacetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histamine and homo-histamine. More specifically, in some embodiments, position 2 of the antagonist/agonist peptide is an amino acid selected from the group consisting of D-serine, D-alanine, proline, glycine Acid, Ν-methyl serine, Ν-methyl alanine and aminoisobutyric acid (Aib). Also, for example, when the peptide comprises PLA as the amino acid at position 4, 5 or 6, the amino acid at position 3 of the peptide may be glutamic acid rather than the native branamine of the native glycein. Acid residue. In an exemplary embodiment of the invention, the peptide comprises an amino acid sequence of any one of SEQ ID NO: 1457-1459 at the N-terminus. 156004.doc • 341 · 201143790 For a peptide containing a compound of the formula ιν, the polymer may be any polymer, and the restriction is that it can react with the hydroxyl group of the PLA. The polymer may be a polymer that naturally or generally comprises a nucleophile having a carbonyl group. Alternatively, the polymer can be a polymer that has been derivatized to include a nucleophile having a carbonyl group. The polymer may be a derivatized polymer of any of the following: polyamine; polycarbonate; polyalkylene and its derivatives, including polyalkylene glycol, polyoxyalkylene, poly(terephthalic acid) Vinegar; polymers of acetoacetate and methyl acrylate vinegar, including poly(methyl methacrylate), poly(ethyl methacrylate), poly(methacrylic acid butyl vinegar), poly (曱Isobutyl acrylate), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl acrylate), poly(methyl acrylate) ), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (octadecyl acrylate); polyethylene polymer, including polyethyl alcohol, polyethylene shout, polyethylene acetate, polyhalogenated B晞, poly(vinyl acetate vinegar) and polyvinylpyrrolidone; polyglycolide; polyoxyalkylene; polyamino carboxylic acid vinegar and copolymer thereof; cellulose 'including alkyl cellulose, hydroxyalkyl cellulose , cellulose ether, cellulose ester, nitrocellulose, mercapto cellulose, ethyl cellulose, hydroxypropyl Cellulose, hydroxy-propyl fluorenyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxyethyl cellulose, triacetate fiber And sodium cellulose sulfate; polypropylene; polyethylene, including poly(ethylene glycol), poly(ethylene oxide) and poly(ethylene terephthalate); and polystyrene. The polymer may be a biodegradable polymer, including synthetic biodegradable polymers (eg, polymers of lactic acid and glycolic acid, polyanhydrides, poly(orthoacid) esters, polyurethanes, poly(butyric acid), Poly(pentanoic acid) and poly(lactide-co-156064.doc •342·201143790 s)), and natural biodegradable polymers (such as alginate and other polysaccharides) including polydextrose and cellulose , collagen, its chemical derivatives (chemical group (eg alkyl, alkyl) substitution, addition, hydroxylation, oxidation and other modified albumin and other hydrophilic proteins routinely performed by those skilled in the art (eg zein and other prolamin and hydrophobic proteins), and any copolymers or mixtures thereof, as such, by enzymatic hydrolysis or exposure to water in vivo, by surface or overall The polymer can be a bioadhesive polymer such as the bioerodible hydrogel described by s Sawhney, c. P' Pathak and J. a. Hubbell, Macromolecules, 1993, 26, 581-587. , the The teachings of the test literature are incorporated into polychlorouric acid, casein, gelatin, gelatin protein, polyanhydride, polyacrylic acid, alginate, polyglucamine, poly(decyl methacrylate), poly(ethyl methacrylate). ), poly(butyl methacrylate), poly(isobutyl methacrylate), poly(hexyl methacrylate), poly(methacrylic acid isodecyl methacrylate), poly(lauryl methacrylate) , poly(methacrylic acid phenyl vinegar), poly (methyl acrylate), poly (isopropyl acrylate), poly (isobutyl acrylate) and poly (propionate octadecyl ketone). In some embodiments The polymer is a water soluble polymer. Suitable water soluble polymers are known in the art and include, for example, polyvinylpyrrolidone, propylcellulose (HPC; Klucel), propylmethyl Cellulose (HPMC; Methocel), nitrocellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, hydroxypropylpentylcellulose, methylcellulose, ethylcellulose (Ethocel), Hydroxyethyl cellulose, various alkyl celluloses and burned 156004.doc - 343- 201143790 base cellulose, various cellulose oximes, cellulose acetate, buffered cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, vinyl acetate/butenoic acid copolymer, poly-methyl Acrylic acid ester, methyl methacrylate via methyl ester, methacrylic acid copolymer, polymethacrylic acid, polymethyl methacrylate, cis-succinic anhydride / methyl vinyl ether copolymer, polyethylene Alcohol 'polyacrylic acid sodium and polyacrylic acid mother, polyacrylic acid, acidic carboxyl polymer, carboxypolymethylene, carboxyvinyl polymer, polyoxyethylene polyoxypropylene copolymer, polymethyl vinyl ether co-cis. Adipic anhydride, carboxyformamide, methyl propylene diacetate copolymer, polyoxyethylene glycol, polyethylene oxide, and its derivatives, salts and combinations. In a particular embodiment, the polymer is a polyalkylene glycol, including, for example, polyethylene glycol (PEG). The carbohydrate may be any carbohydrate, with the proviso that it comprises or is prepared to comprise a carbonyl group having an alpha leaving group. The carbohydrate may, for example, be a carbohydrate that is derivatized to comprise a carbonyl group having an alpha leaving group. In this regard, carbohydrates can be in the form of derivatization of monosaccharides (eg, glucose, galactose, fructose), dienzymes (eg, sugar, lactose, malt-sugar), oligosaccharides (eg, raffinose) , stachyose), polysaccharide (starch, amylase, gelatin powder, cellulose, chitin, tannin, kelp polysaccharide, xylan, mannan, fucoidan, galactomannan). The lipid can be any lipid comprising a carbonyl group having a leaving group. Examples of lipids may be those in which witches are derivatized to contain several groups of lipids. In this regard, the lipid may be a derivative of each of the following. Fatty acid (for example, even a fatty acid, a stannic acid 'prostaglandin' leukocyte tris, a blood test, a sputum-ethanolamine), gan 156004.doc -344- 201143790 Oil lipids (eg monosubstituted, disubstituted, trisubstituted glycerol), glycerophospholipids (eg phospholipid choline, phospholipid creatinine, phospholipid oxime ethanolamine, phospholipid lysine), sphingolipids (eg nerves Sphingosine, neuroketamine), sterol lipids (eg, steroids, cholesterol), pregnenolone lipids, glycolipids or polyketides. In some embodiments, the lipid is oil, wax, cholesterol, sterol, fat-soluble vitamin, monoglyceride, diglyceride, triglyceride or lin. In some embodiments, the molecular weight of R? is about 100 kDa or less, such as about 90 kDa or less, less than about 80 kDa or less, about 70 kDa or less, about 60 kDa or less, about 60 kDa or Below 60 kDa, below 50 kDa or below 50 kDa, below 40 kDa or below 40 kDa. Thus, the molecular weight of r7 may be about 35 kDa or less, about 30 kDa or less, about 25 kDa or less, about 20 kDa or less, about 20 kDa or less, about 15 kDa or less, about 1 k. kDa or below 10 kDa, about 5 kDa or less, or about 1 kDa » In an alternative embodiment, the peptide comprising the general structure ABC comprises a peptide having from 2 to 6 amino acids as a, wherein the peptide The two consecutive amino acids of A are bonded via an ester bond or an ether bond. The ester bond or ether bond can be, for example, between the amino acids 2 and 3, 3 and 4, 4 and 5, or 5 and 6. Optionally, the peptide A can be further modified by covalent attachment to another chemical moiety, including linkage to a polymer (e.g., a hydrophilic polymer), alkylation or deuteration. In a particular embodiment, the above Class 5 peptide comprising PLA is modified to comprise an oxy derivative of PLA, such as an ester of Pla or an ether of PLA. For example, a 'type 5 peptide can comprise amino acid sequences SEq id NO: 1402, 1405-1420, 1422-1425, 1432-1436, 1438, 1439, 1445, 156004.doc-345 - 201143790 1446 and 1451 Any of the above, wherein the PLA is linked to an amino acid, a peptide, a polymer, a thiol group or a burnt group via an ester bond or an ether bond. The amino acid, peptide, polymer, brewing group or alkyl group can be any of those described herein. In the case where PLA is linked to an amino acid or peptide via an ester bond, the peptide of the fifth type can be regarded as a depsipeptide. In yet another particular embodiment, the above-described Class 5 peptide lacking PLA is modified to have two consecutive amino acids between the N-terminus to position 7 (based on the number of native glycosides). Between at least one g key or a shout key is included. In a particular embodiment, the Class 5 peptide comprises at least one ester or ether linkage between two consecutive amino acids. In a more specific embodiment, the Class 5 peptide comprises the N-terminal 6 amino acids of SEQ ID NO: 1401, and the two consecutive amino acids of the N-terminal 6 amino acids are via vinegar or _ linkage Union. Peptide A may comprise any synthetic or naturally occurring amino acid, with the proviso that at least two consecutive amino acids are linked via an ester or ether linkage. In a particular embodiment, 'peptide A comprises an amino acid of native glucosin. The amino acid at position 丨 and/or position 2 can be an amino acid which reduces the likelihood of dipeptidyl peptidase IV causing cleavage. For example, peptide A may comprise, at position 1, an amino acid selected from the group consisting of D-histamine, alpha, alpha-dimethyl meth. Acetic acid (DMIA), N-methylhistamine, α-methylhistamine, imidazoleacetic acid, deaminoglycolic acid, hydroxy-histamine, acetyl-histidine and high-histamine acid. More specifically, in some embodiments 'position 2 of the peptone is an amino acid selected from the group consisting of D-serine, D-alanine, valine, glycine, N-A Baseline acid, N-mercaptoalanine and aminoisobutyric acid (Aib). Also for example, the amino acid at position 3 of peptide a can be the native glutamine 1 residue of glutamic acid rather than native glycosides. Thus, the peptide of the general structure A-B-C may comprise the following amine group 156004.doc • 346·201143790 Acid sequence:

Xaal-Xaa2-Xaa3-Thr-Gly-Phe (SEQ ID NO: 1507); Xaa2-Xaa3-Thr-Gly-Phe (SEQ ID NO: 1508); or Xaa3-Thr-Gly-Phe (SEQ ID NO: 1509) Wherein Xaal is selected from the group consisting of: His, D-histamine, a, a-dimercaptoimidazoleacetic acid (DMIA), N-mercapto histidine, a-mercapto histidine, imidazole Acetic acid, deaminoglycolic acid, hydroxy-histidine acid, acetyl-histidine acid and high-histamine; Xaa2 is selected from the group consisting of Ser, D-serine ruthenic acid, D-propylamine Acid, proline, glycine, N-mercapto-silicic acid, N-methylalanine and aminoisobutyric acid (Aib); and Xaa3 is Gin or Glu. In some embodiments, the B line is modified by up to three amino acid modifications. For example, the B line representing the native amino acid sequence of SEQ ID NO: 1401 is modified by one or more conservative amino acid modifications. In another embodiment, B comprises one or more amino acid modifications selected from the group consisting of (iv) through (X) as described herein. In a particular embodiment, B φ comprises one or both of the amino acid modifications (v) and (vi). In another specific embodiment, in addition to (V) and (vi), B also comprises an amine selected from the group consisting of (iv), (vii), (viii), (ix), and (χ). Combination of a base acid modification or an amino acid modification as described herein, a peptide comprising the general structure ABC may comprise one or more charged amino acids on the C-terminus, for example as Y and/or as described herein. Or in addition, when C comprises XYZ, the peptide comprising the general structure ABC may further comprise one to two charged amino acids at the C-terminus to Z. The charged amino acid may be, for example, Lys, Arg, His, Asp and One of the Glu. In a particular embodiment, 156004.doc •347- 201143790 'Y is Asp. In some embodiments, the peptide comprising the general structure ABC comprises covalently bound to position 1, 16, 20, 21 or 24 (amino acid number according to SEQ ID NO: 1401) comprising a peptide of the general structure ABC. A hydrophilic portion of an amino acid residue or an N-terminal residue or a C-terminal residue. In a particular embodiment, the hydrophilic moiety is attached to a Cys residue comprising a peptide of the general structure A-B-C. In this regard, the amino acid at position 16, 21, 24 or 29 of the native glucagon (SEQ ID NO: 1401) can be substituted with a Cys residue. Alternatively, for example, when the peptide comprising the general structure ABC comprises a C-terminal extension, a Cys residue comprising a hydrophilic moiety can be added to the C-terminus of the peptide comprising the general structure ABC as position 30 or position 40 (above The position is based on the amino acid number of SEQ ID NO: 1401). Alternatively, the hydrophilic moiety can be attached to the PLA comprising the peptide of the general structure A-B-C via the base moiety of the PLA. The hydrophilic moiety can be any of the hydrophilic moieties described herein, including, for example, polyethylene glycol. In a particular aspect, the peptide comprising the general structure A-B-C comprises an alpha helix stabilized by incorporation of intramolecular bridges. In some embodiments, the intramolecular bridge is an intrinsic amine bridge. The indoleamine bridge can be between the amino acid at position 9 and the amino acid at position 12, between the amino acid at position 12 and the amino acid at position 16, at position 16 Between the amino acid of position and the amino acid at position 20, the amino acid at position 20 and the amino acid at position 24, or the amino acid at position 24 and position 28 Between the amino acids (numbering according to the amino acid of SEQ ID NO: 14〇1). In a particular embodiment, the amino acid at position 12 is associated with the amino acid at position 16 or the amino acid at position 16 and the amino acid at position 20 (amino group 156004 according to SEQ ID NO: 1401. Doc -348· 201143790 Acid number) is linked via a decylamine bridge. Covers other internal guanamine bridge positions. Additionally or alternatively, the peptide comprising the general structure abc may comprise an alpha, alpha disubstituted amine group, for example, at any of positions 16, 20, 21 or 24 (based on the amino acid numbering of SEQ ID NO: 1401) acid. In some embodiments, the alpha, alpha disubstituted amino acid is Aib. In a particular aspect, Aib is at position 16 (numbered according to SEQ ID NO: 1401). Alternatively or additionally, the peptide comprising the general structure A-B-C can be modified to include an acidic amino acid at position 16 (numbered according to SEQ ID NO: 1401) which enhances the stability of the alpha helix. In some embodiments, the acidic amino acid is an amino acid comprising a pendant sulfonic acid or a pendant carboxylic acid. In a more specific embodiment, the acidic amino acid is selected from the group consisting of Glu, Asp, glutamic acid, a Cys acid derivative, a tranylalanine, a high performance propylamine, Asp, and Structured Cys alkylated derivative: h2n

H2c COO Η

s x5 , COOH, wherein X5 is CH-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.

In a particular embodiment, the Class 5 peptide can comprise any of the amino acid sequences SEQ ID NO: 1460-1470, 1473-1478, 1480-1488, 1490-1496, 1503, 1504, 1506, and 1514-1518. Or an amino acid sequence comprising peptides 2 to 6 of Table 13, peptides 1 to 8 of Table 14, and peptides 2 to 6, 8 and 9 of Table 15. 156004.doc .349-

201143790 ocs ZL OOCNOO (s inch 00003 Z9L ?) 0UI3IO 趄)) 5蘅 The ^ΞΊϋθ蘅 invites ancient θ^^(6ε-9) _ you are ancient £3, 锲 M M : εκ 0<N 9 Z/OOII 9ΓΟ Ε9 Is Ϊ) SU3 l-dlo sdddvossdoiAvbAljL,CEiv^3aTA:>ISA3sl-vld[(^^€:)0S9I3,63,9V1PH] s&dvossdoimcyAiiaav^wcnA^SAwsl-vld[(鍩is S9I3(N3,63 , 9vld] sdddvossdoimcyA: Iabwa3cnA: SSAaslfe (9), 6a sdd$ossdDimaAdcDiv^HcnA: SSAHSld (single meal e) os9 s, 63 sdddvossdoliMcyAia0wa3cnA: SSA3sld (Sen S) 9S (NS, 6H 8&{ίνο88<Ι01Λ^Λ;Ιααν^3ατλ:^Λ381[1Η913,tNs, 63 inch e τ 156004.doc •350· 201143790

(i#A^4s command life=vd)趄谀蘅^^一-知一^^蘅^龙玑玑古^^3⁄4^(6z-9^6fs-Tt, 6Z-Z, 6z-l)_霹古锲 linkage glycosidic IC50 (nM) 0.2-1.0* 10-30 s 10-30 49(PA) s 130(PA) agonist O «η uww 韬GLP-1 EC5〇(nM) oso CN r - 〇\ m (N 〇\ 00 in s (N iQ CN c5 ο 1 0 > 1 aa ϋ ω 卜 CO CO > 〇W 1^0 〇os' H ^ Q o tJ pj cx 〇> g| C 2 S3 V〇>H ι-HK/ w CO s QQ co ,H v〇<3 C d 〇\ H ^ Q ,[X| ^ Q %〇ε sm ^ QW jl fN >H a ^ W Kfl aq Q w / H v〇<3 < JJ ^ (N v〇〇HSQ sS _ ^ W §§ sg ^ hj V〇>H — w K ,4 SQ 7S 〇^ ^ ω ut Π ω WQ ,hj VO >H t—I K> ω go SQ <1 < J Η 1 as ^ !l 甾s ^ H s° HQ hJ 73⁄4 eg I| ^ Q key ¥ 〇ω sg ω ο , a HQS hJ 7 ^ /—> [tJ 绪Q ίϋ P ω s| ^ < Q ss:c/ 1% si 'W gg si !| |lss E § cloud i ^T3 2 u| 民 3 s ^奚QH·白it o Ϊ1 <N m inch yn VO OB σ σ\ 橥* 156004.doc -351 - 201143790 Glycoside (6-CEX) analogue 762 2008 00 s (N 1451 s VO m 00 v〇 C/D & Oh ϋ Η 1 a Qj atw QX/l Oh g 1 cy & ai Q [I: PL, 〇OQ in eu 〇H 1 O' tLt 1 ω Q hJ a C/D Cju 0 CO ϋ H 1 H a &amp ; σ ί w Q s 00 5 H 1 σ 6 ω QS ζ/5 Η 〇Η Oh ϋ Xfl ϋ H 1 σ 1 ω Q Hl C/3 s H < E9, K12, E16 E9, K12E16 (endoamine E9, E16K20 (indoleamine) D9, K12E20 (indoleamine) [PLA6, Ε9, Κ12Ε20 (indoleamine)] [PLA6, E9, E16K20 (indoleamine)] m inch ΙΟ \o 荽荜 ( ( 6<^-9)60^ invites glucagon IC5〇(nM) T3 -B mv〇1 w 1·^ Oi 〇-700 inch H 1 hJ a £iai C/DQH Oh H 1 σ PH a table ω Q s HH 1 h-1 a > 1 w Q 00 Bu QC/3 H < PLA6, D9, D28 PLA6 ' D9 ' K12E20 (indoleamine) PLA6, D9, E16K20 (internal amine) Bu oo a\

156004.doc • 352· 201143790 In some embodiments, the peptide comprising the general structure A_B_Ci is a class 5 peptide. In a particular embodiment, the peptide exhibits at least about 5 〇 0/ of the maximum agonistic effect achieved by the native GLP-1 on the GLP-1 receptor. And exhibiting at least about 5% inhibition of the maximum response achieved by the native glycein to the glycoside receptor. In another specific embodiment, the peptide exhibits at least about 55%, at least about 6%, at least about 70%, at least the maximum agonistic effect achieved by the native 〇1^_1 for 〇11>_1 receptor. About 80%, at least about 9%, at least about 95%, or about 100%. Alternatively or additionally, the peptide exhibits at least about 55%, at least about 6%, at least about 70%, at least about 80%, at least about 9 Å for the maximum response achieved by the native glucosin to the glycosidic receptor. %, at least about %% or about ι〇〇〇/〇 inhibition. In some embodiments, a peptide having a Class 5 peptide or a combination thereof is provided, comprising: (1) a modification that confers a glycosidic antagonist activity, including but not limited to (a) position 6 Phe is substituted by PLA (numbered according to the amino acid of wild-type glycosidic acid) 'as appropriate, together with the deletion of 1 to 5 amino acids at the N-terminus of wild-type glycoside; or (b) N of wild-type glycoside Deletion of 2 to 5 amino acids at the end; as appropriate, with Asp at position 9 of the wild-type glycein, substituted with sulfamic acid, glutamic acid or cysteic acid sulfonic acid derivative (according to wild-type sucrose And (2) modifications that confer activity to the GLP-1 agonist, including but not limited to: (a) in the amino acid 12 to 29 of wild-type glycosides, for example One, two, three, four in position 16, 17, 18, 19, 20, 21, 24 or 29 (according to the amino acid 156004.doc • 353 · 201143790 acid number of wild type glycosides) Or at least four of them are inserted with an α,α disubstituted amino acid or substituted with an α,α disubstituted amino acid; or (b) an amino glucoside of the wild type glucosinolate 2 to 29 Introducing intramolecular bridges, such as salt bridges or intrinsic amine bridges or another type of covalent bond; or (c) position 2, 3, 17, 18, 21, 23 or 24 (based on the amine group of native glycosides) The amino acid on one or more of the acid numberings is substituted with the corresponding amino acid of GLP-1, for example, Ser2 is replaced by Ala, Gln3 is replaced by Glu, Arg 17 is replaced by Gin, and Arg at position 18 is replaced by Ala. , Asp at position 2 1 is replaced by Glu, Val at position 23 is replaced by lie, and/or Gin at position 24 is replaced by Ala; or (d) Stabilization is substantially at amino acid position 12 to 29 (according to wild Other modifications of the alpha helix structure of the glycosidic amino acid number); and (3) other modifications that enhance the activity of the GLP-1 agonist, such as the replacement of the C-terminal carboxylate with a c-terminal guanamine or ester; Depending on the situation (4) One or more of the following modifications: (a) For example, covalently attached to the terminal end' or position 6, 16, 17, 20, 21, 24, 29, 40 or C-terminal amino acid a hydrophilic moiety, such as polyethylene glycol; and/or (b) deuterated or alkylated; and optionally (1) one or more of the following other modifications: (a) covalently linking the amino acid To the N-end' For example, 1 to 5 amino acids are covalently bonded to the N-terminus, optionally via an ester linkage to the PLA at position 6 (according to the wild-type glycemic number), as appropriate, together with position 丨 or 2, for example Modifications to improve resistance to DPP-IV cleavage as described herein; 156004.doc -354· 201143790 (b) Positions 29 and/or 28, and optionally position 27 (based on wild-type glycemic number) Amino acid deletion; (c) covalent linkage of the amino acid to the C-terminus; (d) non-conservative substitution, conservative substitution, addition or deletion while retaining the desired activity, eg at positions 2, 5, 7 Conservative substitution on one or the other of 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 27, 28 or 29, replacing position 1 with Val or Phe Tyr' replaces Lys at position 12 with Arg, and replaces one or more of these positions with Ala; (e) by, for example, glutamic acid, glutamic acid, sulfoalanine or high sulfo Alanine is substituted to modify aspartic acid at position 15 to reduce degradation; or for example by using threonine, Aib, a face acid or a side chain having a length of 4 atoms Another negatively charged amino acid, or substitution with either branic acid, glutamic acid or sulphosylalanine to modify the serine at position 16 can also reduce Aspl5-Serl6 Degradation by bond cleavage; (f) modification of thiol amide at position 27 to reduce oxidative degradation, for example by substitution with leucine or ortho-amine; (g) by, for example, Ala or Aib Substituting to modify G1n' at position 20 or 24 to reduce degradation by Gin deamination; (h) modifying Asp at position 21, for example by substitution with Glu, to reduce ring formation via Asp dehydration (1) homodimerization or heterodimerization as described herein; and 156004.doc • 355 - 201143790 (k) each of the above a combination of people. It will be appreciated that any modification in the same category may be combined in a combination of modifications and/or different categories. For example, modification (i)(a) can be combined with (2) (a) and (3); (l) (a) can be combined with (2) (b) (eg, an intrinsic amine bridge or a salt bridge) And (3) a combination, (l) (a) may be combined with (2) (c) and (3); (i) (b) may be combined with (2) (a) and (3), (l) ( b) may be combined with (7) (8) (eg, endoamine bridge or salt bridge) and (7); (l) (b) may be combined with (2) (c) and (3); any of the above may be combined with (4) Combination of (a) and / or (4) (b); and any of the above may be combined with any of (5) (a) to (5) (k). In an exemplary embodiment, the alpha, alpha disubstituted amino acid Aib is at one of the positions 16, 20, 21 or 24 (based on the amino acid number of the wild type glycemic acid), two, or three Replaced all. In an exemplary embodiment, the intramolecular bridge is a salt bridge. In other exemplary embodiments, the intramolecular bridge is a covalent bond, such as an internal amine bridge. In some embodiments, the indoleamine bridge is between the amino acid at position 9 and the amino acid at position 12, between the amino acid at position 12 and the amino acid at position 16. , between the amino acid at position 16 and the amino acid at position 20, between the amino acid at position 2 and the amino acid at position 24 or the amine at position 24. Between the base acid and the amino acid at position 28 (based on the amino acid numbering of SEQ ID NO: 1401). In an exemplary embodiment, deuteration or alkylation is carried out at position 6, 10, 20 or 24 or the N-terminus or C-terminus (based on the amino acid number of wild-type glycoside (SEQ ID NO: 1401)) In an exemplary embodiment, the modifications include: 156004.doc • 356- 201143790 (i) Asp at position 15 (numbering according to SEQ ID NO: 1401) via sulfoalanine, glutamic acid, glutamic acid And high sulfoalanine substitution; (ii) at position 16 (according to the numbering of SEQ ID NO: 1401), the Ser is substituted with sulfoalanine, glutamic acid, glutamic acid and high sulfoalanine; Substituting Asn at position 28 with a charged amino acid; (iv) Asn at position 28 is substituted with a charged amino acid selected from the group consisting of Lys, Arg, His, Asp, Glu, propyl propylamine Acid and homotyl alanine; ^ (v) substituted with Asn, Asp or Glu at position 28; (vi) substituted with Asp at position 28; (vii) substituted with Glu at position 28; (viii) Thr at position 29 is substituted with a charged amino acid; (ix) Thr at position 29 is substituted with a charged amino acid selected from the group consisting of Lys, Arg, His Asp, Glu, sulfoalanine and high sulfoalanine; ^ (X) is substituted with Asp, Glu or Lys at position 29; (xi) substituted with Glu at position 29; (xii) at position 29 Insert 1 to 3 charged amino acids; (xiii) insert Glu or Lys after position 29; (xiv) insert Gly-Lys or Lys-Lys after position 29; or a combination thereof. Any of the modifications described above for enhancing GLP-1 receptor agonist activity, glycosidic receptor inhibitor activity, peptide solubility and/or peptide stability may be applied individually or in combination. 156004.doc -357· 201143790 Modification of Enhanced Stability According to some embodiments, the Class 5 peptides disclosed herein may be further modified to include an amine linked to the carboxy terminal amino acid of the Class 5 peptide (position 24). The base acid sequence is SEQ ID NO: 1421 (GPSSGAPPPS) or SEQ ID NO: 1450 and is administered to an individual to induce weight loss or to contribute to body weight maintenance. More specifically, the class 5 peptide comprises a sequence selected from the group consisting of: SEQ ID NO: 1405 'SEQ ID NO: 1406 ' SEQ ID NO: 1407, SEQ ID NO: 1408, SEQ ID NO: 1409, SEQ ID NO: 1412, SEQ ID NO: 1413, SEQ ID NO: 1414, SEQ ID NO: 1416, SEQ ID NO: 1417, SEQ ID NO: 1418, SEQ ID NO: 1419, SEQ ID NO: 1422, SEQ ID NO : 1423, SEQ ID NO: 1424 and SEQ ID NO: 1425, and further comprising an amino acid sequence SEQ ID NO: 1421 (GPSSGAPPPS) linked to the carboxy terminal amino acid of the peptide or class 5 peptide (position 24) Or SEQ ID NO: 1450 for suppressing appetite and inducing weight loss/maintaining body weight. In some embodiments, the administered peptide or class 5 peptide comprises a sequence selected from the group consisting of: SEQ ID NO: 1416, SEQ ID NO: 1417, SEQ ID NO: 1418 and SEQ ID NO: 1419, further comprising an amino acid sequence SEQ ID linked to the carboxy terminal amino acid of the Class 5 peptide (position 24) NO: 1421 (GPSSGAPPPS). In some embodiments, the method comprises administering a peptide or a fifth class comprising the sequence SEQ ID NO: 1445 or SEQ ID NO: 1446. Thus, it is contemplated that the Class 5 peptides disclosed herein can likewise be modified to reduce the likelihood of premature chemical cleavage in aqueous buffers. According to some embodiments 156004.doc - 358 · 201143790, the corresponding native glycoside can be replaced by an amino acid selected from the group consisting of sulfoalanine, glutamic acid 'high glutamic acid and high-performance alanine The native aspartic acid amino acid at position 15 further complements the Type 5 peptide described herein to enhance its stability in aqueous solutions. According to some embodiments ' SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO:

The aspartic acid residue at position 1407 or the peptide of SEQ ID NO: 1408 may be passed through an amine selected from the group consisting of sulfoalanine, glutamic acid, glutamic acid, and homogenyl alanine. Base acid substitution, and in some embodiments, SEQ

ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407 or native aspartic acid at position 10 of SEQ ID NO: 1408 by face acid replacement e. According to some embodiments, there is provided an improved aqueous solution. A class 5 peptide of stability in which the antagonist comprises the modified sequence of SEQ ID NO: 1409, wherein the modification comprises substitution of Asp at position 10 of SEQ ID NO: 1409 with Glu. In some embodiments, a Class 5 peptide comprising a sequence selected from the group consisting of SEQ ID NO: 1422, SEQ ID NO: 1423, SEQ ID NO: 1424, and SEQ ID NO: 1425 is provided. In the case, the fifth type of peptide is amylated. The Asp-Ser sequence at positions 15 to 16 of the native glucagon has been identified as a unique unstable dipeptide that causes premature chemical cleavage of native hormones in aqueous buffer, for example, when at 37 ° C When maintained at 0.01 N HC1 for 2 weeks, more than 50% of the native glycosides can be cleaved into fragments. The two cleavage peptides 1 to 15 and 16 to 29 released are deficient in glycosidic-like biological activity and thus constitute a limitation on the aqueous pre-mixing of glucosamine and its related analogs. The use of Glu selective chemistry to replace the native glucosinus at position 15 has been observed to be practical. 156004.doc • 359-201143790 The chemical cleavage of the 15-16 peptide bond is eliminated. In other exemplary embodiments, any of the above compounds may be further modified to improve stability by modifying an amino acid corresponding to position 15 or 16 of the native glycosidic acid, thereby reducing peptides, particularly in acidic or alkaline buffers. Degradation over time. Modifications to enhance solubility Class 5 peptides can be further modified to improve the physiology of the peptide? The solubility in the aqueous solution is 1^, and in some cases, the activity of the glycoside antagonist and the GLP-1 agonist is retained. Introducing a hydrophilic group at positions 12, 15, 16, 19, and 24 corresponding to the peptide of SEQ m N〇: 14〇5, or at positions 12, 16, 19 or 24 of the peptide of SEQ ID NO: 1406 The introduction of a hydrophilic group improves the solubility of the resulting peptide in a solution having a physiological pH while retaining the glycoside antagonist and GLp agonist activity of the parent compound. Thus, in some embodiments, a Class 5 peptide disclosed herein is further modified to comprise an amino acid covalently linked to a peptide corresponding to 卯〇ID N〇: 14〇5*SEQ m NO: 1406 One or more hydrophilic groups of the amino acid side chains of positions 12, 15, 16, 19 and 24. In another embodiment, the amino S-side bond corresponding to the amino acid positions 16 and 19 of SEq ID NO: 1405 or SEQ ID NO: 1406 is covalently bonded to the hydrophilic group 'and in some embodiments, The hydrophilic group is polyethylene glycol (PEG). The fifth type of ghrelin-related peptide can be modified by introducing a charge at its carboxy terminus to enhance the solubility of the peptide while retaining the agonist properties of the peptide. Increasing the solubility allows the preparation and storage of the glycemic solution at near neutral pH. Formulation at a relatively neutral pH (e.g., a pH of from about 6.0 to about 8 Torr) 156004.doc -360 · 201143790 The glycoside solution improves the long-term stability of the class 5 peptide.

Applicants of the present invention anticipate that the Class 5 peptides disclosed herein can likewise be modified to enhance their solubility in aqueous solutions at relatively neutral pH values (e.g., pH values from about 6.0 to about 8.0), in some cases. Next, the glycosidic antagonist and GLP-1 activity are retained. Therefore, some embodiments relate to SEQ ID

NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407 or SEQ ID NO: 1408, a glycosidic antagonist/GLP-1, which has been mapped relative to wild-type glycosidin (SEQ ID NO: 1401) The native amino acid present on 6 to 29' is further modified to add charge by replacing the native uncharged amino acid with a charged amino acid or by adding a charged amino acid to the carboxy terminus in. According to some embodiments, one to three uncharged native amino acids of the Class 5 peptide disclosed herein are replaced with a charged amino acid. In some embodiments the 'charged amino acid is selected from the group consisting of lysine, arginine, histidine, aspartic acid, and glutamic acid. More specifically, applicants of the present invention have discovered that 'substituting a charged amino acid for the normally occurring amino acid corresponding to position 28 and/or 29 (relative to native glycosidic), and/or will 丨 to 2 The addition of a charged amino acid to the carboxy terminus of the peptide enhances the solubility and stability of the class 5 peptide in an aqueous solution at physiologically relevant pH values (i.e., a pH of from about 6.5 to about 7.5). Thus, such modifications to the Class 5 peptide are expected to have a similar effect on the solubility in aqueous solutions, especially at pH values ranging from about 5.5 to about 8.0, while retaining the biological activity of the parent peptide. According to some embodiments, the peptide of class 5 of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407 or SEQ ID NO: 1408 is by using a negatively charged amino acid (eg aspartic acid or Glutamic acid) substituted 156004.doc -361 · 201143790 The primary amino acid at position 23 and/or 24 of the sequence, and optionally a negatively charged amino acid (eg aspartic acid or glutamic acid) Addition to the carboxy terminus of the peptide and modification. In an alternative embodiment, the fifth class comprising SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407 or SEQ ID NO: 1408 is used Substituting a positively charged amino acid (eg, an amine acid, arginine or histidine) for the native position at position 24 of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, or SEQ ID NO: 1408 The amino acid, and optionally one or two positively charged amino acids (e.g., aminic acid, arginine or histidine) are added to the carboxy terminus of the peptide to be modified. A Class 5 peptide having improved solubility and stability according to some embodiments, wherein the analog comprises the amino acid sequence SEQ ID NO: 1415 or SEQ ID NO: 1451 'Limited as SEQ ID NO: 1415 or SEQ ID NO: at least one amino acid at position 23 or 24 of 1451 is substituted with an acidic amino acid, and/or an additional acidic amino acid is added to the carboxy terminus of SEQ ID NO: 1415 or SEQ ID NO: 1451. In some embodiments, the acidic amino acid is independently selected from the group consisting of Asp, Glu, sulfoalanine, and high sulfoalanine. According to some embodiments, a Class 5 peptide having improved solubility and stability is provided, wherein the antagonist comprises the amino acid sequence SEQ ID NO: 1416, SEQ ID NO: 1417 'SEQ ID NO: 1418 or SEQ ID NO: 1419. According to some embodiments, a glycosidic agonist comprising the sequence of SEQ ID NO: 1416 or SEQ ID NO: 1417 is included. In some embodiments, the Class 5 peptide comprises the sequence of SEQ ID NO: 1420 »

According to some embodiments, a Class 5 peptide comprising the sequence of SEQ ID NO: 1415 or SEQ ID NO: 1451 is provided. In some embodiments, position 4 of SEQ ID 156004.doc -362.201143790 NO: 1415 or SEQ ID NO: 1451 is aspartic acid, glutamic acid, glutamic acid, sulfoalanine or high sulfo Alanine, and in some embodiments, position 4 is aspartic acid, glutamic acid, sulfoalanine or homosulfoalanine, and in another embodiment, SEQ ID NO: 1415 or SEQ ID NO Position 4 of 1451 is aspartic acid or glutamic acid, and in some embodiments, position 4 of SEQ ID NO: 1415 or SEQ ID NO: 1451 is aspartic acid. In some embodiments, a Class 5 peptide comprising the sequence of SEQ ID NO: 1415 or SEQ ID NO: 1451 is provided, wherein position 4 of SEQ ID NO: 1415 is aspartic acid, and position 10 of SEQ ID NO: 1415 For glutamic acid. In another embodiment, the C-terminal amino acid of SEQ ID NO: 1415 or SEQ ID NO: 1451 is modified to replace the primary carboxylic acid group with a charge-neutral group such as a guanamine or ester. Class 5 peptide fusion

In another embodiment, the carboxy-terminal amino acid of the Class 5 peptide described herein is covalently bound to a second peptide comprising a sequence selected from the group consisting of: SEQ ID NOs: 1421, 1426, 1427, and 1450 . For example, in some embodiments, SEQ ID NO: 1415, SEQ ID NO: 1451, SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, SEQ

ID NO: 1408, SEQ ID NO: 1412, SEQ ID NO: 1413, SEQ

ID NO: 1414, SEQ ID NO: 1416, SEQ ID NO: 1417, SEQ

ID NO: 1418, SEQ ID NO: 1419, SEQ ID NO: 1422, SEQ ID NO: 1423, SEQ ID NO: 1424, and SEQ ID NO: 1425, the fifth class peptide is covalently bound to comprise a group selected from the group consisting of The second peptide of the sequence: SEQ ID NO: 1421 (GPSSGAPPPS), SEQ ID NO: 156004.doc • 363· 201143790 1426 (KRNRNNIA) ' SEQ ID NO: 1427 (KRNR) and SEQ ID NO: 1450 (GPSSGAPPPSX) In some embodiments, a Class 5 peptide dimer comprising two sequences independently selected from the group consisting of SEQ ID NO: 1405, SEQ ID NO: 1406, SEQ ID NO: 1407, SEQ ID is provided NO: 1408, SEQ ID NO: 1409, SEQ ID NO: 1422, SEQ ID NO: 1423, SEQ ID NO: 1424, and SEQ ID NO: 1425, further comprising a carboxy terminal amino acid linked to a Class 5 peptide Amino acid sequence SEQ ID NO: 1421 (GPSSGAPPPS) 〇 In some embodiments, a Class 5 peptide can be truncated or deleted by one of the C-terminus of the peptide or two amino acids (ie, truncated native) Further modified by position 29 of the glycoside or amino acid at positions 28 and 29. Preferably, the truncation does not affect the activity of the class 5 peptide (e.g., glycoside antagonism/GLP-1 agonism). Class 5 peptide conjugates also provide a combination of a class 5 peptide wherein the glycosidic peptide is linked to the binding moiety via a covalent linkage and, optionally, via a linker linkage. In embodiments in which the class 5 peptide comprises a polyethylene glycol chain, the polyethylene glycol chain can be in a linear form or can be branched. The average molecular weight of the polyethylene glycol chain according to some embodiments is selected from the range of from about 500 to about 10, in the range of 〇〇〇Dalton. In some embodiments, the polyethylene glycol chain has an average molecular weight selected from the range of from about 1,000 to about 5,000 Daltons. In some embodiments, the average molecular weight of the polyethylene glycol chain is selected from the range of from about 1,000 to about 5,000 Daltons. In some embodiments, the average molecular weight of the polyethylene glycol chain is selected from about 1 000 to about 2,000. Dalton. In some embodiments, the average molecular weight of the polyethylene glycol linkage is 156004.doc -364.201143790 is about 1,000 Daltons. In some embodiments, the PEGylated Category 5 peptide comprises the sequence SEQ. ID NO: 1415 or a peptide consisting of SEQ ID NO: 1451, wherein the polyethylene glycol chain is linked to a position selected from positions 11, 12, 15, 16, 19 and 24 of SEQ ID NO: 1415 or SEQ ID NO: 1451 Amino acids, and the molecular weight of the PEG chain is from about 1,000 to about 5,000 Daltons. In some embodiments, the PEGylated Class 5 peptide comprises a peptide consisting of the sequence seQ ID NO: 1415 or SEQ ID NO: 457, wherein the polyethylene glycol chain is linked to SEQ ID NO: Ml5 or SEQ The amino acid at position 16 or 19 of ID ΝΟ 1_451, and the molecular weight of the PEG chain is from about 1,000 to about 5,000 Daltons. In another embodiment, the modified Class 5 peptide comprises two or more polyethylene glycol chains covalently bound to the peptide, wherein the total molecular weight of the glycosidic chain is from about 1,000 to about 5 , Dalton. In some embodiments, the Class 5 peptide comprises the sequence of SEQ ID N: 1415 or SEQ ID NO: 1451, wherein the polyethylene glycol linkage is linked to positions 16 and 19 of seq id NO: 1415 or SEQ ID NO: 1451 The amino acid of the above, φ and the combined molecular weight of the two PEG chains are from about ί, from 0 〇〇 to about 5,000 Daltons. The fifth glucosinoid-related peptide may comprise the amino acid sequence SEq IQ no 1401-1518. Either as the case may have at least j, 2, 3, 4 戋 $ at the j-glyphin antagonist and GLP-1 agonist activity. Linked Group (L) As described herein, the present invention provides a glycoside superfamily peptide that binds to an NHR ligand having the formula Q-L-Y, wherein l is a linking group or a chemical bond. ° In some embodiments, L is stable in vivo. In some embodiments, l is hydrolyzable in vivo. In some embodiments, ^ is in the form of 156004.doc -365-201143790 in vivo. Q and Y can be linked together via L bonds using standard bonding agents and procedures known to those skilled in the art. In some aspects, Q is directly fused to Υ and l is a bond. In other aspects, Q is fused to hydrazine via a linking group L. For example, in some embodiments, Q and hydrazine are linked together via a peptide bond, optionally via a peptide or an amino acid spacer. In some embodiments, Q and hydrazine are chemically bonded, optionally linked together via a linking group (L). In some embodiments, L is directly bonded to each of Q and Υ. Chemical bonding can be carried out by reacting a nucleophilic reactive group of one compound with an electrophilic reactive group of another compound. In some embodiments, when L is a bond, by reacting a nucleophilic reactive moiety on Q with an electrophilic reactive moiety on gamma, or by reacting an electrophilic reactive moiety on Q with The nucleophilic reactive moiety reacts to bind Q to gamma. In certain embodiments, 'when L is a group that bonds Q to oxime, the nucleophilic reactive moiety on q and/or oxime can be reacted with the electrophilic reactive moiety on L, or Non-limiting examples of binding Q and/or gamma to L » nucleophilic reactive groups by reacting an electrophilic reactive moiety on Q and/or oxime with a nucleophilic reactive moiety on L include an amine group, sulfur Alcohol and hydroxyl. Non-limiting examples of electrophilic reactive groups include carboxyl groups, mercapto vapors, anhydrides, esters, butyl succinimide, alkyl groups, sulfonates, maleimide groups, halogens Mercapto and isocyanate. In the examples where Q and hydrazine are combined by reacting a carboxylic acid with an amine, an activator can be used to form an activated ester of a carboxylic acid. The activated ester of the carboxylic acid can be, for example, hydrazine-hydroxybutanediimide (NHS), tosylate (Tos), mesylate, triflate, carbodiimide or hexa 156004.doc • 366- 201143790 Sulfate. In some embodiments, 'carbodiimide red dicyclohexylcarbalized monoimine (DCC), 1,1'-carbonyldiimidazole (cm), j ethyl-3-(3_monodecylaminopropyl) Carbodiimide hydrochloride (EDC) or 13 diisopropylcarbodiimide (DICD). In some embodiments, the hexafluorophosphate salt is selected from the group consisting of pyridine hexafluorophosphate benzoxanthene (dimethylamino) squama (BOP), benzotriazole hexafluorophosphate ·丨_基·oxytriazolidine-based scale (PyBOP), hexafluorophosphate 2_(1H_7_azabenzotriazole small group)_ 1,1,3,3-tetradecylhydrazine (HATU) and Bismuth hexafluorophosphate_benzotriazole·Ν,Ν,Ν·,;ΝΤ-tetramethyl-anthracene (HBTU). In some embodiments, Q comprises a nucleophilic reactive group capable of binding to an electrophilic reactive group on gamma or L (eg, an amine group, sulphur from a side chain of an amine acid, cysteine, or a serine acid) Alcohol or hydroxyl). In some embodiments, Q comprises an electrophilic reactive group capable of binding to a nucleophilic reactive group on Y or L (eg, a carboxylate group of a side chain of Asp or Glu), in some embodiments 'Q Chemically modified to include reactive groups capable of binding directly to gamma or L. In some embodiments, Q is modified at the C-terminus to comprise a natural or non-natural amino acid having a nucleophilic side chain, such as an amino acid represented by Formula I, Formula II or Formula III as previously described herein. (See 潇和处/6). In an exemplary embodiment, the C-terminal amino acid of Q is selected from the group consisting of lysine, uric acid, serine, cysteine, and homocysteine. For example, the c-terminal amino acid of Q can be modified to include an lysine residue. In some embodiments, Q is modified on a C-terminal amino acid to comprise a natural or non-natural amino acid having an electrophilic side bond, such as Asp and Glu. In some embodiments, the internal amino acid of q is passed through a natural or non-natural amino acid having a nucleophilic side chain, 156004.doc - 367 - 201143790 generation 'the natural or non-natural amino acid, such as previously described herein The amino acid represented by Formula I, Formula II or Formula III (see Trend / 6 and Hu Shi / 6). In an exemplary embodiment, the substituted internal amino acid of Q is selected from the group consisting of lysine, ornithine, serine, cysteine, and homocysteine. For example, Q The internal amino acid can be substituted with an amine acid residue. In some embodiments, the internal amino acid of 'Q is substituted with a natural or non-natural amino acid having an electrophilic side chain such as Asp and Glu. In some embodiments, Y comprises a reactive group capable of binding directly to Q or L. In some embodiments, Y comprises a nucleophilic reactive group (e.g., an amine, a thiol, a hydroxyl group) capable of binding to an electrophilic-reactive group on Q or L. In some embodiments, Y comprises an electrophilic reactive group (e.g., a carboxyl group, an activated form of a carboxyl group, a compound having a leaving group) capable of binding to a nucleophilic reactive group on Q or L. In some embodiments, Y is chemically modified to comprise any nucleophilic reactive group capable of binding to an electrophilic reactive group on Q or L. In some embodiments, Y is chemically modified to comprise an electrophilic reactive group capable of binding to a nucleophilic reactive group on Q or L. In some embodiments, the binding can be via an organodecane, such as a glutaraldehyde treated amine decane; a stanol alcohol based carbonyl diimidazole (CDI); or a dendrimer. A variety of dendrimers are known in the art and include poly(amidinoamine) (PAMAM) dendrimers which are synthesized by divergence using ammonia or an ethylenediamine initiator core reagent as a starting material. PAMAM dendrimer subclass based on ginsamine-extended ethyl-imine core; radially layered poly(amidinoamine-organoindole) dendrimer (PAMAMOS), which is composed of hydrophilic nucleophilic poly Reversal of the internal composition of guanamine amine (PAMAM) and hydrophobic organic hydrazine (OS) 156004.doc • 368· 201143790 molecular microcells; poly(extension imipenem) (PPI) dendrimers, generally Is a poly-alkylamine having a primary amine as a terminal group, and the inside of the dendrimer is composed of a plurality of third ginseng-propylamine; poly(propylammonium) (POPAM) dendrimer; diamine butyl Alkane (DAB) dendrimer; amphiphilic dendrimer; microcyst dendrimer, which is a single molecule microparticle of water-soluble hyperbranched polyphenyl; poly-Amino acid dendrimer; and polybenzoquinone based A dendrimer of ether super-branched skeleton. In some embodiments, the binding can be via olefin metathesis. In some embodiments, Y and Q, Y and L, or Q and L comprise an olefin or alkyne moiety capable of undergoing metathesis. In some embodiments, a suitable catalyst (e.g., copper, ruthenium) is used to accelerate the metathesis reaction. Suitable methods for carrying out the olefin metathesis reaction are described in the art. See, for example, Schafmeister et al., A. J. Am. Chem. Soc. 122: 5891-5892 (2000); Walensky et al. Science 305: 1466-1470 (2004); and Blackwell et al., Angew, Chem., 0 /^M, 37: 3281-3284 (1998) In some embodiments, binding can be performed using click chemistry. The "click reaction" is broad and easy to use, using only reagents that are readily available and insensitive to oxygen and water. In some embodiments, the click reaction is a cycloaddition reaction that forms a triazolyl group between an alkynyl group and an azide group. In some embodiments, the click reaction uses a copper or ruthenium catalyst. Suitable methods for performing a click reaction are described in the art. See, for example, Kolb et al., Drug Discovery Today 8: 1128 (2003); Kolb et al., Angew. Chem., Mo., 40: 2004 (2001): Rostovtsev et al., Angew. Chem. International Edition, 41:2596 (2002); Tornoe et al., */. Org. C/iem. 67:3057 (2002); Manetsch et al.,··· ylm. C/iem 156004.doc •369· 201143790 «Soc· 126:12809 (2004) ; Lewis et al., C/zew. 涿, 41:1053 (2002); Speers, J. Am. Chem. Soc. 125:4686 (2003); Chan et al., Org. Lett. 6:2853 (2004); Zhang et al, ·/· C/zew. 5*oc. 127:15998 (2005); and Waser et al.,/·dw. Chem. Soc. 127:8294 (2005) ° also covers indirect binding via high affinity specific binding partners (eg, streptavidin/biotin or avidin/biotin or lectin/carbohydrate). Chemical Modification of Q and/or Y In some embodiments, Q and/or Y are functionalized with an organic derivatizing agent to comprise

A nucleophilic reactive group or an electrophilic reactive group. The derivatizing agent is capable of reacting with a selected side chain or an N-terminal residue or a C-terminal residue of the target amino acid on Q and a functional group on γ. The reactive group on Q and/or Y includes, for example, an aldehyde, an amine group, an ester, a thiol, an α-dentate group, a maleimide group or a fluorenyl group. Derivatizing agents include, for example, maleic acid imide phenyl sulfenyl succinimide (bonded via a cysteine residue), N-hydroxybutyric imide (via an lysine residue) 'Glutaraldehyde, succinic anhydride or other derivatizing agents known in the art. Alternatively, Q and/or hydrazine may be linked to each other indirectly via an intermediate carrier such as a polysaccharide or a polypeptide carrier. Examples of the polysaccharide carrier include amine-based polydextrose. Examples of suitable polypeptide carriers include polylysine, polyglutamic acid, polyaspartic acid, copolymers thereof, and mixed polymers of such amino acids with other amino acids (e.g., serine) to impart The resulting supported support has the desired solubility characteristics. The cysteamine thiol residue is most often reacted with an alpha _acetate (and the corresponding amine) (such as 156004.doc • 370·201143790 gas acetic acid or gas acetamide) to give a carboxy fluorenyl or carboxy guanylaminomethyl group. derivative. The cysteamine-based residue is also derivatized by reaction with bromotrifluoroacetone, α-bromo-β·(5-imidazolyl)propionic acid, chloroacetate, decane-alkane Cis-butenylene diimide, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-mercaptobenzoic acid ester, 2 gas amalgam _4_ stone Basic discretion or gas-7-wall base benzo-2-° cacao-1,3 - two n sit. The histamine sulfhydryl residue is derivatized by reaction with diethylpyrocarbonate at pH 5.5 to 7.0 because this reagent is relatively specific for the histamine sulfhydryl side chain. It is also suitable for bromoformyl bromo bromide; it is preferred to carry out the reaction at pH 6.0 in sodium decanoate. The amine amide group and the amine terminal residue are reacted with succinic acid or other carboxylic anhydride. Derivatization with such reagents has the effect of reversing the charge of the amine sulfhydryl residue. Other suitable reagents for derivatization of α-amino group-containing residues include sulfhydryl esters (such as 比 曱醯 曱醯 曱醯 ) )), acid-to-acid ratio 哆 brewing, π-ratio, gas shed hydride, Trinitrobenzenesulfonic acid, hydrazine-methylisourea, 2,4-pentanedione and transaminase catalyzed reaction with glyoxylate. The spermine thiol residue is reacted with one or several conventional reagents including phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione and indanone. Modification. Derivatization of arginine residues requires a reaction under base conditions due to the high pKa of the oxime functional group. In addition, such reagents can be reacted with a group derived from an amine acid and an ε-amine group of arginine. The tyramine sulfhydryl residue can be specifically modified by reaction with an aromatic diazonium compound or tetranitromethane with the particular benefit of introducing a spectral label into the tyramine sulfhydryl residue. Most commonly, oxime-imidazolium and tetranitro 156004.doc-371 - 201143790 decane are used to form the 0-acetamido stilbene oxime group and the 3-nitro derivative. The pendant carboxyl group (aspartame or guanamine) is selectively modified by reaction with carbodiimide (RN=C=NR·), wherein R and R· are different alkyl groups, such as 1 -cyclohexyl-3-(2-morphinyl-4-ethyl)carbodiimide or 1-ethyl-3-(4-indolyl 4,4-dimethylpentyl)carbodiimide . In addition, the aspartame and the face amine-based residues are converted to the aspartame and the glutamine amidino residues by reaction with the sigma ion. Other modifications include hydroxylated lysine and lysine, phosphorylating the hydroxyl group of the serine or sulfhydryl residue, methylating the alpha-amino group of the amine, arginine and histidine side chains (Τ. igh. Creighton, Proteins: Structure and Molecular Properties, WH Freeman & Co., San Francisco, pp. 7-86-86 (1983)), which makes aspartame or glutamine alanine, The acetylated N-terminal amine, and/or the guanidine or esterified C-terminal carboxylic acid group. Another type of covalent modification involves the chemical or enzymatic coupling of a glycoside to a peptide. The sugar may be attached to (a) arginine and histidine; (b) a free carboxyl group; (c) a free sulfhydryl group such as a sulfhydryl group of cysteine; (d) a free hydroxyl group such as a serine, a hydroxyl group of threonine or hydroxyproline; (e) an aromatic residue such as an aromatic residue of tyrosine or tryptophan; or (f) an amidino group of glutamic acid It is described in <57/05330 and jp/h and CRC Crit. Rev. Biochem, pp. 259-306 (1981), published September 11, 1987. Structure of L In some embodiments, L is a bond. In these examples, Q and gamma are combined by reacting a nucleophilic reactive moiety on Q with an electrophilic reactive moiety 156004.doc • 372. 201143790 on Y. In an alternate embodiment, ruthenium and gamma are combined by reacting an electrophilic reactive moiety on the oxime with a nucleophilic moiety on gamma. In an exemplary embodiment, L is a guanamine bond formed by the reaction of an amine on Q (e.g., an ε-amine from an amine acid residue) with a carboxyl group on the oxime. In an alternate embodiment, Q and/or hydrazine are derivatized with a derivatizing agent prior to combining. In some embodiments 'L is a linking group. In some embodiments, l is a bifunctional linker and contains only two reactive groups prior to binding to Q and y. In embodiments where Q and oxime have electrophilic reactive groups, L comprises two identical or two different nucleophilic groups (e.g., amine, hydroxyl, thiol) prior to binding to Q and oxime. In embodiments where Q and gamma have a nucleophilic reactive group, L comprises two identical or two different electrophilic groups (eg, an activated form of a carboxyl group, a carboxyl group, and a leaving group) prior to binding to Q and gamma. Compound). In embodiments where one of Q or oxime has a nucleophilic reactive group and the other of Q4Y has an electrophilic reactive group, L comprises a nucleophilic reactive group and one prior to binding to Q and oxime. Electrophilic group. L may be any molecule having at least two reactive groups capable of reacting with each of q and γ (in combination with Q and oxime). In some embodiments, L has only two reactive groups and is difunctional. L (before binding to the peptide) can be represented by Formula VI:

A-bonding group (L) - B wherein A and B are independently nucleophilic or electrophilic reactive groups. In some embodiments, both A and B are nucleophilic groups or are both electrophilic groups. In some embodiments, one of 'A or B' is a nucleophilic group and the other of a or b 156004.doc - 373 · 201143790 is an electrophilic group. A non-limiting combination of A and B is shown below. All are pro-a cough-based sleepy are nucleophilic nucleophilic/electrophilic-based sleepy ABABAB Amino-based carboxy-carboxylamine group: Amino thiol carboxy thiol sulfhydryl amine sulfhydryl amide hydroxy group Carboxylic anhydride amino anhydride thiol amine carboxy ester amine ester thiol thiol carboxy NHS amine NHS thiol hydroxy carboxy halogen amine halogen hydroxy amine carboxy sulfonate amino sulfonate thiol alcohol Cis-butenylene diimide amine-m-butylene imino group via carboxylic acid carboxylic acid hydroxy ethyl amide aryl aryl sulfonyl amide isocyanate Sulfhydryl chloride sulfhydryl chloride thiol brewing base gas sulfhydryl chloride anhydride thiol anhydride thiol ester thiol ester hydrazino chloride NHS thiol NHS brewing base gas halogen thiol halogen sulfhydryl chloride Sulfonate-based thiol sulfonate-based brewing base gas, maleimide, imide, mercaptan, maleimide, mercapto, mercapto Thiol halohydrazinyl sulfonate isocyanate thiol isocyanate anhydride ruthenyl hydroxy phthalic anhydride hydrazino hydroxy hydrazine hydride anhydride anhydride hydroxy anhydride anhydride ester hydroxy anhydride anhydride NHS hydroxy NHS anhydride halogen-based halogen Anhydride sulfonate hydroxy sulfonate anhydride maleic acid imide hydroxy cis-butylene imino acid anhydride halogenated ethyl hydroxy haloacetic acid anhydride isocyanate hydroxy isocyanate ester thiol ester sulfhydryl Chloride ester anhydride ester vinegar NHS ester halogen 156004.doc -374- 201143790

All are pro-; 1 group are all electrophilic groups nucleophilic / electrophilic groups ester sulfonate esters, maleimide, imidazolium esters, halogenated ethyl esters, isocyanate, NHS, NHS, fluorenyl chloride NHS anhydride NHS ester NHS NHS NHS halogen NHS acid acetate NHS maleimide NHS halide NHS isocyanate halogen carboxy halogen fluorenyl halide halogen anhydride halogen NHS halogen halogen halogen sulfonate彘 彘 顺 顺 顺 顺 顺 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 卤素 NH NH NH NH NH NH NH NH NH NH NH NH NH Acid ester sulfonate sulfonate sulfonate succinic acid S succinyl succinyl di S & imido sulfonate aryl aryl sulfonate sulfonate isocyanate Alkylene diimide sulfhydryl hydrazine Dimercaptoacetic anhydride 156004.doc -375 - 201143790 All of the cough groups are electrophilic groups nucleophilic / electrophilic groups maleimide imidyl maleimide NHS maleimide iodide halogen cis-butyl diimide sulfonate-based maleimide iminodiimide iodide-butyl diimide imino halide Maleimide, isocyanate, haloacetate, ruthenium, sulfhydryl, hydrazide, hydrazine, ethyl hydride, halogenated ethyl hydride, NHS, halogenated ethyl halide, halogenated aryl sulfonate Isobutylidene succinimide, fluorinated, ethylidene, fluorinated, isocyanate, isocyanate, isocyanate, isocyanate, isocyanate, isocyanate, isocyanate, isocyanate, isocyanate Sulfonate-based isoflurane-butyleneimide-isocyanate-based haloacetate Cyanate isocyanate groups

In some embodiments, A and B may include olefin and/or alkyne functional groups suitable for use in olefin metathesis reactions. In some embodiments, A and B include moieties suitable for click chemistry (e.g., olefins, alkynes, nitriles, azides). 156004.doc • 376· 201143790 Other non-limiting examples of reactive groups (A and B) include pyridyl dithiol aryl azide, diazabicyclopropene, carbodiimide, and anthracene. In some embodiments, L is hydrophobic. Hydrophobic linkers are known in the art. See, for example, 〇c〇„)^a rec/m0Mei, G. τ Hermanson (Academic Press, San Dieg〇, ca, i996), which is incorporated herein by reference. Suitable for hydrophobic bonds Linked groups are known in the art and include, for example, 8-hydroxyoctanoic acid and 8-mercaptooctanoic acid. The hydrophobic linking group comprises at least two reactive groups (A and B prior to binding to the peptide of the composition). ), as described herein and as follows:

A-Hydrophilic Linking Group-B In some embodiments, the hydrophobic linking group comprises a maleimide or a hard oxime group and a carboxylic acid or an activated carboxylic acid (eg, an NHS ester) as a reaction Sex group. In such embodiments, the cis-indolyl or the thiol group may be coupled to the thiol moiety on Q or Y with or without a coupling reagent' and the carboxylic acid or activated carboxylic acid may be coupled An amine to q or γ. Any coupling agent known to those skilled in the art can be used to couple the carboxylic acid to the free amine such as DCC, DIC, HATU, HBTU, TBTU, and other activators described herein. In a particular embodiment, the 'hydrophilic linking group comprises an aliphatic chain having from 2 to 100 methylene groups' wherein A and B are carboxyl groups or derivatives thereof (e.g., succinic acid). In other specific embodiments, L is iodoacetic acid. η〇Λ^Ύ〇Η ^ΟΗ Succinic acid Dish acetic acid In some embodiments, the linking group is hydrophilic, such as a poly-extension 156004.doc-377-201143790 alcohol. The 'hydrophilic linkage group contains at least two reactive groups (A and B) prior to binding to the peptide of the composition, as described herein and as follows: A hydrophilic linkage group -^ In a particular embodiment, the linking group is polyethylene glycol (ρβ < 3) °. In certain embodiments, the molecular weight of the PEG is from about 100 Daltons to about 1,000,000 Daltons, such as about 500 channels. From about 5,000 Daltons. In one embodiment, the molecular weight of the PEG is from about 10,000 Daltons to about 40,000 Daltons. In some embodiments, the hydrophilic linking group comprises a cis-butyl sulphate or an iodoethylidene group and a carboxylic acid or an activated carboxylic acid (e.g., an NHS ester) as a reactive group. In such embodiments, the 'm-butylene imino or iodoethyl group can be coupled to the sterol moiety on the hydrazine or hydrazine with or without a coupling reagent, and the carboxylic acid or activated carboxylic acid can be coupled An amine to Q or Y. The carboxylic acid can be coupled to an amine, such as DCC, DIC, HATU, HBTU, TBTU, and other activators described herein, using any suitable coupling agent known to those skilled in the art. In some embodiments, the linking group is maleimide-PEG (20 kDa)-COOH, ethoxylated-PEG (20 kDa)-COOH, maleimide-amino group- PEG (20 kDa)-NHS or iodoethinyl-PEG (20 kDa)-NHS. In some embodiments, the linking group comprises an amino acid, dipeptide, tripeptide or polypeptide, wherein as described herein, the amino acid, dipeptide, tripeptide or polypeptide comprises at least two activating groups. In some embodiments, the linking group (L) comprises a moiety selected from the group consisting of amines, ethers, thioethers, maleimide groups, disulfides, guanamines, esters, sulfur Esters, olefins, cycloolefins 156004.doc • 378· 201143790 Hydrocarbons, alkynes, triazolyl, carbamic acid aryl, carbonated, cathepsin B cleavable groups and hydrazine. In some embodiments, L contains a length of ! Up to about 6 atoms, or 3 to 30 atoms or more than 30 atoms, 2 to 5 atoms, 2 to 1 atom, 5 to 1 atom, or 10 to 20 atoms. In some embodiments, the chain atoms are all carbon atoms. In some embodiments, the chain atoms in the backbone of the linker are selected from the group consisting of C, ◦, N, and S. The chain atom and linker φ can be selected according to their expected solubility (hydrophilicity) to provide a more soluble binder. In some embodiments, L provides a functional group that is cleaved under enzyme or other catalyst or hydrolysis conditions found in the target tissue or organ or cell. In some embodiments, the length of L is long enough to reduce the likelihood of steric hindrance. Stability of L in the living raft In some embodiments, L is stable in vivo. In some embodiments, L is stable in serum and maintained for at least 5 minutes, such as '25%, 2%, 15%, 1%, or less 5% of the conjugate cleavage when incubated for 5 minutes in serum. . In other embodiments, L is stable in serum and maintained for at least 1 minute, or 20 minutes, or 25 minutes, or 3 minutes, or 6 minutes or 9 minutes, or 120 minutes, or 3 hours, 4 hours. , 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 1 hour, 12 hours, 15 hours, 18 hours or 24 hours. In these embodiments, L does not contain a functional group capable of undergoing hydrolysis in vivo. In some exemplary embodiments, [stable brigade in serum is maintained to: >, about 72 hours. Non-limiting examples of functional groups that are not capable of significant hydrolysis in vivo include guanamine, shunting, and thioethers. For example, the following compounds are not capable of significant hydrolysis in vivo: 156004.doc -379- 201143790 Ί〇, γ Η 丫. In some embodiments 'L is hydrolyzable in vivo. In these embodiments, L comprises a functional group capable of undergoing hydrolysis in vivo. Non-limiting examples of functional groups capable of undergoing hydrolysis in a living body include esters, acid anhydrides, and thioesters. For example, the following compounds are capable of undergoing hydrolysis in vivo because they contain an ester group: α'ΚΛ^Υ°> Ο 0 In some exemplary embodiments, B is unstable in plasma at 37<t> Substantial hydrolysis was carried out within 3 hours and completely hydrolyzed within 6 hours. In some exemplary embodiments, L is stable. In some embodiments, L is metastable in vivo. In these embodiments, L comprises a functional group (e.g., acid labile, reductive labile or enzymatic labile) capable of being chemically or enzymatically cleaved in vivo over a period of time. In such embodiments, L can comprise, for example, a guanidine moiety, a disulfide L component, or a cathepsin cleavable moiety. When L is metastable, and is not intended to be bound by any particular theory, the Q_L_Y conjugate is stable in the extracellular environment, such as being stable in serum and maintaining the period described above, but = intracellular environment or simulation The conditions within the intracellular environment are unstable so that they cleave upon entry into the cell. In some embodiments, when L is metastable, L is stabilized in serum and maintained for at least about 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 Small 156004.doc -380 * 201143790 hours, 34 hours, 35 hours, 36 hours, 42 hours or 48 hours, such as at least about 48 hours, 54 hours, 60 hours, 66 hours or 72 hours, about 24-48 hours, 48-72 hours, 24-60 hours, 36-48 hours, 36-72 j or 48-72 hours. Q-L-Y conjugate Q and Y can be combined at any position in Q (including any of positions 1 to 29) ^ ^ C

The position in the extension or the C-terminal amino acid) binds Q to v* via L, with the proviso that the activity of Q is retained even if the activity of Q is not enhanced. Non-limiting examples include positions 5, 7, 10, 11, 12, 13, 14, 15, 16, 17 38, 39, 18 ' 19, 20, 21, 24, 27, 28 ' 29 ' 30, 37 40, 4丨, 42 or 43 (amino acid number according to SEQ ID N〇: 16〇1 In some embodiments, Y is at positions 10, 20, 24, 3〇, 37, 38, 39, 4〇, 4 One or more of 32 or 43 is bonded to q via L. In the specific embodiment, Y is bonded via L at the position 1G and/or 4() of Q, and the activity of 疋 is 7 Activity of Nuclear Hormone Receptors In some embodiments, 'Q_L_Y exhibits activity against glycospergic receptors and nuclear hormones. In some cases, (10) (tetracycline receptors, EC5, or relative activity or potency), for example, or relative Activity or potency) differs (higher than or about 5 times. In some implementations:: ': times, about 20 times, about 10 times the difference (above or below) about 25 times, about two = effectiveness and γ effect ^ times, about " times, about 10 times or 156004.doc • 381 · 201143790 about within 5 times. In some embodiments, Q is relative to the relative activity of the glycemic receptor or the 5 bite effect The relative value of Y to nuclear hormone receptor Activity or EC5 or potency. The ratio obtained is less than X or about X, wherein the illusion is selected from the group consisting of just, & 6 〇, $心^(1) ^ in some examples (4) EC5 of the glucosamine receptor Or the potency or relative activity divided by the ratio of ¥ to the nuclear hormone receptor. Or the ratio of efficacy or relative activity is about 5 or less (eg, about 4, about 3 约 about 2, about). In some embodiments, q The ratio of glucagon potency to gamma nuclear hormone potency is less than Z, or about Z, wherein Z is selected from 100 75 60, 50, 40, 30, 20, 15, 10, and 5 in some embodiments The ratio of the glycoside potency of Q's to the nuclear hormone potency of ¥ is less than 5 (eg, about 4, about 3, about 2, about 1}. In some embodiments, Q is a glycoside receptor. The EC5❶ is 2 to 10 times the EC5 of the γ-nuclear hormone receptor (for example, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 pieces, 10 times). - in some embodiments - the relative activity or potency of gamma to the nuclear hormone receptor or EC5. Divided by the relative activity or potency of Q on the glycemic receptor or sigh 5. The resulting value is J at V, or about @自_ n Μ \ 50 '40 > 30 ^ ic ^ , 5, 1 〇 or 5 » In some embodiments, the gamma is equivalent to the EC50 or potency or relative activity of the nuclear hormone, divided by q for the c5 receptor of the glycemic receptor or The ratio of the effect b or the relative activity is less than 5 (10) # is about *, about 3, about 2, about 1, -, in some embodiments, the ratio of the nuclear hormone efficiency of Y to the glycemic potency of the 〇 Less than w, or about w, wherein w is selected from the group consisting of _, 75, 6 〇, 5 〇, 4 (), 3 (), 2 (), 15, 1 (), and 5. In some embodiments, the ratio of 'gamma nuclear hormone potency to sputum glycemic potency is less than 5 (eg, about 4, about 3, about 2, about 2. In some In an embodiment, the EC5^Q of the nuclear hormone receptor is about 2 to about 10 times greater than the heart of the glycemic receptor (eg, 2, 3, 4, 5, 10, 7, 8) I % (e.g., about 5% or 〇5). In some embodiments, the activity exhibited by the gamma to the nuclear hormone receptor is at least 0.1% of the activity of the endogenous ligand. % or more, Φ about 1% or more, about 5% or more, about ίο% or ίο% or higher, or higher) (nuclear hormone potency), and the activity of Q on the glycemic receptor At least %1% of the activity of the native glucagon (eg, about 5% or more than 5%, about 1% or more, about 5% or more, about 10% or more, or High) (glycin potency). Activity against GLP-1 receptor and nuclear hormone receptors In some embodiments, QLY exhibits activity at the GLP-1 receptor and nuclear hormone receptor. In some embodiments, q Activity against GLpq receptors (eg φ EC" or relative activity or potency) differs from gamma to the activity of the nuclear hormone receptor (eg, ECw or relative activity or potency) by about (about) or about 50 times, about 60 times, about 50 times, About 40 times, about 30 times, about 20 times, about 1 time or about 5 times. In some embodiments, the GLp i performance of q differs (higher or lower) than about 25 times, about 5%. 20 times, about 15 times, about 1 time, or about 5 times. In some embodiments, the relative activity of Q on the GLP-1 receptor or EC5〇 or potency is divided by the relative activity of Y on the nuclear hormone receptor or The ratio obtained by ECm or potency is less than X or about X, wherein X is selected from 100, 75, 60, 5, 156004.doc 201143790 20 15, 10 or 5. In some embodiments, q is for glp-1 receptor Ugly (:5 〇 or potency or relative activity divided by the ratio of gamma to EC5 核 or potency or relative activity of the nuclear hormone receptor is about 5 or less (eg, about 4, about 3, about 2, about 1). In some embodiments, the ratio of GLp i efficacy to gamma nuclear hormone potency is less than z, or about z, wherein z is selected from the group consisting of 100, 75, 60, 5, 40, 3 〇, 2〇, 15, 1〇, and 5. In some embodiments, the GLP-1 potency of Q is less than 5 compared to the nuclear hormone potency of gamma (eg, about 4, about 3, about 2, about In some embodiments, q is 2-fold to doubling the EG of the GLP-1 incinerator to the nuclear hormone receptor (eg, 2 fold, 3 fold, 4 fold, 5 fold, 6 fold, 7 fold, 8 times, 9^ times). 'In the case of 狍, γ vs. nuclear load 』 The relative activity or potency of the GLIM receptor or the ratio of EC54 a Q to the GLIM receptor is less than V ' or about V. Wherein v is selected from the group consisting of ι, 75, 5, 4, 30, 20, 15, 1 or 5. In some implementations, the ratio of the EC50 or potency or relative activity of gamma to the nuclear hormone receptor divided by the ec50 or potency or relative activity of the (iv) (10) receptor is less than 5 (eg, about 4, about 3, about 2, about υ) In some embodiments, the ratio of 'gamma nuclear hormone potency to Q's GUM potency is less than w, or about cut, which is selected from (10), 75, 6〇, 50, 40, 3〇, 2〇, 15, 1 and 5. In one embodiment, the nuclear hormone efficiency of Y is less than 5 (e.g., about 4, about 3, about 2, about 2) compared to (4). , the center of γ on the nuclear hormone receptor is 2 times to about Π) of Q to GUM receptor (for example, 2 times, 3 times, 4 times, 5 times, 6 times '7,,, spoon 156004.doc - 384·201143790倍,9倍,10倍). In some embodiments, the activity exhibited by the γ-nuclear hormone receptor is at least 0.1% of the activity of the endogenous ligand (for example, about 0 5% or 〇 5% or more, about 1°/. or 1°/. or more, about 5% or more, about 10% or more, or higher) (nuclear hormone efficiency), and Q to GLP-1 The activity exhibited by the receptor is native GLP-1 At least 〇.丨% (for example, about 5% or 〇5% or more, about 1% or more, about 5% or more, about 1%, or more than 1%, or more) High) (GLP-1 potency). Activity on GIP receptors and nuclear hormone receptors In some embodiments, QLY exhibits activity on GIP receptors and nuclear hormone receptors. In some embodiments, 9 pairs of GIP receptors The activity (eg, EC5 〇 or relative activity or potency) differs from the activity of γ on the nuclear hormone receptor (eg, E c 5 〇 or relative activity or potency) by about 1 〇〇 times about 75 times , about 60 times, about 50 times, about 4 times, about 3 times, about 2 times, about 1 time or about 5 times. In some embodiments, Q<GIp performance is different from γ performance. (above or below) about 25 times, about 2 times, about 15 times, about 1 time, or about 5 times. In some embodiments, the relative activity or EC5q or potency of the 〇> receptor is removed. The ratio of the relative activity of gamma to the nuclear hormone receptor *EC5Q or potency is less than X or about X, wherein the lanthanide is selected from 1 〇〇, 75, 40 3 0 20, 15, 1 〇 or 5. In the embodiment The ratio of q to ECSQ4 potency or relative activity of the GIp receptor divided by the EC" or potency or relative activity of gamma to the nuclear hormone receptor is about 5 or less (eg, about 4, about 3, about 2, about 1). In some embodiments, the Gip performance of Q is less than z' or about z, and z is selected from _, 75, 6 〇, 50, and is greater than z' or about z, compared to the γ nuclear load of 156004.doc 201143790. 40, 3, 2, 15, 1 and 5. In some embodiments, the GIP performance of Q is less than 5 compared to the gamma core efficiency (eg, about 4, about 3, about 2, about). In some embodiments, Q to GIP The anal 5 受体 of the receptor is ¥ 对 to the nuclear hormone receptor. 2 times to Cong (for example, 2 times, 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times called some In an embodiment, the relative activity or potency of gamma to the nuclear hormone receptor or EC^ divided by the relative activity or potency of q to the GIP receptor or the ratio obtained by Ec^ is less than V, or about v, wherein v is selected from 1 〇〇, 75, 6〇, 5〇, 30 20, 1 5, 1 〇 or 5. In some embodiments, the EC^ or potency or relative activity of the nuclear hormone receptor is divided by the GI GIp receptor The ratio of ❶ or potency or relative activity is less than 5 (eg, about 4, about 3, about 2, and '々1). In some embodiments, the ratio of the nuclear hormone potency of Y to the Gip potency of q. Less than W, or about w, wherein w is selected from the group consisting of 1〇〇, 75, 60, 50, 40, 30, 20, 15, 1〇, and 5. In some embodiments, the nuclear hormone efficiency of Y is compared. The ratio of the GIP performance of Q is less than 5 (example) Is about 4, about 3, about 2, about 1). In some embodiments, the ECso of the gamma to the nuclear hormone receptor is about 2 to about 1 fold (e.g., 2 times the EC of the EC to the GIP of the GIP receptor). 3 times, 4 times, 5 times, 6 times, 7 times, 8 times, 9 times, 10 times) In some embodiments, the activity exhibited by Y on the nuclear hormone receptor is the activity of the endogenous ligand. At least 0.1% (eg, about 5% or more than 5%, about 1% or more, about 5% or more, about 10% or more, or higher) (nuclear hormone potency) And the activity exhibited by Q on the GIP receptor is at least 0.1% of the activity of the original GIP of 156004.doc-386-201143790 (eg, about 0.5°/❶ or more, about 10〇/0 or 1°/ Above, about 5% or more, about 10% or more, or higher) (GIP potency) QLY prodrugs In some aspects of the invention, a QLY prodrug is provided, wherein the prodrug comprises A dipeptide prodrug element (AB) covalently linked to the active site of Q via a guanamine bond, such as International Patent Application No. PCT US 09/68745 (2009, December 18, 曰 application) Revised in the manner cited in this document) Subsequent removal of the dipeptide under physiological conditions and in the absence of enzymatic activity restores the full activity of the QLY conjugate. In some embodiments, a QLY prodrug is provided having a general structure ABQLY. In these embodiments , a is an amino acid or a hydroxy acid, and B is an N-alkylated amino acid bonded to Q via a guanamine bond between a carboxyl group of B (AB) and an amine of q. Further, in some embodiments, the amino acid of a, b or Q bonded to AB is a non-coding amino acid, and under physiological conditions φ chemical cleavage of AB from Q in PBS is from about 1 to about 72 〇. Complete at least about 90 hours in an hour. /. . In another embodiment, the chemical cleavage of α·β from q in pBs under physiological conditions completes at least about 5 〇 0 / 〇 in about 1 hour or about 1 week. In some embodiments the 'dipeptide prodrug element (Α_Β) comprises a compound having the following general structure:

R

Wherein 156004.doc 201143790 1 , 114 and 118 are independently selected from the group consisting of: C ^ 8 alkyl, c 2 - 8 8, (Ci_c 丨 8) 〇 H, (kh ^ Base) SH, (C2-C3 alkyl group) SCH3, (Ci_C4 yard base) c〇NH di-diyl) COOH, (Cl_c4 alkyl) NH I 4 >

+ 2 (Ll_C4 alkyl) NHC (nh2)nh2, (c〇_c4 alkyl) (C3_C6 cyclohexyl), (c〇c-based c5 heterocyclic), (CVC4 alkyl) (CVCi aryl) R7, (Ci C4 alkyl) (6) _ q heteroaryl) and cvc, 2 alkyl (Wl) CVc 〖2 alkyl, wherein ^ is a hetero atom selected from the group consisting of N, S and 〇, or R# R2 is formed along with the atoms to which it is attached, together with the atoms to which it is attached (: 3-(:6-cycloalkyl; R3 is selected from the group consisting of: Ci_Ci8 alkyl, (Ci_Ci8 alkyl) 0H , (Cl-Cl8 alkyl group_2, (cvc) 8 炫) SH, (C "C4 group" (c3-c6) cycloalkyl, (C (rC4 alkyl) (C2_C5 heterocyclic), (c 〇_C4院)) (CVC10 aryl) R7 and (Cl_C4 alkyl) ((ν(:9heteroaryl)), or ^ together with the heart and the atoms to which it is attached form a 4, 5 or 6 member Ring; R5 is NHR6 or OH; R6 is H, q-C8 alkyl, or the heart and heart together with the atom to which they are attached form a 4-, 5- or 6-membered heterocyclic ring; and h is selected from the group consisting of : hydrogen, c丨_Cu alkyl, 匕弋 "alkenyl, (cvc4 alkyl) C〇nh2, ((VC4 炫) C00H, (VCj base) NH, (CQ-C4 hospital base) OH and _ groups. In some embodiments, the dipeptide prodrug element is linked to the amine end of 9. In other embodiments, the dipeptide prodrug bond An internal amino acid linked to Q, as described in International Patent Application No. PCTUS 09/68745. 156004.doc • 388- 201143790 Illustrative Examples of QL-Υ In some embodiments of the invention, glycoside The superfamily peptide conjugate can be represented by the following formula:

Q-L-Y wherein Q is a glycoside superfamily peptide, Y is an NHR ligand, and l is a bonding group or a bond. In a particular aspect, Q comprises an amino acid sequence based on the amino acid sequence of native human GLP-1 (SEQ ID NO.: 1603). In some aspects, q comprises a modified amino acid sequence of SEQ ID NO: 1603 comprising 1, 2, 3, 4, 5, 6' relative to the native human GLP-1 sequence (SEQ ID NO: 1603) 7, 8, 9, 10, 11, 12, 13, 14, 15 and, in some cases, 16 or more (eg 17, 18, 19, 20, 21, 22, 23, 24, 25, etc.) amino acid modification, and up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9 or up to 10 Amino acid modification (eg, deuteration, alkylation, PEGylation, truncation at the C-terminus, substitution). For example, q can be GLP-1 (Aib2E16Cex K40) (SEQ ID NO.: 1647), GLP-1 (Aib2A22Cex K40) (SEQ ID NO.: 1648) 'dGLP-lCA'Aib^Cex K40) (SEQ ID NO.: 1649) 'GLP-1 (Aib2E16C24 (PEG-40 kDa) Cex K40) (SEQ ID NO.: 1650). (In a particular aspect, Y is a steroid or a derivative thereof' and acts on estrogen receptors, androgen receptors, glucocorticoid receptors or RAR-related orphan receptors. In some embodiments, Y contains permission Or promoting the structure of agonist activity of 156004.doc-389-201143790 for estrogen receptor, androgen receptor, glucocorticoid receptor or RAR-related orphan receptor, while in other embodiments, γ is estrogen An antagonist of the receptor, androgen receptor 'glucocorticoid receptor or RAR-related orphan receptor. For example, Y can be estradiol, estrone or cholesterol.

In the special state, 'L is stable in vivo. In some embodiments, L comprises, for example, a guanamine, an ether, a urethane, or a thioether. In an alternative aspect, L· can be hydrolyzed in the / tongue. In some embodiments, the ester comprises an ester, an anhydride or a thioester. In other aspects, L is metastable in vivo. In some aspects, 'L has acid instability (e.g., contains a hydrazine moiety), reduction instability (e.g., comprises a disulfide moiety), or enzyme instability (e.g., comprises a cathepsin _ B cleavable moiety). Non-limiting examples of GLp.1-based glycosidic superfamily based binding to estradiol via a stable linkage are shown below (SEQ ID NO.: 1651-1654, 1667).

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• WCJddvowwdoo^AIMVIdm^vvommlAWSA a s lu.ioLU-I^N_HL· awljl Om-IP^N— xz h-mhz o(oo99I,^99l.OMaIa3s)-e-^ 156004.doc 397- 201143790

156004.doc -398- 201143790 In some embodiments, any of SEQ ID NO.: 1-760, 801-919, 1〇〇ι_ 1275, 130l-i371, 1401_1518, 16〇1_1646 may be substituted for the above illustration SEQ ID NO.: 1647-1650 in the Examples. The data herein demonstrates that the combination comprising the glycosidic superfamily peptide (Q) and estrogen (Υ) of the present invention has synergistic pharmacology. The Q portion of these conjugates can be used to direct the estrogen moiety of the conjugate to the desired target away from the typical gynecological tissue to improve glycemic control and energy homeostasis, with therapeutic indices being greatly enhanced. Sputum beta cell dysfunction is characterized by loss of insulin biosynthesis and secretion and loss of functional beta cell mass due to beta cell apoptosis. This cell death is caused by chronic glucose and lipid oxidation (glycolipid toxicity) and compensatory function. Caused by hyperthyroidism (ER stress). Since type 2 diabetes is secondary to ρ cell dysfunction, strategies aimed at protecting insulin-producing beta cells from apoptosis or restoring beta cell functional quality represent an important opportunity for therapeutic intervention in the treatment of type 2 diabetes. Estrogen has a robust anti-apoptotic effect on rodent and human beta cells as well as other tissues in vivo. The extra-pancreatic function of estrogen in the liver to inhibit fat production and restore insulin sensitivity can indirectly improve beta cell function. It also acts on the lower part of the thalamus to reduce food intake and increase energy consumption. However, these estrogen effects may be detrimental to gynecological target tissues, as hormone replacement therapy has been shown to increase breast cancer incidence. Without wishing to be bound by any particular theory, it may be beneficial to selectively direct the action of estrogen to the sputum cells, the liver, and/or the hypothalamus. The clinical application of estrogen is limited by 156004.doc -399- 201143790 due to concerns about its carcinogenic potential and gynecological effects. To enhance the therapeutic index of estrogen, the inductive insulin-based conjugates of the invention allow estrogen to be preferentially targeted to the desired tissue with minimal effect on the breast and endometrial tissue. The data in the examples herein indicate that the combination of a glycoside superfamily peptide and estrogen controls glycemic control (eg, as measured by a decrease in blood glucose levels) and energy homeostasis (eg, as measured by body weight and/or fat mass). It has a beneficial synergistic effect achieved by a combination of insulin-promoting and assimilation activities on pancreatic beta cells and an appetite-lowering effect on the hypothalamus. To study the ability of various components of the conjugate (eg, Glp-1 moiety and estrogen moiety) to regulate blood glucose and body weight, a set of peptide-estrogenic conjugates are synthesized, which range from 0.1% to 100% or more in vitro. It has complete GLP-1 agonism and has linker chemistry (stable, unstable and metastable) that makes differential release of estrogen in plasma. The specific release of estrogen has been determined to vary widely over a wide range of stable chemical forms to other forms of complete release of estrogen within hours. For example, in diet-induced obese mice, the stable-linked estrogen το-full-active GLP-1 agonist consistently proved to be more effective in lowering blood glucose and body weight than the GLP-1 control. Hormone-peptide conjugates have been shown to lack typical estrogenic activity as assessed by the lack of uterotrophic activity in ovariectomized mice, whereas unstable estrogen-peptide conjugates exhibit vegetative activity on the uterus. Chemical derivatives that reject GLpq agonism and/or render beach hormone unstable in plasma exhibit lower efficacy than stable GLP-1/estrogen conjugates, indicating the presence of a combination of GLP-1 and targeted estrogen Achieve excellent blood sugar and weight loss. I56004.doc •400·201143790 prepared; 丨" steady-state peptide-estrogen conjugate is stable in plasma, but can release estrogen after internalization of cells. With a metastable bond, these glycosidic superfamily/estrogen conjugates can reduce blood sugar levels and body weight to a greater extent than conjugates with unstable linkages, while lacking harmful subordinates Nutritional activity. Stable or metastable homeostasis linked to estrogen, the glycosidic superfamily is enhanced in reducing the body weight, food intake, & fat quality of non-diabetic obese mice when compared to appropriate controls. efficacy. • The pharmacologically unstable combination does not have this enhanced effect, and this enhanced effect is not observed for the conjugate that is intentionally inactivated by the glycoside superfamily peptide. The stable linkage of estrogen to the glycoside superfamily peptide and the metastable linkage are devoid of estrogenic activity relative to the unstable conjugate, and contrary to the unstable conjugate, do not present uterine growth, in general, The results of these studies indicate that the stable linkage and metastable linkage of the glycoside superfamily peptide/estrogen conjugate of the present invention have an enhanced effect on metabolically indeficient obese mice, and the drug of the unrestricted female φ hormone Signs of typical estrogen effects for use In an exemplary embodiment, the conjugates are suitable for treating any of the conditions described herein, including but not limited to, hyperglycemic medical conditions, obesity, metabolic syndrome, and NAFLD. Pharmaceutical Compositions Salts In some embodiments, the Q-L-Y conjugates described herein are in the form of a salt, such as a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound which retains the biological activity of the parent compound and is not biologically or otherwise undesirable in the production of 156004.doc • 401-201143790. These salts can be prepared in situ during the final isolation and purification of the conjugate, or separately by reacting the free tester with the appropriate alpha acid. The various compounds disclosed herein are capable of forming acid salts and/or salts due to the presence of amine groups and/or groups or the like. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyric acid Salt, camphorate, camphor sulfonate, digluconate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, thiocyanate, hydrochloride, hydrobromide, hydrogen Iodate, 2-hydroxyethanesulfonate (hydroxyethylsulfonate), lactate, maleate, methanesulfonate, final acid salt, 2-naphthalenesulfonate, oxalic acid Salt, palmitate, pectate, peroxosulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, Phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Salts derived from inorganic acids include hydrochlorides, hydrobromides, sulfates, nitrates, phosphates and the like. Salts derived from organic acids include acetate, propionate, glycolate, propionate, oxalate, malate, malonate, succinate, maleate, reverse Oleate, tartrate, citrate, benzoate, cinnamate, mandelate, methane sulfonate, ethane sulphonate, p-toluene sulphonate, salicylate and the like . Examples of acids which can be used to form pharmaceutically acceptable acid addition salts include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and organic acids such as grass 156004.doc • 402·201143790 acid 'cis. Aenedioic acid, succinic acid and citric acid. The addition salt can also be prepared in situ during the final separation and purification of the source of salicylic acid or by the carboxylic acid-containing moiety with a suitable base such as a hydroxide of a pharmaceutically acceptable metal cation, carbonic acid Salt or bicarbonate) or prepared by reaction with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal based cationic salts such as lithium, sodium, potassium, calcium, magnesium and aluminum salts, and the like; and non-toxic four Grade ammonia and amine cation salts, especially including ammonium salts, tetra-ammonium salts, tetra-ethylammonium salts, cerium ammonium salts, di-ammonium salts, tri-ammonium salts, tri-ethyl sulphate salts, di-ethyl salt and bis-salt salts. Other representative organic amines suitable for use in forming an addition salt include, for example, ethylenediamine, ethanolamine, diethanolamine, pietan, sulphonide, and the like. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, and tertiary amines. Further, the 'basic nitrogen-containing group can be quaternized to a low-carbon alkyl radical such as sulfhydryl, ethyl, propyl and butyl chloride, bromide and iodide; the long chain Halides such as sulfhydryl, lauryl, tetradecyl and octadecyl oxime, bromide and iodide; arylalkyl amides such as benzyl and phenethyl bromide and others. Thereby a water-soluble or oil-soluble or dispersible product is obtained. Formulations A pharmaceutical composition is provided according to some embodiments, wherein the composition comprises a Q-L-oxime conjugate of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutical composition may comprise any pharmaceutically acceptable ingredient, including, for example, an acidulant, an additive, an adsorbent, an aerosol agent, 156004.doc • 403-201143790, a venting agent, a test agent, an anti-caking agent. Agent, anticoagulant, antimicrobial preservative, antioxidant, preservative, matrix, binder, buffer, chelating agent, coating agent, coloring agent, desiccant, detergent, diluent, cleaning agent, disintegrating agent , dispersing agents, dissolution enhancers, dyes, emollients, emulsifiers, emulsion stabilizers, fillers, film formers, flavor enhancers, flavoring agents, flow enhancers, gelling agents, granulating agents, moisturizers, Lubricants, mucoadhesives, ointment bases, ointments, oily vehicles, organic tests, tablet bases, pigments, plasticizers, polishes, preservatives, tongs, skin penetration agents, solubilizers, solvents, stabilizers, Suppository base, surfactant, surfactant, suspending agent, sweetener, therapeutic agent, thickener, tonicity agent, toxic agent, viscosity enhancer, water absorbent, water miscible cosolvent, water softener or wet Agents. In some embodiments, the pharmaceutical composition comprises any one or combination of the following components: gum arabic, ethyl sulfonate sulfamate, acetyl citrate tributyl, ethionyl triethyl citrate, agar, Albumin, alcohol, dehydrated alcohol, denatured alcohol, dilute alcohol, oleic acid, alginic acid, aliphatic polyester, alumina, sulphate, aluminum stearate, gelatinous starch, α-amylose, ascorbic acid, ascorbic acid Palmitate, aspartame, bacteriostatic water for injection, bentonite, soap clay, gasified benzalkonium chloride, benzethon, benzoic acid, benzyl alcohol, phenyl benzoate, bromide Butylated methoxymethoxybenzene, butylated transmethyl toluene, butyl paraben, sodium butyl paraben, calcium alginate, calcium ascorbate, calcium carbonate, calcium cyclohexyl sulfonate, anhydrous Dicalcium phosphate, dehydrated dicalcium phosphate, tricalcium phosphate, calcium propionate, osmanthus acid, calcium sorbate, calcium stearate, calcium sulfate, calcium sulfate hemihydrate 156004.doc 201143790, canola oil, Carbomer, carbon dioxide, calcium carboxymethyl cellulose , sodium carboxymethyl cellulose, β-carotene, carrageenan, castor oil, hydrogenated onion oil, cationic emulsified enamel, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, microcrystalline fiber , powdered cellulose, phthalated microcrystalline cellulose, sodium carboxymethyl cellulose, whale stearyl alcohol, hexadecyl bromide, hexadecanol, chlorhexidine, gas Alcohol, chlorinated phenol, cholesterol, chlorhexidine acetate, chlorhexidine gluconate, chlorhexidine hydrochloride, difluoroethane (HCFC), difluorodecane, chlorofluorocarbon (CFC), gas benzene Oxyethanol, gas diterpene phenol, corn syrup solid, anhydrous citric acid, citric acid monohydrate, cocoa butter, coloring agent, corn oil 'cotton oil, glutinous rice, lenient, neighboring, expecting 、, cross-linking slow sodium cellulose, cross-linked polyvinylpyrrolidone, cyclohexylamine sulfonic acid, cyclodextrin, glucose binder, dextrin, dextrose, anhydrous dextrose, diazolidinyl Urea), dibutyl phthalate, dibutyl sebacate, diethanolamine, diethyl phthalate Difluoroethane (HFC), dimethyl·clothese, cyclodextrin-type compounds (such as Captisol®), diterpene ether, dimethyl phthalate, dipotassium edetate, disodium edetate , diammonium hydrogen phosphate, calcium docusate, potassium docusate, sodium docusate, dodecanoic acid dodecyl ester, broadened lauryl trimethyl ammonium, disodium calcium edetate, edetate, Portuguese Ethylamine, ethanol, ethyl cellulose, ethyl gallate, ethyl laurate, ethyl malt, ethyl oleate, ethyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, Ethyl p-hydroxybenzoate, ethyl vanillin, fructose, liquid fructose, ground fructose, pyrogen-free fructose, powdered fructose, fumarate & gelatin, glucose, liquid glucose, saturated plant fatty acid glycerin 156004.doc -405· 201143790 Ester mixture, glycerin, glyceryl phthalate, glycerol monooleate, glyceryl monostearate, self-emulsifying glyceryl monostearate, glyceryl palmitate, gan Amino acid, monool, tetrahydroethylene glycol, guar gum, heptaoxypropane (HFC), hexadecanol bromide Methylammonium, high fructose syrup, human serum albumin, hydrocarbon (HC), dilute hydrochloric acid, hydrazine-type hydrogenated vegetable oil, hydroxyethyl cellulose, 2-ethyl-β-cyclodextrin, propyl propyl cellulose, Low-substituted propyl propyl cellulose, 2-hydroxypropyl-β-cyclodextrin, hydroxypropyl methylcellulose, hydroxypropyl fluorenyl phthalate, imidazolidinyl urea, blush, ion Exchange agent, iron oxide, isopropanol, isopropyl myristate, isopropyl palmitate, isotonic saline, kaolin, lactic acid, lactitol, lactose, lanolin, lanolin alcohol, anhydrous lanolin, egg Phospholipids, magnesium aluminum silicate, magnesium carbonate, normal magnesium carbonate, anhydrous magnesium carbonate, magnesium carbonate hydroxide, magnesium hydroxide, magnesium lauryl sulfate, magnesium oxide, magnesium citrate, magnesium stearate, three Magnesium citrate, anhydrous magnesium tricaprate, malic acid, malt, maltitol, maltitol solution, maltodextrin, malt, maltose, mannitol, medium chain triglyceride, glucosamine, mint Alcohol, methyl cellulose, methyl methacrylate, methyl oleate, p-hydroxyl Methyl formate, potassium hydroxybenzoate, sodium hydroxybenzoate, microcrystalline cellulose and sodium sulfonate, mineral oil, light mineral oil, mineral oil and lanolin alcohol , oil, eucalyptus oil, monoethanolamine, montmorillonite, octyl gallate, oleic acid, palmitic acid, paraffin, peanut oil, petrolatum, petrolatum and lanolin alcohol, pharmaceutical glaze, phenol, liquefied phenol, phenoxy Ethanol, this oxypropanol, this ethanol, phenylmercuric acetate, phenylmercuric acid, phenylmercuric acid, polacrilin, polakolin potassium, poloxamer 156004.doc •406- 201143790 (poloxamer), polydextrose, polyethylene glycol, polyethylene oxide, polypropylene kSa, polyethylene-polyoxypropylene-enephrass polymer, polymethyl methacrylate, polyoxyethylene oxime Bismuth, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyvinyl alcohol, polyethylene pyrrolidone, potassium alginate, potassium benzoate, carbonic acid Potassium hydrogen, potassium bisulfite, chlorination clock, citric acid unloading, anhydrous potassium citrate, potassium hydrogen hydride, partial sulfite Acid hydrogen unloading, acid-lowering dihydrogen unloading, propionic acid unloading, sorbic acid unloading, poly-dimensional _, propanol, propionic acid, carbonic acid propylene vinegar, propylene glycol, alginic acid propylene glycol, propyl gallate, p-hydroxyl Propyl benzoate, propyl hydroxy succinate, sodium propyl benzoate, protamine sulfate, rapeseed oil, Ringer's solution, saccharin, ammonium saccharin, saccharin Calcium, saccharin sodium, safflower oil, saponite, gold albumin, sesame oil, colloidal Shishi stone, colloidal silica dioxide, sodium alginate, sodium ascorbate, sodium benzoate, sodium hydrogencarbonate, sodium hydrogen sulfite, gas Sodium, anhydrous sodium citrate, dehydrated sodium citrate, sodium chloride, hexamethylene hexanoate, sodium edetate, sodium decyl sulfate, sodium lauryl sulfate, sodium metabisulfite, acid Hydrogen disodium, sodium dihydrogen phosphate, trisodium citrate, anhydrous sodium propionate, sodium propionate, sodium sorbate, sodium starch glycolate, sodium stearate, sodium sulfite, sorbic acid, sorbitan Alcohol ester (sorbitan fatty acid ester), sorbitol, 70 ° /. Sorbitol solution, soybean oil, cetyl wax, starch, corn starch, potato starch 'pregelatinized starch, bactericidal corn starch, stearic acid, purified stearic acid, stearyl alcohol, sucrose, sugar, compressible sugar, Sugar powder (confecti〇ner, s sugar), sugar pills, invert sugar, sucrose-invert sugar polymer (Sugartab), sunset yellow FCF, synthetic paraffin, talc, tartaric acid, tartrazine, tetrafluoroethane 156004.doc • 407- 201143790 (HFC), cocoa butter, thiomersal, titanium dioxide, alpha tocopherol, tocopherol acetate, tocopheryl succinate, beta-tocopherol, δ-tocopherol, gamma-tocopherol, tragacanth, three Glyceryl acetate, tributyl citrate, triethanolamine, triethyl citrate, tridecyl-β-cyclodextrin, trimethylstilbene tetraammonium bromide, tricarboxymethylaminomethane buffer (tris buffer) ), trisodium edetate, vanillin, type I hydrogenated vegetable oil, water, soft water, hard water, carbon dioxide-free water, pyrogen-free water, water for injection, sterile inhalation water, sterile water for injection, sterile irrigation water, butterfly, Anionic emulsified enamel, Brazilian palm quinone, Cationic emulsifying wax, cetyl ester wax, microcrystalline wax, nonionic emulsifying wax, suppository, white peony, astragalus, white petrolatum, lanolin, xanthan gum, xylitol, zein, c Zinc acid, salt, zinc stearate, or //<3^2 00 free of Pharmaceutical Excipients, 3rd edition, AH Kibbe (Pharmaceutical Press, London, UK, 2000) (which is cited in full by Any of the excipients incorporated herein. And Pharmaceutical Sciences, 16th Ed., EW Martin (Mack Publishing Co., Easton, Pa., 1980), which is incorporated herein by reference in its entirety, discloses the entire disclosure of Components and known techniques for their preparation. In addition to any conventional agents that are incompatible with pharmaceutical compositions, they are intended for use in pharmaceutical compositions. Supplementary active ingredients can also be incorporated into the compositions. In some embodiments, the above components may be present in the pharmaceutical composition at any concentration, such as at least A, wherein A is 0.0001% w/v, 0.001% w/v, 0.01% w/v, 0.1% w/v, 1% w/v, 2% w/v, 5% w/v, 10% w/v, 20% w/v, 30% w/v, 40% w/v, 50% w/v, 60 % 156004.doc 408- 201143790 w/v, 70% w/v, 80% w/v or 90% w/v. In some embodiments, the above components may be present in the pharmaceutical composition at any concentration, such as up to B, wherein B is 90% w/v, 80% w/v, 70% w/v, 60% w/v, 50% w/v ' 40% w/v ' 30% w/v ' 20% w/v ' 10% w/v ' 5% w/v ' 2% w/v, 1% w/v, 0.1% w/v, 0.0011⁄4 w/v or 0.0001%. In other embodiments, the above components may be present in the pharmaceutical composition at any concentration ranging, such as from about A to about B. In some embodiments, A is 0.0001% and B is 90%. The pharmaceutical compositions can be formulated to achieve a physiologically compatible pH. In some embodiments, the pH of the pharmaceutical composition can be at least 5, at least 5.5, at least 6, at least 6.5, at least 7, at least 7.5, at least 8, at least 8.5, at least 9, at least 9.5, at least 10, or at least 10.5. Up to and including pH 11, depending on the formulation and route of administration. In certain embodiments, the pharmaceutical compositions can include a buffer to achieve a physiologically compatible pH. Buffering agents can include any compound that is capable of buffering at the desired pH, such as phosphate buffers (eg, PBS), triethylamine, tris-carbyl decane, Tris, N-di(hydroxyethyl) ) Biceine, TAPS, tricine, HEPES, TES, MOPS, PIPES, dicaprate, MES and other buffers. In certain embodiments, the buffer has a concentration of at least 0.5 mM, at least 1 mM, at least 5 mM, at least 10 mM, at least 20 mM, at least 30 mM, at least 40 mM, at least 50 mM, at least 60 mM, at least 7 〇 mM, at least 80 mM, at least 90 mM, at least 100 mM, at least 120 mM, at least 150 mM, or at least 200 mM. In some embodiments, the concentration of the buffer is at most 300 mM (eg, at most 200 mM, at most 1 〇〇 156 004. doc • 409-201143790 mM, at most 90 mM, at most 80 mM, at most 70 mM, at most 60 mM, Up to 50 mM, up to 40 mM, up to 30 mM, up to 20 mM, up to 1 mM, up to 5 mM, up to 1 mM). Routes of Administration The following discussion of the route of administration is provided solely to illustrate the exemplary embodiments and should not be construed as limiting the scope of the invention in any way. Formulations suitable for oral administration may consist of a liquid solution, such as an effective amount of a combination of the invention dissolved in a diluent such as water, physiological saline or orange juice; (b) capsules, medicinal lozenges, lozenges , mouth-containing tablets and sugar-coated tablets, each containing a predetermined amount of the active ingredient, in solid or granule form; (phantom powder; (d) a suspension in a suitable liquid; and (e) a suitable emulsion. The liquid formulation may be added With or without the addition of a pharmaceutically acceptable surfactant, a diluent such as water and an alcohol such as ethanol, benzyl alcohol and polyvinyl alcohol may be used. The capsule form may be a generally hard or soft shell gelatin type containing, for example, interfacial activity. Agents, lubricants and inert fillers, such as lactose 'sucrose, calcium phosphate and corn starch. Tablet forms may include one or more of the following: lactose, sucrose, mannitol, corn starch, potato starch, oleic acid, micro Crystal cellulose, gum arabic, gelatin, guar gum, colloidal cerium oxide, crosslinked strontium cellulose, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid and Excipients, colorants, diluents, buffers, disintegrating agents, wetting agents, preservatives, flavoring agents, and other pharmacologically compatible excipients. The ingot form may be included in the perfume (usually sucrose) And a combination of the present invention in a gum arabic or tragacanth, and a tablet, emulsion, 156004.doc-410. 201143790 in an inert matrix such as gelatin and glycerin or sucrose and gum arabic. Glues and analogs thereof, which additionally contain such excipients as are known in the art. The combinations of the invention, alone or in combination with other suitable components, can be delivered via the pulmonary administration and can be formulated into aerosols. Formulations for administration via inhalation. Such aerosol formulations can be placed into acceptable pressurized propellants (such as di- nitro-methane, propane, nitrogen, and the like), which can also be formulated to A drug in a non-pressurized formulation in a nebulizer or nebulizer. The spray formulations can also be used to spray a mucosa. In some embodiments, the conjugate is formulated into a powder blend or microparticle or nanoparticle. Particles. Suitable for lungs Formulations are known in the art. See, for example, Qian et al, Int J Pharm 366: 21 8-220 (2009); Adjei and Garren, Pharmaceutical Research, 7(6): 565-569 (1990); Kawashima et al. Person, J Controlled Release 62 (1-2): 279-287 (1999); Liu et al, Pharm Res 10(2): 228-232 (1993); International Patent Application Publication No. w/2007/133747 and WO 2007/141411. Formulations suitable for parenteral administration include: aqueous and non-aqueous isotonic sterile 'primary solutions, which may contain antioxidants, buffers, bacteriostatic agents and make the formulation acceptable The isotonic solute of the blood; and the aqueous and non-aqueous I. s. suspensions, which may include suspending agents, solubilizers, thickeners, stabilizers, and preservatives. The term "parenteral" means not passing through the digestive tract but by some other means such as subcutaneous, intramuscular, intraspinal or intravenous. The combination of the present invention may be added with or without the addition of a pharmaceutically acceptable interface active hydrazine (such as soap or detergent), a suspending agent (such as gelatin, carbomer, methylcellulose, light propyl methylcellulose). Or methicone or emulsifier and its 156004.doc -411 · 201143790 in a pharmaceutical adjuvant, together with a physiologically acceptable diluent, such as a sterile liquid or liquid Compounds, including water; physiological saline; aqueous dextrose and related sugar solutions; alcohols such as ethanol or decyl alcohol; glycols such as propylene glycol or polyethylene glycol; disulfoxide; glycine; ketal, Such as 2,2-dimercapto-153-dioxolan-4-methanol; ether; poly(ethylene glycol) 4 hydrazine; oil; fatty acid; fatty acid ester; or glyceride, or acetylated fatty acid glycerin g purpose. Oils useful in parenteral formulations include petroleum, animal, vegetable or synthetic oils. Specific examples of the oil include peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, petrolatum oil, and mineral oil. Fatty acids suitable for use in parenteral formulations include oleic acid, stearic acid and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty acid alkali metal salts, money salts and diethanolamine salts' and suitable cleaning agents include (a) cationic detergents, such as halogenated dimethyl diketone bases and toothed burns. (b) anionic detergents; (b) anionic detergents such as alkyl, aryl and dilute acid vinegar, alkyl, olefin, hydrazine and monoglyceride sulfate, and sulfosuccinate; Ionic cleaners, such as fatty amine oxides, fatty acid alkanolamines and polyoxyethylene polypropylene copolymers; (d) amphoteric detergents such as alkyl-β-aminopropionates and 2-alkyl-imidazoles a quaternary ammonium salt; and (e) a mixture thereof. The parenteral formulation typically contains from about 0.5% to about 25 weight percent of the QLY conjugate of the invention in solution. Preservatives and buffering agents may be employed. To minimize or eliminate irritation to the injection site, the compositions may contain one or more of a non-ionic interface activity 156004.doc • 412-201143790 having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant + soil in the formulation is usually between about 5 wt%/〇 to about Within a range of 15% by weight. Suitable for the boundary < surfactants include polyethylene glycol sorbitan fatty acid vinegar, such as sorbitan monooleic acid vinegar, and Ethylene Ethylene and Ethylene Acetate High molecular weight adduct 1 of the hydrophobic matrix formed by condensation with propylene glycol can be present in unit dose or multi-dose sealed containers (such as ampoules and vials) and can be stored in cold-drying (dry) conditions. Next, it is only necessary to add (iv) a liquid excipient (such as water) for injection prior to use. The injectable solutions and suspensions can be prepared from sterile powders, granules and lozenges of the type previously described. Injectable formulations In accordance with the present invention, the requirements for an effective carrier for an injectable composition are well known to those of ordinary skill (see, for example, Pharmaceutics and Pharmacy Practice, JB Lippincott).

Company, Philadelphia, PA, Banker and Chalmers, pp. 238-more U9 2~) ‘Anti-ASHP Handbook on Injectable Drugs, Toissel, 4th edition, pp. 622-630 (1986)). Further, the combination of the present invention can be formulated into a suppository for rectal administration by mixing with a variety of substrates such as an emulsifying base or a water-soluble base. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations, which, in addition to the active ingredient, are also known in the art. These carriers. Those skilled in the art will appreciate that in addition to the pharmaceutical compositions described above, the combinations of the present invention may also be formulated as inclusion complexes, such as cyclodextrin inclusion complexes or liposomes. Dosage 156004.doc • 413- 201143790 The QL-Υ conjugate of the present invention is suitable for use in a method for treating a disease or a medical condition in which a glycosidic receptor agonist, GLP-1 Receptor agonism, GIP receptor agonism, coglycoceptor/GLP-1 receptor co-activism, glucoglucagon receptor/GIp receptor co- agonism, GLP-1 receptor/GIP Receptor co-activism or the triple agonist effect of the glycoside receptor/(1 _ 1 receptor/GIP receptor). The amount or dose of the conjugate of the invention administered for the purposes of the present invention It should be sufficient to achieve, for example, a therapeutic or prophylactic response in an individual or animal over a reasonable time frame. For example, the dose of the conjugate of the invention should be sufficient for about 分钟 to 4 minutes, 1 to 4 hours or 1 to the time after administration. Stimulate cellular cAMp secretion or reduce mammalian blood glucose, fat, food intake or body weight as described herein for a period of 4 weeks or more (eg, 5 to 2 weeks or more). In some embodiments, the period may be even longer. The dosage will be the result of a particular combination of the invention. The effect is determined by the condition of the animal (e.g., human) and the weight of the animal being treated (e.g., human). A variety of assays for determining the dose are known in the art. For the purposes herein, the following assays can be used to determine The initial dose administered to a mammal, the test comprising comparing the extent of the decrease in the amount of sugar 3 after administration of a predetermined dose of the conjugate of the invention to a group of mammals each administering a different dose of the combination. The extent to which the blood glucose level is reduced after a dose can be detected by methods known in the art, including, for example, the methods described herein. The dose of the conjugate of the invention is also determined by the specifics of the invention. The existence, nature, and extent of any adverse side effects of conjugate administration are determined. 156004.doc -414· 201143790 Often, the attending physician will consider a variety of factors (such as age, weight, general health, diet, gender, The combination of the invention, the route of administration and the severity of the condition to be treated, the combination of the invention is determined to treat each individual By way of example and not intended to limit the invention, the dosage of the combination of the invention may be from about 0.0001 to about 1 g per kilogram of body treated per day, from about 1 to about 10,000 per kilogram of body weight per day. 〇〇1 g, or about 1 mg to about 1 g per kilogram of body weight per day. In some embodiments, the pharmaceutical composition comprises any combination not disclosed herein that is suitable for administration to a patient. In some embodiments, the conjugate has at least about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%. Purity, and pharmaceutically acceptable diluents, carriers or excipients. In some aspects, the pharmaceutical compositions comprise a combination of the invention at a concentration of at least A, wherein a is about 0.001 mg/ml, about 〇.〇1 mg/ml, about mgmg/mi, about 5 mg/ml, about 1 mg/mi, about 2 mg/m, about 3 mg/ml, about 4 mg/mi, φ about 5 mg /ml, about 6 mg/ml, about 7 mg/ml, about 8 mg/ml, about 9 mg/ml, about 1 mg/ml, about 11 mg/ml, about 12 mg/mi, about 13 mg/ Ml, about 14 mg/ml, about 15 mg/ml, about 16 mg/ml About 17 mg/ml, about 18 mg/ml, about 19 mg/ml, about 20 mg/ml, about 21 mg/ml, about 22 mg/ml, about 23 mg/ml, about 24 mg/ml, about 25 Mg/ml or above 25 mg/ml. In some embodiments, the pharmaceutical composition comprises a combination of concentrations up to B, wherein B is about 3 mg/ml, about 25 mg/ml, about 24 mg/m, about 23 mg/ml, about 22 mg/ Ml, about 21 mg/ml, about 20 mg/ml, about 19 mg/ml, about 18 mg/ml, about 17 156004.doc -415- 201143790 mg/ml, about 16 mg/ml, about 15 mg/ml , about 14 mg/ml, about 13 mg/ml, about 12 mg/ml, about 11 mg/ml, about 10 mg/mi, about 9 mg/ml, about 8 mg/ml, about 7 mg/ml, About ό mg/ml, about 5 mg/ml, about 4 mg/ml, about 3 mg/m, about 2 mg/m, about 1 mg/mi or about 0.1 mg/ml. In some embodiments, the compositions may contain a combination of concentrations ranging from 8% to mg mg/ml, such as from about 0.001 to about 3 〇 mg/ml. Dry Forms It will be readily apparent to one of ordinary skill in the art that the guanidine-ruthenium conjugates of the present invention can be modified in any number of ways to enhance the therapeutic or prophylactic efficacy of the conjugates of the invention via modification. For example, the conjugates of the invention may be directly or indirectly linked via a linker to a dry-portion K-conjugate (eg, a glycosyl conjugate as described herein) for binding to a targeting moiety. It is known in the art. See, for example, Wadhwa et al., j Drug Targeting, 3, 1 U_127 (1995) and U.S. Patent No. 5, 〇 87 616, the term "Cycle." used herein to specifically recognize and bind to the cell surface. Any molecule or drug of the receptor is thus directed to direct delivery of the conjugate of the invention to a cell population on the surface representing the receptor (glycoside receptor, GLIM receptor). But not limited to antibodies or fragments thereof, flavonoids, growth factors, cytokines, and any other natural or non-natural ligands that bind to cell surface receptors (eg, epidermal growth factor receptor (egfr), tau cell receptors Body (TCR), B cell receptor (BCR), CD28, platelet-derived growth factor receptor (PDGF), type II receptor (nAchR), etc. As used herein, "linker" is used to A group of bonds, molecules, or knives in which two separate entities bind to each other. The linker provides an optimal spacing between the two entities, or may be 156004.doc 201143790 further provides an unstable linkage that allows the two entities to be separated from one another. The unstable bond includes a photocleavable group, an acid labile moiety, a base labile moiety, a hydrolyzable group, and an enzyme cleavable group. In some embodiments, the term "linker" refers to any agent or molecule that bridges a conjugate of the invention to a targeting moiety. One of ordinary skill in the art will recognize that the conjugates of the invention are not required for the function of the conjugates of the invention and can serve as a site for ligating the linker and/or the desired portion of the targeting moiety, with constraints such as linkers and/or targeting. Part of the ability to interfere with the function of the conjugate of the invention, i.e., to stimulate the ability of cells to secrete cAMP, treat diabetes or obesity, after attachment to a conjugate of the invention. A person skilled in the art can recognize that the peptide (q) of the present invention is not a peptide of the present invention (for example, a glycoside agonist peptide, a glycosidic antagonist peptide, a GLP-1 agonist peptide, a GIp agonist peptide or The function of a combination of any of the above) is required and can serve as a site for ligating the linker and/or the desired portion of the stem portion, with the proviso that the linker and/or the targeting moiety are linked to the peptide of the present invention. (Q) does not interfere with the function of the peptide of the present invention. A controlled release formulation or 'glycoside conjugate as described herein can be modified into a reservoir form to control the release of the conjugate of the invention into its intended body relative to time and location in the body ( See, for example, U.S. Patent No. 15 )). The sump form of the conjugate of the present invention may be, for example, an implantable composition comprising a conjugate of the present invention and a fumarous or non-porous material, such as a polymer, wherein the conjugate of the present invention Degradation or diffusion of the material and/or non-porous material throughout the material. The reservoir is then implanted in the desired location in the body and the inventive combination is released from the implant at a predetermined rate. 156004.doc • 417· 201143790 In certain aspects, the pharmaceutical compositions are modified to have any type of in vivo release profile. In some aspects, the pharmaceutical composition is an immediate release, controlled release, sustained release, extended release, delayed release or biphasic release formulation. Methods of formulating peptides or conjugates for controlled release are known in the art. See, for example, Qian et al., j pharm 374: 46 52 (2〇〇9) and International Patent Application Publication No. WO 2008/130158, No. WO 2004/033036, WO 2000/032218 and WO 1999 /040942 number. The compositions of the present invention may further comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide extended storage and/or delivery. The disclosed pharmaceutical formulations can be administered according to any protocol, including, for example, daily (3 times a day, 3 times a day, 4 times a day, 5 times a day, 6 times a day, 6 times a day), every two days - every time Three days - times, every four days, every five days, every six days, every week - times, every two weeks, once every three weeks, once a month, once every two months 0 Use based on this article for the first time In view of the information, it is contemplated that the QLY conjugates and related pharmaceutical compositions described herein are suitable for use in the treatment of a disease or medical condition in which, for example, a lack of glycosidic receptor, GLP-1 receptor, GIP style Or the activity of the combination of any of the above mentioned factors constitutes a factor in the onset and/or progression of the disease or medical condition. The present invention provides a method for treating or preventing a disease or medical condition of a patient in which the disease or medical condition is lack of GLIM receptor activation and/or glycosidic receptor activation and /156004.doc 201143790 or GIP activation A disease or medical condition associated with the onset and/or progression of a disease or medical condition. The method comprises providing a conjugate according to any of the agents herein to an amount effective to treat or prevent the disease or medical condition. In some embodiments, the disease or medical condition is metabolic syndrome. Metabolic syndrome is also known as metabolic syndrome x, insulin resistance syndrome or Reaven's syndrome, which is a condition involving more than 50,000 Americans. Metabolic syndrome is usually characterized by at least one of the following risk factors Or above the cluster: ()) abdominal obesity (excessive adipose tissue in and around the abdomen); (2) atherogenic dyslipidemia (dyslipidemia including high triglyceride, low HDL cholesterol and high LDL cholesterol, which enhances plaque buildup on the arterial wall); (3) elevated blood pressure; (4) insulin resistance or glucose intolerance, (5) prothrombotic state (eg high fibrinogen or plasmin in the blood) Pro-activator inhibitors υ 及; and (6) pro-inflammatory states (eg, elevated risk factors for C-reactive protein in the blood may include aging, hormonal imbalance, and genetic predisposition. Metabolic syndrome and coronary heart disease and others Increased risk of vascular plaque build-up disorders such as stroke and peripheral (IV) disease (known as atherosclerotic cardiovascular disease (ASCVD)) Guan. Patients with metabolic syndrome can progress from the early onset of resistance to the onset of oxytocin to a fully developed risk of ASCVD. Without any specific theory, insulin resistance, metabolism The relationship between syndrome and vascular disease: may involve one or more coexisting pathogenesis, including insulin-stimulating blood swelling disorder, decreased insulin resistance-related NO availability due to increased oxidative money, and derived from fat cells An abnormality of hormones (such as AFP 156004.doc -419- 201143790) (Lteif and Mather, Can. J. Cardiol 20 (Supplement b): 66B-76B (2004)). Adult treatment according to the 2001 National Cholesterol Education Program The 2001 National Cholesterol Education Program Adult Treatment Panel (ATP III), the presence of any of the following three characteristics of the same individual meets the criteria for metabolic syndrome: (a) abdominal obesity (male waist circumference exceeds 102 cm, and female waist circumference) Peripheral length over 88 cm); (b) serum triglyceride (150 mg/dl or 150 mg/dl or more); (c) HDL cholesterol (male 40 mg/dl) Or 40 mg/dl or less, and women 50 mg/dl 45〇mg/dUx); (d) blood pressure (130/85 or above 130/85); and (e) fasting blood glucose (11〇mg/dl or 110 mg) /dl or higher). According to the World Health Organization (W〇rld Health Organization 'WHO') individuals with high insulin content (either elevated fasting blood glucose or postprandial blood glucose) and having at least two of the following criteria are eligible for metabolic syndrome Guidelines: (a) abdominal obesity (a ratio of waist circumference to hip circumference greater than 0.9, a body mass index of at least 3 〇 kg/m 2 , or a waist circumference measurement greater than 37 吋); (b) showing a triglyceride content of at least 15 〇 mg/di or hdl cholesterol below 35 mg/dl cholesterol range; (c) blood pressure 14 〇 / 9 〇 or 140/90 or higher, or ongoing hypertension treatment (Mathur, RucM, "Metabolic Syndrome," Shiel, Jr., William C., MedicineNet.com, May ii, 2009). For the purposes of this document, an individual is considered to be suffering from metabolic syndrome if the individual meets the criteria of either or both of the criteria set forth by the Adult Cholesterol Education Program of the US National Cholesterol Education Program or the WHO. Without knowing any particular theory, the Q_L_Y conjugate described herein 156004.doc -420. 201143790 is suitable for the treatment of metabolic syndrome. Accordingly, the present invention provides a method of preventing or treating a metabolic syndrome in a subject or alleviating one, two, three or more risk factors thereof, comprising providing the individual with an amount effective to prevent or treat metabolic syndrome or a risk factor thereof The conjugates described herein. In some embodiments, the method treats a hyperglycemic medical condition. In some aspects, the medical condition of hyperglycemia is insulin-dependent or non-insulin-dependent diabetes mellitus, type I diabetes, type π diabetes, or gestational diabetes. φ In some aspects, the method treats hyperglycemic medical conditions by reducing one or more complications of diabetes, including kidney disease, retinopathy, and vascular disease. In some aspects, the disease or medical condition is obesity. In some aspects, obesity is drug-induced obesity. In some aspects, the method treats obesity by preventing or inhibiting weight gain in a patient or promoting weight loss. In some cases, the method treats obesity by suppressing appetite, reducing food intake, reducing the amount of lipid in the patient, or reducing the rate of food transfer through the stomach. Since obesity is associated with the onset or progression of other diseases, the method of treating obesity is further applicable to methods for alleviating complications associated with obesity, including vascular disease (coronary artery disease, stroke, peripheral area). Vascular disease, ischemia-reperfusion, etc., high-grade, type π diabetes mellitus' hyperlipidemia and musculoskeletal diseases. The invention thus provides methods of treating or preventing such obesity-related complications. m The disease or medical condition is non-alcoholic fatty liver disease (nAFLD). NAFLD refers to a wide range of liver diseases ranging from simple fatty liver (steatosis) to non-156004.doc -421 - 201143790 Alcoholic Fatty Hepatitis (NASH) to cirrhosis (irreversible advanced liver disease). At all stages of NAFLD, fat (fat infiltration) accumulates in liver cells. Simple fatty liver is a type of fat (ie, triglyceride) that accumulates abnormally in liver cells without inflammation or garden marks. In NASH, fat accumulation is associated with varying degrees of inflammation (hepatitis) and scarring (fibrosis) in the liver. Inflammatory cells can destroy liver cells (hepatocytes are bad). 8 In the terms "lipid hepatitis" and "fat necrosis", fat refers to fat infiltration, hepatitis refers to inflammation of the liver, and necrosis refers to destruction of liver cells. NASH can eventually lead to scarring of the liver (fibrosis) and then to irreversible late scarring (cirrhosis). Cirrhosis caused by NASH is the late and most severe stage of NaflD. (Mendler, Michel, "Fatty Liver: Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)," Schoenfield,

Edited by Leslie J., MedicineNet.com, August 29, 2005). Alcoholic liver disease or alcohol-induced liver disease covers the following three types of liver diseases that are related to excessive drinking alcohol or pathology caused by excessive consumption of alcohol: fatty liver (steatosis), chronic or acute hepatitis, and cirrhosis. Alcoholic hepatitis can be changed from mild hepatitis (where abnormal laboratory tests are only indications of disease) to severe liver dysfunction, and severe liver dysfunction has the following complications: such as jaundice (skin vapour caused by bilirubin retention) ), hepatic encephalopathy (neurofunction caused by liver failure), ascites (flow volume in the abdomen), esophageal varices bleeding (varicose veins in the esophagus), coagulation abnormalities and coma. Alcoholic hepatitis has the following characteristic appearance in histology: hepatocyte balloon-like degeneration, neutrophilic white blood 156004.doc -422· 201143790 disease and sometimes Mallory body (Mall〇ry b〇dy) (The cell filament protein is abnormally aggregated). Cirrhosis is characterized in that it is characterized by extensive nodules and fibrosis in the liver. (Worman, Howard j., rAlc〇h〇Hc Liver

Disease", Columbia University Medical Center website). Without being bound by any particular theory, the Q_L_Y conjugates described herein are useful for treating alcoholic liver disease, NAFLD, or any stage thereof, including, for example, steatosis, fatty hepatitis, hepatitis, liver inflammation, NASH, cirrhosis, or Its complications. Accordingly, the present invention provides a method of preventing or treating an alcoholic liver disease, NAFLD or any stage thereof in an individual comprising providing to the individual a conjugate as described herein effective to prevent or treat alcoholic liver disease, NAFLD or a stage thereof. Such treatments include inhibition of one, one or more of the following: liver fat content, onset or progression of cirrhosis, onset of hepatocellular carcinoma, signs of inflammation (eg liver enzyme content (eg aspartate) Aminoase AST and / or alanine transaminase ALT or LDH) abnormalities, elevated serum ferritin, elevated serum bilirubin and / or fibrosis _ signs (such as elevated levels of TGF-β). In a preferred embodiment, the Q-L-Y conjugates described herein are used to treat patients who have progressed beyond the range of simple fatty liver (fatty degeneration) and exhibit signs of inflammation or hepatitis. Such methods can cause, for example, a decrease in AST and/or ALT levels. GLP-1 and the incretin analog _4 have been shown to have some neuroprotective effects. The invention also provides the use of a conjugate as described herein for the treatment of a neurodegenerative disease, including but not limited to Alzheimer's disease, Parkinson's disease Symptoms, multiple sclerosis, amyotrophic lateral sclerosis, other myelin deprivation related diseases 156004.doc • 423- 201143790 disease, senile dementia, subcortical dementia, arteriosclerotic dementia, AIDS-related dementia or other dementia , central nervous system cancer, traumatic brain injury, spinal cord injury' stroke or cerebral ischemia, cerebral vasculitis, epilepsy, Huntington's disease, Tourette's syndrome, lattice - Guiliain Barre syndrome, Wilson's disease, pick, s disease, neuroinflammatory disease, encephalitis, encephalomyelitis or viral source I. Sexual or bacterial-derived meningitis, or other central nervous system infections, prion diseases, cerebellar ataxia, cerebellar degeneration, spinal cord cerebellar dementia syndrome, Fried Reich's ataxia, ataxia telangiectasia, spinal dystrophy, progressive pruritus, dystonia, muscle spasm, tremor, retinitis pigmentosa, striatum and substantia nigra Degenerative, mitochondrial myopathy, neuronal waxy lipofuscinosis, liver encephalopathy, renal encephalopathy, metabolic encephalopathy, toxin-induced encephalopathy, and radiation-induced brain injury. In some embodiments, disease or medical condition Hypoglycemia. In some embodiments, the patient is a diabetic and hypoglycemia is induced by administration of a membrane. In a particular aspect, the method comprises providing a combination of the invention in combination with insulin such that The conjugate slows down the hypoglycemic effect of rapid administration of insulin. In some embodiments, the Q_L_Y conjugate is used in a hospital configuration along with parenteral administration of nutrients for non-diabetic patients, for example for receiving parenteral nutrition or Parenteral nutrition patients. Non-limiting examples include surgical patients, comatose patients, gastrointestinal diseases or non-functional gastrointestinal tracts (eg 156004.doc 424-201143790 due to surgical excision as' absorption capacity blockage or disorders, Crohn's disease

John's disease), ulcerative colitis, gastrointestinal obstruction, gastrointestinal fistula, acute pancreatitis, lack of intestinal tract, large gastrointestinal surgery, some congenital gastrointestinal abnormalities, long-term abdominal or surgery-induced short bowel syndrome) Patients, shock patients, and healed (4) patients often receive non-(four) administration of carbohydrates and various combinations of lipids, electrolysis f, mineral f, vitamins and amino acids. Q-L-Y conjugate and parenteral nutrition composition can be administered simultaneously,

Administration at different times (before or after each other), the restriction is 〇忒_; the composition exerts the desired biological effect when the parenteral nutrition composition is being digested. For example, 'parenteral nutrition can be administered i times, 2 times or 3 times a day, while sucrose, conjugates are administered every __ days, three times a week, twice a week, It is administered once a week, once every 2 weeks, once every 3 weeks, or once every month. The terms "treatment" and "prevention" as used herein, and the words derived therefrom, are not necessarily meant to mean a complete or complete treatment or prevention. In fact, there are varying degrees of treatment or prevention that are recognized by the average skilled person as having the potential benefit of a therapeutic effect. In this regard, the method of the present invention can provide any amount of any degree of treatment or prevention of a disease or medical condition of a mammal. In addition, the 4 treatments or pre-treatments provided by the sleeve may include "or a plurality of conditions or symptoms for treating or preventing a disease or medical condition. For example, a method for treating obesity in some embodiments, The method reduces or reduces the patient's food intake. For the purposes of this document, "prevention" may encompass delaying the onset of a disease or its symptoms or condition. For the above treatment methods, the patient is any subject. In some embodiments 156004.doc • 425 · 201143790, the subject is a mammal. The term "mammal" as used herein refers to any vertebrate of the mammalian class including, but not limited to, any monoporous, marsupial, and placental mammal. In some embodiments, the mammal is one of a rodent mammal (such as a mouse and a hamster) and a Logomorpha mammal (such as a rabbit). In some embodiments, the mammal is from Carnivora, including Feline (cat) and Canine (dog). In certain embodiments, the mammal is from Artiodactyla, including cattle and pigs, or from Perssodactyla, including Equine (horse). In some cases, 'mammals are from Primates/Ceboids/Simoids (monkeys) or Anthropoids (humans and apes). In a particular embodiment, the mammal is a human. Combinations The Q-L-Y conjugates described herein can be administered alone or in combination with other therapeutic agents that are intended to treat or prevent any of the diseases or medical conditions described herein. For example, the Q-L-Y conjugates described herein can be co-administered with (simultaneous or sequential) anti-diabetic or anti-obesity agents. Anti-diabetic agents known or under investigation in the art include insulin, leptin, YY (PYY), pancreatic peptide (PP), fibroblast growth factor 21 (FGF21), Y2Y4 receptor agonist, Urea, such as toluene gland (mountain enzyme), acetophenone cyclohexylurea (acesulfame), tolazamide (oxazide), chlorpropamide (special secretion) , gliclazide (Rui Yining), glibenclamide (Daan, glibenclamide, glibenclamide), glimepiride (Marle pancreas) or gliclazide kelong; Nai, such as repaglinide (Nuo and Long) or 156004.doc -426· 201143790 nateglinide (to make sugar release); double sputum, such as bismuth bismuth (Gehuazhi) or phenformin, sold out bite Diketones, such as rosiglitazone (Vatican), glitazone (Etoposide) or troglitazone (Resulin), or other PPARy inhibitors; alpha-glucosidase inhibition that inhibits carbohydrate digestion Agents such as miglitol (Glesset), sugar sulphate (acarbose/baisepine); exenatide (Bermectone) or pramlintide; dipeptidyl peptidase-4 (DPP) -4) Formulations, such as vildagliptin or sitagliptin; SGLT (sodium-dependent glucose transporter 1) inhibitor; glucokinase activator (GKA); glycoside receptor antagonist (gra); or FBPase (fructose) 1,6-bisphosphatase) inhibitor. Anti-obesity agents known or under investigation in the art include appetite suppressants, including phenethylamine-type irritants, phentermine (as appropriate, together with flumethamine or dextroamphetamine), diethylamine phenyl propyl amide ( Tenuate®), phthalocyanine (Prelu_2®, Bontilil®), benzylidene (Didrex®), Meridia® (Reductil®); Rimonabant (Acomplia®), other cannabinoids Body antagonist; acid-regulating hormone; pheroxantine hydrochloride (Prozac); Onisa (topiramate and phentermine), Esserlin (butylamine acetonide and zonisamide) or Kangqu (butyl acetophenone and naltrexone); or lipase inhibitors, similar to Xenical (Roche fresh) or selisestat (also known as ATL-962), or GT 389-255 ° in some implementations In one embodiment, the QLY conjugates described herein are co-administered with a medicament for the treatment of nonalcoholic fatty liver disease or NASH. Agents for the treatment of nonalcoholic fatty liver disease include ursodeoxycholic acid (also known as Actigall, URSO and Ursodiol), metformin (German), rosiglitazone ( Vatican, Clofibrate, Gemfibroz 156004.doc -427· 201143790 (Gemfibrozil), Polymixin B and Betaine. In certain embodiments, the Q-L-Y conjugates described herein are co-administered with a medicament for treating a neurodegenerative disease, such as Parkinson's disease. Anti-Parkinson's agents are further known in the art and include, but are not limited to, levodopa, carbidopa, anti-cholinergic agents, bromocriptine, Pramipexole and ropinirole, amantadine and rasagiiine. In view of the above, the present invention further provides pharmaceutical compositions and kits that additionally comprise one of these other therapeutic agents. Other therapeutic agents can be administered simultaneously or sequentially with the conjugates of the invention. In some aspects, the conjugate is administered prior to the other therapeutic agent, while in other aspects, the conjugate is administered after the other therapeutic agent. The set of QLY conjugates of the present invention can be part of a set according to an embodiment. The form is provided. &' In some embodiments, a kit for administering a Q-L-Y conjugate to a patient in need thereof is provided, wherein the kit comprises a Q-L-Y conjugate as described herein. In one embodiment the device of the composition, such as a female syringe. The set Μ όΐ The set has a Q-L-Y composition group administered to the patient

Like, optionally containing one or more containers, such as syringes, cartridges, wheeled liquid injectors, prefilled pen devices, and lyophilized or aqueous solutions thereof, as small as prefilled with drugs Form of glycoside 156004.doc 201143790 conjugate. In some embodiments, the kit includes instructions for use. The device according to an embodiment' set is an aerosol dispensing device wherein the composition is pre-packaged within the aerosol device. In another embodiment, the kit includes an injector and a needle' and in one embodiment, the sterile glycosidic composition is pre-packaged in a syringe. The following examples are given only to illustrate the invention and not to limit its scope in any way. EXAMPLES Example 1: Peptide Fragments of Synthetic Glycosyl Superfamily Peptides Materials All peptides described herein were guanamiled unless otherwise specified. MBHA (4-mercaptobenzylideneamine polystyrene) resin was used during peptide synthesis. MBHA resin (1〇〇 to 18〇, 1% divinylbenzene (DVB) crosslinked polystyrene; loading: 0-7 to 1.0 mmol/g), Boc protected (tributyl carbamic acid) and Fmoc protected (9-mercaptomethyl carbamic acid) amino acid was purchased from

Midwest Biotech. Solid phase peptide synthesis was performed using a Boc protected amino acid on an Applied Biosystem 430A peptide synthesizer. Fmoc protected amino acid synthesis was performed using an Appiied Biosystems Model 433 peptide synthesizer. In a particular embodiment, the following procedure can be used: General Peptide Synthesis Protocol Using Boc Chemistry Strategy Peptide synthesis was performed using Boc chemistry on an Applied Biosystem Model 430A Peptide Synthesizer. Synthetic peptides were constructed by sequentially adding amino acids to a filter cartridge containing 2 mm 〇l Boc protected amino acids. In particular, 3-(diethoxyphosphoniumoxy)-3H-benzo[(1][1,2,3]triazine-4-156004.doc-429 is used in a single coupling. - 201143790 Synthesis of a ketone (DEPBT) or HBTU as a coupling agent. At the end of the coupling step, the peptidyl-resin is treated with trifluoroacetic acid (TFA) to remove the oxime-protecting group, followed by dimercaptocarboxamide ( DMF) The resin was washed repeatedly and this repeated cycle was repeated for the required number of coupling steps. Boc amino acid and HBTU were obtained from Midwest Biotech (Fishers, IN). The general side bond protecting groups used were: Arg (Tos), Asn ( Xan), Asp (OcHex), Cys (pMeBzl), His (Bom), Lys (2Cl-Z), Ser (OBzl), Thr (OBzl), Tyr (2Br-Z) and Trp (CHO). Boc-Glu (OFm)-OH and Boc-Lys(Fmoc)-OH (Chem-Impex, Wooddale, IL) were used in the amine bridging site. After assembly of the peptide, Fmoc was removed using 20% piperidine treatment. The protecting group for the protected side chain. For internal amidation, a vertical protecting group (eg Glu(Fm), Lys(Fmoc)) is selected for Glu and Lys. After removal of the protecting group and before HF cleavage, as previously Cyclicization (see, for example, international patent application) Initiation of WO 2008/101017. HF treatment of peptidyl-resins. Treatment of peptidyl-resins with anhydrous HF in the presence of p-cresol and dioxon, usually yielding about 350 mg (about 50% yield) The crude peptide from which the protecting group is removed. Specifically, the peptidyl-resin (30 mg to 200 mg) is placed in a hydrogen fluoride (HF) reaction vessel for cracking. Next, 500 μL of p-cresol is added to the vessel. As a cesium ion scavenger. The vessel was connected to an HF system and immersed in a methanol/dry ice mixture. The vessel was evacuated with a vacuum pump and 丨0 mL HF was distilled into the reaction vessel. The peptidyl-resin was stirred at 0 °C. The reaction mixture of HF formed a vacuum after 1 hour' and the HF was quickly withdrawn (10 to 15 minutes). Carefully removed from the vessel and filled with about 35 mL of diethyl ether to precipitate the peptide and extract p-cresol and from 156004.doc • 430-201143790 HF The resulting small molecule organic protecting group is treated. The mixture is filtered using a Teflon filter and repeated twice to remove all excess cresol. The filtrate is discarded. The precipitated peptide is dissolved in about 20 mL 10 % acetic acid (aqueous solution). Collection containing the desired peptide The filtrate was lyophilized. Analytical HPLC analysis of the dissolved crude peptide under the following conditions [4.6 x 30 mm Xterra C8, 1.50 ml/min, 220 nm, A buffer: 0_1% TFA/10% acetonitrile (CH3CN) , B buffer: 0.1% TFA/100% CH3CN, gradient: 5% to 95% B, the extract was diluted twice with water for 15 minutes and loaded on a Waters HPLC system at 2.2x25 cm Vydac C4 preparative reverse phase column And eluted with acetonitrile gradient (A buffer: 0.1% TFA/10% CH3CN, B buffer: 0.1% TFA/10% CH3CN and gradient: 0% to 100% B, after 120 minutes, flow rate: 15.00 ml/min ). HPLC analysis of the purified peptide indicated a purity greater than 95% and electrospray ionization mass spectrometry was used to determine the identity of the peptide. General Peptide Synthesis Protocol Using Fmoc Chemistry Strategy: Standard Fmoc Chemistry was used on an ABI 433A automated peptide synthesizer with Rink MBHA guanamine resin or first amino acid-linked Wang resin (Novabiochem, San Diego, CA) The peptide was synthesized using DIC/HOBT as a coupling reagent. The side bond protecting group of Na-Fmoc[N-(9-fluorenyl)nonyloxycarbonyl]amino acid is as follows: Arg, Pmc; Asp, OtBu; Cys, Trt; Gin, Trt; His, Trt; Lys, Boc ; Ser,tBu ; Tyr, 1811; and Ding Yin, 8〇〇(?111〇=2,2,5,7,8-pentamethylbenzohydropyran-6-sulfonyl, OtBu=第Tri-T ester group, Trt = trityl, Boc = third butyloxycarbonyl, and tBu = tert-butyl). Fmoc-Glu(0-2-PhiPr)-156004.doc-431 - 201143790 OH and Fmoc-Lys(Mmt)-OH (Novabiochem, San Dieg〇, CA) were added to the indoleamine bridged salty site. After solid phase synthesis, 2-phenylisopropyl (2-PhiPr) on Glu and 4-decyloxytrityl (Mmt) on Lys were removed by washing the peptidyl resin with 1% TFA/DCM. . To form the indoleamine bridge, 150 mg (〇.5 mmol, 5 times) of BEPBT is typically added to 10% DIEA/DMF and allowed to react for 2 to 4 hours until the indanone test is negative. The peptide was cleaved from the resin with a cleavage mixture containing 85% TFA, 5% benzene, 5% water and 5% thiobenzoquinone scale (2.5% ® EDT was added when the peptide contained cysteine). The crude peptide was precipitated in diethyl ether, centrifuged and lyophilized. The peptide was then analyzed by analytical HPLC and verified by ESI or MALDI-TOF mass spectrometry. The peptide was purified by a general HPLC purification procedure. Peptidation Deuteration The deuterated peptide was prepared as follows. Peptides were synthesized on solid support resin using a CS Bio 4886 peptide synthesizer or an Applied Biosystems 43 0A peptide synthesizer. In situ neutralization chemistry is used as described by Schnolzer et al., Int. J. Peptide Protein Res. 40: 180-193 (1992). For the brewing peptide, the target amino acid residue to be deuterated is replaced with an Νε-FMOC lysine residue (for example, position 1 〇, relative to the amino acid position of SEQ ID NO: 1601, numbered with 20% piperidine The DMF solution was treated with the BOC-protected peptide on the N-terminus for 30 minutes to remove the FMOC/mercapto group by using a 10-fold molar excess of FMOC-protected spacer amino acid (eg, FMOC-Glu-OtBu) or Mercapto chain (eg CH3(CH2)14-COOH) and benzotriazol-1-yl-oxytripyrrolidinyl ruthenium (PyBOP), N,N,-diisopropylcarbodiimide (DIC) or 156004.doc -432· 201143790 DEPBT coupling reagent is reacted in DMF/diisopropylethylamine (E>IEA) to couple to the free ε-amino-based Lys residue. The spacer amino acid is then removed. The FMOC group, followed by repeated coupling with the hydrazino chain, was finally treated with 100% TFA to remove any side chain protecting groups and N-terminal BOC groups. The peptide resin was neutralized with 5 ° / 〇 DIEA / DMF, Dry, and then cleave the self-supporting solution for 1 hour using HF/p-methyl (95:5). After extraction with diethyl ether, the crude peptide was solvated using 5% acetic acid (HOAc) solution, followed by ESI-MS. The sample of the solution contained the peptide of the correct molecular weight. The correct peptide was purified by reverse phase (RP) HPLC using a linear gradient of 10% CH3CN/0.1% TFA to 100% CH3CN with 0.1% TFA. Vydac C18 22 mm><250 The mm protein column was used for purification. The deuterated peptide conjugate was generally completely dissolved by a buffer ratio of 20: 80. The fractions were combined and the purity was checked on analytical RP-HPLC. The pure soluble fraction was lyophilized to give a white solid peptide. If the peptide comprises an intrinsic amine bridge and a target residue to be deuterated, the fermentation is carried out as described above after the addition of the p-amino acid to the peptide backbone. The PEGylation forms a thioether linkage. Peptide the peptide, using the minimum amount of solvent required to dissolve the peptide and PEG into a clear solution (typically 2 mL or less for reactions using 2 to 3 mg of peptide) to make 40 kDa methoxy poly (Ethylene) Alcohol)Iodoacetamide is reacted with a molar equivalent of peptide in 7 guanidine urea, 50 mM tricarboxymethylaminomethane-hydrochloric acid buffer. Stirring is vigorously started at room temperature for 4 to 6 hours, and Analytical RP-HPLC analysis of the reactants. The PEGylated product does not appear to be related to the starting material. The residence time is shortened. Purification can be carried out on a Vydac C4 column under conditions similar to those used for the initial peptide purification. The dissolution is carried out at a ratio of about 50:50 buffer 156004.doc -433 - 201143790. The PEGylated peptide was lysed and lyophilized. The yield is higher than 50% and each reaction is different. Peptide PEGylation to form a maleimide linkage to PEGylate the peptide 'The cysteine-containing peptide is dissolved in phosphate buffered saline (5 to 0 mg/mL) and Add 〇.〇1 μ ethylenediaminetetraacetic acid (10% to 15% of the total volume) Add excess (2 times) of the maleimide methoxy PEG reagent (Dow) and stir at room temperature The reaction was monitored while the reaction progressed by high performance liquid chromatography (HPLC). After 8 to 24 hours, the reaction mixture was acidified and loaded onto a preparative reverse phase column using 0.1% tetrafluoroacetic acid (TFA) / acetonitrile. Purification by gradient. Combine the appropriate fractions and freeze-dry to give the desired PEGylated derivative. Analyze using mass spectrometry Mass spectrometry was performed using a Sciex API-Ill electrospray quadrupole mass spectrometer with a standard ESI ion source. The conditions are as follows: ESI in positive ion mode; ion spray voltage: 3.9 kV; pore potential: 60 V. The atomization and air curtain gas used is nitrogen, and the flow rate is 〇·9 liters/min. Mass spectra were recorded from 600-1800 Thompsons at 2 msec dwell time. Samples (about 1 Mg/mL) was dissolved in a 50% aqueous solution of acetonitrile containing 1% acetic acid and introduced at a rate of 5 μl/min by external injection of the pump. When the peptide was analyzed by ESI MS in PBS solution, the first use of 〇6 was used. The ZipTip solid phase extraction head for gL C4 resin is based on the instructions provided by the manufacturer (MilIip〇re Corporation, Billerica, MA, at millipore.com/ catal〇gue.nsf/docs/C5737, see MUUp〇re's World Wide Web site Desalting it. 156004.doc •434- 201143790 High Performance Liquid Chromatography (HPLC) Analysis: Using High Performance Liquid Chromatography (HPLC) and MALDI Analysis in Phosphate Buffered Saline Solution (PBS) Buffer (pH 7.2) A preliminary analysis of these crude peptides was performed to obtain an approximate value of their relative conversion. The crude sample was dissolved in PBS buffer at a concentration of 1 mg/mL. 1 mL of the resulting solution was stored in a 1.5 mL HPLC vial. It was then sealed and incubated at 37° C. A 100 μΐ aliquot was taken at various time intervals, cooled to room temperature and analyzed by HPLC. HPLC analysis at 214 nm using a Beckman System Gold chromatography system using a UV detector At 1 50 mm><4.6 mm C1 HPLC analysis was performed on a 8 Vydac column at a flow rate of 1 ml/min. Solvent A contained distilled water containing 0.1% TFA, and solvent B contained 90% CH3CN containing 0.1% TFA. A linear gradient (40% to 70% B in 15 minutes) was used. Data were collected and analyzed using peak simple chromatography software. Example 2 The ability of each peptide to induce cAMP was measured in a firefly luciferase-based reporter assay. The amount of cAMP production induced is directly proportional to the glycosidic fragment that binds to the glycoside receptor or the GIP receptor or the GLP-1 receptor. HEK293 cells co-transfected with the receptor and the luciferase gene linked to the cAMP response element were used for this biological assay. The cells were removed by culturing for 16 hours in Dulbecco-modified Minimum Essential Medium (Invitrogen, Carlsbad, CA) supplemented with 0.25% bovine growth serum (HyClone, Logan, UT), and then "Biocoat" plate coated with 96-well poly-D-lysine at 37 ° C, 5% C02 (BD Biosciences, 156004.doc -435 - 201143790

San Jose, CA) was incubated with serial dilutions of the glycoside fragment for 5 hours. At the end of the incubation, 1 μM LucLite Luminescent Reagent (Perkin Elmer, Wellesley, ΜΑ) was added to each well. The plate was briefly shaken, incubated for 10 minutes in the dark and the light output was measured on a MicroB-1450 liquid scintillation counter (卩64111-Elmer, Wellesley, ΜA). The 50% effective concentration (EC5〇) and the 50% inhibitory concentration (IC5〇) were calculated by using the Origin software (OriginLab, Northampton, MA). All EC5 and IC50 are reported in nM in the following examples unless otherwise indicated. Example 3: Preparation of GLP-1/Estrogen (3-Ether) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1, which had a Boc-Lys(Fmoc)-OH residue on the C-terminus. (The Fmoc group protecting the side chain amine on the lysine residue was removed with 20% piperidine/DMF for 30 minutes before the addition of product 4.)) Estradiol 17-acetate was used with 2-bromide The ethyl acetate reaction was derivatized at the 3 position. The derivatized estradiol is hydrolyzed and reacted with the C-terminal amino acid of the GLP-1 analog to produce a GLP-1/estrogen (3-ether) conjugate, as shown below: Estradiol 17·B Ethyl 2-bromoacetate

+

Br-Y0,

KaC03. Two pits. Reflux for 16 hours.

Rotating off dioxane by rotary evaporation with DCA4, resuspending in DCMt, dropping into HC1 to acidify

Ο 2

Specifically, the molar amount of estradiol 17-acetate (1) and ethyl 2-bromoacetate (2) are dissolved in dioxane/K2C03 and stirred under reflux conditions 156004.doc - 436· 201143790 Reactant for 16 hours. The reaction solvent was evaporated in vacuo and the product (3) was resuspended in dioxane. NaOH (1 N) was added slowly and stirred for 2 hours. The reaction solvent was evaporated in vacuo and the product (4) was washed three times and resuspended in dichloromethane. HC1 (1 N) was added slowly to acidify the product. The product 4 and the resin-bound peptide were mixed in HOBt/DIC/NMP for 4 hours, filtered, treated with trifluoroacetic acid, and cleaved from the resin by treatment with hydrofluoric acid. The peptide-estrogen conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. Example 4: Preparation of GLP-1/Estrogen (17-Amino decanoate) A GLP-1 analogue was synthesized using the Boc protocol disclosed in Example 1, which has a Boc-Lys(Fmoc)-OH residue at the C-terminus base. (Removal of the Fmoc group protecting the side chain amine on the lysine residue by 20 °/. piperidine/DMF for 30 minutes before binding to the estrogen derivative) > β-estradiol 3-benzoquinone The acid ester is derivatized at the 17 position by reaction with 4-nitrophenyl phthalate. The derivatized estradiol is reacted with the C-terminus of the GLP-1 analog to the amino acid to produce a GLP-1/estrogen (17-ester) conjugate, as shown below: Ρ-estradiol 3-benzoic acid 4-nitrophenyl ester of β-nitroester, 17-nitrophenyl ester 3-p-formate

In particular, β-estradiol 3-benzoate (1) and 2-fold excess of 4-nitrophenyl phthalate (2) in pyridine, toluene and DMAP under reflux conditions (2) 156004 .doc -437- 201143790 Mix together for 24 hours. The reaction solvent was evaporated in vacuo and the product β-estradiol 17-nitrophenyl ester 3-benzoate (3) was resuspended in ethyl acetate. The reaction product was washed twice with an aqueous HCl solution (0.01 Torr) and then washed once with water. Ethyl acetate was evaporated in vacuo and product (3) was precipitated from hexane. The product 3 and the resin-bound peptide were mixed in NMP/5% DIEA for 4 hours, filtered, treated with TFA' and lysed from the resin by HF treatment. The estrogen-conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. Example 5: Preparation of GLP-1/Estrogen (17-Ester) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1, which had a Boc-Lys(Fmoc)-OH residue on the C-terminus. The Fmoc group protecting the side chain amine on the lysine residue was removed with 20% piperidine/DMF for 30 minutes before binding to the estrogen derivative. Estradiol was derivatized at 17 position by reaction with succinic anhydride. The derivatized estradiol is reacted with the C-terminus of the GLP-1 analog from the amine to produce a GLP-1/estrogen (17-ester) conjugate as shown below:

Wash with 0.01NHC1+ water and purify by HPLC

Specifically, 'at a room temperature, β-estradiol 17-acetate (1) is stirred with a 1 〇 excess of succinic anhydride (2) in DMF and DMAP containing 5 〇/0 DIEA 48 hour. After 48 hours, the reaction solvent was evaporated in vacuo and the product (3) 156004.doc: 438. 201143790 was resuspended in ethyl acetate. The reaction product (3) was washed twice with an aqueous solution of hydrazine (0·〇ι N), followed by washing once with water. Ethyl acetate was evaporated in vacuo and product (3) was resuspended in a mixture of Me 〇 H / acetonitrile / water. The estrogen-derived product (3) was purified by reverse phase HPLC. The lyophilized product (3) was mixed with the resin-bound peptide in H〇Bt/DIC/NMP for 4 hours, transitioned, treated with TFA, and cleaved from the resin by HF treatment. The peptide-estrogenic conjugate was purified using reverse phase HpLC and characterized by ESI mass spectrometry.

Example 6: Preparation of GLP-1/Estrogen (3-Ester) The glp-1 analog was synthesized using the Boc protocol disclosed in Example 1, which has B〇C-Lys(Fm〇C)-〇 at the C-terminus. H residue. (Removing the Fmoc group of the side-bonding amine on the amino acid residue with 203⁄40 Chenbit/DMF for 30 minutes in combination with the estrogen derivative ^'s estradiol 17-acetate by The succinic anhydride reaction is derivatized at the 3 position. The derivatized estradiol is reacted with the guanine of the gLP·anthraquinone analog to produce an GLP-1/estrogen (3) conjugate, as shown below:

Estradiol 17-acetate succinate liver Estradiol 3 · succinate 17-acetate

3

Specifically, β-estradiol 17-acetate (1) was mixed with a 10-fold excess of succinic anhydride (2) for 48 hours at room temperature in DMF and DMAP containing 5% Diea. After 48 hours, the reaction solvent was evaporated in vacuo and the product (3) 156004.doc: 439 - 201143790 was resuspended in ethyl acetate. The reaction product (3) was washed twice with an aqueous HCl solution (0.01 N), followed by washing once with water. Ethyl acetate was evaporated in vacuo and product (3) was resuspended in a mixture of MeOH / acetonitrile / water. The estrogen-derived product (3) was purified by reverse phase HPLC. The lyophilized product (3) and the resin-bound peptide were mixed in HOBt/DIC/NMP for 4 hours, filtered, treated with TFA, and cleaved from the resin by HF treatment. The peptide-estrogenic conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. Example 7: Preparation of GLP-1/estrone (3-ester) A GLP-1 analog having a Boc-Lys(Fmoc)-OH residue on the C-terminus was synthesized using the B〇c scheme disclosed in Example 1. (The Fmoc group protecting the side chain amine on the lysine residue was removed with 20% piperidine/DMF for 30 minutes before binding to the estrogen derivative.) The estrone was reacted with succinic anhydride at the 3 position. Derivatization. The derivatized estrone is reacted with the C-terminus of the GLP-1 analog from the amine acid to produce a GLP-1/estrone (3-ester) conjugate, as shown below:

Wash with O.OlNHCl + water. Purify by HPLC.

Specifically, estrone (1) and a 10-fold excess of succinic anhydride (2) were stirred for 48 hours at room temperature in DMF and DMAP containing 5% DIEA. After 48 hours, the reaction solvent was evaporated in vacuo and product (3) was resuspended in ethyl acetate. The reaction product (3) was washed twice with an aqueous HCl solution (0.01 N), followed by washing with water once at 156004.doc • 440-201143790. Ethyl acetate was evaporated in vacuo and product (3) was resuspended in a mixture of MeOH / acetonitrile / water. The estrone derivative product (3) was purified by reverse phase HPLC. The lyophilized product (3) and the resin-bound peptide were mixed in HOBt/DIC/NMP for 4 hours, filtered, treated with TFA, and lysed from the resin by HF treatment. The peptide-estrogen conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. Example 8: Preparation of GLP-1/Estrogen (17-腙) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1. use

The peptide was synthesized based on Boc's in situ neutralization chemistry with a Boc-Cys(4-MeBzl)-OH residue at the C-terminus to aid in the addition of estrogen. Estrone was derivatized at position 17 by reaction with maleimide hexyl oxime. The derivatized estrone is reacted with the C-terminal cysteine of the GLP-1 analog to produce a GLP-1/estradiol (17-腙) conjugate, as shown below: estrone, maleimide Acryl-β-estradiol 17-m-butyleneimine hexanide

Specifically, the molar amount of estrone (1) was stirred with ε-m-butylene imino ruthenium (2) in MeOH containing 0.1% TFA for 4 hours at room temperature. . After 4 hours, the reaction solvent was evaporated in vacuo and the product (3) was precipitated in cold diethyl ether and purified on a silica column. Mix 5 times excess of product 3 with lysed and purified peptide for 24 hours at room temperature at pH 7.5 in a mixture of DMF, ACN, tricarboxymethylaminomethane and water 156004.doc -441 - 201143790 , producing a peptide-estrogen conjugate. The peptide-estrogen conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. Example 9: Preparation of GLP-1/estrogen (17-urethane disulfide) (hindered and sterically hindered) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1. The peptide was synthesized using a Boc-based in situ neutralization chemistry with a Boc-Cys(4-MeBzl)-OH residue at the C-terminus (to produce a sterically hindered disulfide conjugate) or Boc-Pen (4) -MeBzl)-OH residue (used to produce a sterically hindered disulfide conjugate) to aid in the addition of estrogen. The β-estradiol 3-benzoate was derivatized at the 17 position by reaction with 4-nitrophenyl chloroformate. The intermediate is then reacted with pyridyldithio-ethylamine-HC1 and disulfide exchange with the C-terminal cysteine of the GLP-1 analog to produce GLP-1/estradiol (17-amino group) a formate disulfide) conjugate, as shown below: 2,2'-dithiodipyridine (Aldrithiol-2)

1 2-mercaptoethylamine

2 pyridyldithio-ethylamine->- MeOH, 2% AcOH 48 hours 八ΝΗ, ΗΟ in the mystery of Shen Dian 3 β-estradiol 3-benzoate 4-nitrophenyl chloroformate --estradiol 17-nitrophenyl ester 3-p-formate

First, an equivalent molar amount of 2,2'-dithiodipyridine (Aldrithiol-2) (l) and 2-mercaptoethylamine hydrochloride (in MeOH containing 2% AcOH) 2) - Stir for 48 hours. After 48 hours, the reaction solvent was evaporated in vacuo and product (3) was precipitated from cold diethyl ether. Secondly, under reflux conditions, β-estradiol 3-benzoate (4) and 2-fold excess of 4-nitrophenyl formate were added to pyridinium 156004.doc • 442· 201143790 pyridine, toluene and DMAP. (5) - Stir for 4 hours. The reaction solvent was evaporated in vacuo and the product β-estradiol 17-nitrophenyl ester 3-benzoate (6) was resuspended in ethyl acetate. The reaction product was washed twice with an aqueous HCl solution (0.01 Torr), then washed once with water and removed in a separating funnel. Ethyl acetate was evaporated in vacuo and product (6) was precipitated from hexane. β-Estradiol 17 urethane S-S-NPy3·Phenyl benzoate β*Estradiol 17-Aminocarbamic acid 睦S-S*NPy

Equivalent molar amount of pyridyldithio-ethylamine hydrochloride (3) and β-estradiol 17-nitrophenyl 3-benzene in pyridine containing 5% DIEA and DMAP at room temperature The formate (6) was stirred for 48 hours. After 48 hours, the reaction solvent was evaporated in vacuo and product (7) was resuspended in ethyl acetate. The reaction product was washed twice with an aqueous HCl solution (0.01 Ν), then washed with water, and ethyl acetate was evaporated in vacuo. Removal of the 3-benzoate group on product (7) by treatment with 0.25% K2C03 in dioxane and decyl alcohol for 3 hours at room temperature yielded the product β-estradiol 17-amino decanoic acid The ester SS-NPy (8) was purified on a ruthenium dioxide column. Mix a 5-fold excess of product 8 with the cleaved and purified peptide (with cysteine residue or penicillamine at position 40) in NMP and tricarboxymethylaminomethane at pH 7.5 at room temperature (at room temperature) The penicillamine) residue, 48 hours, produces a peptide-estrogen conjugate. The peptide-estramine conjugate was purified using reverse phase HPLC and characterized by ESI mass spectrometry. 156004.doc -443- 201143790 Example 10: Preparation of GLP-1/Estrogen (17-Cathepsin Diaminoethane) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1. The peptide was synthesized using Boc-based in situ neutralization chemistry with Z-His(BOM)-OH residues on the N-terminus and Boc-Lys(Fmoc)-OH on the C-terminus to facilitate the addition of dipeptides The spacer and the estrogen beta-estradiol 17-nitrophenyl ester benzoate are derivatized at position 17 to produce a GLP-1/estradiol (17- cathepsin diaminoethane) conjugate, As shown below:

Fmoc-Phy-Lys(Cl-Z)-OH(l) was synthesized on the basis of Fmoc-based in situ neutralization chemistry and was cleaved from the resin by TFA/DCM. The molar amount of Fmoc-Phe-Lys(Cl-Z)-OH(l) was stirred with Boc-ethylenediamine (2) in HOBt, DIC and DCM for 4 hours at room temperature. The reaction product was washed twice with aq. After the washing step, the reaction product was treated with 20% piperidine in DMF for 30 minutes to remove the N-terminal Fmoc group, yielding NH2-Phe-Lys(Cl-Z)-EDA-Boc(3) in a vacuum. The piperidine/DMF solvent was removed and precipitated in cold diethyl ether. Stir NH2-Phe-Lys(Cl-2)_151) in DMF, 5% DIEA and DMAP at room temperature for 8 hours (^) and 2 times excess of succinic anhydride (4) for 16 hours. The solvent was evaporated in the air at 156004.doc • 444 - 201143790 and resuspended in MeOH, acetonitrile and water. The reaction product succinate-Phe-Lys(Cl-Z)-EDA- was purified by reverse phase HPLC. Boc (5). Mix 5 times excess of lyophilized product (5) with resin-bound peptide in HOBt/DIC/NMP for 16 hours, filter and treat with TFA to produce product GLP-1 + Succinate-Phe -Lys(Cl-Z)-EDA(6). The product of the binding resin (6) and 5 times excess of β-estradiol 17-nitrophenyl ester 3-benzoic acid were mixed in NMP/5% DIEA. The ester (7) was filtered for 16 hours, and was cleaved from the resin by HF to give the final product (8). The peptide-estrogen conjugate was purified by reverse phase HPLC and characterized by ESI mass spectrometry. Example 11: Preparation GLP-1/cholesterol (3-decylamine) The GLP-1 analog was synthesized using the Boc protocol disclosed in Example 1. The peptide was synthesized using Boc-based in situ neutralization chemistry with Boc-Lys on the C-terminus ( Fmoc)-OH residue. Make cholesterol 3-tannic acid Reaction with the amino acid of the C-terminus of the GLP-1 analog produces a GLP-1/cholesterol (3-decylamine) conjugate as shown below:

Specifically, cholesterol 3-carboxylic acid (1) and resin-binding peptide were mixed in HOBt/DIC/NMP for 16 hours, filtered, treated with TFA, and lysed from the resin by HF treatment. The Fmoc group protecting the side chain amine on the lysine residue was removed with 20% piperidine/DMF for 30 minutes prior to the addition of product 4. The peptide-cholesterol conjugate (2) was purified using reverse phase HPLC and characterized by ESI mass spectrometry. 156004. Doc -445- 201143790 If the PEGylated peptide backbone is added to the position 24 in the sequence, a cysteine residue is added to aid in the addition of the PEG moiety. The PEG moiety is at 7 Μ urea / 0. 05 Μ Tricarboxymethyl decyl decane buffer at pH 8. The molar amount of mothyl thiol 40 k PEG and the conjugate were added to the peptide-cholesterol conjugate for 5 hours. Example 12: Estrogen Receptor Binding Assay Estrogen receptor binding assay was performed using the following reagents using the purified ERa & Millip® filter plate (Phospholmager) protocol: Ligand Binding Buffer (pH 7_6) 50 mM HEPES-sodium salt, 1 mM CaCl2, 5 mM MgCl2, 0. 5% BSA, sucrose buffer (pH 7. 6), 20% sucrose, 120 mM NaCl, 40 mM tricarboxymethylamino decane-HC 〇 4〇 / 〇 BSA, poly (ethyl imino) (PEI) and 0. 25% PEI. Titration of "cold" estradiol A cold estradiol stock dilution solution having a concentration of 5 times the concentration of the most southern test is prepared. The most common concentration of the measured s is 1 〇 μΜ. Therefore, prepare a 50 μΜ stock solution with a total volume of 500 μΐ. 40 μL of binding buffer was accurately added to each well of the titration plate, excluding U and 12 rows. The 6 〇 μ1 stock concentrate was accurately added to each well of row 11 of the titration plate. The 3-fold titration was carried out by transferring 20 μΐ to the first row from the 丨 丨 row and mixing. Titrate each subsequent line until the first action. Transfer each well of the 20 μΐ self-titration plate precisely to the corresponding well on the assay plate. Add 20 μM of binding buffer to the “Total Binding” well (well 12 (A-D)). 2〇 μ121〇〇 μΜ cold estradiol was accurately added to the “non-specifically bound” well (well 12 (Ε_Η)). I56004. Doc -446- 201143790 A constant concentration of "hot j-estradiol" is prepared at a concentration of 5 times the desired test concentration of the labeled estradiol stock solution, the required test concentration is 〇·〇5 nM. Therefore, preparation of 〇. The stock of 25 nM labeled estradiol has a total volume of at least 2. 3 mL. The labeled estradiol was made into a 100 ΐ volume of 1 〇 solution, and the solution was used at a conversion rate of 22 Torr. The concentration of 45 nM is correlated with 2 for 2 3 mL. 25 nM stock solution, will be 12. 65 pL of labeled estradiol was added to 2. 29 ml in binding buffer. The 20 吣 stock solution was accurately added to each well of the test plate according to the design. Titration of purified estrogen by listening to a to 1. The purified estrogen receptor was tested at a concentration of 5 nM. Since the 6 雌 estrogen receptor was added to each well, i. 667 times the reserve concentration. For 1. 5 nM test concentration, preparation 2. Reserve concentration of 5 nM. By adding 8.4 μί of stock solution to 6. The volume was prepared by adding 99 mL of binding buffer to 7. 0 mL of 2. 5 nM receptor. The 6 〇 pL receptor is then accurately transferred to the appropriate wells in the assay plate. Detection The assay plate (containing the cold ligand 'hot ligand and cell lysate') was incubated for 2 hours at room temperature. Will be 25 pL of 0. 25% PEI was accurately added to each well of the filter plate. The filter plates were incubated for 20 minutes, after which the wells were cleaned by vacuum. The 80 μL suspension in the assay plate was accurately transferred to a PEI-coated filter plate. The sample was evacuated via a filter plate using a vacuum manifold. The filter plate was washed with a binding buffer and dried in the right direction and packaged in a cell 〇phane. The plates were fixed on the surface of the phosphor imaging screen, and the bottom of the hole was closest to the firefly 156004. Doc -447- 201143790 Curtain. The phosphor imaging screen and plate were placed in a radiation film pouch and exposed for 48 hours. The imaging screen is scanned using a squama imager and the exposure standard is collected. Example 13 Mice (db/db, N=6, mean initial body weight = 54 g) were injected subcutaneously four times a day with vehicle or 40 pg/kg or 400 pg/kg: (a) GLP-l (Aib2A22CexK4i)) (4 micrograms per kilogram per day), (b) GLP-l (Aib2A22CexK4i>)/estrogen (17-ester) (4 micrograms per kilogram per day), or (c) GLP-1 (Aib2A22CexK4. ) / estrogen (17_ ester) (4 〇〇 Φ micrograms per kilogram per day). Body weight was measured after 23 days and body weight change was determined (Fig. 2a). The weight of mice dosed with high doses of GLP-1 (Aib2A22CexK4())/estrogen (17-ester) conjugate was greater than that of administration alone. Mice of GLP-1. The effect of GLP-1 (Aib2A22CexK40)/estrogen (17-ester) conjugate on cumulative food intake over a 23 day period was also determined. Mice administered high doses of GLP-1 (17-ester)/estrogen (17-ester) conjugates consumed less food than mice administered GLP-1 alone. Lutu 2b and 2c show the effect of GLP_l (Aib2A22CexK40)/estrogen (17-vinegar) conjugate on blood glucose content (mg/dL). Mice that were administered high doses of GLP-1 (Aib2A22CexK4〇)/estrogen (17-ester) conjugates on Days to Day 14 had the greatest reduction in blood glucose levels. Example 14.  In vivo effects of GLP-1/estrogen conjugates in vehicle-induced obesity (DIO) mice once daily with vehicle or 4 pg/kg, 40 pg/kg or 400 gg/kg (N=8) , 6 mice per group, flat 156004. Doc • 448- 201143790 Average initial weight = 58 g) Subcutaneous injection for four weeks: (a) GLP-l (Aib2E16CexK40) (4 micrograms per kilogram per day), (b) GLP-1 (Aib2A22CexK, (4 per kilogram per day) 〇 micrograms), or (c) GLP-l (Aib A22CexK40) / estrogen (17 esters) (4 micrograms per kilogram, 40 micrograms or 400 micrograms per day). At the 0th minute on day 7 and day 21, A physiological saline solution containing 25% (v/v) glucose was injected at a dose of 5 grams per kilogram of body weight. On the 7th day and the 21st day, the second, the 15th minute, the 3rd minute, the 6th minute And at the 120th minute, the jk sugar was measured (Fig. 3a). After 23 days, the body weight was measured and the body weight change, fat mass change and lean meat quality change were determined (Fig. 3b-d). High dose glp·1 was administered (Fig. 3) Aib2A22CexK40)/ estrogen (17-ester) conjugate mice had the greatest reduction in body weight and fat mass, while the mass loss of scorpion meat was the smallest. Also determined 01^-1 (into 丨1»2 八22〇6\1 !:4())/Estrogen (17_ester) conjugate effects on cumulative food intake over a 23-day period. High doses of glp_ • KAiVAUCexK40)/Estrogen The amount of food eaten (eta-ester) of a minimum mice. Figure 3e shows the effect of GLP-1 (Aib2A22CexK40)/estrogen (17-ester) conjugate on blood glucose changes. Mice administered high doses of GLp-1 (Aib2A22CexK4Q)/estrogen (17-ester) conjugates on day 0 to day 14 had the greatest reduction in blood glucose levels. These results indicate that the addition of estrogen to the weak GLP-1 agonist based on A22 increases dose-dependent efficacy. Example 15 Using a vehicle or one of the following once a day for diet-induced obesity (DI〇) 136004. Doc -449- 201143790 Mice ((iv) 'average initial body weight = 59g) were injected subcutaneously for four weeks: (a) GLP-1 (AVE%ex κ, (4 micrograms per kilogram per day or 4 micrograms per kilogram)' (b) GLP-1 (Aib2El6CeX K40) / estrogen (17-brewed) (40 micrograms per kilogram or 400 micrograms per kilogram), or (4) GLP-1 (AibfCex K, / although hormones (3,) (4 micrograms per kilogram per day or 400 Micrograms) A physiological saline solution containing 2,V) glucose was injected at a dose of 15 grams per kilogram of body weight at the 0th minute of the second day. At the first minute, the 15th minute, the 30th minute, the 60th minute, and the first The blood glucose level was measured at the 12-minute time point. Figure 4a presents the data for this experiment. After 21 days, the body weight was measured and the total weight of the slave and the change in fat mass were measured (Fig. I 0. Administration of high doses of GUM/estrogen conjugate) The overall weight loss of mice was greatest (Fig. 4b). The amount of fat f was reduced in animals treated with high doses of estrogen ether conjugate compared to vehicle treated animals (the effect of conjugates on overall weight was greater than Ether conjugates, and ether conjugates have a greater effect on fat quality than ester conjugates. Aib^Cex K4〇)/ Although the hormone conjugates were administered to mice with GUM/hormone conjugates over a 21-day period, the mice consumed less than the individual GUMMibhMcex κ40 mice. Figure 4d shows GLP·i (Aib) Effect of V6cex κ40)/Estrogen Conjugate on Gray Sugar Content (IV)胤. On Days G to 21, mice were dosed at high doses with either -GLiM (Aibfcex Κ4.)/estrogen conjugate. Blood sugar level 156004. Doc •450- 201143790 The degree of change was greater than that of mice administered with GLP-1 alone (Aib2E16Cex K4.). Example 16 A subcutaneous injection of a vehicle with a vehicle or a hypoxia diet for 9 months (Ν=8, 11 months old, average body weight 60 g): (a) GLP-1 (Aib2E16Cex K4.) ( (4 micrograms per kilogram or 4 micrograms per day)' (b) GLP-l (Aib2E16Cex K40) / estrogen (3 · ether) (4 micrograms per kilogram or 400 micrograms per kilogram), (c) dGLP-l^ Ail^AUCex K4G)/estrogen (3-ether) (40 micrograms per kilogram or 400 micrograms per kilogram), (4) GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K4.) / estrogen (3_ether) (per kilogram per day) 40 μg, 400 μg), (e) GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K40) / estrogen (3_ether) (40 micrograms per kilogram per week), or (f) GLP-1 (Aib2E16C24 (PEG) -40kDa) Cex K40) (4 micrograms per kilogram per week). Body weight was measured after 7 days and body weight changes were determined (Fig. 5a). Mice administered high doses of GLP-1/estrogen conjugates had the greatest reduction in body weight, whereas mice dosed with low daily doses of GLP-1/estrogen conjugates also had significant weight loss. Also identified as GLP-1 (Aib2E16K40Cex) / estrogen (3 · ether), (JGLP-1 (AkibWex K4.) / estrogen (3_ ether) and GLP-1 (Aib2E16c24 (PEG-40kDa) Cex K4Q) / estrogen Effect of (3·ether) conjugate on cumulative food intake over a 7-day period. GLp 156004 administered at high or low doses. Doc -451 - 201143790 (Aib2E16K4 °Cex) / estrogen (3-ether) and GLP-1 (Aib2E 6K4 ° Cex) or low-dose GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K4.) Rats eat the least amount of food. Figure 5b shows GLP-1 (Aib2E16K40Cex)/estrogen (3-ether), dGLP-1 (Akib^AUCex K4.) / estrogen (3-ether) and GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K4G) /Estrogen (3-ether) conjugate effects on changes in blood glucose levels (mg/dL). Mice administered high-dose or low-dose glP-1 (Aib2E16K4QCex) and mice administered high doses of glP-1 (Aib E K Cex)/estrogen (3-趟) had the greatest degree of blood glucose changes. Example 17 A diet-induced obesity (DIO) mouse (N=8, mean initial body weight = 65 g) was administered subcutaneously once a week with vehicle or 40 pg/kg of the following: (a) GLP-l ( Aib2E16Cex K40), (b) dGLP-lCA^ib^^Cex K40).  (c) GLP-1 (Aib2A22 Cex K40), (d) GLP-1 (Aib2E16Cex K4.) / estrogen (3_趟), (e) dGLP-KAlibWkex K4. ) / estrogen (3,), (f) GLP-1 (Aib2A22Cex Κ4.) / estrogen (3_趟), (g) GUM (Aib2E, 6CeX Κ4.) / estrogen (17_ brew), ( h) dGUM (AiAib2A22Cex π) / estrogen (17 vinegar), or (i) LP-1 (Aib2A22Cex K40) / estrogen (17_stuff). After 7 days, the body weight was measured and the body weight and the quality of the fat ribs were determined (Fig. 6a-b) 〇 156004. Doc •452· 201143790 Mice that were administered either estrogen conjugate had the greatest overall weight loss. The analysis of fat mass (Fig. 6b) was relatively constant under overall weight loss. Figure 6c shows the effect of GLP-1/estrogen conjugates on changes in blood glucose (mg/dL). Mice that administered GLP-1 (Aib2E16K40Cex)/estrogen (3_ether) or GLP-1 (Aib2E16K4GCeX)/estrogen (17-ester) conjugates had the greatest degree of blood glucose change from day 0 to day 7. Example 18 A subcutaneous injection of subcutaneous injection was administered to a mouse fed a diabetic diet for 9 months (N=8, 11 months old, average body weight 6 〇g) once daily with vehicle or 400 pg/kg: (a) GLP-1 (Aib2E16Cex K40), (b) GLP-1 (Aib2E16Cex K4°) / estrogen (3-趟), (c) GLP-1 (Aib2E16Cex K40) / estrogen (17-ester), (d) dGLP-lCA^ib^^Cex K40) » (4) dGLP-UA'iVAUCex Κ4. )/Estrogen (3_ether), (f) dGLP-UA'Ail^AUCex K4°)/Estrogen (17-g), (g) GLP-1 (Aib2A22Cex K40), (h) GLP-1 (Aib2A22cex K4〇)/estrogen (3·ether), or (1) GLP-1 (Aib2A22Cex κ40)/estrogen (17-vinegar). After 7 days, the body weight was measured and the change in body weight was determined (Fig. 73) and the total weight of the mice in the estrogen conjugate was significantly lower than that in the unconjugated to estrogen. - Although the hormone conjugate shows a greater weight loss in vivo, it is also confirmed that the GLP-1/estrogen conjugate has a cumulative food intake of 156,004 over a 7-day period. Doc •453- 201143790 The impact of quantity. Mice administered GLP-1 (Aib2A22Cex Κ40)/_hormone conjugates consumed the least amount of food. Figure 7b shows the effect of GLP-1/estrogen conjugates on changes in blood glucose (mg/dL). Mice that administered GLP-1 (Aib2A22Cex K40)/estrogen conjugates had the greatest degree of blood glucose change from day 0 to day 7. None of the A22-containing peptides or the d-amino acid-containing peptides exhibited a large degree of reduction relative to the GLP-1 (Aib2E16Cex K4G)/estrogen conjugate. In addition, the estrogen conjugate of GLP-1 (Aib E Cex K40) is significantly more potent than the non-estrogen form of the same peptide. Example 19 A subcutaneous injection of mice (N=8, mean body weight 55 g) was administered once a day with vehicle or one of the following: (4) GUM (Aib2El6Cex Κ 4°) (120 micrograms per kilogram or 400 micrograms per day) ' (8) GUM (Aib2El6CeX Ο estrogen (4)) (12 〇 micrograms or 400 micrograms per kilogram per day), (c) dGLP-WA^it^AnCex K4V for a total of eight a μ eight mothers kg 400 micrograms or 1200 micrograms), or (4) dGLP_1 (AlAib2A22CeX K4°V estrogen (3-vinegar) (400 micrograms per kilogram or 1200 micrograms per kilogram). The peptide containing d-amino acid is inferior to the peptide containing 1-amino acid in all effects. After 7 days, the body weight was measured and the body weight change was confirmed (Fig. Right and force in the absence of estrogen, there is a clear difference in the presence of the peptide. + $ 156004. Doc •454- 201143790 The map shows the effects of various GLp-i/estrogen conjugates on changes in blood glucose levels (mg/dL). From day 3 to day 7, mice administered GLp i (Aib2El6 Cex KV estrogen (3-ester) conjugate had the greatest changes in blood glucose levels in vivo, much larger than those treated with the same peptide but not estrogen. Animals. This indicates a direct improvement in blood glucose regardless of body weight differences. Figure 8c illustrates the effect of administration of the indicated combinations on changes in fat mass. Example 20 Using vehicle or 40 pg/kg, 400 pg/kg, 1200 pg/kg or 4000 pg/kg One of the following daily dose-induced obesity mice (DI〇) (N=8, mean weight 61 g) was administered to the subcutaneous injection for one or two weeks: (a) GLP-l (Aib2E16Cex K40) / estrogen (3-趟) (4 〇 micrograms per kilogram per day), (b) dGLP-UAWAUCex K40) (4000 micrograms per kilogram per day), (c) dGLP-UAiAiVAUCex Κ40) / estrogen (3-ester (400 micrograms per kilogram, 1200 micrograms per kilogram, 4000 micrograms per day), (d) GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K4.) (40 micrograms per kilogram per day), (e) GLP-1 (Aib2E16C24 (PEG) -40kDa) Cex K4°) / estrogen (3-ether) (40 micrograms per kilogram per day), or (f) GLP-1 (Aib2E16C24 (PEG-40kDa) Cex K40) / cholesterol (per day Pounds 40 micrograms). Body weight was measured after 7 days and body weight changes were determined. Mice that were administered GLP-1/estrogen (3-ester) conjugates had the greatest weight loss (Fig. 9a) and fatty mass 156004. Doc -455- 201143790 The smallest amount (Figure 9b). The effect of GLP_1/estrogen (3_ester) conjugates on cumulative food intake over a 7-day period was also determined. Mice fed GUM (Aib2E 6Cex κ, / estrogen (3 vinegar) conjugate (no PEG) consumed significantly less food than mice administered GLP-1 alone. Figure 9c shows GLP-1/female Effect of hormonal (3_ester) conjugates on blood glucose changes. On day 0 to day 7, GLpi/estrogen (3 ester) conjugates containing d-amino acids have a significant dose-dependent blood glucose lowering effect, At the highest dose, this dose-dependent blood glucose lowering effect was enhanced relative to mice administered GLP-1 alone (Fig. 9c). Example 21 Mice fed a diabetic diet once daily with vehicle or one of the following (N=8 '14 months old) for subcutaneous injection for one week: (a) d-GLP-UA^il^AnCex K4.)/Estrogen (3. ester) (12〇〇pg/kg, 4000 pg/kg) ), (b) d-GLP-UAliVAUCex K4. ) / estrogen (3_ ether) (12 〇〇 gg / kg, 4000 gg / kg), or (c) d-GLP-l (Aib2E16K4 ° Cex) (4000 pg / kg). Body weight was measured after 7 days and body weight changes were determined (Fig. a). The mouse is administered a GLP-1/estrogen conjugate containing d-amino acid, wherein the estrogen is covalently linked by stabilizing the guanamine or an unstable ester form in vivo. Animals treated with the unstable vinegar combination had the greatest overall weight loss. The effect of GLP-1/estrogen conjugates on cumulative food intake over a 7-day period was also determined. The food consumed by mice administered with unstable ester conjugates was significant 156004. Doc •456- 201143790 Less mice than the remaining conjugates. The effect of GLP-1/estrogen conjugates on changes in blood glucose levels (mg/dL) was also determined. Figure 10b illustrates that on day 0 to day 7, mice administered a D-amino acid-containing GLP-1/estrogen ester conjugate have a greater change in blood glucose levels than a comparable d-amino acid-containing compound. Peptide but this peptide is administered to mice in the form of a stable estrogen conjugate. Example 22·In Vitro Test for Active GLP-1/Estrogen Conjugates Serial dilutions of the following compounds were prepared: (1) Estradiol, (Π) GLP-1, (iii) Estrogen Stabilizing Activity GLP-1/ Estrogen (3-ether) conjugate, (iv) estrogen-stable active GLP-1/estrogen (3. ester) conjugate, (v) estrogen-stable active GLP-1/estrogen (17_ Ester) conjugate, (vi) active, metastable acid-labile GLP_丨/estrogen (丨7_腙) conjugate, (vii) active metastase thiol reduction unstable GLP-1/estrogen (17 _ urethane disulfide) conjugate, and (viii) active estrogen labile active glP-1 / estrogen vinegar, 17_ OAc). GLP-1 activity (cAMP induction) · co-transfection of serial dilutions of (ii), (m) and (w) with GLP-1 receptor and luciferase gene fused to cAMP response element (CRE) The HEK293 cells were incubated together. Luminescence was measured after cell lysis and incubation with luciferin. The results shown in the table below indicate that binding of GLp-1 to estrogen does not affect the intrinsic activity of GLP-1 on the GLP-1 receptor. GLP-1 binding: serial dilutions of (ϋ), (in) and (iv) with (^1>_1 by 156004. Doc •457- 201143790 Somatic cell membrane extract, [I125]-GLP-1 and agglutinin-coated SPA beads were incubated together and then measured for scintillation. The results shown in the table below indicate that binding of GLP-1 to estrogen does not affect the binding of GLP-1 to the GLP-1 receptor. Conjugate GLP-1 ECso(nM) GLP-1 ICso(nM) GLP-1 0. 011 士 0. 002 0. 381±0. 043 GLP-1/estrogen (3-ether) 0. 012±0. 003 0. 717±0. 135 GLP-1 / estrogen (3-ester) 0. 014±0. 001 0. 627±0. 046 Estrogen activity: Serial dilutions of (i), (iii) and (iv) were incubated with T47D cells transfected with the luciferase gene fused to the estrogen response element (ERE). Luminescence was measured after cell lysis and incubation with luciferin. The results shown in the table below indicate that the stable attachment of estrogen to GLP-1 significantly reduces the intracellular estrogenic activity of estrogen, while the unstable binder exhibits a high degree of intracellular estrogenic activity. ERot Binding: Serial dilutions of (i), (iii) and (iv) were incubated with purified ERa and [1125]-estradiol. After filtration, the radioligand binding is quantified by phosphor imaging. The results shown in the table below indicate that the stable attachment of estrogen to GLP-1 significantly reduces the ability of estrogen to bind to the estrogen receptor, while the unstable binder exhibits estrogen receptor binding, which is under bioassay conditions. A function of the instability of the ester conjugate. Conjugate ERa EC5〇(nM) ERa IC5〇(nM) Estradiol 0·004±0. 001 12. 01±1. 832 GLP-1/Engraving Hormone (3-Ether) 108. 2±15. 73 1200±301·1 GLP-1/estrogen (3-ester) 0. 013±0. 001 198·0±16·75 GLP-1 activity (cAMP induction): serial dilutions of (ii), (iii), (iv), (v), (vi), (vii) and (viii) Pass through the GLP-1 receptor and fuse to 156004. Doc-458- 201143790 HE-cell culture of co-transfection of luciferase gene of CAMP response element (CRE). The luminescence was measured after cell lysis and incubation with luciferin. The active metastable GLP-I/Estrogen conjugate has the same activity on the GLPd receptor (Fig. 11a). Hormone activity: serial dilutions of (1), (iii), (iv), (v), (vi), (viWviii) and luciferase genes fused to an estrogen response element (ere) The cells are incubated together. Luminescence was measured after cell lysis and incubation with Rao. The active metastable GUM/estrogen conjugate has variable activity on the estrogen receptor (Fig. Ub). When such active metastable conjugates are intentionally treated with, for example, an acid, a thiol or an enzyme (e.g., cathepsin), the metastable G L P _ 1 / estrogen conjugate restores near full estrogen potency. Thus, the active metastable GLP-1/estrogen conjugate exhibits reduced estrogenic activity in the form of a covalent conjugate and requires release to be active. Example 23. In Vitro Receptor Assay for Inactive GLP-1/Estrogen Conjugates Serial dilutions of the following compounds were prepared: Lu (1) Inactive GLP-1, (11) Estrogen Stabilized Inactive GLP-1/Estrogen (3- An ether) conjugate, and (Ul) an estrogen-labile inactive GLP-1/estrogen (3-ester) conjugate. Gum activity (cAMP induction): serial dilutions of (1), (ii) and (iii) are combined with HEK293 cells co-transfected with the GLP-1 receptor and the luciferase gene fused to the cAMp response element (CRE) Cultivate. Luminescence was measured after cell lysis and incubation with luciferin. The results are shown in the table below. 156004. Doc -459· 201143790 Conjugate GLP-1 EC5〇(nM) Active GUM --- 0. 028±0. 001 Inactive GLP-1 (containing d-amino acid) 480. 5±12. 76 inactive GUM (including d · face estrogen (3-ester) 562. 2±26. 87 inactive GLP-1 (containing igtV estrogen (3-ether) 418. 3 士 16. 75 Example 24 Administration of diet-induced obesity mice (DIO) (N=8, mean body weight 51 g) to subcutaneous injections with vehicle or 400 pg/kg or 4000 pg/kg once daily Week: (a) GLP-1 (A丨Aib2E16K4°Cex) containing d-amino acid (4000 pg/kg), (b) GLP-UAkiWAUCex K4G) with d-amino acid/Estrogen (3- Vinegar) (400 pg/kg, 4000 pg/kg), or (c) GLP-UAiAit^AUCex K4G) with d-amino acid/Estrogen (3-mystery) (400 pg/kg, 4000 pg/kg) ° ° Measure weight after 15 days and determine weight changes. Mice that were inactive with estrogen-stable inactive d-amino acid GLP-1/estrogen (3. ester) conjugates had the greatest reduction in body weight, and this effect was more pronounced at high doses (Fig. 12a). The effect of inactive GLP-1 and inactive GLP-1/estrogen conjugates on cumulative food intake over a 15-day period was also determined. Mice fed a GLP-1/estrogen (3-ester) conjugate with an estrogen-labile, inactive, d-amino acid-containing conjugate consumed significantly less food than administration of inactive GLP-1 alone or administered Mice with stable estrogen-stable inactive D-amino acid-containing GLP-1/estrogen (3-ether) conjugates were more pronounced at high doses (Fig. 12b). Figure 12c shows the effect of inactive GLP-1 and inactive d-amino acid-containing GLP-1/estramine conjugates on blood glucose changes. On day 12 to day 14, high doses of inactive D-amino acid-containing GLP-1/estrogen (3-ester) conjugates reduced blood 156004. Doc •460· 201143790 Sugar. Liver weight was measured after 15 days and liver weight changes were determined. Mice administered with estrogen-labile, inactive d-amino acid-containing glu/estrogen (3 ether) conjugates have reduced liver weight greater than estrogen-stable inactive d-amino acids. Mice of GLP-1/estrogen (3_stuff) conjugate 12d) The uterus weight was measured after 15 days and the change in uterine weight was determined. The degree of uterine weight increase in mice administered with GLP-1/estrogen (3-ester) conjugates of inactive d-amino acid, which is unstable to estrogen, is significantly greater than that of administration of inactive GLP-1 alone or Mice administered with estrogen-stabilized inactive GLp-丨/estrogen (3-ether) conjugate containing 3-amino acid (Fig. 12e). Example 25 C57BI/6 mice on a standard diet (N=8, mean body weight 19. 6 g) Ovariectomy was performed and allowed to recover for 5 days, after which the subcutaneous injection was administered once daily for 7 days with vehicle or 4 〇〇〇Kg/kg: Lu (a) GLP-l agonist, Containing (1-amino acid 〇1^-1 (八1八丨1)2 八22〇6\1^4.)/estrone (3-brewed), (c) containing d-amino acid GLP-UAkiPAKCex K4G) / estrogen (3-mystery), or (d) GLP-1 agonist / estrogen (3-ether). Mice were sacrificed at the end of the study and the uterus was collected and weighed. Body weight was measured after 7 days and body weight changes were determined. Mice administered an estrogen-stable active GLP-1 agonist/estrogen (3-eether) conjugate have a greater degree of weight loss than administration of an active GLP-1 agonist alone (Fig. 13A), administration of estrogen 156004. Doc -461 - 201143790 Unstable inactive GLP-1/estrone (3-ester) conjugate containing d-amino acid, or GLP-1 inactive with estrogen-stabilized inactive d-amino acid / Estrogen (3-ether) conjugate in mice. Administration of GLP-1 agonist, administration of estrogen-labile inactive D-amino acid-containing GLP-1/estrone (3-ester) conjugate, and administration of estrogen-stable active GLP-1 Mice with agonist/estrogen (3-ether) conjugates showed reduced fat mass (Fig. 13B) » Also determined the effect of GLP-1 conjugates on cumulative food intake over a 7-day period. Estrogen stable The active GLP-1 agonist/estrogen (3-ether) conjugate of the mouse consumes less food than the active GLP-1 agonist alone, and the estrogen-labile inactive d-amine a GLP-1/estrone (3-ester) conjugate of a base acid, or a mouse administered with an estrogen-stable, inactive D-amino acid-containing GLP-1/estrogen (3-ether) conjugate ( Figure 13C). Figure 1 3D shows the effect of GLP-1 conjugates on blood glucose changes. Involvement of estrogen-labile, inactive D-amino acid-containing GLP-1/estrone (3-ester) conjugate or administration of active stable GLP-1 agonist/estrogen (3-ether) conjugate The mice had a lower blood glucose level than the mice that were administered the vehicle. The mice administered with the estrogen-stabilized inactive D-amino acid-containing GLP-1 / estrogen (3 · ether) conjugate did not exhibit a decrease in sugar content. Uterine weight was measured after 7 days and changes in uterine weight were determined. Mice with a GLP-1/estrone (3-ester) conjugate of an inactive estrogen-stable inactive d-amino acid had a significantly greater increase in uterine weight than administration of GLp-1 alone, and estrogen stabilization. Inactive GLpq/estrogen (3_ether) conjugate containing d-amino acid, or mouse administered estrogen-stabilized active GLP-1/estrogen (3_ether) conjugate (Fig. 13E) . 156004. Doc -462- 201143790 Example 26 For mice on a standard diet (N=8' average body weight was 19. 1 g) Ovariectomy was performed and allowed to recover for 5 days, after which subcutaneous injection was administered once daily for 7 days with vehicle or 4000 pg/kg: (a) GLP-1 agonist/estrone (3-ester) ), (b) GLP-1 agonist/estrogen (17-urethane disulfide), (c) GLP-1 agonist/estrogen (17-腙), or (d) GLP -1 agonist / estrogen (17- cathepsin). Mice were sacrificed at the end of the study and the uterus was collected and weighed. Body weight was measured after 7 days and body weight changes were determined. The weight of the body weight and fat mass of mice administered with a metastable GLP-1 agonist/estrogen conjugate was greater than that of the active GLP-1 agonist or the elastogenic instability of GLP-1. Mice/estrone (3-ester) conjugate mice (Figures 14A and 14B). Administration of a metastable enzyme labile conjugate and an acid labile conjugate (GLP-1 agonist/estrogen (17- cathepsin) and GLP-1 agonist/estrogen (17-腙)) The degree of weight loss in mice was initially maximal, while the metastable thiol reduction inducible conjugate (GLP-1 agonist/estrogen (17-amino phthalate disulfide)) showed overall body weight over a 7-day study. The biggest drop. Figure 14C shows the effect of a metastable GLP-1 conjugate on blood glucose changes. β administration of a metastable thiol reduction unstable conjugate and an acid labile conjugate, respectively (GLP-1 agonist/estrogen (17-amine) Mice with bismuth phthalate disulfide and glP-Ι agonist/estrogen (17-knee) decreased blood glucose levels during the study compared to administration of unstable GLP-1 agonist/female _ ( 3_vinegar) conjugate of mouse 0 156004. Doc -463- 201143790 The uterine weight was measured after 7 days and the uterine weight change was determined. Mice administered with the estrogen-labile GLP-1/estrone (3-ester) conjugate experienced a significantly greater increase in uterine weight than mice administered a metastatic GLP-1/estrogen conjugate (Figure 14D) » Example 27 Subcutaneous injection of subcutaneous injections in diet-induced obesity mice once daily for two weeks with vehicle or 40 pg/kg or 400 pg/kg: (a) GLP-1 agonist, ( b) GLP-1 agonist/estrogen (3-ester), or (c) GLP-1 agonist/estrogen (3-ether). Body weight was measured after 15 days and body weight changes were determined. Mice that were administered estrogen-stabilized active GLP-1 agonist/estrogen (3_ether) conjugates had significantly less weight loss than either administration of active GLP-1 agonist alone or estrogen instability Mice with active GLP-1 agonist/estrogen (3-acetate) conjugate (Fig. 15A). The effect of active GLP-1 and active GLP-1/estrogen conjugates on cumulative food intake over a 15-day period was also determined. "Estrogen-stabilized activity glp-1 agonist/estrogen (3-ether) binding Mice eat significantly less food than mice that are administered an active GLP-1 agonist alone or with an estrogen-stable active GLP-1 agonist/estrogen (3-ester) conjugate (Figure 15B) » Example 28. Stability analysis of GLP-1/estrogen conjugates in 100% human plasma at pH 7. Peptide conjugates (1 mg/mL) were incubated at 4 and 37 °C. Aliquots were taken and plasma proteins were precipitated and removed by microcentrifugation. As described in Example 1, it was divided into 156004 by HPLC and MS analysis. Doc -464 - 201143790 sample. Although hormone-stabilized active GLP-1/hormone (3. ether) conjugate (eg, Example 3) does not exhibit estrogen release over 72 hours, estrogen is unstable, and the tongue is GLP-1/estrogen ( The 3-acetate) conjugate (e.g., Example 6) exhibited significant estrogen release after 3 hours and demonstrated complete estrogen release within 6 hours (Figure 16). The acid labile conjugate (GLP-1/estrogen (17-腙)) (e.g., Example 7) does not exhibit estrogen release at physiological pH for 48 hours in blood pooling, but is exposed to acid (pH 5. 0) Estrogen is released within 3 hours, and estrogen is released within 6 hours (Figure MB). The sterically hindered thiol reduction unstable conjugate (eg, Example 9) exhibits significant estrogen release after 24 hours and exhibits complete gonadotropin release within 48 hours, while sterically hindered thiol reduction unstable conjugate (GLPd/estrogen) (17-Amino phthalate disulfide)) (e.g., Example 9) did not exhibit estrogen release in plasma for 72 hours (Fig. 16C). This hindered thiol-reduced unstable conjugate also showed no estrogen release at extracellular glutathione concentrations (eg, 15 μΜ), but released females within 6 hours at 15 mM intracellular glutathione concentration. Hormone (Figure 16D). The enzyme-labile GLP-1/estrogen (cathepsin) conjugate (e.g., Example 10) did not exhibit estrogen release in plasma for 72 hours (Fig. 16E). Example 29 A diet-induced obesity mice were administered subcutaneously daily for seven days with vehicle or 400 pg/kg of one of the following: (a) GLP-1 agonist, (b) GLP-1 agonist/ Estrogen (3-ether), (c) GIP agonist, (d) GIP agonist/estrogen (3-ether), 156004. Doc •465· 201143790 (e) Glucagon agonist, or (f) Glycoglycan agonist/estrogen (3-ether). Body weight was measured after 7 days and body weight change was determined (Fig. 17A) ^ Mice who were administered GLP-1 agonist/estrogen (3-ether) conjugate had the greatest degree of weight loss, and the degree of weight loss was significantly greater than that of the cast. Mice with GLP-1 agonist alone. Mice administered with a GIP agonist alone exhibited similar degrees of weight loss to mice administered a GIP agonist/estrogen (3_ linkage) conjugate. Mice that were administered GIP agonist and GIP agonist/hormone (3 - mystery) conjugates exhibited a greater reduction in body weight than mice administered vehicle. Mice administered with a single glycosidic agonist exhibited a similar degree of weight loss as mice administered a glycosidic agonist/estrogen (3-ether) conjugate. The degree of weight loss in mice administered with a glycemic agonist or a glycoside agonist/estrogen (3-ether) conjugate was similar to that of mice administered vehicle. Without wishing to be bound by any particular theory, 'dry to the GLP-1 receptor displays excellent estrogen stem cell abilities' where it can make a meaningful difference in body weight. In this experiment, the conjugate of GLP-1 active peptide (GLP-1 agonist) outperformed the peptide that primarily targets the GIP receptor or the glycosidic receptor (GIp agonist or sucrose) in weight loss. Agonist) The effect of conjugates on cumulative food intake was also determined (Fig. 17B) ^Mice that elicited estrogen conjugates of GLP-1 'mice that elicited estrogen conjugates of gip and ewe The hormone conjugated mice consumed less food than mice administered the GLP-1 agonist, mice administered the Gip agonist, or mice administered the glycosidic agonist. Mice administered GLP-丨 agonist/estrogen (3-ether) conjugates consumed the least amount of food during the 7-day period. 156004. Doc -466- 201143790 Also determines the effect of conjugates on blood glucose changes. Mice administered with GLpq agonist and GLP-1 agonist/estrogen (3-ether) conjugate showed a decrease in glycogen content after 7 days, in which mice with which the conjugate was administered were reduced. Big. The mice administered with the GIP agonist and the GIP agonist/estrogen (3_ether) conjugate showed a decrease in blood glucose levels over 7 days. Mice administered with the glycosidic agonist showed an increase in blood glucose levels over 7 days, whereas mice administered the glycosidic agonist/estrogen (3_ 趟) conjugate showed a decrease in blood glucose levels over 7 days (Figure 17). c). I Example 30 Using a vehicle or 400 pg/kg once a day for diet-induced obesity wild-type mice, estrogen receptor beta knockout (ER|3 κ〇) mice, and estrogen receptor alpha rejection ( ERa ΚΟ) mice were administered subcutaneously for two weeks: (a) GLP-1 agonist, or (b) GLP-1 agonist/estrogen (3-Saki). Body weight was measured after 14 days and body weight changes were determined (Fig. 8A). Wild-type mice administered GLp_^ agonist/estrogen (3-ether) conjugates exhibited a lower degree of φ reduction than the vehicle administered or the GLP-1 agonist. Wild-type mice administered vehicle showed approximately 3% D/❶ weight gain over a two-week period, exhibited approximately 3% weight gain upon administration of the GLP-1 agonist, and were administered GLp_! agonist/ The estrogen (3-ether) conjugate exhibited a decrease in body weight of about 1%. The GLp-1 agonist/estrogen (3-ether) conjugate 2ERa κ 〇 mice exhibited a decrease in body weight greater than that at the time of administration of the vehicle or administration of the GLP-1 agonist. ERa ΚΟ mice did not show changes in body weight when administered with vehicle, and showed a decrease in body weight of about 丨〇% with GLP-1 agonist, and were administered GLp_ j agonist/estrogen (3-ether) The combination showed a decrease in body weight of about 2%. To 156004. Doc 467· 201143790 GLP-1 agonist/estrogen (3_ether) conjugate ERp κ〇 mice exhibited a similar degree of weight loss compared to mice administered GLP-1 agonist ❶ERp κ〇 mice Approximately 2% weight loss was demonstrated when the vehicle was administered, and approximately 15% weight loss was exhibited upon administration of the glP-1 agonist or administration of the GLP-1 agonist/estrogen (3_ether) conjugate. Without wishing to be bound by any particular theory, such information indicates that the Aβ receptor is responsible for additional weight loss. When the ERp receptor was knocked out, the mice did not show differences in the degree of weight loss between the GLP-1 agonist and the GLP-1 agonist/estrogen ether conjugate. The effect of GLP-1 conjugates on cumulative food intake in wild-type and knockout mice was also determined (Fig. 18B). The knockout mice administered GLP-1 agonist/estrogen (3-ester) conjugates consumed the least amount of food. The effect of GLP-1 conjugates on blood glucose changes in wild-type and knockout mice was also determined. The ERa KO mice administered with the GLP-1 agonist/estrogen (3_vinegar) conjugate exhibited the greatest reduction in blood glucose levels (Fig. 18C). Example 3 1 Male db/db mice with a blood glucose level of 5 〇〇 mg/dl were administered a subcutaneous dose of vehicle or 50 nmol/kg: (a) GLP-1 agonist, (b) GLP - l agonist / estrogen (3-ether), or (c) GLP-1 agonist / estrogen (3-ester). Mice administered GLP-1 agonist exhibited the worst blood glucose reduction (except vehicle) over 48 hours' while administering estrogen-stabilized GLP-1 agonist/estrogen (3-ether) conjugate The mice showed the most effective blood glucose reduction over 48 hours (Figure 19) 〇136004. Doc -468- 201143790 The results of the above experiments are consistent with the results of the use of streptozotocin (STZ) induced diabetes molding (type I diabetes model). BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows an alignment of the amino acid sequences of various glycoside superfamily peptides or related fragments thereof. The amino acid sequence presented is GHRH (SEQ ID NO: 1619) 'PHI (SEQ ID NO: 1622) > VIP (SEQ ID NO: 1620) 'PACAP-27 (SEQ ID NO: 1621), Incretin Analog-4 (SEQ ID NO: 1618), GLP-1 (SEQ ID NO: 1603), Glycosin (SEQ ID NO: 1601), Acid Regulator (SEQ ID NO: 1606), GIP (SEQ ID) NO: 1607), GLP-2 (SEQ ID NO: 1608) and secretin (SEQ ID NO: 1624). The alignment shows the position of the amino acid position of the glycemic glycoside with the position of the amino acid in the other glycosidic superfamily peptide. Figure 2 illustrates the effect of administration of the indicated GLP-1 conjugate on changes in body weight and blood glucose levels in db/db mice. Figure 2a shows that mice administered a high dose of GLP-1 (Aib2A22CexK4Q)/estrogen (17-ester) conjugate have a slightly lower body weight than mice administered GLP-1 alone, but are similar to the vehicle group. Figures 2b and 2c show that mice administered high doses of GLP-1 (Aib2A22CexK4G)/estrogen (17-ester) conjugates on day 12 to day 14 had the greatest reduction in blood glucose levels, indicating enhanced ability to improve blood glucose. And has nothing to do with weight changes. Figure 3 illustrates the effect of administration of the indicated GLP-1 conjugate on blood glucose, body weight, fat mass and carcass quality in diet-induced obese mice. Figure 3a illustrates the results of the 21st day ipGTT test. Figure 3b-d illustrates changes in body weight (Fig. 3b) and changes in fat mass in diet-induced obese mice administered with the indicated GLP-1 conjugate (Fig. 156004. Doc •469· 201143790 3c) and ^ quality. The impact of changes (Figure 3d). The weight and fat mass of the mice with high doses of (d) 'A Μ _ (17,) conjugates: the greatest degree of decline and the smallest change in the quality of the meat. Figure 3e illustrates the induction of diet by tfGUM conjugate The effect of blood glucose changes in obese mice was 2 to 2. On the second day to the 14th day, the dose (10) (AM CeXKV estrogen (17,) conjugate mice had the greatest reduction in blood sugar levels.矣Ba 寻,,,. The results indicate that the addition of estrogen to the weak GLP-1 agonist based on A22 can increase the dose-dependent efficacy. Figure 4 illustrates the administration of the indicated GLp_u# compound to blood glucose content, body weight change, fat mass Changes and effects of changes in blood glucose. _ Explain the effect of the indicated (10)·1 conjugate on blood glucose levels in diet-induced obese mice after fourteen daily doses in the intraperitoneal glucose dose test. The effect of the indicated GUM conjugate on body weight change and fat mass change in diet-induced obese mice. The mice with high doses of estrogen conjugates had the greatest overall weight loss (Fig. 4b). Animal phase treated with hormone ether conjugate For vehicle-treated animals, the fat mass was reduced (Fig. 4, 10, 4d, indicating the effect of administration of the indicated GLp_u# compound on blood glucose changes in diet-induced obese mice. From Days to Days The blood glucose level of the mice administered the ren-hormone conjugate at a high dose was greater than that of the mice administered with GLP_丨 (Aib2El6Cex K4G) alone. Figure 5 illustrates the combination of the GLP-1 conjugate and the diet induced Effects of changes in body weight and changes in blood glucose in obese mice. Mice who received high doses of estrogen conjugates had the greatest weight loss (Fig. 5a) ^ cast high doses or 156,004. Doc •470· 201143790 Mice with low doses of GLP-1 (Aib2Ei6K, ex) and mice dosed with high doses of GLP-1 (Aib2E16K4QCex)/estrogen (3-ether) had the greatest degree of blood glucose change (Fig. 5b) ). Figure 6 illustrates the effect of administration of the indicated GLP-1 conjugate on body weight changes, changes in fat mass, and changes in blood glucose in diet-induced obese mice. Mice that were administered either estrogen conjugate had the greatest overall weight loss (Fig. 6a). The analysis of the fatty stems (Fig. 6b) was relatively constant under overall weight loss. Changes in blood glucose levels in mice given GLP-1 (Aib2E16K4()Cex)/estrogen ether) or GLp_l (Aib E 6K4GCex)/estrogen (17-ester) conjugates from Day 3 to Day 4 The degree is the greatest (Figure 6c). Figure 7 illustrates the effect of administration of the indicated GLP-1 conjugate on body weight changes and blood glucose changes in diet-induced obese mice. Mice administered estrogen conjugates had the greatest reduction in overall body weight (Fig. 7a) and blood glucose levels (Fig. 7b) over a 7-day period. None of the A22-containing peptides or the aminoglycolic acid-containing peptides showed a large degree of decrease relative to GUM (Aib2E 6Cex K4〇}/estrogen conjugate. In addition, GLp-l (Aib2E16CeX K4.) The estrogen conjugate is significantly more potent than the non-estrogen form of the same peptide. Figure 8 illustrates the effect of administration of the indicated GLp-丨 conjugate on changes in body weight, blood glucose, and fat mass. The peptide containing d-amino acid is All efficacy measures were significantly inferior to peptides containing 1-amino acids. Figure 8a illustrates the effect of administration of the indicated GLp_l# compound on body weight changes in diet-induced obese mice. Peptides in the presence and absence of estrogen These doses showed little apparent difference in weight loss. However, in the map, the effect of the indicated GLP-1 conjugate on blood glucose changes in diet-induced obese mice was shown. Doc -471· 201143790 On days 0 to 7, mice infused with GLP-1 (Aib2EuCex K40)/estrogen (3-Θ) conjugates had the greatest changes in blood glucose levels in vivo, much larger than An animal that is identical but not treated with estrogen. This suggests a direct improvement in blood glucose regardless of weight differences. Figure 8c illustrates the effect of administration of the indicated GLP-丨 combination on changes in fat mass. Figure 9 illustrates the effect of administration of the indicated GLp-1 conjugate on body weight change, amount of fat mass, and blood glucose change in diet-induced obese mice. The degree of weight loss in mice administered with a D-amino acid-containing GLP-1/estrogen (3-ester) conjugate at elevated doses relative to mice administered a 1-amino acid-containing control Max (Fig. 9a) 'and has the least amount of fat mass (Fig. 9b). From day 3 to day 7, D-amino acid-containing GLP-1/estrogen (3-ester) conjugates have a significant dose-dependent blood glucose lowering effect, and at the highest dose relative to administration of GLP alone This dose-dependent blood glucose lowering effect was enhanced in mice of -1 (Fig. 9c). Figure 10 illustrates the effect of administration of the indicated GLP-1 conjugate on changes in body weight and changes in jk sugar content in diet-induced obese mice. The mouse is administered a GLP-1/estrogen conjugate containing d-amino acid, wherein the estrogen is covalently linked by stabilizing the guanamine or in an unstable ester form in vivo. Animals treated with the labile ester conjugate had the greatest overall weight loss (Fig. 1a). Figure 1〇b shows that the mice in the GLpq/estrogen ester conjugate containing d-amino acid changed the amount of sugar content from day to day 7 to a greater extent than the equivalent d-amino acid. Peptide but this peptide is administered to mice in the form of a stable estrogen conjugate. Figure 11 illustrates the activity of the conjugates on GLp_丨 receptors and estrogen receptors. Activity of active metastable GLP-1/estrogen conjugates to gLP_丨 receptors 156004. Doc • 472- 201143790 is equivalent (Fig. 11a) and its activity on the estrogen receptor is variable (panel m). Figure U illustrates the administration of the indicated GUM conjugate to changes in body weight, food intake, blood glucose, liver weight, and uterine weight in diet-induced obese mice. Estrogen-labile inactive amino acid-containing acid "The hormonal (3-vinegar) conjugate mice had the greatest weight loss, and this effect was more pronounced at high doses (Fig. 12a). Figure 12b shows that mice fed the inactive estrogen-stable inactive d-amino acid-containing GLpq/estrogen (3_vinegar) conjugate have significantly less food for φ than for the inactive d-amine alone. Mice with GLIM or sputum and estrogen-stabilized D-amino acid-containing GLu/estrogen (3_ether) conjugates were more pronounced at high doses. Figure 12c shows the high dose of estrogen-labile inactive GLp-i/estrogen ester-containing conjugates of lowering blood glucose levels relative to vehicle-treated animals. Figure i2d shows that the degree of liver weight reduction in mice with sputum and estrogen-stable inactive DLp_〗/estrogen (3 _ ether) conjugates with d-amino acid is subtle and greater than the inactive estrogen-stable A mouse containing a d-amino acid Guy/estrogen (3 ether) in combination with φ. Figure 12e shows that the degree of uterine weight increase in mice administered with the eligogenically unstable inactive D-amino acid-containing GLP-1/estrogen (3. ester) conjugate is significantly greater than the administration of inactive GLP_丨 alone. Or a mouse that is administered with an estrogen-stable, inactive D-amino acid-containing GLP-1/estrogen (3_ether) conjugate. Figure 13 illustrates the effect of administration of the indicated GLP-1 conjugate on body weight, fat mass, food intake, blood glucose levels, and uterine weight in ovariectomized mice. Figure 13A shows that mice administered an estrogen-stable active GLp_i agonist/estrogen (3-ether) conjugate have a greater degree of weight loss than administration of an active GLP-1 agonist alone, and estrogen instability Inactive core-containing amine 156004. Doc -473- 201143790 GLP-1/estrone (3-ester) conjugate of acid, or GLP-1/estrogen (3-ether) conjugate with estrogen-stable inactive d-amino acid Mouse. Figure 13B shows the administration of a GLP-1 agonist, an inactive estrogen-labile inactive D-amino acid-containing GLP-1/estrone (3-ester) conjugate, and administration of estrogen-stabilizing activity Mice of the GLP-1 agonist/estrogen (3-ether) conjugate exhibited a decrease in fat mass. Figure 13C shows that mice fed the estrogen-stable active GLP-1 agonist/estrogen (3-mystery) conjugate consume less food than the active GLP-1 agonist alone, and do not administer estrogen. Stable inactive GLP-1/estrone (3-ester) conjugate containing carboxy-amino acid, or GLP-1/estrogen (3-ether) administered with estrogen-stabilized inactive d-amino acid a conjugate of mice. Figure i3D shows GLP-1/estrone (3-ester) conjugates administered with estrogen-labile inactive d-amino acids or GLPs with estrogen-stable inactive d-amino acids -1 estrogen (3-ether) conjugate, or estrogen-stabilized active GLP-1 agonist/estrogen (3-ether) conjugate, reduced blood glucose levels in mice greater than the vehicle group, Furthermore, mice administered an estrogen-stable, inactive d-amino acid GLP-1/estrogen (3-ether) conjugate did not exhibit a decrease in blood glucose levels. Figure 13E shows that the uterine weight gain of mice administered with the estrogen-labile inactive d-amino acid-containing GLp·1/estrone (3-ester) conjugate was significantly greater than that of GLP-1 alone. GLP-1 / estrogen (3-ether) conjugate with estrogen-stable inactive d•amino acid, or conjugated with estrogen-stabilized active GLP-1/estrogen (3·ether) Mouse. Figure 14 illustrates the effect of administration of the indicated GLp_丨 conjugate on body weight, fat mass, blood glucose and uterine weight in ovariectomized mice. The weight and fat mass of mice administered with a stable GLP-1 agonist/estrogen conjugate 156004. Doc • 474· 201143790 The degree of decline was greater than that of mice administered with active GLP-1 agonist alone or with estrogen-stable active GLP-1 agonist/estrone (3-acetate) conjugate (Fig. 14A and 14B). Administration of a metastable enzyme labile conjugate and an acid labile conjugate (GLP-1 agonist/estrogen (17- cathepsin) and GLP-1 agonist/estrogen (17-腙)) The degree of weight loss in mice was initially maximal, while the metastable thiol reduction inducible conjugate (GLP-1 agonist/estrogen (17-urethane disulfide)) exhibited the greatest decrease in overall body weight. Figure i4C shows the administration of a metastable thiol reduction unstable conjugate and an acid labile conjugate (GLP-1 agonist/estrogen (17-urethane disulfide) and glP-1 efficacies, respectively. Mice/estrogen (17-腙) mice had a lower blood glucose level than mice administered the estrogen-labile GLP-1 agonist/estrone (3-ester) conjugate. Figure 14D shows that mice administered Estrogen-labile GLP-1/estrone (3·vinegar) conjugates experienced significantly greater uterine weight gain than administration of three metastable GLP-1/estrogen conjugates. Any of the mice. Figure 15 illustrates the effect of administration of the indicated GLp-丨 conjugate on changes in body weight and cumulative food intake. Mice that were administered estrogen-stabilized active GLp_丨 agonist/estrogen (3-ether) conjugates had significantly less weight loss than either administration of active GLP-1 agonist alone or estrogen instability Mice with active glp" agonist/estrogen (3-ester) conjugate (Figure 15A). Figure 15B shows that mice fed the estrogen-stabilized active GLPU agonist/estrogen (3_ether) conjugate consumed significantly less food than either the active GLP-1 agonist or the estrogen alone. A stable GLp_丨 agonist/estrogen (3_ester) conjugate of mice. Figure 16A E also, 'a illustrates the 1 / estrogen conjugate at 37 under 156004. Doc -475- 201143790 HPLC overview of stability in human plasma. The estrogen-stabilized GLP-1/estrogen (3-ether) conjugate did not exhibit estrogen release over 72 hours, while the estrogen-labile GLP-1/androgen (3-ester) conjugate exhibited after 3 hours. Significant estrogen release and complete estrogen release within 6 hours. Figures 17A-C illustrate the effect of administration of the indicated conjugates on percent body weight, cumulative food intake, and blood glucose levels in diet-induced obesity mice. Figures 18A-C illustrate the percentage of body weight of the indicated combination to diet-induced obesity wild-type mice, estrogen receptor beta knockout (ΕΙΙβ KO) mice, and estrogen receptor alpha knockout (ERcx®) mice. The effects of changes in cumulative food intake and blood sugar levels. Figure 19 illustrates the effect of the indicated GLP-1 conjugate on blood glucose levels over time. Mice dosed with GLP-1 agonist had the least effective reduction in blood glucose displayed over 48 hours (except for vehicle) and were administered with estrogen-stabilized GLpq agonist/estrogen (3-ether) The mice showed the most effective reduction in blood glucose over 48 hours. 156004. Doc •476· 201143790 Sequence Listing <110> American Indiana University Technology Research Corporation <120> Glycosin superfamily peptide having nuclear hormone receptor activity

<130> 31135/44822B <140> 100116893 <141> 2011-05-13 <150>61/334,435; 61/432,077 <151>2010-05-13; 2011-01-12 <160&gt 1668 <170> Patentln version 3.5 <210> 1 <211> 29 <212> PRT <213> Homo sapiens

<400> 1

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 2 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (16)..(16) <223> Glu, Gin, homofacial acid or high sulfoalanine <220>

<221> MOD RES <222> (17)..(17) <223> Arg, Cys, Om, homocysteine or acetylalanine <220><221> MOD RES <;222> (27)..(27) <223> Met, Leu or Nle <400> 2

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Xaa Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr 20 25 <210> 3 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD.RES 156004-sequence table.doc 201143790 <222> (16)..(16) <223> Glu, Gin, glutamic acid or high sulfoalanine <220>

<221> MOD.RES <222> (20..(21) <223> Asp, 0ys, Om, homocysteine or acetylalanine <220><221> MOD RES <;222> (271..(27) <223> Met, Leu or Nle <400> 3

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Xaa Phe Val Gin Trp Leu Xaa Asn Thr 20 25 <210> 4 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (16)..(16) <223> Glu, Gin, glutamic acid or high sulfoalanine <220><221> MOD RES <222> (24).. (24) <223> Gln, 0ys, Om, homocysteine or acetylalanine <220><221> M0D.RES <222> )..(27) <223> Met, Leu or Nle <400> 4

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 <210> 5 <21l> 29 <212> PRT <213>Artificial Sequence<220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (16)..(16) <223> Glu, Gin, glutamic acid or high sulfoalanine <220>

<221> MOD RES <222> (211..(21) <223> Asp, Cys, Om, homocysteine or acetylalanine • 2

156004· Sequence Listing.doc 201143790 >>>> ^ >>> 01643 &1643 2222 2222 <2<2<2<2<2<2<2<2 MOD RES (24) ..(twenty four)

Gin, Cys, Om, homocysteine or acetyl phenylalanine MOD RES (27)..(27)

Met, Leu or Nle <400>

His Ser Gin Gly Thr Phe Tnr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Xaa Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 <210> 6 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MOD RES <222> (21)..(21) <223> Asp, 0ys, Om, homocysteine or acetylated amphetamine <220><221> MOD. RES <222> (27)..(27) <223>Met,Lei^Nle <400> 6

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Xaa Phe Val Gin Trp Leu Xaa Asn Thr 20 25 <210> 7 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (24).. (24) <223> Gln, Cys, Om, homocysteine or acetylated albinoic acid <220><221> MOD.RES <222> (27)..(27) <223> Met, Leu or Nle <400> 7

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Gin Asp Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 <210> 8 <211> 29 <212> Staring <213>Artificial Sequence<220><223> Synthetic Glycoside <220><221> MOD.RES <222> (16)..(16) <223> Glu, Gin, homoprosin or high sulfoalanine <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 9 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> M0D_RES <222> (27)..(27) <223> Met, Leu or Nle <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr 20 25 <210> 10 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <400> 10

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 35

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 11 <211> 29 <212> PRT < 213 > Artificial Sequence <220> -4- 156004 · Sequence Listing.doc 201143790 <223> Synthetic Glucagon Analog <220><221> MISC FEATURE <223> C-terminal imidization <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Aig Arg Ala Gin Asp Phe Val Gin Tip Leu Met Asn Thr 20 25 <210> 12 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Synthetic Glucagon Analog

<220><221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <400> 12

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 13 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC FEATURE <222> (16).. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <400> 13

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 14 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC.FEATURE 156004-sequence table.doc 201143790 <222> (22)..(24) <223> between the side chain on position Ϊ22 and the side chain on position 24. Endo-amine ring <400> 14

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Lys Asp Phe Val GIu Trp Leu Met Asn Thr 20 25 <210> 15 <21]> 29 <212> PRT <213>Artificial Sequence <220> Synthetic Glycosin Analog <220><221> MISC.FEAOJRE <222> (24)..(28) <223> The intrinsic amine ring formed between the side chain at position 24 and the side chain at position 28

<400> 15

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 <210> 16 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220> <221> MISC FEATURE <222> (12) 7. (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>

<221> MISC.FEATURE <222> (20)..(24) <223> The intrinsic amine ring between the side chain at position 20 and the side chain at position 24 <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 <210> 17 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog 156004· Sequence Listing.doc 201143790 <220><221>MISCJWURE<222> (16)..(20) <223> 醯 between the side chain at position 16 and the side chain at position 20 Amine ring <220><221> MISC FEATURE <222> (24) 7. (28) <223> The indole ring between the side chain at position 24 and the side chain at position 28 <400> 17

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Set Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Asp Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 <210> 18 <211> 29 <212> PRT <213>

<220><223> Synthetic glycosidin analogue <220><221> MISC FEATURE <222> (16) 7. (20)

<223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <400> 1S

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 <210> 19 <211> 30 <212> PRT <213> Artificial Sequence <220><223> Synthetic Glucagon Analog

<221> MISC FEATURE <223> C-terminal amide hydration <220><221> MOD RES <222> (30).. (30) <223> Variable amino acid <400> 19

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Xaa 20 25 30 <210> 20 <211> 29 <212> PRT <213>Artificial Sequence 156004 - Sequence Listing.doc 201143790 <220〉 <;223> Synthetic glycosidin analog <220><221> M0D.RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfo group Alanine <220>

<221> MOD RES <222> (20).. (20) <223> 01n, Lys, Aig, Om or citrulline <220><221> MOD.RES <222> )..(24) <223> Gin or Glu <220><221> M0D-RES <222> (28)..(28) <223> into sn, Asp or Lys <220><22l> M0D_RES <222> (29)..(29) <223> Thr or Gly <400> 20

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 <210> 21 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC FEATURE <223> C-terminal imidization <220><221> MOD RES <222> (2) 7. (2) <223> Xaa is D-Ser , Ala, Gly, N-methyl Ser or AIB <400> 21

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 22 <21l> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog 156004-Sequence List.doc 201143790 <220><221> MISC FEATURE <223> C-armed helmet amination <220>

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <400> 22

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 23 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC.FEATURE <223> terminal amination <220><221> MOD RES <222> (17)..(17)

<223> Cys-PEG <220><221> MOD.RES <222> (27)..(27) <223> Met, death eu or Nle <400> 23

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr 20 25

<220〉 <223> 24 29

PRT artificial sequence synthesis of glycoside analogue <220><221> MISC FEATURE <223> C-terminal amide hydration <220>

<221> MOD RES <222> (21)..(21) <223> Cys-PEG <220><221> MOD.RES <222> (27)..(27) 156004- Sequence Listing .doc 201143790 <223> Met, Leu or Nle <400> 24

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Xaa Asn Thr 20 25 <210> 25 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC_FEATURE <223> C-terminal amide <220><221> MOD RES <222> (24)..(24)

<223> Cys-PEG <220><221> MOD RES <222> (27)..(27) <">23> Met, Leu or Nle <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Xaa Asn Thr 20 25 <210> 26 <211> 10 <212> PRT <213>Artificial sequence <220><223> represents incretin analogue Synthetic peptide fragment of 10 amino acids at the carboxy terminal of -4 <400>

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 <210> 27 <211> 8 <212> PRT <213>Artificial Sequence <220><223> represents the carboxyl terminus of acid-regulating Synthetic peptide fragment of 8 amino acids <400> 27

Lys Arg Asn Arg Asn Asn lie Ala -10-

156004. Sequence Listing. doc 201 143790 <210> 28 <211> 4 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide <400> 28 Lys Arg Asn Arg <210>29<211> 10 <212> PRT < 213 > artificial sequence <220><223> represents a synthetic peptide fragment of 10 amino acids of the carboxy terminal of incretin analog-4 <220>;<221> MISC FEATURE <223> C-terminal amide hydration <400> 29 60 ού li ο pr ο pr ο pr 3 A1 y g15 Γ 6 s Γ 6 s r0 column T-work 3039PR person 0>1>2>3><21<21<21<21<220><223> Synthetic glycosidin analogue <220><221> MOD RES <222> (27T..(27) <223> Met, Leu or Nle <400> 30

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 31 <211> 37 <212> PRT <213>Artificial Sequence<220><223> Synthetic Glycosin Analog <220><221>; MOD-RES <222> (27)..(27) <223> Met' Leu^Nle 156004 · Sequence Listing, doc - 11 - 201143790 <400> 31

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 l〇 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr Lys Arg Asn 20 25 30

Arg Asn Asn lie Ala 35 <210> 32 <211> 33 <212> PRT <213>Artificial sequence <220><223> Synthetic glycoside analogue <220><221> MOD .RES <222> (27)..(27) <223> Met, Leu or Nle <400> 32

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Thr Lys Arg Asn 20 25 , 30

Arg <210> 33 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic glycosidic analogue <220><221> MOD RES <222> (15)..(15) <223> Asp, Glu, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MOD RES <222> (16).. (16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220>

<221> MOD RES <222> (20)..(20) <223> όΐη or Lys <220><221>MOD RES <222> (24)..(24) <223> Gin or Glu <220><221> MOD.RES <222> (28)..(28) <223> Asn, Lys or Acid Amino Acid 12-156004-Sequence List_doc 201143790 <220><221> M0D.RES <222> (29)..(29) <223> Thr, Gly or acid amino acid <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 <210> 34 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MOD RES <222> (15)..(15) <223> Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220><221> MOD RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> MOD RES <222> (20) .. (20) <223> Gin or Lys <220><221> MOD RHS <222> (24)..(24) <223> Gin or Glu <220><221> M0D_RES <222> (28)..(28) <223> Asn, Asp or Lys <220><221> M0D_RES <222> (29)..(29) <223> Thr or Gly &lt ;400> 34

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 <210> 35 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <400> 35 13- 156004-sequence table.doc 201143790

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 36 <211> 39 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <400> 36

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 37 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glycosin Analog <220><221>; MOD RES <222> (24).. (24) <223> 2-butyrolactone linked via thiol group of Cys <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 38 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (24).. (24) <223> Carboxyl group bonded via thiol group of CyS <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 • 14· 156004· Sequence Listing. doc 201 143790 <210> 39 <211> 39 <212> PRT <213>Artificial Sequence<220>;<223> Synthetic Glucagon Analog <400> 39 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 <210> 40 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glycin Analog <220><221>;<223><220><221><222><223> MISC FEATURE C-terminal aminated MODJES (15)..(15) Glu or Asp (>>>> ( > 012 3 ο 2222 ο 2 ςΜ 2 ςΜ 4 < V < V < M0D_RES (28)..(28) Glu or Asp 40

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Xaa Thr 20 25 <210> 41 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC FEATURE <223> C-terminal nitrile; endoamine ring between the side chain at position 12 and the side chain at position 16.

<220><221> MISC FEATURE <223> C-terminal amide hydration <220><221> M3SC FEATURE 156004-sequence table.doc 15-201143790 <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (15)..(15) <223> Glu or into sp <220><221> M0D.RES <222> (28)..(28)

Glu or 乂sp <400> 41

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 1.5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Xaa Thr 20 25 <210> 42 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MISC FEATURE <223> C-terminal amide; the indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MISC FEATURE <223> C-terminal amide hydration <220><221> MOD RES <222> (15)..(15) <223> Glu or into sp <220><221> MISC FEATURE <222> 16).. (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (28).. (28) <223> blu or into sp <400> 42

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Xaa Thr 20 25 <210> 43 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog 16-

156004-sequence table.doc 201143790 <220><221> MISC FEATURE <223> C-terminal amide <220><221> 221 MOD RES <222> (15)..(15) <223> Glu or Asp <220><221> MISC.FEATURH <222> (20), (24) <223> 醯 between the side chain at position 20 and the side chain at position 24. Amine ring <220><221> MOD RES <222> (28)..(28) <223> Glu or Asp <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 15 10 15

Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Xaa Thr 20 25 <210> 44 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC_FEAT\JRE <223> C-terminal amide <220><221> MOD RES <222> (15T..(15) <223> Glu or Asp <220><221> MISC.FEATURE <222> (24)..(28) <223> The intrinsic amine ring between the side chain at position 24 and the side chain at position 28 <220>;221> M0D.RES <222> (291..(29) <223> Glu or Thr <400> 44

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Glu Trp Leu Met Lys Xaa 20 25 <210> 45 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog 17- 156004-Sequence List.doc 201143790 <220><221> MOD RES <222> (12)..(12) <223> Lys or άΐιι <220><221> MOD RES <222> (15Τ·.(15) <223> Asp, Glu, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MOD RES <222> (16). (16) <223> Ser, Gin, Glu, Lys, glutamic acid, sulfoalanine or high sulfoalanine <220><221> MOD RES <222> (20).. (20) <223>Gln, Gh^Lys <220><221> MOD RES <222> (24)..(24) <223> Gin, L^ys or Glu <220><;221> M0D.RES <222> (287-.(28) <223> Asn, Lys or acid amino acid <220><221> hK)D_RES <222> (291..(29 ) <223> Thr, Gly or Acid Amino Acid <400> 45

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Xaa Tyr Leu Xaa Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 <210> 46 <211> 29 <212> PR Ding <213>Artificial Sequence <220><223> Synthetic Glucagon <220><221> M0D_RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> MOD RES <222> (20)..(20) <223> Gin or ilys <220><221> M0D.RES <222> (24)..(24) <223> Gin or Glu <400> 46

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15 18· 156004· Sequence Listing.doc 201143790

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Asn Thr 20 25 <210> 47 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <400> 47

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 48

<211> 29 <212> PRT <213> Artificial sequence <220><223> Synthetic glycosidic analogue <400> 48

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Asn Thr 20 25 <210> 49 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <400> 49

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Glu Trp Leu Met Lys Thr 20 25 <210> 50 <211> 31 <212> PRT <213> Homo sapiens <400> 50

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 <210> 51 <211> 29 -19- 156004 - Sequence Listing.doc 201143790 <212> PRT <213>Artificial Sequence<;220><223> Synthetic glycosidin analog <220><221> MOD-RES <222> (15)..(15) <223> Asp, Glu, homoprolin, sulfonate Alkalamine or high-base alanine <220> <221> MOD RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfopropylamine Acid <220>

<221> M0D.RES <222> (20)..(20) <223> όΐη, Lys, Aig, Om or citrulline <220>

<221> M0D.RES <222> (21)..(21) <223> Asp, Glu, homofacial acid or high sulfoalanine <220><221> MOD RES <222> (24)..(24) <223> Gin or Glu <220> <221> M0D_RES <222> (28T..(28) <223> Asn, Lys or acidic amino acid <220><221> MOD RES <222> (29) (29) <223> Thr: Gty or acidic amino acid <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 15 10 15

Arg Arg Ala Xaa Xaa Phe Val Xaa Trp Leu Met Xaa Xaa 20 25 <210> 52 <211> 30 <212> PRT <213>Artificial sequence <220><223> Synthetic peptide <220><221> M1SC FEATOE <223>〇; § amination &<400> 52

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly Arg 20 25 30 <210> 53 •20-

156004 Sequence Listing.doc 201143790 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glycin Analog <220><221> M0D.RES <222> (3)..(3) <223> Glu, Om or Nle <220><221> MOD_RES <222> (15)..(15) <223> Asp, Glu, high bran Amine acid, sulfoalanine or high sulfoalanine <220><221> M0D.RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid Or high sulfoalanine. <220>

<221> M0D „RES <222> (20): (20) <223> Gin or Lys <220><221> MOD RES <222> (24)..(24) <223> Gin or Glu <220><221> MOD RES <222> (28)..(28) <223> Asn, Lys or acid amino acid <220><221> MOD RES <;222> (29)..(29) <223> Thr or acid amino acid <400> 53

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Xaa

<210> 54 <211> 29 <212> PRT <213> Artificial sequence <220><223> Synthetic glycoside analogue <220><221> MOD RES <222> 17)..(17) <223> Arg or Gin <220><221> MOD RES <222> (181..(18) <223> Aig or Ala <220><221> MOD RES <222> (21)..(21) 156004. Sequence Listing.doc -21- 201143790 <223><220><221><222><223>

Asp or Glu M0D.RES (23)..(23) Val or lie

>>>> 012 3 222 2 < V < V MOD RES (24)..(24) Gin or Ala <400> 54 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 ]0 15

Xaa Xaa Ala Lys Xaa Phe Xaa Xaa Trp Leu Met Asn Thr 20 25 <210> 55 <211> 29 <212> PRT <2I3> Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (1)..(1) <223> His, D-His, (desamino)His, hydroxy-His, acetyl-His, high -Hisic^a-dimethylimidazoliumacetic acid (DMIA), hydrazine-methyl-His, a-mercapto-His or imidazoleacetic acid <220><221> MOD RES <222> (2)..(2) <223> Ser, D-Ser, Ala, D-Ala, Va Bu Gly, N-methyl Ser, AIB or N-mercapto Ala <220><221> MOD RES <222> (3) ..(3) <223> 01n, Glu, Om or Nle <220><221> MOD RES <222> (10)..(10) <223> Tyr or Trp <220><;221> MOD.RES <222> (12)..(12) <223> Lys, citrulline, Om or Aig <220><221> MODJRES <222> (15)..( 15) <223> Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine <220><221> MOD RES <222> (161..(16) <223> Ser, Glu, Gi n, high face acid or high sulfoalanine <220><221> M0D.RES <222> (17)..(17) <223> Aig, Gin, Lys, Cys, Om, high Cysteine or acetophenone <220> 156004. Sequence Listing.doc •22·201143790 <221> MOD.RES <222> (18)..(18) <223> Aig, Ala , Lys, Cys, Om, homocysteine or acetyl phenylalanine <220>

<221> M0D_RES <222> (20)..(20) <223> 01n, Lys, Aig, Om or citrulline <220>

<221> M0D_RES <222> (21)..(21) <223> Gin, Glu, Asp, Lys, Cys, Om, homocysteine or acetylalanine <220><221> MOD RES <222> (23)..(23) <223> Val^Ile <220><221> M0D.RES <222> (24)..(24) <223> Ala 'Gin, Glu, Lys, Cys, Om' homocysteine or acetyl phenylalanine <220>

<221> M0D.RES <222> (27)..(27) <223> Met, Leu or Nle <220><221> M0D_RES <222> (28)..(28) <;223> Asn, Aig, citrulline '〇m, Lys or Asp <220><221> MOD RES <222> (29)..(29) <223> Thr, Gly, Lys, Cys ,Om, homocysteine or ethyl phenylalanine <400> 55

Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Xaa Ser Xaa Tyr Leu Xaa Xaa 15 10 15

Xaa Xaa Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 <210> 56 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MOD RES <222> (1), (1) <223> His, D_His, (desamino)His, hydroxy-His, acetyl-His, high-His, DMIA, N - mercapto-His, α-methyl-His or misoacetic acid <220>

<221> MOD.RES <222> (2)..(2) <223> Ser, D-Ser, Ala, D-Ala, Val, Gly, N.Methyl Ser, AIB or N-A Ala <220><221> MOD RES <222> (3) 7. (3) <223> όΐη, Giu, Om or Nle 23-156004-sequence table.doc 201143790 <220>< 221> M〇D_RES <222> (15)..(15) <223> Asp, Glu, sulfoalanine, glutamic acid and high sulfoalanine <220><221> MOD RES <222> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> M0D_RES <222> (20).. (20) <223> όΐη, Lys, A^g, Om or citrulline <220>

<221> M0D_RES <222> (21)..(21) <223> Gin, Glu, Asp, Cys, Om, homocysteine or acetyl phenylalanine <220><221> M0D_RES <222> (23)..(23) <223> Val or lie <220>

<221> MOD RES <222> (24)..(24) <223> Ala, Gin, Glu, Cys, Om, homocysteine or acetylalanine <220><221>; MOD RES <222> (27)..(27) <223> Met, Lei^Nle <220><221> M0D.RES <222> (28)..(28) <223>; Asn, iys or Asp <220><221> MOD.RES <222> (29)..(29) <223> Thr, Gly, Lys, Cys, Om, homohasic acid or B Nonylphenylalanine <400> 56

Leu Xaa Xaa 15

Xaa Xaa Xaa Gly Thr Phc Thr Ser Asp Tyr Ser Lys Tyr 1 5 10

Arg Arg Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 <210> 57 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MOD.RES <222> (1)..(1) <223> His, D-His, (desamino)His, hydroxy-His, acetyl-His, high-His, DMIA, N_methyl His, ct_甲&His or savory acetic acid<220〉

<221> MOD RES <222> (2)..(2) <223> Ser, D-Ser, Ala, D-Ala, Val, Gly, N-methyl Ser, AIB or N-methyl Ala 24· 156004_ Sequence Listing.doc 201143790 <220><221>MOD RES <222> (3) 7. (3) <223> όΐη, Giu, Om or Me <220><221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (15)..(15) <223> Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine <220><221> M0D.RES <222> (2 〇T..(20) <223> 01n, Lys, Aig, Om or citrulline <220>

<221> MOD RES <222> (21)..(21)

<223> Gin, Glu, Asp, Cys, Om, homocysteine or acetylalanine <220><221> MOD RES <222> (23)..(23) <223>; Val or lie <220><221> MOD RES <222> (24)..(24) <223> Ala, Gin, Glu, Lys, Cys, Om, high-semi-carnitine or ethyl Base Phe <220><221> MOD.RES <222> (27)..(27) <223> Met, Leu or Nle <220><221> MOD RES <222> (28 )..(28) <223> Asn, Lys or Asp <220><221> MOD RES <222> (29)..(29) <223> Thr : 'Gly, Lys, Cys, Om, homocysteine or acetylated amphetamine <400> 57

Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 15 10 15

Arg Arg Ala Xaa Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 <210> 58 <2H> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD.RES <222> (1) 7. (1) <223> His, D-His, (desamino)His, hydroxy-His, acetyl-His, High-His, DMIA, N-mercapto His, α-mercapto His or imidazoleacetic acid 25-156004-sequence table.doc 201143790 <220><221> MOD^RES <222> (2)..( 2) <223> Ser, D-Ser, Ala, D-Ala, Val, Gly, N. thiol Ser, AIB or Ν·methyl Ala <220> <221> MOD^RES <222> (3)..(3) <223> Gln, Glu, 0m or Nle <220><221> M0D_RES <222> (15)..(15) <223> Asp, 01u, item base Alanine, high-fat acid or high-grade alanine <220><22l> MISC FEATURE <222> (16) 7. (20) <223> Side chain at position 16 and position 20 Intrinsic amine ring between side chains <220><221> M0D „RES <222> (21)..(21) <223> Gin, Glu, Asp, Lys, Cys, Om, high half Cysteine or acetophenone <220><221> M0D.RES <222> (23)..(23) <223> 丨 lie or lie <220><221> M0D. RES <222> (24)..(24) <223> Ala, Gin, Glu, Lys, Cys, Om, homocysteine or acetylmethionine <220><221> MOD^ RES <222> (27)..(27) <223> Met'Leu^Nle <220><221> M0D_RES <222> (28)..(28) <223> Asn, tys Or Asp <220><221> M0D.RES <222> (29)..(29) <223> Thr: 'Gly, Lys, Cys, Om, homocysteine or acetopheniramine Acid <400> 58

Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Glu 15 10 15

Arg Arg Ala Lys Xaa Phe Xaa Xaa Trp Leu Xaa Xaa Xaa 20 25 <210> 59 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MOD RES <222> (1)..(1) <223> His, D-His, (desamino)His, hydroxy-His, acetyl-His, high -His, DMIA, N-mercapto His, alpha-mercapto His or feeding. Sitting acetic acid • 26-

156004· Sequence Listing.doc 201143790 <220〉

<221> MOD RES <222> (2)..(2) <223> Ser ·, 'D-Ser, Ala, D-Ala, Val, Gly, N-mercapto Ser, AIB or N· Methyl Ala <220><221> MOD RES <222> (3)..(3) <223> ύΐη, Glu, Om or Nle <220><221> MOD RES <222> (15)..(15) <223> Asp, Glu, sulfoalanine, oleic acid and homogenyl alanine <220><221> MOD RES <222> (16).. (16 <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> MISC.FEATURE <222> (20) 7. (24)

<223> The indole ring between the side key at position 20 and the side key at position 24 <220><221> MOD RES <222> (21)..(21) <223> Όΐη, Glu, Asp, Lys, Cys, Om, homo-hemo-amino acid or acetyl phenylalanine <220><221> M0D.RES <222> (23)..(23) <223> Val or lie <220><221> MOD RES <222> (27)..(27) <223> Met, Leu*Nle <220><221> MOD RES <222> (28 )..(28) <223> Asn, Lys or Asp <220><221> MOD RES <222> (29T..(29) <223> Thr : 'Gly, Lys, Cys, Om , homocysteine or acetylalanine <400> 59

Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15

Arg Arg Ala Lys Xaa Phe Xaa Glu Trp Leu Xaa Xaa Xaa 20 25 <210> 60 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> M0D.RES <222> (1)..(1) <223> His, D-His, (desamino)His, hydroxy-His, acetyl-His, high- His, DMIA, N-mercapto His, α-methyl His or imidazoleacetic acid 27-156004 · Sequence Listing_doc 201143790 <220>

<221> MOD RES <222> (2)..(2} <223> Ser·,·D-Ser, Ala, D-Ala, Va Bu Gly, N-methyl Ser, AIB or Ν· Methyl Ala <220><221> MOD RES <222> (3)..(3) <223> Gin, Glu, Om or Nle <220><221> MOD RES <222> (15T..(15) <223> Asp, Glu, resveryl alanine, homofacial acid and high sulfoalanine <220><221>MOD RES <222> (16)..( 16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><221> MOD RES <222> (20)..(20) <223> 01n, Lys, Aig, Om or citrulline <220><221> MOD RES <222> (21)..(21) <223> Gin, Glu, Asp, Lys, Cys, Om, high Amine acid or acetyl methacrylic acid <220><221> MOD RES <222> (231..(23) <223> Val or lie <220><221> MISC FEATURE <222> (24).. (28) <223> The indole ring between the side chain at position 24 and the side chain at position 28 <220><221> MOD RES <222> (27). .(27) <223> Met' Leu^N Le <220><221> MOD.RES <222> (29)..(29) <223> Thr, Gly, Lys, Cys, Om, homocysteine or acetylated amphetamine <400> 60

Xaa Xaa Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 1 5 10 15

Are Arg Ala Xaa Xaa Phe Xaa Glu Trp Leu Xaa Lys Xaa 20 25 <210> 61 <211> 40 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220>

<221> MISC.FEATURE <223> Only when position 29 is Gly, positions 30 to 40 exist; see the description of the substitution and preferred embodiment in the specification of the application 28-

156004-Sequence List.doc 201143790 <220><221> MOD RES <222> (1) ·. (1) <223> His, D-His, (desamino)His, thio-His , Ethyl-His, High-His, DMIA, N-Mercapto His, α-Methyl His or Imidazoleacetic acid <220><221> MOD RES <222> (2)., (2) <;223> Ser, D_Ser, Ala, Val, Gly, N-methyl Ser, Aib, N.methyl Ala or D-Ala

<220><221> MOD RES <222> (18)..(18) <223> Ala or Arg <220><221> MOD RES <222> (24)..(24 <223> Ala, Gin or Cys-PEG <220><221> MOD RES <222> (29)..(29) <223> Thr-CONH2, Cys-PEG or Gly <220>;<221> M0D_RES <222> (40)..(40) <223> Cys-PEG or not present <400> 61 Xaa Xaa Gin

Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 5 15

Arg Xaa Ala Lys Asp Phe Val Xaa Trp Leu Met Asn Xaa Gly Pro Ser 20 25 30 Ser Gly Ala Pro Pro Pro Ser Cys 35 40

<210> 62 <211> 40 <212> PRT < 213 > artificial sequence <220><223> Synthetic glycosidic analogue <220><221><223> MISC.FEATURE Only when position 29 is Gly, there is a substitution and a detailed description of the preferred embodiment for positions 30 to 40: see <220><221><222><223> MOD RES(1) in the specification of the application. (1) His, D-His, (desamino) His, hydroxy-His Ν·Methyl His, α-methyl His or imidazolium acetate-His, high-His, DMA, <220><221><222><223> M0D.RES(2)..(2) Ser, D-Ser, Ala, Val, Gly, Ν·Methyl Ser, ABO, Ν·曱基 Ala Or D-Ala <220> 156004. Sequence Listing.doc •29_ 201143790 <221> MOD RES <222> (18)..(18) <223> Ala or Ai^ <220><221> MOD.RES <222> (24*).. (24)

<223> Ala, Gin or Cys-PEG <220><221> MOD-RES <222> (29)..(29) <223> Thr-CONH2, Cys-PEG or Gly <220>;<221> MOD-RES <222> (40)..(40) <223> Cys-PEG or non-existent <400> 62

Xaa Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Xaa Ala Lys Glu Phe lie Xaa Trp Leu Met Asn Xaa Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 <210> 63 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic glycosidic analogue <220>

<221> MOD RES <m> (16)..(16) <223> Ser, Glu, Gin, glutamic acid or high sulfoalanine <220><22t> MOD RES <222> (20)..(20) <223> 01n or Lys <220><221> MOD-RES <222> (21)..(21) <223> Asp, Lys, Cys ' Om, homocysteine or acetophenone <220><221> MOD RES <222> (24)..(24) <223> Gin, Lys, Cys, Orn, homocysteine Amine acid or acetyl methacrylic acid <220><221> MOD RES <222> (27T..(27) <223> Met, Leu or Nle <400> 63

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Xaa Phe Val Xaa Trp Leu Xaa Asn Thr 20 25 •30· 156004 Sequence Listing.doc 201143790 <210> 64 <211> 38 <212> PRT <213>Artificial Sequence<220><223> Synthetic glycosidin analog <220><221> MOD-RES <222> (15)..(15) <223> Asp, Glu, glutamic acid, sulfoalanine Or high sulfoalanine <220><221> MOD RES <222> (16)..(16) <223> Ser, Ghi, Gin, glutamic acid or high sulfoalanine <220><221><222><223><220><221><222><223><220><221><222><223> MOD RES (20 )..(20) Gin or Lys M0D_RES (24)..(24) Gin or 01u MOD.RES (28T..(28) into sn, Lys or Asp <400> 64 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Xaa Gly Gly Pro Ser 20 25 30

Ser Gly Pro Pro Pro Ser 35 <210> 65 <211> 11 <212> PRT < 213 > artificial sequence <220><223> represents incretin analog "10 carboxy terminal 10 amines Synthetic peptide fragment of base acid >>>> 012 3 2 22 2 <2<2<2<2

MOD RES (11)..(11) Cys-PEG <400> 65 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Cys 1 5 10 <210> 66 <211> 29 <212> PRT <213> Artificial sequence 156004. Sequence Listing. Doc 31·201143790 <220><223> Synthetic Glycosin Analog <220><221> MISC FEATURE <222> (12).. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220>

<221> MOD RES <222> (281..(28) <223> Asp or into sn <220><221> M0D.RES <222> (29)..(29) <223> Thr or Gly <400> 66

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Ding yr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Xaa Xaa 20 25 <210> 67 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC FEATURE <222> (16).. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (28)..(28) <223> Asp or Asn <220><221> MOD-RES <222> (29)..(29) <223> Thr or Gly <400> 67

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Xaa Xaa 20 25 <210> 68 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Synthetic Glucagon Analog <220><221> MISC FEATURE <222> (20)7.(24) 32-

156004. Sequence Listing.doc 201143790 <223> The intrinsic amine ring between the side chain at position 20 and the side chain at position 24 <220><221> MOD.RES <222> (28). (28) <223> Asp or person sn <220><221> M0D.RES <222> (29T..(29) <223> Thr or Gly <400> 68

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15

Arg Arg Ala Lys Asp Phe Val Glu Trp Leu Met Xaa Xaa 20 25

<210> 69 <211> 29 <212> PRT <213>Artificial sequence <220><223> Glycoside analogue <220><221> MISG.FEATURE <222> 24).. (28) <223> The indole ring between the side chain at position 24 and the side chain at position 28 <220><221> M0D.RES <222> (29). .(29) <223> Thr or Gly <400> 69

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Glu Trp Leu Met Lys Xaa 20 25 <210> 70 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Synthetic Peptide<220><221> MISC FEATURE <223> C-terminal tortoise <400> 70

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 71 <211> 29 -33- 156004. Sequence Listing.doc 201143790 <212> PRT <213>Artificial Sequence<220><223> Synthetic peptide <220><221> MISC.FEATURE <223> 0 terminal amidation <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 >>>>>> 0123 o 3 n 11 1i 11 ofc 2 2 2 ΛΖ 2 2 V <v << 72 29

PRT artificial sequence synthetic peptide <220><221> MISC FEATURE <223> 0 terminal amidation <220><221> MISCJEATURE <222> (16)..(20) <223> . The inner guanamine ring between the side key on the 16 and the side chain on the position 20 <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 73 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> C-terminal amidation <220><221> MISC.FEATTJRE <222> (12)..(16) <223> Side chain and position at position 12 Intrinsic amine ring between side chains on 16 <400> 73

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 • 34- 156004· Sequence Listing.doc 201143790 <210> 74 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Synthetic peptide <220><221> MISC FEATURE <223> 〇: terminal amidation <220><221> MISC FEATURE <222> (12) 7. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <400> 74 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 75 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC.FEATURE <223> 0 terminal amination <220><221> MISC FEATURE <222> (16)..(20) <223> Side chain and position at position 16 Intrinsic amine ring between the side chains on 20 <400> 75 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 >>>> 012 3 <21<21<21<21 76 29 PRT Artificial Sequence <220><223> Synthetic Peptide<;220><221> MISC FEATURE <223> C-terminal tortoise <400> 76 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 156004 - Sequence Listing.doc 35 - 201143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 ζΜ ςΝ 2 2 VV < 77 29 PRT Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> C-terminal amide <220><221><222><223> MISC FEATURE (16).. (20) side chain at position 16 and side chain at position 20 Inter-amylamine ring <400> 77 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 78 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> terminal amination <220><221> MISC FEATURE <222> (12)..(16) <223> Side chain and position 16 at position 12. Intrinsic amine ring between the upper side chains <400> 78 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala A.a Gin Asp Phe Va. Gin Trp Leu Met Asn

<210> 79 <211> 29 <212> PRT < 213 > artificial sequence <220><U3> synthetic polypeptide <220><221> MISC FEATURE <223><220><221> MISC.FEATURE 156004. Sequence Listing.doc -36- 201143790 <222> (12)..(16) <223> Sidechain at position 12 and side chain at position 16 Between the indole ring <400> 79

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

b >>> 012 3 2 ΛΖ 2 < V < V column order oo\RT^x 82P/ <220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> C-terminal amide hydration <220><221><222><223> MISC FEATURE (16).. (20) 醯 between the side chain at position 16 and the side chain at position 20. Amine ring <400> 80 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Yal Gin Trp Leu Met Asn Thr 20 25 ^ >>> 012 3 2222 81 29 PRT Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC. FEATURE <223> C-terminal amide hydration <400> 81 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 82 <211> 29 <212> PRT <213>Artificial sequence <220><223>

<220><221> MISC FEATURE 156004. Sequence Listing.doc •37-201143790 <223> Amination <220><221> MISC.FEA7URE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 83 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MI SC FEATURE <223> 龟 龟 龟 &<220><221> MISC.FEATTJRE <222> (16) 7. (20) <223> Indole ring between side chains at position 20 <400> 83

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 84 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC_FEATURE <223> C-terminal amide <400> 84

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 85 <211> 29 <212> PRT <213>Artificial Sequence<220><223>Synthetic Polypeptide•38- 156004 Sequence Listing.doc 201143790 <220><221> MISC FEATURE <223> C-terminal tortoise <220><221> MISC FEATURE <222> (12)..(16) <223>; the inner guanamine ring between the side chain at position 12 and the side chain at position 16 <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Lea Val Lys Gly 20 25 <210> S6 <211> 29 <212> PRT <2]3> Artificial sequence

<220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> 0: terminal amidation <220><221> MISC FEATURE <222> (16)..( 20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly 20 25 <210> 87 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC.FEATTJRE <223> C-terminal amide hydration <220><221> MOD RES <222> (1)..(1) <223> (desamino group) His <400> 87

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 £:: 156004· Sequence Listing.doc •39- 201143790 <210> 88 <211> 29 <212> PRT <213>Artificial Sequence<;220><2illusion> Synthetic polypeptide <220><221> M1SC FEATURE <223> C-terminal amide hydration <220><221> MOD RES <222> (1).. (1) <223> (desamino group) His <400> 88

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 89 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPolypeptide<220><221> MISC.FEATOE <223> C-terminal amidation <220><221> MOD RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (16).. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 90 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> C-terminal amide--40- 156004-sequence table.doc 201143790 <220><221> MOD RES <222> (1)..(1) <223> (Deamino)His <220><221> MISC FEATURE <222> (12)..(16) <223> Inside the side chain at position 12 and the side chain at position 16 Amidoxime ring <400> 90

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 91 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> C-terminal amide hydration <220><221> MOD RES <222> (1)..(1) <223> (desamino group) His <220>;<221><222><223> MISC FEATURE (12) 7. (16) Endoamine ring between the side chain at position 12 and the side chain at position 16 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Pne 20

Va

Gin

Trp Leu Met Asn Thr 25 b> Λ > Q 1 2 3 <21<21<21<21 92 29 PRT artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <;223> C-terminal amination <220><221> M0D_RES <222> (1) 7. (1) <223> (desamino group) His <220><221> MISC FEATURE <;222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 156004 - Sequence Listing.doc • 41 · 201143790 <400> 92 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15 Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 2 Λζ Λν 2 < VV < 93 29 PRT Artificial Sequence <220><223> Synthetic polypeptide <220><221><222><223><220><221><222><223><400> Xaa Si MOD RES (l) T. (D (desamino)) His MISC. FEATURE (29) 7. (29) C-terminal amide agitation 93 Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 5 10 15

Arg

Ala Lys Asp Phe Val Gin Trp Leu Met Asa Thr 20 25 <210> 94 <21l> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPolypeptide<220>221> MISC FEATURE <223> terminal amination <220><221>MOD.RES<222> (1)..(1) <223> (desamino group) His <220><;221> MISC.FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <400> 94 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 95 <211> 29 156004 - Sequence Listing.doc • 42-201143790 <212> PRT <213>Artificial Sequence<220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> 0: terminal amidation <220><221> MOD RES <222> (1) (1) <223> (desamino)His <220><221> MISC FEATURE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Endoamine ring <400> 95

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 96 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> (: terminal imidization <220><221> MOD RES <222> (1)..(1) <223> (desamino group) His <220>

<221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 97 <211> 29 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220>

<221> MISC.FEATURE 156004-Sequence Listing.doc • 43·t;: 201143790 <223> C-terminal amidation <220>

<221> M0D.RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC.FEATURE <222> (16)..( 20) <223> The intrinsic amine ring between the side key at position 16 and the side key at position 20 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 98 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> terminal amination <220>

<221> MOD RES <222> (1)..(1) <223> (desamino group) His <220> <221> MISC.FEATURE <222> (12)..(16 )

<223> Intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <400> 9S

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 99 <211> 29 <212> PRT <213>Artificial Sequence<220><223>SyntheticPeptide<220><221> MISC FEATURE <223> 0 terminal amidation <220><221> MOD RES <222> (1)..(1) <223> (desamino group) His <220>;<221> MISC.FEATURE <222> (12)..(16) •44- 156004·SEQ ID NO.doc 201143790 <223> Between the side chain at position 12 and the side chain at position 16 Endoamine ring <400> 99

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 100 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221> MISC FEATURE <223> 〇: terminal amination

<220>

<221> MOD_RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC.FEATURE <222> (16)..(20) <223> The indole ring between the side chain at position 16 and the side bond at position 20 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 101 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MISC FEATURE <223> C-terminal amide hydration <220><221> MOD RES <222> (1) 7. (1) <223> (desamino group) His <400>; 101

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25

<210> 102 <211> 29 <212> PRT • 45·156004 Sequence Listing.doc 201143790 <213>Artificial Sequence<220><223> Synthetic Polypeptide<220><221> MISC .FEATURE <223> C-terminal amide <220>

<221> MOD RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC.FEATURE <222> (12)..(16 <223> The indole ring between the side chain at position 12 and the side chain at position 16 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 103 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Synthetic Peptide <220><221> MI SC FEATURE <223> C-terminal amide <220>

<221> MOD-RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (16).. (20 <223> The indole ring between the side chain at position 16 and the side chain at position 20 <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 104 <211> 29 <212> PRT <213>Artificial sequence <220><223>Synthetic polypeptide <220>

<221> MOD.RES <122> (2)..(2) -46·

156004· Sequence Listing.doc 201143790 <223> Xaa is AIB <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amide hydration <400> 104

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyt Leu Asp Glu 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 105 <211> 29 <212> PRT <213>Artificial sequence <220><223>

<221> M0D_RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC.FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Indole ring <220><221> MOD RES <222> (29)..(29) <223> 〇: terminal amidation <400> 105

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 106 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220>

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC.FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Endoamine ring <220><221> M0D.RES <222> (29T..(29) <223> 〇: terminal amidation 156004. Sequence Listing. doc 47·

S 201143790 <400> 106

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 107 <211> 29 <212> PRT <213>Artificial sequence <220><223> Synthetic polypeptide <220><221> MOD.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Indole ring <220><221> MOD RES <222> (29)..(29) <223> terminal amidation <400> 107

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 108 <211> 29 <2I2> PRT <213>Artificial Sequence <220><223> Synthetic Peptide <220><221〉 MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (12) 7. (16) <223> The side chain at position 12 and the side chain at position 16 Amidoxime ring <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amidation <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr .48- 156004 - Sequence Listing.doc 25201143790 <210> 109 <211> 29 <212> PRT <213>Artificial Sequence<220>< 223 > Synthetic polypeptide <220><221> M0D_RES <222> (2)..(2) <223> Xaa is AIB <220><221> MISC FEATURE <222> (16). (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D.RES <222> (29).. (29 <223> C-terminal amidation <400> 109 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 >>>> 0 12 3 2 2 ζΝ < V <N/ 110 29 PRT Artificial Sequence <220><223> Synthesis Peptide

<220〉 <221> M0D.RES <222> (2)..(2) <223> Xaa is AIB

<221> M0D.RES <222> (29)..(29) <223> terminal amidation <400> 110 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> Π1 <211> 29 <212> PRT <213>Artificial Sequence<220><223>Synthetic Peptide 156004 - Sequence Listing .doc 49- 201143790 <220〉 <221> MOD.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Amidoxime ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 112 <211> 29 <212> PRT <213> Artificial Sequence <220><2 is > Synthetic Peptide<220><221> MOD RES <222> (2)..(2)

<223> Xaa is ABB <220> <221> MISC.FEATURE <222> (12)..(16) <223> between the side chain at position 12 and the side chain at position 16. Endoamine ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 113 <211> 29 <212> PRT <2I3>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD RES <222> (2) 7. (2) <223> Xaa is AIB <220>

<221> MISC_FEATORE • 50-

156004-Sequence List.doc 201143790 <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> M0DJRES <222> (29)..(29) <223> Terminal amidation <400> 113 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 114 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221>MOD.RES<222> (2)..(2) <223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221><222><223> MOD RES (29)..(29) C-terminal amide hydration <400> 114 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 115 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glucagon Analogue>;>>>>>>> 0123 0123 2222 2222

MOD RES (2):.(2) Xaa is AIB MOD RES (29)..(29) C-terminal amide amination

<400> 115 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 IS 156004-Sequence List.doc -51 - 201143790

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 116 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glucagon Analog <;220><221> MOD RES <222> (2)..(2)

<223>Xaa is AIB <220><22]> MISC FEATURE <222> (12)..(16) <223> j side check 12 side money and position 16 side key Intercalated amine ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 012 3 <21<2I<21<21 117 29

PRT artificial sequence <220><223>glycoside analogue <220><221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Amidoxime ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 118 -52- 156004 - Sequence Listing.doc 201143790 <2Π> 29 <212> PRT <213>Artificial Sequence<220><223> Glycosin analogue <220>

<221> M0D_RES <222> (2)..(2) <223> Xaa is ΑΙΒ <220><221> M0D.RES <222> (29)..(29) <223>; C-terminal amide hydration <400> 118

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly

<210> 119 <211> 29 <212> PRT < 213 > artificial sequence <220><223> Glycoside analogue <220><221> MOD.RES <222> 2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Amidoxime ring <220><221> M0D_RES <222> (29)..(29) <223> 0: terminal amidation <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 120 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (2)..(2) <223> Xaa is AIB -53 - 156004 - Sequence Listing.doc 201143790 <220> <221> MISC.FEATURE <222&gt (16).. (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D.RES <222> )..(29) <223> Amination <400> 120

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 121 <211> 29 <212> PRT <2I3>Artificial Sequence<220> Glycoside Analog <220>;221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MOD.RES <222> (29)..(29) <223>; C-terminal amide hydration <400> 121

His Xaa Gin Gly Thr Fhe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 122 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Ascension Analogue <223>;220><221> MOD.RES <222> (2)..(2) <223> D-Aia <220><221> MOD.RES <222> (29)..( 29) <223> C-terminal amidation <400> 122

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 54-

156004· Sequence Listing.doc 201143790 20 25 <210> 123 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <220>

<221> MOD_RES <222> (2)..(2) <223> D-Ala <220><221> MISC.FEATURE <222> (16)..(20) <223>; the inner guanamine ring between the side chain at position 16 and the side chain at position 20 <220>

<221> MOD RES <222> (29)..(29) renminylation <400> 123

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 124 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (2)..(2) <223> D-Ala

<220><221> MISC FEATURE <222> (12): (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amidation <400> 124

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 125 <211> 29 <212> PRT <213> Artificial Sequence -55 - 156004 Sequence Listing.doc 201143790 <220><223> Glycosin analogue <220>

<221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MISC.FEATURE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D_RES <222> (29)..(29) <223> Amination <400> 125

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 126 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (16)..(20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD^RES <222> (29)..(29) <223> Terminal amination <400> 126

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 127 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220>

<221> MOD.RES -56-

156004· Sequence Listing.doc 201143790 <222> (2)..(2) <223> D-Ala <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide <400> 127

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 128 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220>

<221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (16)..(20) <223>; the inner guanamine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223><: Terminal amination <400> 128

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 0>1>12>3><21<21<21<21 129 29

PRT artificial sequence <220><223> Glucagon analogue <220><221> MOD RES <222> (2) 7. (2) <223> D-Ala <220><;221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D_RES <222> (29)..(29) <223> C-terminal amide cleavage 57-156004. Sequence Listing.doc 201143790 <400> 129

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 130 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (12) 7. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221>M0D'RES<222> (29)..(29) <223>; C-terminal amide hydration <400> 130

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

>>>> 0 12 3 <21<21<21<2I

131 29

PRT artificial sequence <220><223> Glucagon analogue <220><221> MOD RES <222> (2) 7. (2) <223> D-Ala <220><;221> MISC FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D .RES <222> (29)..(29) <223> 0: terminal amination <400> 131

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 156004-Sequence List, doc -58- 25 201143790 <210> 132 <211> 29 <212> PRT <213>Artificial Sequence<220>;223> Glucagon Analogs <220><221> MOD_RES <222> (2)..(2) <223> D-Ala <220><221> MOD RES <222> (29)..(29) <223> (: terminal amination <400> 132

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 133 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D_RES <222> (29)..(29) <223> Terminal amination <400> 133

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 012 3 1i u 11 11 <2<2<2<2 134 29

PRT artificial sequence <220><223> Glycoglycan analogue 59-156004-sequence table.doc 201143790 <220><221> M0D.RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (16)..(20) <223> The side chain between the side chain at position 16 and the side chain at position 20 Ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide <400>

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 135 <211> 29 <212> PRT <213> Manual Sequence <220><223>;220><221> MOD RES <222> (2)..(2) <223> D-Ala <220><221> MOD.RES <222> (29)..(29 ) <223> C-terminal amide <400> 135

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 136 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (12)..(16 <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>

<22]> M0D.RES 60-

156004-Sequence List.doc 201143790 <222> (29)., (29) <223> C-terminal amidation <400> 136 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly 20 25 >>>> 012 3 2222 <<<< 137 29 PRT Artificial Sequence <220><223> Glucagon Analog <220><221> MOD RES<222> (2)..(2) <223> D-Ala <220><221> MISC FEATURE <222> (16)..( 20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29).. (29) <223> C-terminal amide hydration <400> 137 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25

>>>>> 012 3 2 ςΜ 2 2 VV <v 138 29 PRT Artificial Sequence <220><223> Glycoside Analog <220><221> M0D.RES <222&gt (29)..(29) <223> C-terminal amide hydration <400> 138 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 >>>> 012 3sad 139 29 PRT Artificial Sequence 156004 - Sequence Listing. doc • 61 · 201143790 <220><223> Prime analog <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 140 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC-FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;<221> M0DJRES <222> (29)..(29) <223> C-terminal amidation <400> 140

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 141 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISCFEATURE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 • 62· 156004 Sequence Listing.doc 201143790 <210> 142 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside analogue <220><221> MISC.FEATURE <222> (12)..(16) <223> side chain at position 12 and side chain at position 16 Inter-endoxime ring <220><22】> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <W0>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phc Val Gin Trp Leu Met Asn Thr 20 25 <210> 143 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC.FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

His Ser Glu Gly Thr Fhe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 144 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (29)..(29) <223> terminal amination <400> 144

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 63- 156004 - Sequence Listing.doc 201143790 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Ding rp Leu Met Asn Thr 20 25 <210> 145 <211> 29 <212> PRT <213>Artificial sequence <220><223><220><221> MISC FEATURE <222> (16).. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> (: terminal amination <400> 145

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 146 <2ll> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>;221> MOD RES <222> (29)..(29) <223> C-terminal amide <400> 146

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 147 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MISC^FEATURE 64- 156004-sequence table.doc 201143790 <222> (12)..(16) <223> 醯 between the side chain at position 12 and the side chain at position 16. Amine ring <220><221> MOD RES <222> (29).. (29) C-terminal amide hydration <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 ^ >>> ffl23 <21<21<21<21 148 29 PR Ding Artificial Sequence

<220><223> Glycosin analogue <220>221> MISC.FEATURE <222> (16)., (20) <223> Positional position on position 16 and position 20 The indoleamine ring between the side chains <220><221> MOD.RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 149 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Ascension Analogue <223>;220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 012 3 <21<21<21<21 150 29

PRT artificial sequence -65- 156004-sequence table.doc 201143790 <220><223>glycoside analogue <220><221> MISC FEATURE <222> (12) 7. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> Terminal amidation <400> 150

His Ser Glu Cly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Thr 20 25 <210> 151 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC.FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> terminal amination <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 152 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 G, n Ala Ala Lys G, u Phe lie Ala Trp Leu Val Lys Gly • 66-

156004-Sequence List.doc 201143790 <210> 153 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <220><221> MISC FEATURE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400> 153

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 154 <21]> 29 <212> PRT <213>Artificial sequence <220><223><220><221> MISC FEATURE <222> (16) 7. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;<221> MOD.RES <222> (29)..(29) <223> terminal amination <400> 154

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 155 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> RES <222> (1) 7. (1) <223> (desamino group) His <220> -67- 156004 - Sequence Listing.doc 201143790 <221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 156 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> MOD.RES <222> (1)..(1) <223> (desamino group) His <220><221> MOD RES <222> (29). (29) <223> C-terminal amidation <400> 156

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 157 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RHS <222> (1)..(1) <223> (desamino group) His <220><221> Ml SC FEATURE <222> (16) ..(20) The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223&gt ; C-terminal amides <400> 157

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 -68 ·

156004-Sequence List.doc 201143790 <210> 158 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <220><221> MOD RES <222> (1) 7. (1) <223> (desamino group) His <220><221> MISC.FEATURE <222> (12)..(16) <223> Intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> C-terminal guanamine Chemical

<400> 158

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 159 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> M0D_RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (12)..(16) <;223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amides <400> 159

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 20 <210> 160 <211> 29 <212> PRT <213> Manual Sequence <220>

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr -69- 156004 - Sequence Listing.doc 201143790 <223> Glycosin Analogs <220><221> M0D_RES <222> (1) 7. (1) <223> (desamino group) His <220><221> MISC.FEATURE <222> (16) 7. (20) <223> Positional position on position 16 and position 20 The indoleamine ring between the side chains <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amide hydration <400>

Xaa Ser GIu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

>>>> 0123 ςνί 2 ζΝ 2 VvV V 161 29

PRT artificial sequence <220><223>glycoside analogue <220><221> MOD.RES <222> (1)..(1) <223> (desamino group) His &lt ;220><221> MOD RES <222> (29)..(29) <223> terminal amidation <400> 161 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 162 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog < 220> MOD RES < 222 > (1) (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20-70-156004-sequence table.doc 201143790 <220><221> MOD RES <222> (29)..(29) <223> terminal amination <400> 162

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 163 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (12)..(16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amides <400> 163

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 164 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (1)..(1) <223> (desamino group) His <220> <221> MISC FEATURE <222> (12) 7. (16 <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223>; C-terminal amide hydration <400> 164 71- 156004 · Sequence Listing.doc 201143790

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 165 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (16). (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide <400> 165

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 166 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<22l> MOD RES <222> (1)..(1) <223> (desamino group) His <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide <400> 166

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 167 <211> 29 <212> PRT <2丨3> Artificial sequence • 72-

156004-Sequence List.doc 201143790 <220><223>glycoside analogue <220>

<221> M0D.RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (12) 7. (16 <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD.RES <222> (29)..(29) <223> 〇: terminal amination <400> 167

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <2i0> 168 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (1)..(1) <223> (desamino group) His <220><221> MISC FEATURE <222> (16).. (20 <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D_RES <222> (29)..(29) <223> C-terminal amides <400> 168

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 169 <2il> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> M0D_RES -73- 156004-sequence table.doc 201143790 <222> (1)..(1) <223> (desamino group) His <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400> 169

Xaa Ser Gla Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Me Ala Trp Leu Val Lys Gly 20 25 <210> 170 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (1).. (1) <223> (desamino group) His <220><221> MiSC FEATURE <222> (12)7 (16) <2?3> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..( 29) <223> C-terminal amidation <400> 170

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 35

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 171 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (1) 7. (1) <223> (desamino group) His <220><221> MISC FEATURE <222> (16). (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D_RES <222> (29)..(29) <;223> 〇: terminal amidation 74-

156004· Sequence Listing.doc 201143790 <400> 171

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 172 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB

<220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 173 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MOD.RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 . . 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 174 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoglycan Analog 75 - 156004· Sequence Listing.doc 201143790 <220><221> M0D.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Amidoxime ring <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 175 <211> 29 <212> PRT <213>Artificial Sequence<220><2U> Glycoside Analog <;220><221> MOD.RES <222> (2)..(2)

<223> xaa is AIB <220><221> MISC.FEATTJRE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Endoamine ring <220><221> M0D_RES <222> (29)..(29) <223> C-terminal amidation <400>

His Xaa Glu Gly Thr Phe Tlir Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 176 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD RES <222> (2) 7. (2) <223> Xaa is AIB <220> 76·

156004-Sequence List.doc 201143790 <221> MISC_FEATURE <222> (12) 7. (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D_RES <222> (29)..(29) <223> C-terminal amidation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 177 <211> 29 <212> PRT <213>

<220><223> Glycoside analogue <220><221> MOD-RES <222> (2)..(2)

<223> Xaa is ABB <220><221> MISC.FEATURE <222> (16)..(20) <223> between the side chain at position 16 and the side chain at position 20 Endoamine ring <220><221> M0DJRES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr

<210> 178 <211> 29 <212> PRT <213>Artificial sequence <220><223> Glycoside analogue <220><221> MOD.RES <222> 2)..(2)

<223> Xaa is AIB <220><221> M0D_RES <222> (29)..(29) <223> Terminal amylation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 77- 156004 - Sequence Listing.doc 201143790 5 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 179 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> MOD.RES <222> (2)..(2) <223> Xaa is AIB <220><22l> MISC_FEATURE <222> (16)..(20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400> 179 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 ^ >>> o 1 z 3 2 0-22 <v << 180 29 PRT Artificial Sequence <220><223> Glycin analogue <220><221> MOD RES <222> (2)..(2) <223> Xaa is AIB <220><221> MISC.FEAOJRE <222> 12).. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220>221> MOD RES <222> (29).. (29) <223> 〇: terminal amidation <400> 180 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 .15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 156004-Sequence List.doc .78- 201143790 <210> 181 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glucagon analog >>>> Q 1 2 3 2222 ΛΖ 2 2 V < V <

MOD RES (2)7.(2) Xaa is AIB <220><221><222><223><220><221><222><223><400> MISC FEATURE (12)..(16) The intrinsic amine ring MOD RES between the side chain at position 12 and the side chain at position 16 (29).. (29) C-terminal amide 181

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 182 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (2)..(2) <223> Xaa is AIB <220><221> MISC.FEATORE <222> (16)..(20 <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400> 182 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 183 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog 156004 - Sequence Listing.doc -79- 201143790 <220><221> MOD RES <222> (2)..(2)

<223> xaa is AIB <220><221> MOD.RES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 184 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Indole ring <220><221> MOD-RES <222> (29Τ..(29) <223> terminal amination <400> 184

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 185 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> M0D_RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Amidoxime ring <220> 80·

156004· Sequence Listing.doc 201143790 <221> MOD-RES <222> (29)..(29) <223> Amylation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 186 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD-RES <222> (2)..(2) <223> Xaa is AIB <220><221> MOD.RES <222> (29)..(29) <;223> C-terminal amide <400> 186

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Vai Lys Gly 20 25 <210> 187 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220>

<221> MOD.RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC.FEATURE <222> (12)..(16) <223> Between the side chain at position 12 and the side chain at position 16 Endoamine ring <220> <221> M0D_RES <222> (29)..(29) <223> terminal amidation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 -81 - 156004. Sequence Listing.doc 201143790 <210> 188 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycosin analogue <220><221> MOD-RES <222> (2)..(2)

<223> Xaa is AIB <220><221> MISC FEATURE <222> (16)..(20) <223> Between the side chain at position 16 and the side chain at position 20 Indole ring <220><221> MOD RES <222> (29)..(29) <223> terminal amidation <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 189 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analogue 13⁄4 E 0>1>2>3> 2 222 <2<2<2<2

<220><221> MOD RES <222> (29)..(29) <223> 〇: terminal amidation <400> 189

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 190 <211> 29 <212> PRT. <213>Artificial Sequence <220><223> Glucagon Analog <220>

<221> MOD.RES 156004. Sequence Table.doc -82-201143790 <222> (2)..(2) <223> Xaa is D-Ala <220><221> M0D_RES <222&gt (29)..(29) <223> 〇: terminal amination <400> 190

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 191 <211> 29 <212> PRT <213>Artificial sequence <220>

<223> Glycoside analogue <220><221> MOD.RES <222> (2) 7. (2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222> (16)..(20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D_RES <222> (29)..(29) <223> terminal amidization <400> 191

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Trp Leu Met Asn Thr 20 25 <210> 192 <211&gt <220><221> MOD.RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222> (12). (16) <223> The intrinsic amine ring between the side chain at position 12 and the hydrazine chain at position 16 <220><221> M0D.RES <222> (29).. (29 ) <223> C-terminal amide-83· 156004· Sequence Listing.doc 201143790 <400> 192

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 193 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222> (12)..( 16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D.RES <222> (29j..(29) <223> C-terminal amide <400> 193

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 ΛΖ 2 2 V <v < 194 29

PRT artificial sequence <220><223> Glucosin analogue <220><221> MOD-RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC.FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400> 194

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys I 5 10 35

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 84- 156004 - Sequence Listing.doc 201143790 20 25 <210> 195 <211> 29 <212> PRT <213>Artificial Sequence<220>;223> Glucagon analog <220><221> M0D_RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222>(16)..(20)<223> The indole ring between the side chain at position 16 and the side chain at position 20 <220>

<221> M0D.RES <222> (29)..(29) <223> terminal amination <400> 195

His Xaa GIu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 196 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Glucagon Analog <;220><221> MOD.RES <222> (2)..(2) <223> iCaa is D-Ala

<220><221> MISC FEATURE <222> (16) 7. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> M0DJRES <222> (29)..(29) <223> C-terminal amide hydration <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr 'Leu Asp Glu 1 .5 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 197 <211> 29 <212> PRT < 213 > Artificial Sequence - 85 - 156004 · Sequence Listing. doc 201143790 <220><223> Glucagon analog <220><221> M0D-RES <222> (2)..(2) <223>Xaa is D-Ala <220><221> MISC .FEATOE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> M0D.RES <;222> (29)..(29) <223> C-terminal amidation <400> 197

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 <210> 198 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC.FEATURE <222> (12). (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29)

<223> C-terminal amide <400> 198

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

20 <210> 199 <211> 29 <212> PRT <213> Artificial sequence <220><223> Glycoside analogue <220><221> MOD.RES

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 86· 156004 - Sequence Listing.doc 201143790 <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC.FEATURE <222> (16) 7. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D. RES <222> (297..(29) <223> terminal amination <400> 199

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

<210> 200 <211> 29 <212> PRT <213>Artificial sequence <220><223> Glycoside analogue <220><221> MOD.RES <222> 2)..(2) <223> Xaa is D-Ala <220><221> M0D_RBS <222> (29)..(29) <223> C-terminal amide hydration <400> 200

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu ] 5 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Thr 20 25 <210> 201 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (2) 7. (2) <223> Xaa is D-Ala <220><221> MI SC FEATURE <222> (12) 7. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <;223> C-terminal amidation 87- 156004-sequence table.doc 201143790 <400> 201 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 012 3 <21<21<21<21 202 29 PRT artificial sequence <220> <223> Glycoside analogue <220>221>MOD.RES<222> 2)..(2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222> (16)..(20) <223> Side chain and position at position 16 Intrinsic amine ring between the side chains on 20 <220><221> M0DJRES <222> (29)..(29) <223> 〇: terminal amidation <400> 202 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 <210> 203 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221>M0D_RES<222> (2)..(2) <223>Xaa is D-Ala <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400> 203 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly 20 25 <210> 204 156004-Sequence List.doc -88 - 201143790 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycosin analogue <220>

<221> M0D_RES <222> (2)..(2) <223> Xaa is D_Ala <220><221> MISC FEATURE <222> (12)..(16) <223> Intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (29)..(29) <223> C-terminal guanamine <400> 204

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 205 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220>

<221> M0D_RES <222> (2)..(2) <223> Xaa is D-Ala <220><221> MISC FEATURE <222> (16)..(20)

<223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D_RES <222> (29)..(29) <223> Intrinsic amine ring between the side chain on ϊΐδ and the side chain on position 20 <400>

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 <210> 206 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoglycan Analog 89 - 156004 - Sequence Listing.doc 201143790 <220><221> M0D.RES <222> (24)..(24) <223> PEGylation <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amidation <400> 206

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 207 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29).. (29 ) <223> C-terminal amide <400> 207

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 208 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <223>;220><221> MISC FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;221> MOD RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (291..(29) <223> C-terminal amide hydration <400> 208

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 90-

156004-sequence table.doc 201143790 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 209 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>;221> MOD RES <222> (24)..(24)

<223> PEGylation <220><221> MOD.RES <222> (297..(29) <223> C-terminal amide hydration <400>

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 210 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>;221> MOD RES <222> (24)., (24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223>; C-terminal amide hydration <400> 210

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 -91- 156004 - Sequence Listing.doc 201143790 0>1>2>3><21<21<21<21 211 29 PRT Artificial Sequence <220&gt <223>glycoside analogue <220><221> MISC.FEATURE <222> (16)..(20) <223> side chain at position 16 and side chain at position 20 Between the indoleamine ring <220><221> MOD RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400> 211 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 >>>> 012 3 22 2 <<<v 212 29 PRT Artificial Sequence <220><223> Glucagon Analog <220> <221> MISC FEATURE <222> (16) 7. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD.RES <222> (24)..(24) <223>polyethylene glycol 匕<220><221> M0D_RES <222> (29)..(29 <223> 〇: terminal amidation <400> 212 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 213 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glucagon Analog 156004 - Sequence Listing. doc -92· 201143790 20 on the chain side of the cyclic amine oxime and JkTL20 on the chain side 7 on FE/ "16 sc6": 5 MI (1 position 0 > 1 > 2 > 3 > 2 222 <2<2<2<2

E <220><221> MODJffiS <222> (24)..(24) <223> PEGylation <220><221> MOD RBS <222> (29)..( 29) <223> C-terminal amide <400> 213

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 214 <211> 29 <212> PRT <213:>Artificial sequence <220><223><220><221> MISC FEATURE <222> (12) 7. (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>;<221> M0D.RES <222> (24)..(24) <223> PEGylation <220><221> - MOD RES <222> (29)..(29 ) <223> C-terminal amide <400> 214

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 215 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC_FEATURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 93-156004 .doc 201143790 <220><22I> MOD RES <222> (24)..(24) <223> Polyethylene 2 <220><221> M0D_RES <222> .(29) <223> Extremely aminated <400> 215

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 216 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><22l> MISC FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;221> M0D_RES <222> (24)..(24) <223> PEGylation <220><221> M0D_RES <222> (29)..(29) <223> Terminal amination <400> 216

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 217 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD.RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..( 29) <223> C-terminal amide <400> 217

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr LeusAsp Glu 94-

156004· Sequence Listing.doc 201143790 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 <210> 218 <211> 29 <212> PRT <2]3>Artificial sequence <220><223><220><221> MISC FEATURE <222> (12) 7. (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220>;

<221> M0D.RES <222> (241..(24) <223> PEGylation <220><221> MOD.RES <222> (29)..(29) <;223> C-terminal amide hydration <400> 218

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 <210> 219 <211> 29 <212> PRT <2]3>Artificial sequence <220><223> Object

<220><221> MISC.FEATURE <222> (16)..(20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>;<221> M0D_RES <222> (24)..(24) <223> PEGylation <220><221> M0D-RES <222> (29)..(29) <;223> C-terminal amide <400> 219

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 156004 · Sequence Listing _doc -95-

t:; teiP 15 201143790 <210> 220 <211> 29 <212> PRT <213>Artificial sequence<220><223> Glycoside analogue <220><221> M0D. RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> Amination <400> 220

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly 20 25 <210> 221 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MISC.FEAIURE <222> (12)..(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (24)..(24) <223> PEGylation <220><221> M0D.RES <222> (29)..(29) <;223> C-terminal amide <400> 221

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 <210> 222 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Glycin Analog <;220><221> MISC FEATURE <222> (16) 7. (20) <223> The intrinsic amine ring 96- between the side chain at position 16 and the side chain at position 20.

156004-Sequence List.doc 201143790 <220><221> MOD RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> C-terminal amidation <400> 222

His Ser Gin Gly Thr Phe Thr Set Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 <210> 223 <211> 29 <212> PRT <213>

<220><223> Glycoside analogue <220><221> MOD_RES <222> (1) 7. (1) <223> Xaa is (desamino)His <220><221> MOD.RES <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)., (29) <;223> Extremely aminated <400> 223

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 224 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> MOD.RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MOD RES <222> (24) <223> PEGylation <220> 97·156004. Sequence Listing.doc 201143790 <221> MOD RES <222> (29)..(29) <223> Terminal amination <400> 224

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 225 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <223> 220> MOD RES < 222 > (1) (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> MOD RES <222> (24)..( 24) <223> PEGylation <220><221> M0D.RES <222> (29)..(29) <223> C-terminal amide hydration <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 226 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> MOD.RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC.FEATURE <222> 12).. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (24).. (24) 98-

156004-Sequence List.doc 201143790 <223>PEGylation<220><221> M0D.RES <222> (29)..(29) <223> C-terminal amide hydration <400>; 226

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 227 <211> 29 <212> PRT <213> Artificial Sequence <220><223> Glycin Analog <;220><221> MOD RES <222> (l) T. (l) <223> Xaa is (desamino)His <220><221> MISC FEATURE <222> (12) 7. (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (24).. (24 <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 228 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220>

<221> MOD RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC FEATURE <222> (16)7. 20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 99- 156004-sequence table.doc 201143790 <220><221> MOD RES <222> 24).. (24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> 〇: terminal amidation <400>; 228

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 229 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD-RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> M0D_RES <222> (24) .. (24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> C-terminal amide hydration <400>

Xaa Ser G.n Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp G!u

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 230 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC.FEATURE <222> (16 7. (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 <220>

<221> M0D.RES 100-

156004-Sequence List.doc 201143790 <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <;223> C-terminal amide hydration <400> 230 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 231 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (1) 7. (1) <223> Xaa is (desamino)His <220><221> MISC.FEATURE <222> (12 (16) <223> The indole ring between the side chain at position 12 and the side chain at position 16 <220><221> MOD RES <222> (24)..( 24) <223> PEGylation <220><221><222><223> M0D.RES (297..(29) C-terminal amide hydration <400> 231 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 >>>> 012 3 <21<21<21<21 232 29 PRT Artificial Sequence <220><223> Glucagon Analog <220><221> MOD.RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC FEATURE <222> (12)7.(16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 is 156004 - Sequence Listing. doc 101 · 201143790 <220><221> M0D.RES <222> (24)..(24) <223> Polyethylene 2 <220><221> M0D_RES <222> (29)..(29) <223> Terminal amination <400> 232

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 233 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> MOD.RES <222> (1)..(1) <223> Xaa is (desamino)His <220> <221> MISC.FEATWE <222> 16).. (20) <223> The indole ring between the side chain at position 16 and the side chain at position 20 <220><221> M0D.RES <222> (24) .. (24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223> 〇: terminal amidation <400>

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 <210> 234 <211> 29 <212> PRT <213>Artificial Sequence <220><223> Glycoside Analog <;220><221> M0D_RES <222> (1)..(1) <223> Xaa is (desamino)His <220>

<221> M0D„RES 102-

156004-Sequence List.doc 201143790 <222> (24)..(24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <;223> C-terminal amide <400> 234

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 <210> 235 <211> 29 <212> PRT <213>Artificial Sequence <220>

<223> Glycosin analogue <220><221> MOD RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC „FEATURE <222> (12) 7. (16) <223> The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 <220><22I> MOD RES <222> (24)..(24) <223> PEGylation <220><221> M0D.RES <222> (29)..(29) <223> Alanine <400> 235

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 <210> 236 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <;220><221> MOD RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MISC.FEATURE <222> (16 (20) <223> The intrinsic amine ring between the side chain at position 16 and the side chain at position 20-103·156004-sequence table.doc 201143790 <220><221> MOD RES <222> (24).. (24) <223> PEGylation <220><221> MOD RES <222> (29)..(29) <223><400> 236

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 <210> 237 <211> 29 <212> PRT <213>Artificial Sequence<220><223> Glycoside Analog <223>;220><221> MOD.RES <222> (1)..(1) <223> Xaa is (desamino)His <220><221> MOD RES <222> (24) <223> PEGylation <220><221> MOD.RES <222> (29)..(29) .<223> C-terminal amide hydration <400>; 237

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Lea Val Lys Gly 20 25 &lt;210&gt; 238 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; <220> &lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt; 104-

156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29) ..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 238

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Scr Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 239 &lt;211&gt; 29 &lt;212&gt; PR Ding &lt;213&gt; Artificial Sequence

&lt;220&gt;&lt;223&gt; Glycoside analogue &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; Alanine &lt;400&gt; 239

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 240 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24T..(24) 105· 156004· Sequence Listing.doc 201143790 &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 241 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (291..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 242 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2)

&lt;223&gt; Xaa is MB &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between the side chain at position 16 and the side chain at position 20 Endoamine ring &lt;220&gt;&lt;22】&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt; 106- 156004-sequence table.doc 201143790 &lt;lt ;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 242

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 243 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is ΑΪΒ &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Glycolization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr

&lt;210&gt; 244 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)7. 2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; between the side chain at position 12 and the side chain at position 16 Amidoxime ring &lt;220&gt;&lt;221&gt; MODJRES &lt;222&gt; (24)..(24) 107- 156004-sequence table.doc 201143790 &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 244

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 245 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; between the side chain at position 16 and the side chain at position 20 Amidoxime ring &lt;220&gt;&lt;221&gt; M0D..RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 29)..(29) &lt;223&gt; (: terminal amination &lt;400&gt; 245

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 246 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221>MOD RES &lt;222> (24)., (24) &lt;223&gt;Pegylated 108- 156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; 〇: terminal amination &lt;400&gt;; 246

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 IS

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 247 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide

&lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Between the side chain at position 16 and the side chain at position 20醯 醯 & 220 220 220 220 220 220 220 220 220 )..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 247

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 248 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is ΑΪΒ &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt;; the inner guanamine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;

&lt;221&gt; MOD.RES 109-156004. Sequence Listing.doc 201143790 &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 248 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 012 3V &lt;v &lt; 249 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2) 7. (2) &lt;;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; between the side chain at position 12 and the side chain at position 16 Amidoxime ring &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;22\&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 249 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 012 3 2 2 ΛΖ 2&lt;&lt;v&lt; 250 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring 156004 between the bond and the side chain at position 16 - Sequence Listing.doc 110- 201143790 &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amidation &lt;400&gt; 250

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 251 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;

&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2) 7. (2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 251

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 252 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; misc.feature &lt;11Ύ&gt; (1, (2) &lt;223&gt;Xaa# is any naturally occurring amino acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 -Ill · 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 253 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt; 223 &gt; between the side chain at position 16 and the 恻 chain at position 20 Amidoxime ring &lt;220&gt;&lt;221&gt; M0D-RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;223&gt; MOD^RES &lt;222&gt; 29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 253

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Aia Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 254 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221>MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; 〇: terminal amination &lt;400&gt; 254

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 •112· 156004 Sequence Listing.doc 201143790 &gt;&gt;&gt;&gt; 012 3 11 It - - &lt;2&lt;2&lt;2&lt;2 255 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;;400&gt; 255 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 256 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Location 16 The indole ring between the side chain and the side chain at position 20 &lt;220&gt;&lt;22I&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (29).. (29) C-terminal amide hydration &lt;400&gt; 256 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly 20 25 156004-Sequence List.doc -113- 201143790 &lt;210&gt; 257 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; 3 (aa is D_Ala &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt; 400> 257

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 258 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; 3iaa is D_Ala &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt; 223 &gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (291..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 259 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence • 114· 15 6004-sequence table.doc 201143790 &lt;220&gt ; &lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 259

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 260 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;;223&gt; The indole ring between the side chain at position 12 and the side button at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 261 &lt;211&gt; 29 -115- 156004 - Sequence Listing.doc 201143790 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (24)..(24) 1 &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;;223&gt; Extremely aminated &lt;400&gt; 261

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 262 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (29)..(29) &lt;223&gt; 0: terminal amidation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 -116· 156004· Sequence Listing.doc 201143790 &lt;210&gt; 263 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic peptide

&lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24). (24) &lt;223&gt; Polyethylene dimerization &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; (: terminal amination &lt;400&gt; 263 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 ^ &gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 &lt;220&gt;&lt;223&gt; 264 29 PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt; M0D „RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC.FHATURE &lt;222&gt; (16)..( 20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; mojss &lt;222&gt; (24)..(24) &lt;223&gt; Pegylated &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (293..(29) &lt;223&gt; terminal amidation &lt;400&gt; 264 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 265 156004 - Sequence Listing.doc -117- 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D_Ala &lt;220&gt;&lt;221&gt; MISC_FEAT\JRE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;22i&gt; MOD.RES &lt;222&gt; (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 265 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Va! Cys Trp Leu Met Asn Thr 20 25

Q1 z 3 22 22 &lt;&lt;&lt; V 266 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; mojBS &lt;222&gt; (2), (2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; between the side chain at position 12 and the side chain at position 16 Amidoxime ring &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29) ..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 266 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 156004. Sequence Listing. doc -118· 201143790 &lt;210&gt; 267 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223:&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 24)..(24) &lt;223&gt; PEGylation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (29T..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 267

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 268 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amidation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 . 25 &lt;2]〇&gt; 269 •119- 156004-sequence table.doc 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt;M0D&apos;RES&lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 270 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Pegylated &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 -120- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 271 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223>Xaa is D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;- &lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223;&gt;&lt;400&gt; 271

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 272 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D_Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Ethylene glycolate &lt;220&gt;&lt;221&gt; M0D.RRS &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 273 -121 - 156004 · Sequence Listing.doc 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; ffiD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt;(16)..(20)&lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; 24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 273

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 274 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) &lt;223&gt; (: terminal amination &lt;400&gt; 274

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 275 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide 122-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 275

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 276 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; 醯 between the side chain at position 16 and the side chain at position 20. Amine ring &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;^23&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; 29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 276

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr

&lt;210&gt; 277 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12). (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt;M0D&apos;RES&lt;222&gt; (247..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) 123- 156004 - Sequence Listing.doc 201143790 &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 277

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 278 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) C-terminal amide amination &lt;400&gt; 278

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 279 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Alanine &lt;400&gt; 279

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15 124-

156004-sequence table.doc 201143790

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 280 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 280

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 281 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal guanamine &lt;400&gt; 281

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 282 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-125- 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; between the side chain at position 12 and the side chain at position 16 Amidoxime ring &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; 29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 282

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 283 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;222&gt; (12).. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; Alanine &lt;400&gt; 283

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 284 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;

156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; )..(29) &lt;223&gt; 〇: terminal amidation &lt;400&gt; 284 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Giu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 285 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24). (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 285 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 286 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 286 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 156004-sequence table.doc 127- 201143790 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 287 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; : Terminal amination &lt;400&gt; 287

His Ser Glu Giy Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 288 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (29)..(29) &lt;;223&gt; C-terminal amide &lt;400&gt; 288

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 289 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt; -128- 156004 · Sequence Listing.doc 201143790 &lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; 醯 between the side chain at position 12 and the side chain at position 16. Amine ring &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation. &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; )..(29) &lt;223&gt; 〇: terminal amination &lt;400&gt; 289

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly

&lt;210&gt; 290 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation. &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29)

&lt;223&gt; 0-terminal amidation &lt;400&gt; 290

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;2]0&gt; 291 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; M0D „RES &lt;222&gt; (1)7, (1) &lt;223&gt; Xaa is (desamino)His -129- 156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amides &lt;400&gt; 291

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 292 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..( 24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 293 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..( 20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;

156004· Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29) ..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 293

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 kxg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 294 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; Xaa is (desamino)His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 294

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1. 5 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 295 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. 16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 · 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 295

Xaa Ser GIu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;2I0&gt; 296 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (1)..(1) &lt;223&gt; xaa is (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 297 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino group) His &lt;220&gt;

&lt;221&gt; MOD.RES 132- 156004-sequence table.doc 201143790 &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 297

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 298 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino)His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 16).. (20) &lt;223&gt; The indole ring between the side button at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; 0 terminal amidation &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 299 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino)His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)7. 16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 133 - 156004 - Sequence Listing.doc 201143790 &lt;220> &lt;221&gt; MOD RES &lt;222&gt; 24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 299

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 300 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is (desamino)His &lt;220&gt;&lt;221&gt; M1SC.FEATURE &lt;222&gt; (12).. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (247..(24) &lt; 223 &gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amidation &lt;400&gt; 300

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 301 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD_RES - 134 - 156004 - Sequence Listing. doc 201143790 &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222 〉 (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24j ..(twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 301

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 302 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal guanamine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24) ..(twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 302

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 303 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (desamino group) His &lt;220&gt;;

&lt;221&gt; MISC_FEATURE 135-156004-sequence table.doc 201143790 &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEC &lt;400&gt; 303

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 304 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt;; MOD.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 304

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe lie Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 305 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (l) T. (l) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MOD-RES 136·

156004-sequence table.doc 201143790 &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 305

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 306 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amidization

&lt;221&gt; MOD.RES &lt;222&gt; (1).. (1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16 &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24)

&lt;223> Cys-PEG &lt;400&gt; 306

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 307 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 龟 龟 龟 &&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt; 137-156004 - Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 307 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Gly Phe lie Cys Τϊρ Leu Val Lys Gly 20 25 012 3 2 2 2 2 &lt;&lt;&lt;&lt; 308 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;&lt;223&gt;&lt;220&gt;&lt;22l&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; MI SC FEATURE C-terminal amide amination M0D_RES (2)..(2) Aminoisobutyric acid MOD RES (24)..(24) Cys-PEG 308

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Lea Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 012 3 222 2 &lt;&lt;&lt;&lt; 309 29 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide &lt;220&gt;&lt;221&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; His Χί 1 MISC FEATURE C-terminal vegetable amination MOD^RES (2)..(2) Aminoisobutyric acid MOD RES (24T..(24) Cys-PEG 309 i Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 5 10 15 156004 · Preface List.doc 138- 201143790

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 310 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20)

&lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 310

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 311 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 is &gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 311

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 -139- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 312 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;22]&gt; MISC.FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;;&lt;221&gt; M0D_RHS &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 312

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 313 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 313

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 140- 156004 · Sequence Listing.doc 201143790 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 314 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid

&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 314

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 315 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATIJRE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 315

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 -141 - 156004 - Sequence Listing.doc 201143790 &lt;210> 316 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; terminal amidization &lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 316

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Ding rp Leu Met Asn Thr 20 25 &lt;210&gt; 317 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;&lt;221&gt; MISC_FEAT\JRE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (12).. (16 &lt;223&gt; The indole ring between the side key at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 317

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 142-

156004-sequence table _doc 25 201143790

1 1* n 1 2 2 ofc vV &lt;V

318 29 PRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chains at position 20 &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 318

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 319 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt; M0D_RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 319

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 320 -143- 156004 - Sequence Listing.doc 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amidation &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 320

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 321 &lt;211> 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC „FEATTJRE &lt;222&gt; (16) 7. (20) &lt;223&gt; The inner guanamine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 321

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin AJa Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 144

156004-Sequence List.doc 201143790 &lt;210&gt; 322 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;;223&gt; C-terminal tortoise &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24).. (24 )

&lt;223&gt; Cys-PEG &lt;400&gt; 322

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 323 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 323

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 324 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence - 145 - 156004 · Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (241..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 324

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 325 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 325

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 326 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide 146-

156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 326

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 327 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amine &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222> (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 327

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 328 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; terminal imidization-147. 156004. Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; • 醯 between the side chain at position 12 and the side chain at position 16. Amine &lt;220&gt;&lt;221>MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 328

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 329 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: 端化化化&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 329

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Vai Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 330 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC_FEAT\JRE 148·

156004· Sequence Listing.doc 201143790 &lt;223&gt; (: terminal amination &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; {2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 330

His Xaa Clu Gly Thr Phe Thr Ser Asp Tyr SeT Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 331 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;&lt;220&gt;

&lt;221&gt; ft «D_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 331

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 332 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;

&lt;221 &gt; MOD.RES &lt;222&gt; (2)..(2) -149- 156004. Sequence Listing.doc 201143790 &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The side chain at position 16 and the indole ring between the chains at position 20 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; .(twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 332

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 333 &lt;231&gt; 29 &lt;212&gt; FRT &lt;213&gt; Artificial Sequence Synthetic Peptide

&lt;220&gt;&lt;223&gt;&lt;220&gt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RBS &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(]6) &lt;223&gt; between the side chain at position 12 and the side chain at position 16 Indole ring &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24),.(24)

&lt;223&gt; Cys-PKJ &lt;400&gt; 333

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 334 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES 150- 156004-sequence table.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (12 7. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24).. (twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 334

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 335 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal guanamine &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16 &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 335

His Xaa Glu G]y Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 336 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 〇: terminal amidation &lt;220&gt; 151- 15 6004-sequence table.doc 201143790

&lt;221&gt; MOD^RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;22l&gt; MOD^RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 336

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 337 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATORE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Aia &lt;220&gt;&lt;221&gt; MiSC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223>Cys-PEG &lt;400&gt; 337

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Fhe He Cys Trp Leu Met Asn Thr 20 25 &lt;210> 338 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala -152·

156004-Sequence List.doc 201 143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Between the side chain at position 16 and the side chain at position 20 Endoamine ring &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 338

His Xaa Glu Giy Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 0123 2 2 ΟΑ 2 \?&lt; V &lt; Column Order 9 T 3329 is a person &lt;220&gt;&lt;223&gt Synthetic peptide &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D -Ala &lt;220〉 &lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 339

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Val Lys Gly 20 25 340 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; C-terminal stupidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2). (2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; Side chain at position 12 and side at position 16 Intrinsic amine ring between chains 153· 156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 340

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Giu Phe lie Cys Trp Leu Val Lys Gly 20 25 &lt;210&gt; 341 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RHS &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;22!&gt; MISC.FEATliRE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 341

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Ding rp Leu Val Lys Gly 20 25 &lt;210&gt; 342 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;223>C-terminal 0S amination &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PHG &lt;400&gt; 342

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 154-

156004-Sequence List.doc 201143790 15 10 15 Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 0123 11 u li 11 &lt;2&lt;2&lt;2&lt;2 343 29 PRT Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATORE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (16).. (16 &lt;223&gt; Cys-PEG &lt;400&gt; 343 His Ser Gin Gly Thr Phc Thr Scr Asp Tyr Scr Lys Tyr Leu Asp Cys 15 10 15

Arg Ala Ala Lys Asp Phe Vat Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 344 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2丨3&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;22)&gt; MISC FEATURE C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 345 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amidation 156004. Sequence Listing. doc-155-201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEC &lt;400&gt; 345 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Scr Lys Tyr Leu Asp Cys 15 10 15

On Ala Ala Lys Glu Phe Me Ala Trp Leu Val Lys Gly 20 25 &lt;210&gt; 346 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (1): (1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MOD RBS &lt;222&gt;&lt;16..(16)&lt;223&gt; Cys-PEG &lt;400&gt; 346 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 b&gt;&gt;&gt; Q ] z 3 &lt;21&lt;21&lt;21&lt;21 347 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;;220&gt;&lt;221&gt; MISC_FEAl\fRE C-terminal amination &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (1)..(1} &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 347 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 156004 List.doc 156- 201143790 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 012 3 V &lt;&lt; 348 348 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Amination &lt;220&gt;&lt;221&gt; MOD RES . &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 348 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 012 3 11 11 11 II &lt;2&lt;2&lt;2&lt;2 349 29 PRT Artificial Sequence &lt;220〉 &lt;223&gt; Synthetic Peptide &lt;220&gt;;221&gt; MISC.FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; C^s-PEG &lt;400&gt; 349 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 &lt;230&gt; 350 &lt;211&gt; 29 156004 - Sequence Listing.doc 157- 201143790 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence&lt;220&gt;;&lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;;223&gt; (desamino)His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 350

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 351 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortochemical &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2): (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 351

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

20 &lt;210&gt; 352 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr -158- 156004 · Sequence Listing, doc 201143790 &lt;223&gt; 0-terminal amidation &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 352

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Thr 20 25

&lt;210&gt; 353 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Amino-based peric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16). .(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 353

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly 20 25 &lt;210&gt; 354 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 蕴 蕴 & 220 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-Ala &lt;220&gt;

&lt;221&gt; MOD.RES -159- 156004-sequence table.doc 201143790

&lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 354

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 355 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;22&gt; MOD RES &lt;222&gt; (2), (2) &lt;223&gt; D-Ala &lt;220&gt;;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 355

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 IS

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 356 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222〉 (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 356

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15 -160-

156004· Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 357 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 357

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 &lt;210&gt; 358 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 358

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 359 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt; -161 - 156004 - Sequence Listing.doc 201143790 &lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 359

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 360 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 360

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin AJa Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 361 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;22〇&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 361

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 &lt;210&gt; 362 -162-

15 6004 Sequence Listing.doc 201143790 &lt;2Π&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Amineralization &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (desamino group) His &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (16Τ..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 362

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 363 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221>MISC FEATURE &lt;223&gt; 0: terminal amination &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His

&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 363

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 364 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt; -163- 156004-sequence table.doc 201143790 &lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal aminated &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (l)T.(l) &lt;223&gt ; (Deamino)His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 365 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 365

Xaa Ser Giu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 &lt;210&gt; 366 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt; -

156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; C^s-PEG &lt;400&gt; 366

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 367 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amidation

&lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 367

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 368 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC_FEA7\JRE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 368

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15 165- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 369 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 369

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys Gly 20 25 &lt;210> 370 &lt;211&gt; 29 &lt;212&gt; PR Ding &lt;2I3&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;&lt;221&gt; MISC-FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Cys-PEG &lt;400&gt; 370

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys ] 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210> 371 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence -166 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATXJRE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 371 His Xaa Glu Gly Thr Phe

Arg Ala Ala Lys Asp Phe 20

Thr Ser Val Gin

Asp

Sp

Leu

Ser Met

Lys Asn

Tyr Leu Thr

Asp Cys 15 &lt;210&gt; 372 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2丨3&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 &gt;&lt;: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Cys-PEG &lt;400&gt; 372 His Xaa Glu Gly Thr Phe

Gin Ala Ala Lys Glu Phe 20

Thr Ser lie Ala

Asp

Sp

Tyr 10

Leu

Ser Met

Lys Asn

Tyr Leu Thr

Asp Cys 15 &gt;&gt;&gt; 0 12 3 V &lt;N/&lt; 373 29 PRT Artificial Sequence &lt;220> &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;223&gt; C-terminal amides &lt;220&gt; 156004. Sequence Listing.doc •167·201143790 &lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (2):.(2) D-Ala ^ &gt;&gt;&gt; 012 3 222 2 22 22 &lt;&lt;&lt;&lt;&lt;400〉 MOD RES (16)..(16) C^s-PEG 373

His Xaa Glu Gly Thr Phe

Gin Ala Ala Lys Glu Phe 20

Thr Ser lie Ala

Asp Tyr 10

Trp Leu 25

Ser Val

Lys Lys

Tyr Leu Gly

Asp Cys 15 &gt;&gt;&gt;&gt; 012 3 374 29 PRT Artificial Sequence &lt;220〉 &lt;223&gt; Synthetic Peptide &lt;220&gt;221&gt; MISC FEATURE &lt;223&gt; (: Terminal Tortoise &lt;400&gt; 374 His Ser Gin Gly Thr Phe

Arg Arg Ala Gin Asp Phe 20

Thr Ser Val Gin

Asp Tyr 10

Trp Leu 25

Ser Met

Lys Asp

Tyr Leu Thr

Asp Glu 15 &lt;210&gt; 375 &lt;21l&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 03⁄4 Transport Amination &lt;400&gt; 375 His Ser Gin Gly Thr Phe 1 5

Arg Arg Ala Lys Asp Phe 20

Thr Ser Val Gin

Asp Tyr 10

Trp Leu 25

Ser Met

Lys Asp

Tyr Leu Thr

Asp Glu 15 &gt;&gt;&gt;&gt; 012 3 ςνί ςΝ 〇 2 VV &lt;&lt; Column Order 6 T-Work 79R 32 ρ Λ &lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt; 156004-Sequence Listing .doc -168· 201 143790 &lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic amine ring between the upper side chain and the side chain at position 20 &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 11 11 11 11 CM 2 2 2 V &lt;&lt;&lt;

377 29 PRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Ser.Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 378 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; Side chain and position at position 12 Indole ring between side chains on 16 &lt;400&gt; 378

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 379 156004 - Sequence Listing.doc -169-

S 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amidation &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Ser Gin Gly Thr Phe Tht Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 380 &lt;211&gt; 29 &lt;212> PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;223&gt; 0-terminal amidation &lt;400&gt; 380

His Ser G]n Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 381 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide amide; endoamine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 382 -170- 156004 - Sequence Listing.doc 201143790 &lt;211&gt; 29 &lt;212> PRT &lt;213&gt; Artificial Sequence Synthetic Peptide&lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;22I&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 383 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;; 383

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 384 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220> &lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Side chain and position at position 16 Intrinsic amine ring between the side chains on 20 &lt;400&gt; 384 171 - 156004-sequence table.doc 201143790

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 385 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;400&gt; 385

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Cln Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 386 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0 terminal amidation &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; Side chain and position 16 at position 12. Indole ring between the side chains &lt;400&gt; 386

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 387 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) • 172 - 156004 - Sequence Listing.doc 201143790 &lt;223&gt ; the inner guanamine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 · &lt;210&gt; 388 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amidation

&lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;400&gt; 388

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 389 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 蕴 蕴 & &&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;400&gt; 389

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 390 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide•173· 156004 Sequence Listing.doc 201143790 &lt;220> &lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223;&gt; side chain at position 16 and side chain at position 20 Between the indole ring &lt;400&gt; 390

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr 10

Leu Asp Glu 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 391 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;; 391

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 392 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; misc_feature &lt;222&gt; (1)..(1) &lt;223&gt; Xaa can be any naturally occurring amino acid &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu -174-

156004-sequence table.doc 201143790 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 393 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His

&lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 393

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 394 &lt;231&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1).. (1) &lt;223&gt; (desamino group) His &lt;400&gt; 394

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 395 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide e 156004-Preorder List .doc -175- ^ 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;;223&gt; (desamino)His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Between the side chain at position 16 and the side chain at position 20 Indole ring &lt;400&gt; 395 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 396 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MISC FEATTJRE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD.RES &lt;222> (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;; 396 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 397 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide amination &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt;&lt;223&gt; 156004-sequence table.doc •176·201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 398 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; ^ The inner guanamine ring between the side chain at 416 and the side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 399 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;400&gt;; 399

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 -177- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 400 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0-terminal tortoise &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (Deamino)His &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The side chain at position 12 and the side chain at position 16 Amidoxime ring &lt;400&gt; 400

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie A]a Trp Leu Met Asp Thr 20 25 &lt;210&gt; 401 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 402 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide -178-

156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;;223&gt; Aminoisobutyric acid &lt;400&gt; 402

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 403 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 403

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 404 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; (2-terminal amidization &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 179- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 405 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; C-terminal i&amp; amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 406 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;22丨&gt; MI SC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;; 406

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 407 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence -180-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 053⁄4 Amination &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr

&lt;210&gt; 408 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Terminal amylation &lt;400&gt; 408

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 409 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0: terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid-181 - 156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222> (16)..(20) &lt;223&gt; between the side chain at position 16 and the side chain at position 20 Amidoxime ring &lt;400&gt; 409

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 410 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal IK amination · &lt;220&gt;

&lt;22l&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 410

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 411 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12).. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 182·

156004-sequence table.doc 201143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 412 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthesis&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16)

&lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 413 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; c-terminal amidation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 414 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt; -183- 156004-sequence table.doc 201143790 &lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; Between the side chain at position 12 and the side chain at position 16 Endoamine ring &lt;400&gt; 414 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asp Thr 20 25 &lt;2I0&gt; 415 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC.FEATORE (16).. (20) The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 415 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 • · Λ 11 22 22 &lt;&lt;&lt;&lt; 416 29 PRT Artificial Sequence &lt;220〉 &lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;223&gt; Synthetic peptide MISC_FEATURE C-terminal amidation &gt;&gt;&gt;&gt; 0123 2222 ΛΖ 2 2 2 V &lt;&lt;&lt;&lt;400&gt; MOD.RES (2)..(2) D-Ala 416 156004-Sequence List_doc •184· 201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; ^ &gt; 012 3 &amp; 3 li 1* 1 11 τώ &lt;2&lt;2&lt;2&lt;2&lt;2&lt;2 417 29 PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; c-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; D-Ala &lt;400&gt; 417 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 418 &lt;;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; c-terminal amination &lt;220&gt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (16) 7. (20) The indole ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 418 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 419 29 PRT Artificial Sequence

S 156004-Sequence List.doc -185-201143790 &lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD_RES &lt;;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (12) 7. (16) Side chain at position 12 The indole ring between the side chain at position 16 &lt;400&gt; 419 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 420 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;221&gt; MISC FEATORE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 420 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 012 3 2 2 ΛΖ 2 &lt;&lt; V &lt; 421 29 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide &lt;220〉 &lt;221&gt ; MISC FEATURE &lt;223&gt; C-terminal IK amine also &lt;220&gt; 156004-sequence table.doc -186 - 201143790 &lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D -Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 ;400&gt; 421

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 422 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;

&lt;223&gt;Synthetic peptide &lt;220&gt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;;223&gt; D-Ala &lt;400&gt; 422

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 423 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu .1 5 10 15 -187- 156004 · Sequence Listing.doc 201143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 424 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;223&gt; C-terminal alkalization &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 424 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 425 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;&lt;222&gt; (12). Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 426 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence 156004 · Sequence Listing.doc -188- 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; M0D RES &lt;222&gt; (2) 7. (2) &lt;223&gt; DA.la &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The side chain between the side chain at position 16 and the side chain at position 20 Ring &lt;400&gt; 426

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg A1a Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr

&lt;210&gt; 427 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FRATURE &lt;223&gt; Amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-Ala &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 428 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala 189- 156004-preface List .doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 428

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 429 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;223&gt; C-terminal alkalization &lt;220&gt;&lt;221&gt;M0D&apos;RES&lt;222&gt; (2)7.(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 430 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: Tortoise Aromatization &lt;400&gt; 430

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 012 3 1L 11 11 11 2 ΛΖ 2 &lt; V V &lt; 431 29

PRT Human Process 歹 4 • 190· 156004 Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortochemical &lt;400> 431

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 432 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt;. MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic amine ring between side chains at position 20 &lt;400&gt; 432

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 433 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;

&lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222> (16).. (16 &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 • 191 - 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 434 &lt;2Π&gt; 29 &lt;212&gt; PRT &lt;213&gt; Manual Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt;; the inner guanamine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 435 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC_FEATORE &lt;223&gt; Terminal amination &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Side chain and position 20 at position 16 Indole ring between the side chains &lt;400&gt; 435

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 .15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;2I0&gt; 436 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; C-terminal amide &lt;400&gt; 436

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 192- 156004 - Sequence Listing.doc 201143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 437 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal IK amination &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 438 &lt;2H&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal stupidization &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; Side chain and position 16 at position 12. Indole ring between the side chains &lt;400&gt; 438

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 439 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (32) 7. (16) &lt;223&gt; Side chain and position 16 at position The indoleamine ring between the upper side chains 193-156004-sequence table.doc 201143790 &lt;400&gt; 439

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 440 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Positional position on position 16 and position 20 Indole ring between side chains &lt;400&gt; 440

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Lea Met Asp Thr 20 25 &lt;210&gt; 441 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Alkaloid Amination &lt;400&gt;

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 442 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal IS amination 194·156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FHATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 442 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 ^ &gt;&gt;&gt; 0123 2 ο* 2 &lt; VV &lt; 443 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;;&lt;221&gt; MISC-FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (16)..(20) Side chain at position 16 The indole ring between the side chain at position 20 &lt;400&gt; 443 His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 444 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;400&gt; 444 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 445 &lt;211> 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence 156004 - Sequence Listing.doc -195- 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223 〉 (Deamino)His &lt;400&gt; 445

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 446 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 447 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;220&gt;

156004· Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; (desamino group) His &lt;400&gt; 447

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 448 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1).. (1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt;'&gt;&gt; 0123 03 1i «1 1 1i oz Ol 449 29

PRT artificial sequence synthetic peptide &lt;220> &lt;221&gt; MISC.FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino)His &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (16)..(20) &lt;223&gt; Between the side chain at position 16 and the side chain at position 20 Indole ring &lt;400&gt; 449

Xaa Ser Glu Gly Thr Fhe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15 156004 · Sequence Listing, doc -197- 201143790

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 0123 2 Λζ ΛΥ 2 &lt;vv &lt; 450 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;400&gt; 450

Xaa Ser GIu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 451 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal alkalization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (I).. (1) &lt;223&gt; (desamino group) His &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222> (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 452 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide 156004 .doc -198- 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)7.(1) &lt;223 〉(desamino)His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; Between the side chain at position 12 and the side chain at position 16 Endoamine ring &lt;400&gt; 452 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 ^ &gt;&gt;&gt; 012 3 11 11 11 1 &lt;2&lt;2&lt;2&lt;2 453 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE (: terminal amination &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (1)..(1) &lt;223&gt; )His &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (12).. (16) The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; 453 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Gla 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 454 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATORE C-terminal amidation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino)His 156004-sequence table.doc • 199- 201143790 &lt;220&gt;&lt;221&gt; MISC.FEAITJRE &lt;222&gt; (16)..(20) &lt;223&gt; The side chain between the side chain at position 16 and the side chain at position 20 Ring &lt;400&gt; 454

Xaa Ser Glu G】y Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 455 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;^23&gt; Synthetic Peptide &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (1).. (1) &lt;223&gt; (desamino)His &lt;400&gt; 455

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 456 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12): (16) &lt;223&gt; The indole ring between the side chain at position £12 and the side chain at position 16 &lt;400&gt;

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe ile Ala Trp Leu Met Asp Thr 20 25 •200·

156004· Sequence Listing.doc 201143790 &lt;210> 457 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal vegetable amination &lt;220&gt;&lt;22i&gt; MOD RES&lt;222&gt; (l)T.(l) &lt;223&gt; (desamino group) His &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 457 Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210> 458 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 458 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 459 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide 156004 - Sequence Listing. doc 201 - 201143790 7 7 7 7 ^ 012 3 Av 2 2 22 o 2 o- 2 4 &lt; VV &lt;&lt; MOD RES (2).. (2) Aminoisobutyric acid 459

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt; 012 3 CM 2 2 2 V &lt;&lt;&lt; 460 29 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthesis Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side key at position 16 and the side key at position 20 &lt;400&gt; 460 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Lea Met Asp Thr 20 25 &lt;210&gt; 461 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2)..(2) &lt;223&gt; Amino-based fecal acid &lt;220&gt;;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position S16 &lt;400&gt; 461 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 156004-Sequence List.doc -202- 201143790

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 462 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt; His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 2 2 2 V &lt; V &lt; 463 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 463 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 464 &lt;211&gt; 29 &lt;212&gt; PRT 156004. Sequence Listing. doc - 203 - 201143790 &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 464

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 465 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Amination &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (20 ) &lt;223&gt; The intrinsic amine ring between the side chain on the top 16 and the side chain on position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;2)0&gt; 466 &lt;211&gt; 29 &lt;2]2&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid 156004-Sequence List.doc -204-201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12), (16) &lt;223&gt; The side chain at position 12 and the side chain at position 16 Inter-amylamine ring &lt;400&gt; 466

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 467 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 468 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2), (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 205- 156004 - Sequence Listing.doc 201143790 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 469 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 469

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 470 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 】 5 10 15

Gin Ala Ala Lys Glu Phe Me Ala Trp Leu Mel Asp Thr 20 25 &lt;210&gt; 471 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide •206-

156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0-terminal amidation &lt;220&gt;

&lt;22]&gt; M0D_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;222&gt; (16) 7. (20 &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 &lt;210&gt; 472 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2), (2) &lt;223&gt; D-Ala &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp 20

Phe

Va

Gin

Trp Leu Met Asp Thr 25 &lt;2&lt;2&lt;2&lt;2&lt;2&lt;2 012 3 0&gt;3&gt; 473 29 PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal Amination &lt;220&gt;

&lt;221&gt; MOD』ES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;400&gt; 473

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 207- 156004 - Sequence Listing.doc 201143790 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 474 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr 10

Leu Asp Glu 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 475 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The indole ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 476 &lt;211&gt; 29 156004-sequence table.doc -208- 201143790 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; D-AIa &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; between the side chain on the top of the emperor 12 and the side chain on the position 16 Amidoxime ring &lt;400&gt; 476

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phc Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 477 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Arg Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 478 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE -209· 156004-sequence table.doc 201143790 &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;400&gt; 478 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 】5

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 0123 &lt;21&lt;21&lt;21&lt;21 479 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; Ml SC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side bond at position 20 &lt;400&gt; 479 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 0164 3 22 22 480 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC.FEATURE C-end aminated MOD RES (2).. (2) D-Ala b &gt;&gt;&gt;&gt; 012 3 o 2222 o &lt;&lt; VV &lt; MISC.FEATURE (12) 7. (16) The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 156 156004 · Sequence Listing. •210. 201143790

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 4S1 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala

&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12) 7. (16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;; 481

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

^ &gt;&gt;&gt; 012 3 2 ΛΖ 2 &lt; V &lt; V 482 29

PRT artificial sequence &lt;220&gt;&lt;223&gt;synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; terminal amidation &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15

Arg Ala Ala Glu Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 483 &lt;211&gt; 29 &lt;212&gt; PRT -211 · 156004· Sequence Listing.doc 201143790

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15 &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Terminal k amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-Ala &lt;400&gt; 483

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asp Thr 20 25 &lt;210> 484 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine ring between the side chain at position 12 and the side chain at position 16 &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 0 12 3 Column 5 T4289 叩人&lt;220&gt;&lt;223&gt;Syntheticpeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD^RES &lt;222&gt; (2)..(2) &lt;223&gt; D-Ala -212- 156004-sequence table.doc 201143790 &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;400&gt; 485 His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asp Thr 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 486 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt;;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE C-end aminated MOD.RES (2).. (2) Aminoisobutyric acid

MOD RES (24)..(24) Cys-PEG &lt;400&gt; 486 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 487 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (297..(29) &lt;223&gt; Cys-PESG &lt;400&gt; 487 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 156004· Sequence Listing .doc 213- s 201143790 15 10 15 Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Cys 20 25 &gt;&gt;&gt;0123&lt;&lt;vv 488 40 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2)..(2) &lt;223&gt; Butyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; Cys-PEG &lt;400&gt; 488 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 489 &lt;211&gt; 40 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MISC.FEATURE &lt;223&gt; 蕴 蕴 &&lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; Cys-PEG &lt;400&gt; 489 His Xaa Gin Gly Thr Pife Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 156004-Sequence List.doc 214- 201143790 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 490 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;

&lt;221&gt; MOD RES . &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 490

His Xaa Gin Gly Thr Phe Thr

Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 491 &lt;211&gt; 39 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 of 3&gt; Aminoation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG 215-156004-sequence table.doc 201 143790 &lt;400&gt; His Xa 1 Gin A1 491 a Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Ser a Ala Lys Glu Phe Me Cys 20

Trp Leu 25

Met

Lys Tyr Leu Asti Gly Gly 30

Asp 15

Pro

Glu Ser

Ser Gl y Ala Pro Pro Pro 35 &gt;&gt;&gt;&gt;&gt;&gt; 0123 03 1111 22 2222 22 &lt; V &lt;&lt;&lt;&lt; 492 29 PRT Artificial Sequence Synthetic Peptide &lt;220&gt;&lt;;221&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; His Χί 1 MISC_FEATTJRE c-terminal m Aminated MOD RES (2)..(2) Aminoisobutyric acid MOD RES (24)..(24) Cys-PEG 492 a Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Ser

Arg a Ala Lys Asp Phe Val Cys 20

Trp Leu 25

Met

Lys Tyr Leu Asn Thr

Asp 15

Giu &lt;210&gt; 493 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt; Amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; )..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 493 His Xaa Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Ser 156004-sequence table.doc

Lys Tyjr Leu 216-

Asp 15

Glu 201 143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Cys 20 25 &lt;210&gt; 494 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;U3&gt; c-terminal amidation &lt;220&gt;&lt;22l&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;

&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 494 rg ysn G L2 G, ps 5 A1 u Le Γ Ty s Ly Γ es Γ Tylo ps Γ 6 s Γ c ph Thr5 cso pr y lo G 3 y Gl nst Me u Le p Γ 5 T2 nmva e ph ps CV40 Γ £ so pr o pr ro column p order 3 Γ- ]5 5 TJ A34940PR person y G, &gt;&gt;&gt;&gt; 0 12 3 6 2 2 2 s &lt; V &lt;&lt;&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Amidolation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40).. (40)

&lt;223&gt; Cys-PEG &lt;400&gt; 495

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 217· 156004 - Sequence Listing.doc 201143790

Arg Ala Ala Lys Asp Phe Val Gin Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 496 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 496 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu l 5 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 497 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; 〇: terminal also aminated &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;;223&gt; The indole ring between the side button at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 497 218-

156004· Sequence Listing.doc 201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 498 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; C-terminal Ik amination

&lt;220&gt;&lt;221&gt; M0D_RES &lt;m&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24).. (twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 498

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr Ala 20 25 30 &lt;210&gt; 499 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 499

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Cys -219- 156004. Sequence Listing.doc 201143790 20 25 &lt;210&gt; 500 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40).. (40)

&lt;223&gt; Cys-PEG &lt;400&gt; 500

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu I 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 501 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (40)..(40) &lt;223&gt; Cys-PK5 &lt;400&gt; 501

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Gly Gly Pro Ser 220·

156004-sequence table.doc 201143790 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 502 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;2W&gt; C-terminal imidization &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid

&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 502

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 503 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 503

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu . 221 - 156004 - Sequence Listing.doc 201143790 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 504 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC. FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt;; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 504

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp G]u 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 505 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (1)..(1) &lt;223&gt; c^a-dimethyl meth. Glycolate &lt;220&gt;&lt;221&gt; MISC_FEATORE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the side chain at position 16 and the side bond at position 20 &lt;220&gt;;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) 222-

156004-Sequence List.doc 201143790 &lt;223&gt; Cys-PEG &lt;400&gt; 505 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 ^ &gt;&gt;&gt;&amp; 1 2 3 2 ΛΖ 2 2 VV &lt;&lt; 506 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide

&lt;220&gt;&lt;221&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; MISC FEATURE C-terminal imidization MOD RES(1)..(1) ο^α-二申基咪唾 acetic acid MISC.FEATURE (16)7,( 20) The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 M0D.RES (29)..(29) Cys-PEG 506

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Cys 20 25 &lt;210&gt; 507 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt;〇^-二曱Imidazolacetic acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 ;220&gt;&lt;221&gt; M0D.RES 156004 - Sequence Listing.doc -223 - 201143790 &lt;222&gt; (40)..(40)

&lt;223&gt; Cys-PEG &lt;400&gt; 507

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 40 35 &lt;210&gt; 508 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1).. (1) &lt;223&gt; οςα-dibenyl imidazoleacetic acid &lt;220&gt;&lt;221&gt; MJSC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (40)..(40)

&lt;223&gt; Cys-PEG &lt;400&gt; 508

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Gly Gly Pro Ser

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;2t0&gt; 509 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; _ RES &lt;222&gt; (1)..(1) &lt;223&gt; c^a-dimethylimidazoleacetic acid 224-156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 509

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 510 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt; a-dimethylimidazoleacetic acid &lt;220&gt;&lt;221&gt; misc feature &lt;222&gt; (2) .7(2) &lt;223&gt; Xaa may be the side of any naturally occurring amino acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indole ring between the chain and the side chain at position 20 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 510

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 511 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-225 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)7.(2) &lt;;223&gt; c^ot-dimethyl methacetic acid &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; positional position on position 16 and position 20 The indole ring between the side chains &lt;220&gt;&lt;221&gt; M0D.RES &lt;222> (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 511

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 512 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Dimethylimidazoleacetic acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29)

&lt;223&gt; Cys-PEG &lt;400&gt; 512

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Cys 20 25 &lt;210&gt; 513 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide 226-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-side i&amp; amination &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (l)T (l οςα-二&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between the side key at position 16 and the side chain at position 20 Amidoxime ring &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 514 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; 龟terminal tortoise &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between the side chain at position 16 and the side chain at position 20 Indole ring &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24j..(24)

&lt;223&gt; Cys-PBG &lt;400&gt; 514

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu'Asp GIu 15 10 15

Gin Ala Ala Lys GIu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 515 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;400&gt; 515 • 227· 156004· Sequence Listing.doc 201143790

Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 &lt;210&gt; 516 &lt;211&gt; 12 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (121..(12) &lt;223&gt; Cys-PEG &lt;400&gt; 516

Giy Gly Pro Ser Ser Gly Ala Fro Pro Pro Ser Cys l 5 10 &lt;210&gt; 517 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0 terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indole ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;&lt;221&gt;; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 517

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 518 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide amination. 228·

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 518

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 519 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (1)..(1) &lt;223&gt; c^a-dimethylimidazoleacetic acid &lt;;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 519

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 520 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; c^cx-dimercaptoimidazoleacetic acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29)

&lt;223&gt; Cys-PEG &lt;400&gt; 520

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 229- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Cys 20 25 &lt;2i0&gt; 521 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;400&gt; 521

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 522 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; C-terminal amide &lt;400&gt; 522

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 523 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; C-terminal amide also &lt;400&gt; 523 •230·

156004-sequence table.doc 201143790

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 524 &lt;211&gt; 39 &lt;212> PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; 〇: terminal amination

&lt;400&gt; 524

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Val Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 525 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; C-terminal vegetable amination &lt;400&gt; 525

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 526 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt; 231 - 156004 - Sequence Listing. Doc 201143790 &lt;221&gt; MISC FEATURE &lt;223&gt; Extremely aminated &lt;400&gt; 526

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asp Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 527 &lt;211&gt; 30 &lt;212&gt; PRT &lt;2丨3&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;223&gt; (:end amination &lt;400&gt; 527

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin Ala Ala Lys Glu Phe ile Ala Trp Leu Val Lys Gly Gly 20 25 30 &lt;210&gt; 528 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine ring between the side chain at position 16 and the side chain at position 20 &lt;220&gt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 528

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 -232- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 529 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-armed helmet amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (1) 7. (1) &lt;223&gt; α^α-di-based imidazoleacetic acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24Τ..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 529

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 530 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (1)..(1) &lt;223&gt; cmx-dimethylimidacetic acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 530

Xaa Ser G)n Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 0 12 3 ςΜ 2 ςΜ 2 V &lt;v &lt; 531 40

PRT artificial sequence -233 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (247..(24)

&lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (407..(40)

&lt;223&gt; Cys-PEG &lt;400&gt; 531

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Glu Phe He Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 532 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40)..(40)

&lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (41)..(41)

&lt;223&gt; Cys-PEG &lt;400&gt; 532

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30-234-

J 56004· Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser Cys Cys 35 40 &lt;210&gt; 533 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide^&gt;&gt;&gt; Q ] 2 3 22 22 &lt;2&lt;2&lt;2&lt;2 MOD-RES acid

&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24),. (24) &lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (24) 7. (24) C-terminal amide hydration &lt;400&gt; 533 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 534 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt;MISC.FEATURE&lt;;223&gt; Chimeric i2AIB2K10-C8Cys24-40K &lt;22Q&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..( 2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt;&lt;220&gt; fatty acid deuterated &lt;220&gt;&lt;221&gt; RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 534 156004 - Sequence Listing.doc 235 - I. 201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 535 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Chimera 2 ADB2 K10-C14 Cys 24-40K &lt;220&gt;&lt;221>MISC-FEATURE&lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;22l&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt;;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 535 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 012 3 2222 V &lt;&lt;&lt; Column Order 6th 5329§£人

&lt;220〉 &lt;223&gt;synthetic peptide

&lt;221>MI SC-FEATURE &lt;223&gt; Chimera 2AIB2K10-C16Cys24, 40K &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES 156004. Sequence Listing.doc 236·201143790 &lt;222&gt; (10)..(10 &lt;223&gt; with 0:16 fatty acid deuteration &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 536 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu 1 5 10

Asp Glu 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 537 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;223&gt; Chimeric it2AIB2K10-C18Cys24-40K &lt;220&gt;&lt;221&gt; MISC^FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD^RHS &lt;222&gt; (10)..(10) &lt;223&gt; (:18 fatty acid deuteration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24), (24) &lt;223&gt; Cys-PEG &lt;400&gt; 537 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu 1 5 10

Asp Glu 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 538 &lt;2\\&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;223&gt;;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Chimera 2K10-C18Cys24-40K &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; Alanine 156004 - Sequence Listing.doc 237-201143790 &lt;220&gt ;

&lt;221&gt; MOD RES &lt;222&gt; (l〇T..(10) &lt;223&gt; is deuterated by 08 fatty acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 538

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 539 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Glycoside E16K20K10-C18 Cys 24-40K &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:18 fatty acid deuteration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..( twenty four)

&lt;223&gt; (^s-PEG &lt;400&gt; 539

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 540 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Glycol·^: E16K20K10-W-C18 &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;223&gt; C-terminal amidation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bound to a Tip residue comprising a C18 fatty acid 156004. Sequence Listing. doc 238-

201143790 &lt;400&gt; 540

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 541 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221 &gt; MISC FEATURE &lt;223&gt; Glycoside E16K20K10-C16Cys24-40K &lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10)

&lt;223&gt; covalently bonded to a Tip residue containing a C16 fatty acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;400&gt; 541

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 542 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Glycose &gt; E16K20K10-C16 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 0: terminal amination &lt;220&gt;

&lt;221&gt; MODJRES &lt;222&gt; (l〇T..(10) &lt;223&gt; covalently bonded to C16 fatty acid &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 -239- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 543 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; Glycorose^: E16K20K10-C16 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; covalently bound to Tip residue containing C16 fatty acid &lt;400&gt; 543 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 012 3 2 0-22 &lt; V &lt;&lt; 544 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220〉 &lt;221&gt;; MISC.FEATTJRE &lt;223&gt; Glycoside E16 K20 K10-C18 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;22&gt;&gt; MOD RES&lt;222&gt; (l〇T..(10) &lt;223&gt; Covalently bound to C18 fatty acid &lt;400&gt; 544 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 545 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC.FEATTJRE 156004. Sequence Listing. doc -240-201 143790 &lt;223&gt; Glycoside E16K20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0: terminal amidation &lt;400&gt; 545 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;;21&lt;21&lt;21 546 29 PRT artificial sequence &lt;220> &lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Glycoside E16 K20 K10-W-C16 Cys 24-40K &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to include C16 Tip residue of fatty acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt; 546 His Ser Gin Gly Tbr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 547 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Glucose j: E16K20K10-C18Cys24-40K &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;22l&gt; MOD.RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C18 fatty acid &lt;220&gt; 156004-sequence table.doc 241 - 201143790 &lt;223&gt; MOD RES &lt;222&gt; (24).. (twenty four)

&lt;223&gt; C^s-PEG &lt;400&gt; 547

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 548 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Glycoside E16K20K10-C18Cys24-40K &lt;220&gt;&lt;221&gt; MISC.FEATOE &lt;223&gt; 0: terminal amidation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to Tip residue containing C18 fatty acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24) ..(twenty four)

&lt;223&gt; Cys-PEG &lt;400&gt; 548

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 549 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Glycoside E16K20K10-C16 guanamine &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10).. (10) &lt;223&gt; covalently bonded to Glu residue containing C16 fatty acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; 24)..(24) 156004·Sequence List.doc -242·

201143790 &lt;223&gt; Cys-PEG &lt;400&gt; 549

His Ser Gin Gly Thr Phc Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 550 &lt;211&gt; 28 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; truncation of an amino acid chimera 2

&lt;400&gt; 550

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn 20 25 &lt;210&gt; 551 &lt;211&gt; 27 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; truncation of two amino acid chimeras 2 &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met 20 25 &lt;210&gt; 552 &lt;211&gt; 28 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Amino acid 1-28 E16 K20 C-terminal decylamine &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal amide 243 - 156004 - Sequence Listing.doc 201143790 &lt;400> 552

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn 20 25 &lt;210&gt; 553 &lt;211&gt; 27 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; M1SC_FEATURE &lt;223&gt; Amine base 1-27 E16K20C terminal decylamine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal toramine &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Lys Met 20 25 &lt;210&gt; 554 &lt;211&gt; 29 &lt;2i2&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;221&gt; mSCJEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt;-white leucine &lt;400&gt;

His Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Xaa Asn Thr 20 25 &lt;210&gt; 555 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt; -244-

156004-Sequence List.doc 201143790 &lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The side chain at bridge position 16 and the inner chain amine at the side position at position 20&lt;400&gt; 555 Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 556 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Chimera 2 with AIB at 16 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;221&gt; W)D RES &lt;222&gt; (16) ..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 556 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25

0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21 557 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal guanamine &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (167.. (16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 557 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 156004-Sequence List.doc •245 · 201143790 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 558 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MI SC FEATORE &lt;223&gt; C-terminal tortochemical &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;22l&gt; MI SC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to Trp residue containing &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 167..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210> 559 &lt;2Π&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; ΜI SC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to Tip residue containing C16 fatty acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 16)..(16) 156004·Sequence List.doc 246-

201143790 &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 559 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15 Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

ο Π 2 3 2^1213⁄4 &lt; V &lt; V

560 29 PRT human procedure 歹J &lt;220> &lt;223> synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 is &gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; Covalent bond To Tip residue containing C16 fatty acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16).. (16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; RES &lt;222&gt; ~ &lt;223&gt; (20)..(20) Amine Tomb Butyric Acid &lt;220&gt;&lt;22]&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt Cys-PEG &lt;400&gt; 560 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 561 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES 156004-sequence table.doc -247- 201143790 &lt;222&gt; (2)..(2 &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10) 7. (10) &lt;223&gt; Covalently bonded to Tip residue containing C16 fatty acid &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 561

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa ] 5 10 15

Arg Arg Ala Xaa Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 562 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Amine erythroisobutyrate &lt;400> 562

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Fhe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 563 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; (: terminal amination &lt;220&gt;

&lt;221&gt; MOD.RES -248-

156004-Sequence List.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (10)..(10) &lt;;223&gt;&lt;220&gt;&gt;221&gt; MOD^RES &lt;221> (16)·(16) &lt;223&gt; amine tomb isobutyric acid &lt;400&gt; 563 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 564 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE C-terminal amidation M0D_RES (2)., (2) Aminoisobutyric acid&gt;&gt;&gt;&gt; Q 1 2 3 2222 &lt;2&lt;2&lt;2&lt;2 M0D.RES (10). (10) C13 fat thiol via Ala-Ala spacer hydrogenation &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; MOD RES (16)..(16) Aminoisobutyric acid 564

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 565 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC.FEAnJRE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES 156004. Sequence Listing. doc • 249·201143790 &lt;222&gt; (2)..( 2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221>TO RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via Y-Ghi&quot;Y -Glu spacer radicalization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt;amine*isobutyric acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

&lt;210&gt; 566 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt;&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10) .. (10) &lt;223&gt; is converted to p-Ala-p-Ala spacer by 0:16 fat thiol &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16).. (16 ) &lt;223&gt; Aminoisobutyric acid

&lt;400&gt; 566

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 567 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt; 156004. Sequence Listing. doc-250-201143790 &lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt; 223 &gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D3ES &lt;222&gt; (10)..(10) &lt;223&gt; is deuterated by 6-aminocaproic acid spacer with (:16 fat sulfhydryl group) &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt;amine tomb isobutyric acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

&lt;210&gt; 568 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal guanamine &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10) .. (10) &lt;223&gt; is (&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; by (:16 fat sulfhydryl group via Leu-Leu spacer modification &lt;220&gt; Aminoisobutyric acid &lt;400&gt; 568

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 569 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amidation-251 - 156004-sequence table.doc 201143790 b &gt;&gt;&gt; b &gt;&gt;&gt; o 1 3 Q1Z3 2222 2222 2220Λ 2ΛΖ20Λ &lt; v &lt;V &lt;V &lt;v MOD^RES (2)7.(2) Amino-butyric acid M0D.RES(10)..(10) Deuterated via a Pro-Pro spacer with a C16 fatty thiol group &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;400&gt; M0D.RES (16).. (16) Aminoisobutyric acid 569

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 570 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; brewing with €14 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16).. (16 &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;400&gt; 570 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;2I0&gt; 571 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt; 156004-Sequence List.doc -252 - 201 143790 &lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt;M0D.RES&lt;222&gt; (10)..(10) &lt;223&gt; C4 fatty thiol group via y»G1u Glu spacers &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..( 24) &lt;223&gt; Polyethylene glycol 4匕&lt;400&gt; 571 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 0 12 3 2 2 οώ V &lt;&lt;v 572 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt;M0D_RES&lt;222&gt; (10)..(10) &lt;223&gt; is converted to &lt;220&gt;&lt;221&gt; MOD by y-G1u-y-G1u spacer with 0:14 fat sulfhydryl group RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 572 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 156004-Sequence List.doc •253 · 201143790 &lt;210&gt; 573 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEAT\JRE &lt;223&gt; C-terminal k-amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:14 fat sulfhydryl group via Ala-Ala spacer hydrogenation &lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..( 24) &lt;223&gt; PEGylation &lt;400&gt; 573

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 574 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;2D&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (101..(10) &lt;223&gt; is (&lt;220&gt;&lt;221&gt; M0CLRES &lt;222&gt; by (A14-fat thiol via Ala-Ala spacer) (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa -254· 156004· Sequence Listing.doc 201143790 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 575 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯16 fat thiol via Ala-Ala spacer condensed &lt;220&gt;&lt;221&gt; M0D - RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt; 575

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 576 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;;&lt;221&gt; MODJRES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat thiol via Y-GhifGlu spacer hydrogenation &lt;220&gt; 255 - 156004-sequence table.doc 201143790 &lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24 ) &lt;223&gt;PEGylation &lt;400&gt; 576

His Xaa Gin Gly Thr Phe llir Ser Asp Lys Ser Lys Tyr Leu Asp Xaa I 5 10 15

Arg Arg Ala Gin Asp Phe Vai Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 577 &lt;211&gt; 29 &lt;2I2&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0: terminal amidation &lt;220&gt;&lt;221&gt; mDJRES · &lt;222&gt; (10)..(10) &lt;223&gt; with 0:16 fat base匕&lt;400&gt; 577

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 578 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC „FEATURE &lt;223&gt; C-terminal amidation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; to (:16 fat sulfhydryl Deuteration via γ-GlutGlu spacer &lt;400&gt; 578

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 •256-

156004· Sequence Listing.doc 201143790 &lt;210&gt; 579 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;;223&gt; AA-016 sucrose decylamine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10 &lt;223&gt; by 016 fat thiol via Ala-Ala spacer hydrogenation &lt;400&gt; 579

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 580 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Chimerized 2, A1B2, LyslO, Cys24-PEG &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24)..(24) &lt;223&gt;PEGylation&lt;400&gt; 580

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 581 &lt;211&gt; 30 &lt;212&gt; PRT &lt;2]3&gt; Artificial Sequence -257· 156004 Sequence Listing.doc 201143790 &lt; 220> &lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; Peptide dS2E16K20K30-C14 Glue guanamine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt; 220> &lt;221&gt; MOD RES &lt;222&gt; (2):.(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30..(30 ) &lt;223&gt; Concentrates with C14 fat base &lt;400&gt; 581

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 1 5 10 15

Ar8 Arg Ala Lys Asp Phe Val Gn Trp Leu Met Asn Lys &lt;210&gt; 582 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;221&gt; MISC FEATURE &lt;223&gt; Peptide ί!5·ΐΚ10((:14)Ε16Κ2(Μ31ικ: guanamine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; c-terminal IK amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt;; C14 fat based hydrogenation &lt;400&gt; 582

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 583 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt; -258-

156004-Sequence List.doc 201143790 &lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;223&gt; Peptide (15'^: 161^0100-06 Glue decylamine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 0-terminal amidation &lt;220&gt;&lt;221&gt;; MOD.RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is d, Ser &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (30)..(30) &lt;223&gt; at 0:16 fat base 醯&gt;1匕&lt;400&gt; 583

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 584 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;

&lt;22l&gt; MISC FEATURE &lt;223&gt; Peptide 682〇0 (0:16洱16{:20-0111(: guanamine &lt;220&gt;&lt;221&gt; MISC.FEATLJRE &lt;223&gt; C-terminal amide &lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; condensed with C16 fat base &lt;400&gt; 584

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 585 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-259-156004 - Sequence Table. doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Peptide Embedding&gt;Body 2 - 冚 2 - 10 - 10 醯 &lt; 220 &gt;&lt;221&gt; MISC FEATURE &lt; 223 &gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES (10). (10) &lt;222&gt;&lt;223&gt; Brewing with C18 fat thiol group &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt; 585

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 586 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Peptide Embedding&gt; Body 2_人©2-反30-醯化&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal pain aromatization &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt; Purification with C18 fat base &lt;400&gt;

His Xaa Gin G.y Thr Phe Ser Asp Tyr Ser Lys Tyr Leu Asp Glu

Gin Ala Ala Lys Glu Phe Me Cys Trp Leu Met Asn Thr Lys 20 25 30 -260-

156004-Sequence List.doc 201143790 &lt;210&gt; 587 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortoise &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (1)..(1) &lt;223&gt; DMIA &lt;400&gt; 587 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 012 3 222 2 &lt;&lt;&lt;&lt; 588 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: 端化化化&lt;220&gt;&lt;221&gt;MOD_RES&lt;222&gt; (1)..(1) &lt;223&gt; DMA &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;400&gt; 588 Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 589 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Terminal amidation 156004 - Sequence Listing, doc • 261 201143790 &lt; 220〉

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 590 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; Cloud Over-Amination &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RHS &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt; 590

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 591 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is branamide analog &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. ( 27) &lt;223&gt; Xaa is orthanoic acid &lt;400&gt;

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 •262-

156004· Sequence Listing.doc 201143790 &lt;210&gt; 592 &lt;211&gt; 29 &lt;212&gt; PRT c213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is branamine analog &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 592

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Val

Arg Arg Ala Ala Asp Phe 20

Ala Trp Leu Met Asp Glu 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 593 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ortho-amino acid &lt;400&gt; 593 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 594 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MODJES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamido decyl-cysteine &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ortho-amino acid &lt;400&gt; 594 156004 - Sequence Listing. doc -263 - 201143790

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 595 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27) ..(27) &lt;223&gt; Xaa is orthanoic acid &lt;400&gt; 595

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 596 &lt;211&gt; 29 &lt;2I2&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is amine-mercaptodiaminopropionic acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; )..(27) &lt;223&gt; Xaa is orthanoic acid &lt;400&gt; 596

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15 ^rg Arg A!a Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 10&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;;21&lt;21&lt;220&gt;&lt;223&gt; 597 29

PRT artificial sequence synthetic peptide &lt;220&gt; 156004-sequence table.doc -264- 201143790 &lt;221&gt; MOD_RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is thioglycolic acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is orthanoic acid &lt;400&gt;

His Ser Xaa Gly Thr Phc Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 598 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xss is a sulfite sub-bowl (&lt;220> &lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is orthanoic acid &lt;400&gt; 598

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 599 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; acetamidine &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt;; Xaa is orthanoic acid &lt;400&gt; 599

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 -265 - 156004 - Sequence Listing.doc 201143790 &gt;&gt;&gt;&gt;&gt;&gt; 0123 03 11111i n rtyfc ΛΖ &lt;2&lt;2&lt;2&lt ;2&lt;2&lt;2 600 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (167..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 600

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Gh 20 25 &lt;210&gt; 601 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; )..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 601

His Ser Xaa Gly Thr Phe .Thr Sier Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 602 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is thioglycolic acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..( 16) &lt;223&gt; Xaa is amine tomb isobutyric acid &lt;400>602

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa -266· 156004· Sequence Listing.doc 201143790 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 603 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16). (16) &lt;223&gt; Xaa is aminoisobutyric acid

&lt;400&gt; 603

His Ser Xaa Gly Thr Phe Thr Scr Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 604 &lt;211&gt; 39 &lt;212&gt; FRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiamine butyl Acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt;

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 605 &lt;211&gt; 29 &lt;212&gt; PRT 267-156004. Sequence Listing.doc 201143790 &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222> (16)..(16) &lt;;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 605

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ser Asp Phe Val Ser Trp Leu Leu Asp Glu 20 25 0 12 3 &lt;21&lt;21&lt;21&lt;21

606 29

PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetaminodiaminobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt;

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Thr Asp Phe Val Thr Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 607 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Total #binding to C14 fat thiol-268 · 156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (36)..(20) &lt;223&gt; The indoleamine ring between the side chain of the acid group and the side chain of the amino acid at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210> 608 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1)

&lt;223&gt; DMIA &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C16 fat sulfhydryl &lt;220&gt;&lt;221&gt; M0D.RES &lt;;222&gt; (16)..(20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg At a Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 609 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; DMA &lt;220&gt; 269·156004-sequence table.doc 201143790 &lt;221&gt; MOD.RES &lt;222&gt; (10) .. (10) &lt;223&gt; covalently bonded to C18 fat sulfhydryl &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(20) &lt;223&gt; Amino acid at position 16 The indoleamine ring between the side chain and the amino acid side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 610 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (107..(10) &lt;223&gt; covalently bonded to C14 fat sulfhydryl &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16).. (16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 610

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 611 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortochemical &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid-270-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C16 fat sulfhydryl &lt;220&gt;&lt;221&gt; M0DJRES &lt;;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 611

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 612 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; 〇: terminal manganese amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C18 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (16)..(16) &lt;223&gt;amine 4 isobutyric acid &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 613 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC_FHATTJRE &lt;223&gt; C-terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; j (aa is d-Ser 271 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C14 fat sulfhydryl &lt;400&gt; 613 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser 1 5 10

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met 20 25

Lys Tyr Asn Thr

Lea Asp Glu 15 &lt;210&gt; 614 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; : terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; ^Caa is d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bound to C16 fat sulfhydryl &lt;400&gt; 614 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser 1 5 10

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met 20 25

Lys Tyr Asn Thr

Leu Asp Glu 15 &lt;210&gt; 615 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide

&lt;220&gt;&lt;221&gt;&lt;223&gt; MISC FEATURE C-terminal amidation

&gt;&gt;&gt;&gt;&gt;&gt;&gt; 0123 0123 2222 2222 2222 2222 &lt; V &lt;&lt;&lt;&lt; V &lt; V MOD RES (2): (2) Xaa is d-Ser MOD RES (10)..(10) Covalently binds to C18 fat thiol &lt;400&gt; 615 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser

Lys Tyr

Lea Asp Glu 156004 · Sequence Listing. doc 272- 201143790 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 616 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid

&lt;220&gt;&lt;221&gt; MODJES &lt;222&gt; (107..(10) &lt;223&gt; covalently bonded to C14 fat sulfhydryl &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16). (16) Aminoisobutyric acid &lt;400&gt; 616

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 617 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C14 fat sulfhydryl group via the Y_GlufGlu spacer&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; )..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 617 •273· 156004 Sequence Listing.doc 201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 618 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal tortochemical &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C14 fat sulfhydryl group &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; via Ala-Ala spacer 167..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 618 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 ^ &gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 619 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to C16 fat thiol via a dipeptide spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 619 156004-Sequence List.doc •274·201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 620 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;221&gt; MOD-RES &lt;222&gt; (10)., (10) &lt;223&gt; Covalently bound to C16 fat thiol via Ala-Ala spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16).. (16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 620

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 621 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C16 fat sulfhydryl &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (36)..( 16) &lt;223&gt; Aminoisobutyric acid 275 - 156004 - Sequence Listing.doc 201143790 &lt;400&gt; 621

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 622 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C16 fat sulfhydryl &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16). (16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 622

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 623 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;

&lt;221&gt; M1SC FEATURE &lt;223&gt; p_Ala-p_Ala-C16 lglycidylamine &lt;220&gt;&lt;221&gt; MISC_FEATORE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; MI SC FEAT\JRE &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via p-Ala+Ala spacer hydrogenation &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Ser 15 10 15 -276- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 624 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE

&lt;223&gt; Chimeric surplus-2 Aib2C24Mal40KPEG &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG via a PEG reaction of a peptide with a maleimide-activated PEG &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 624

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 625 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt; MISC.FEATURE

&lt;223&gt; Chimeric^-2Aib2E16K20 indoleamine C24Mal40KPEG &lt;m&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indoleamine ring between the amino acid hydrazone 1 hydrazine chain at position 16 and the amino acid side bond at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (241..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG via a PEG reaction of a peptide with a maleimide-activated PEG &lt;220&gt; 277-156004. Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 625

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 626 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC.FEA71JRE &lt;223&gt; Glycoside Aib2E16K20 indoleamine C24 guanamine Mal40KPEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between the amino acid side chain at position 16 and the amino acid side chain at position 20 Amidoxime ring &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG via a peptide and a cis-decene diimine-activated PEG reaction to &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) &lt;;223&gt; amide &lt;400&gt; 626

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 627 &lt;400&gt; 627 000 &lt;210&gt; 628 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE -278-

156004·SEQ ID NO.doc 201143790 &lt;223&gt; Glycoside DmialE16K20 indoleamine C24Mal40KPEG &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (1)..(1) &lt;223>Xaa is Dmia &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG via a PEG reaction of a peptide with a maleimide-activated PEG &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 628

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 629 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; sucrose ^DmialE16K20 valine C24Mal40KPEG &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24).. (24 )

&lt;223&gt; Covalently bonded to a 40 kDa PEG &lt;400&gt; 629 via a thioether produced by reacting a peptide with a maleimide-activated PEG reaction

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 . 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 630 -279- 156004 - Sequence Listing.doc 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Glycemic tone DmialE16K20 indoleamine C24 oxime ether 40KPEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (l)T.(l) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The position between the amino acid side chain at position 16 and the amino acid side chain at position 20 Indole ring &lt;220&gt;&lt;221> MOD-RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG via a peptide-functional thiol-activated PEG reaction to &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 630

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 631 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Chimera 2Aib2E3C24·thioether 40KPEG &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to the 40 kDa PEG via the PEG reaction of the dentate-activated PEG to &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 631 280- 156004 Sequence Listing.doc 201143790

His Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr 20 25

Xaa Ser Glu Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr 10

Leu Glu Glu 15 &lt;210&gt; 632 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Covalently bonded to 40 kDa PEG &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 632

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 633 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Glycoside Aib2Aibl6C24K10(iErE-C16) C24PEG40K guanamine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to C14 fat sulfhydryl group via γ-Glu^y-Glu spacer&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Covalently bonded to a 40 kDa PEG-281 - 156004-sequence table via a peptide-activated PEG reaction with a gingival group. doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29) &lt;223&gt; Alanine &lt;400&gt; 633 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;0123&lt;v&lt;v 634 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;升糖吾八》&gt;2义1?16100(八人七14)€24?£04(^76醯amine&lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; 2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C14 fat via Ala_Ala spacer醯 &&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (247..( 24) &lt;223&gt; Covalently bonded to the thioether produced by the reaction of the peptide with the functional thiol-activated PEG to 40 kDa PEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;; amide hydration &lt;400&gt; 634 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 635 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt; 156004· Sequence Listing, doc 282·201 143790 &lt;221&gt; MISC FEATURE &lt;223&gt; Glycoside Aib2Aibl6K10 (AA-C16) decylamine &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2). (2) &lt;223&gt; x^a is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222> (10)..(10) &lt;223&gt; Covalently bonded via Ala-Ala spacer to C16 fat sulfhydryl &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (167..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29) ..(29) &lt;223&gt; Alanine &lt;400&gt; 635 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 636 &lt;2Π&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt;&lt;223&gt; M1SC FEATURE sucrose ^TAib2Aibl6K10(rErE-a6) guanamine, 77r\7 0123 2222 ΛΖ222 V &lt;&lt;&lt;&lt; MOD.RES (2)..(2) 3( Aa is Aib &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD.RES (l〇&gt;.. (10) covalently bonded to C16 fat sulfhydryl group via the Y-GlufGlu spacer&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 636 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 156004. Sequence Listing. doc -283 - 201143790 &lt;210&gt; 637 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Syntheticpeptide&gt;&gt;&gt;&gt;&gt;&gt;&gt;&gt; 0123 0123 2222 2222 MOD RES (2)..(2) kaa is Aib MOD.RES (16)..(16) 3iaa is human ib &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (29).. (29) amide &lt;400&gt; 637

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 638 20 DNA artificial sequence &lt;220&gt;&lt;223&gt; Synthesis primer &lt;400&gt; 638 caaggtccag ggaggttgtg &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 639 24 DNA artificial sequence &lt;220> &lt;223&gt; synthetic primer &lt;400&gt; 639 ccaaaggtaa gctgtccata agga &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 640 22 DNA artificial sequence &lt;220&gt;&lt;223&gt; synthetic primer &lt;400&gt; 640 ctctcccaag agtcacatgt cc

&lt;210&gt; 641 &lt;211&gt; 22 &lt;212&gt; DNA 156004-sequence table.doc 284- 22 22201 143790 &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt; Synthesis primer &lt;400&gt; 641 caataactcg gtcccctaca ac 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21 642 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;400&gt; 642 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Ding rp Leu Met Asp Thr 20 25 &lt;210&gt; 643 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;;&lt;221&gt; MISC^FEATURE &lt;223&gt; Remote Amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat thiol via γ-Glu spacer &&lt;400&gt; 643 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 644 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES 156004-sequence table.doc 285 - 201143790 &lt;222&gt; (2)..(2 &lt;223&gt; Xaa is d_Ser &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; is 0:16 fat thiol via y-Glu-y-Glu Spacerization &lt;400&gt; 644

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 645 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; M0D_RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat thiol via γ-Glu spacer condensed &lt;400&gt; 645

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 646 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via y-Glu-Y-Glu spacer 286- 156004-sequence table.doc 201143790 &lt;lt ;400&gt; 646

His Xaa Gin Gly Thr Phc Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 647 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt;蕴端蕴化化&lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; kaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to 016 fat base &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 648 &lt;21l&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat thiol via y-Glu*y-Glu spacer hydrogenation &lt;400&gt; 648

His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 IS

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 • 287- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 649 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to 4006 fat thiol via γ-Glu spacer &lt;400&gt;

His Xaa Gin Gly Thr Phe lie Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 650 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;22t&gt; MiSC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by C16 fat thiol via y^Glu-Y-Glu spacer hydrogenation &lt;400&gt; 650

His Xaa Gin Gly Thr Phe lie Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 651 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-288- 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISCLFEATURE &lt;223&gt; 〇: terminal amination &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (1) 7. (1) &lt; 223 &gt; 3 (aa is Dmia &lt; 220 &lt; 221 &gt; MOD RES &lt; 222 &gt; (10) .. (10) &lt; 223 &gt; 〇: 16 fat sulfhydryl groups via γ-Glu spacers &lt;220&gt;&lt;221>MISCLFEATURE&lt;222&gt; (16)..(20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side bond at position 20 ;400&gt; 651

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 652 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1) 7. (1) &lt;223&gt;; kaa is Dmia &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to (:16 fat sulfhydryl via fGlu-y-Glu spacer &lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

&lt;210&gt; 653 &lt;21]&gt; 29 &lt;212&gt; PRT -289 - 156004 - Sequence Listing.doc 201143790 &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MISC_FEATURE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29)

&lt;223&gt; by (:1^fatty thiol via γ-Glu spacer hydrogenation &lt;400&gt; 653

Lys Tyr Leu Asp Glu 15 Asn Lys

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser 1 5 10

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met 20 25 &lt;210&gt; 654 &lt;211&gt; 29 &lt;212> PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MISC_FEATIJRE &lt;222&gt; (16)..(20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) &lt; 223 &gt; (: 16 fat sulfhydryl groups via γ-GlufGlu spacers &lt;400&gt; 654

Xaa Ser Gin Gly Thr Phe rrhr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 . 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Lys 20 25 -290- 156004 · Sequence Listing.doc 201143790 &lt;210&gt; 655 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Brewing with γ-GlufGlu spacers with C16 fat sulfhydryl groups &lt;220〉

&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 655

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 656 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; (: terminal amination &lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to γ-Glu spacer by 06 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16) ..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 656

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Ding rp Leu Met Asp Thr 291 · 156004 · Sequence Listing.doc 201143790 20 25 &lt;210&gt; 657 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) &lt;223&gt; C16 fat thiol via dipeptide spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 657

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 658 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal tortochemical &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (l〇T..(10) &lt;223&gt; via C14 fat thiol via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 16).. (16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;400&gt; 658 156004 - Sequence Listing.doc -292-

201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 659 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)., (2) &lt;223&gt; Aminoisobutyric acid

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; 匚14 fat thiol via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 659

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 660 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FHATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223:&gt;&lt;220&lt;220&gt;&lt;221&gt; MOD RES &lt;220&gt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;220&gt; -293-156004. Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24 &lt;223&gt; PEGylation &lt;400&gt; 660 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt; 012 3 n 2 2 2 V &lt;&lt;&lt; 661 29 PRT Artificial Sequence &lt;220〉 &lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;223&gt; 0: terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; 〇6 Fat thiol is digested via a dipeptide spacer &lt;400&gt; 661 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 662 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Peptide 382 £16 〇 0 ft 30-(: 14 6111 (: guanamine &lt; 220 &lt; 221 &gt; 221 &gt; MISC. FEATURE &lt; 223 &gt; C-terminal amide hydration &lt; 220 &gt;;&lt;221&gt; MOD.RES &lt;222> (2)..(2) &lt;223&gt; D-"Aminic acid, D. alanine, valine, amino-n-butyric acid, glycine, N -Methyl-silic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (30)..(30) &lt;223&gt;&lt; 014 fat-based hydrogenation &lt;400&gt; 662 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 156004-Sequence List.doc 294- 201143790

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 663 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Peptide 45*^: 10 (0:14疋161:20-0111(: guanamine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt;&lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, valine, amino-n-butyric acid, glycine,

N-mercaptosine acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:14 fat thiol based brewing &lt;400&gt; 663

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 664 &lt;21l&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; Peptide (13'^: 161^201^30-(:16 Glue decylamine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; terminal amidation &lt;;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, valine, amino-n-butyric acid, glycine, N-mercapto Serine, Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (30)..(30) &lt;223&gt; with (:16 fat thiol brewing &lt;400&gt; 664

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 -295 - 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 665 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Peptide "^31&lt;:10(〇16)£161&lt;:20石111(: guanamine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 is &gt; 〇 : terminal imidization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D_alanine, proline, amino-n-butyl Acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (101..(10) &lt;223&gt; Purification &lt;400&gt; 665

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 666 &lt;21]&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;22l&gt; MISC.FEATURE &lt;223&gt; 0 terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, proline, amino-n-butyric acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10). (10) &lt;223&gt; covalently bonded to C14 fat sulfhydryl &lt;400&gt; 666

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr -296· 156004 - Sequence Listing.doc 201143790 20 25 &lt;210&gt; 667 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D•serine, D·alanine, valine, amino-n-butyric acid, glycine, N_mercaptosine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt;; (10)..(10)

&lt;223&gt; covalently bonded to C16 fat sulfhydryl &lt;400&gt; 667

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 668 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; terminal amidization

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D_serine, D_alanine, valine, amino-n-butyric acid, glycine Acid, N-mercapto-silicic acid, aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to C18 fat sulfhydryl &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 669 &lt;21]&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence - 297 - 156004 · Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt; synthetic peptide

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Amino-based Acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bound to C14 fat thiol via hydrazine dipeptide spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Aminoisobutyric acid &lt;400&gt; 669 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

012 3 2 2 2 &lt;&lt;&lt;&lt; V 670 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; sucrose per serving 62^^16€ 24 幻0(圯也-(:16)€24?£0401[醯amine&lt;220&gt;&lt;221&gt;M0D.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C14 fat thiol via a dipeptide spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24T..(24) &lt;223&gt; via ▲ and dentate-activated PEG reaction The resulting thioether is covalently bound to 40 kDa PEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (291..(29) &lt;223&gt; amide hydration &lt;400&gt; 670 156004-sequence table.doc 298- 201143790

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 671 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Ligose ^: Aib2Aibl6K10(rErE-C16) guanamine &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib

&lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C16 fat thiol via a dipeptide spacer&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 671

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 672 &lt;2)1&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminic acid, D-alanine, valine, amino-n-butyric acid, glycine, N-thiol Amine acid, aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via acid amino acid spacer 299-156004. Sequence Listing. doc 201143790 &lt;400&gt ; 672

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 012 3 2 2 2 2 &lt;&lt; V &lt; 673 29

FRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;221&gt; MISC_FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2). (2) &lt;223&gt; D•serine, D-alanine, valine, aminobutyric acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯16 fat thiol via dipeptide spacer hydrogenation &lt;400&gt; 673

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Me Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 674 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC_FEATTJRE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via acid amino acid spacer &lt;400&gt; 674

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 156004-Sequence List.doc -300· 201143790 &lt;210&gt; 675 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D &lt; 221 &lt; 222 &gt; (10).. (10) &lt; 223 &gt; 〇 6 fat thiol via dipeptide spacer hydrogenation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu l 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 676 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATIJRE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; 3iaa is Aib &lt;220&gt;&lt;;221> MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by &lt;:16 fat thiol via dipeptide spacer &lt;400&gt; 676

His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15 20 &lt;210&gt; 677 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Met Asn Thr -301 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0-terminal amidation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by &lt;:16 fat sulfhydryl group via acid amino acid spacer &lt;400&gt;

His Xaa Gin Gly Thr Phe He Ser Asp Lys Ser Lys Tyr Leu Asp GIu l 5 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 678 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; C-terminal amination &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; oxidized via dipeptide spacers with &lt;400&gt;

His Xaa Gin Gly Thr Phe lie Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Me Ala Trp Leu Met Asn.Thr 20 25 &lt;210&gt; 679 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide &lt;220&gt;&lt;22&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; ^aa is Dmia -302 - 156004 - Sequence Listing.doc 201143790 &lt;220〉

&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯16 fat sulfhydryl group via acidic amino acid spacer hydrogenation &lt;220&gt;&lt;221&gt; M1SC FEATORE &lt;222&gt; (16).. (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 680 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;

&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;2 is &gt; terminal amidation &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (1) 7. (1) &lt;223>jiaa is Dmia &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via dipeptide spacer Baseline &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between the amino acid side chain at position 16 and the amino acid side chain at position 20 Indole ring &lt;400&gt; 680

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 681 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; C-terminal M amination &lt;220&gt;

&lt;221&gt; MOD.RES 156004-sequence table.doc -303 - 201143790 &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Dmia &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;;222&gt; (29)..(29) &lt;223&gt; by (:16 fat sulfhydryl group via acidic amino acid spacer hydrogenation &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu t 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Lys 20 25 &lt;210&gt; 682 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; terminal amination &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; j (aa is Dmia &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The indoleamine ring between the amino acid side chain at position 16 and the amino acid side chain at position 20 220> MOD RES &lt;222&gt; (29) .(29) &lt;223&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Lys 20 25 ^ &gt;&gt;&gt; 0 12 3 2 2 0-2 &lt;&lt;v&lt; 683 29

PRT artificial sequence &lt;220> synthetic peptide &lt;223&gt;&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; C-terminal amide 156004. Sequence Listing. doc - 304 - 201143790 &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat sulfhydryl group via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt;; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 683

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 684 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt;&lt;: Terminal amination &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯16 fat sulfhydryl group via acidic amino acid spacer hydrogenation &lt;220&gt;&lt;221&gt; M0D.RES &lt;;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 684

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 685 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES • 305 · 156004 - Sequence Listing.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; misc feature &lt;222&gt; (16) 7. (16) &lt;223&gt; Xaa may be any naturally occurring amino acid &lt;220&gt;&lt;221&gt; misc feature &lt;222&gt; (20) 7. (20) &lt;223&gt; Xaa Is any naturally occurring amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (291..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 685 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr 1 5 10

Gin Ala Ala Xaa Gly Phe lie Ala Trp Leu 20 25

Ser Met

Lys Asn

Tyr Leu Thr

Asp Xaa 15 012 3 ζΜ 2 2 VV &lt;&lt; 686 29 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; With (:16 fat based hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is AEB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29j..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 686 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys 1 5 10

Ala Ala Gin Asp Phe Va, Gin Trp Leu

Ser Met

Lys Asp

Tyr Leu Thr

Asp Xaa 15 &lt;210&gt; 687 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide 156004 - Sequence Listing. doc 306 - 201143790 &lt;220&gt;&lt;221&gt;; MODJRES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; The fatty thiol group is digested via a dipeptide spacer &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; M0D_RES &lt;;222&gt; (29)..(29) &lt;223&gt; Terminal amidation &lt;400&gt; 687 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 0123 2 ΛΖ 2 2 &lt; V &lt;&lt; 688 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..( 10) &lt;223&gt; with (:18 fat thiol via dipeptide spacer hydration &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is AEB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 688 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 689 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence 156004 - Sequence Listing.doc -307· 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; is digested with dipeptide spacer by &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 690 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt;&lt;220&gt;&lt;220&gt;;221&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;400&gt; 690

His Xaa Gin Gly Thr Phe lie Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg A.a Ala Gin Asp Phe Va. Gin Trp Leu Met Asp T,r &lt;210&gt; 691 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide 308·

156004· Sequence Listing.doc 201143790 &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;220> &lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; (: terminal amination &lt;400&gt; 691

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr 10

Leu Asp Glu 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25

&lt;210&gt; 692 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MODJRES &lt;222&gt; (2) 7. 2) &lt;223&gt; ^aa is ΑίΒ &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; with (;16 fat thiol via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amylation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Glu Xaa 15 10 15 20 &lt;210&gt; 693 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide

Arg A!a Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr -309- 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (10)..(10) &lt;223&gt; with (:16 fat sulfhydryl group via dipeptide spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt;&lt;223&gt;

(16)..(16) Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 693 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 694 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; (:16 fat thiol via dipeptide spacer hydration &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is ABB &lt;220&gt;&lt;;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 694 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Aa Ala Gin Asp Phe Val Gin Trp Leu Leu Asp ΤΙ, γ &gt;&gt;&gt;&gt; 012 3 2222 &lt;&lt; V &lt; 695 29 PRT Artificial Sequence &lt;220&gt; 156004 · Sequence Listing. doc • 310 - 201143790 &lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is ΑίΒ &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt (10)..(10) &lt;223&gt; with (:16 fat thiol via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; C-terminal amide &lt;400&gt; 695

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Leu Asp Thr

&lt;210&gt; 696 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2). .(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; is oxidized by γ-Glu spacer with 016 fat thiol &lt;220&gt;;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 696

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 697 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; jfaa is 311 311 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10 (10) &lt;223&gt; is converted to 22016 fat thiol via γ-Glu spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 698 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt; 222 &gt; (107.. (10) &lt; 223 &gt; 016 fat thiol via γ-Glu spacer hydrogenation &lt;220&gt;&lt;;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;; C-terminal amides &lt;400&gt; 698

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Lea Asp Thr 20 25 &lt;210&gt; 699 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES 312-

156004· Sequence Listing.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10) &lt;;223&gt; 醯 G fat thiol via γ-Glu spacer &&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (30)..(30) &lt;223&gt; PEGylation &lt;220&gt;; - &lt;221&gt; M0D-RES &lt;222&gt; (30)..(30) &lt;223&gt; 〇: terminal amidation &lt;400&gt; 699 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Gin Trp Leu Leu Asp Thr Cys 20 25 30

&gt;&gt;&gt;&gt; 0 12 3 &lt; V &lt; V 700 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10) .. (10) &lt;223&gt; with (;16 fat thiol via γ-Glu spacer chemistry &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 700 His Ala Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &gt;&gt; 012 3 1* 11 1— li 2 ΛΖ 2 2 &lt;v &lt;&lt; 701 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser 156004-sequence table.doc -313·201143790 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; is condensed by γ-Glu spacer with Cil6 fat thiol &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; 29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 701

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 702 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Purification by (:16 fat thiol via γ-Glu spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 702

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 703 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; (:16 fat sulfhydryl group via γ-Glu spacer group &lt;220&gt; -314-156004. Sequence Listing. doc 201 143790 &lt;221&gt; MOD^RES &lt;222&gt; (29).. (29 &lt;223&gt; 〇: terminal amidation &lt;400&gt; 703 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 704 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt;M0D_RES&lt;222&gt; (10)..(10) &lt;223&gt; 16 Fat sulfhydryl groups via γ-Glu spacers &lt;400&gt; 704 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 V &lt;v &lt; 705 31 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt;(&lt;220&gt;&lt;221&gt; MOD RES &lt;220&gt; (311..(31) &lt;223&gt; C-terminal amidation &lt;400&gt; 705 by (:16 fat sulfhydryl group via γ-Glu spacer) His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Gly Glu 20 25 30 156004 - Sequence Listing.doc -315· 201143790 &lt;210&gt; 706 &lt;2U&gt; 31 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD.RES &lt;;222&gt; (10)..(10) &lt;223&gt; is converted to γ-Glu spacer by C16 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt; 706

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Gly Gly 20 25 30 &lt;210&gt; 707 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10 &lt;223&gt; PEGylation with (:16 fat thiol via γ-Glu spacer chemistry &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt;&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 707

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 708 &lt;211&gt; 30 •316· 156004 Sequence Listing.doc 201143790 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; M0D „RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (30)..(30) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (30)..(30)

&lt;223&gt; C-terminal amide &lt;400&gt; 708

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Leu Asp Thr Cys 20 25 30 &lt;210&gt; 709 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to γ-Glu spacer by 06 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (241..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (30)..(30) &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 709

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Glu 20 25 30-317- 156004. Sequence Listing.doc 201143790 &lt;210&gt; 710 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence&lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) By (:16 fat thiol via γ-Glu spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24) ..(24) PEGylation &lt;400&gt; 710

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Cys 20 25 30 &lt;210&gt; 711 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)7.(1)

&lt;223&gt; Xaa is DMA &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via γ-Glu spacer 醢&gt;i匕&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 712 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt; •318·

156004-Sequence List.doc 201143790 &lt;223&gt;Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt;Deamino-His &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is converted to γ-Glu spacer by C16 fat thiol &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; )..(29) &lt;223&gt; terminal amidation &lt;400&gt; 712 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 713 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (1)..(1) &lt;223&gt; Ac-His &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; PEGylation by (:16 fat thiol via γ-Glu spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).*(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 713 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21 714 29 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide 156004 List .doc •319· 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is ABB &lt;220&gt;&lt;22]&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is characterized by (:16 fat thiol via γ-Glu spacer &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25 &lt;210&gt; 715 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RHS &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat-based hydrogenation &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 715

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu l 5 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25 &lt;210&gt; 716 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220〉

&lt;221&gt; M0D_RES 320 -

156004-Sequence List.doc 201143790 &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;;223&gt; 〇: terminal amination &lt;400&gt; 716

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe He Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 717 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; M0D_RES (29).. (29 ) C-terminal amides &lt;400&gt; 717

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25

&lt;210&gt; 718 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Cys Ding rp Leu Met Asn Thr 20 25 • 32 156004 · Sequence Listing. doc 201143790 &lt;210&gt; 719 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Manual Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 719

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp G!u 15 10 15 GIu Ala Val Arg Leu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 720 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221>MOD-RES&lt;222&gt; (2) 7. (2) &lt;223&gt; d-Ser &lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Terminal amylation &lt;400&gt; 720

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

20 &lt;210&gt; 721 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr -322· 156004 - Sequence Listing.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 721

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 722 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (10).. (10) &lt;223&gt; with (:16 fat sulfhydryl group via acid amino acid spacer &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt; (: terminal amination &lt;400&gt; 722

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25

&lt;210&gt; 723 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯 醯 fat thiol via γ-Glu spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 723

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25 .323. 156004. Sequence Listing.doc 201143790 &lt;210&gt; 724 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC.FEAIURE &lt;222&gt; (16).. (20) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (17)..(21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Terminal amidation &lt;400&gt; 724 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210> 725 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide b &gt;&gt;&gt; o 1 of 3 22 22&lt;v&lt;v

MOD RES (2)7.(2) Xaa is AIB &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;

MOD RES (16)..(16) Xaa is ABB MISC.FEATURE (16)..(20) Yanqiao MISC FEATURE (17)7.(21) Yanqiao 156004. Sequence Listing.doc -324- 201143790 &lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29)..(29) &lt;223&gt;; C-terminal amide &lt;400&gt; 725

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt;&gt;&gt; 012 3 Q 3 n 11 u 1 2 2 Λζ ΛΖ 2 2 2 &lt;VN/&lt;&lt;&lt; 726 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (2)7.(2) d-Ser ΜISC FEATURE (16)..(20) Yanqiao MISC_FEATURE (17)7.(21) Yanqiao MOD.RES (24''(24) PEGylated MOD.RES (29)..(29) C-terminal Alanine &lt;400&gt; 726

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 727 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) -325 - 156004 - Sequence Listing.doc 201143790 &lt;223&gt; d-Ser &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (161..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEAT\JRE &lt;222&gt; (16)..(20) &lt;223&gt;Salt Bridge&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (17)..(21) &lt;223&gt;Salt Bridge&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Polyhexamethylene &lt;220&gt;;22l&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;4〇〇&gt; 727

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr · 20 25 &lt;210&gt; 728 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; d-Ser &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt; 223 &gt; Salt Bridge &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (17)..(21) &lt;223&gt;Salt Bridge&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (29). (29) &lt;223&gt; C-terminal amide &lt;400&gt; 728

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Lys Arg Ala Lys Glu Phe Val GJn Ding rp Leu Met Asn Thr 20 25 -326- 156004 · Sequence Listing.doc 201143790 &lt;210&gt; 729 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Manual Sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; D-serine, D-alanine, valine, amine N-butyric acid, glycine acid, N-mercapto-silicic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D-RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Salt Bridge

&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (17)..(21) &lt;223&gt;Salt Bridge&lt;220&gt;&lt;221&gt; M0D-RES &lt;222&gt; (29).. (29) &lt;223&gt; C-terminal amidation &lt;400&gt; 729

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Lys Arg Ala Lys Glu Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 730 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D_serine, D_alanine, valine, amino-n-butyric acid, glycine, N- Thiolsic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; with 06 fat thiol via γ-Glu spacer 醯&lt;220&gt;&lt;221&gt; MISC FEAIURE &lt;222&gt; (15)..(20) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16 )

&lt;223&gt; Xaa is AIB 327-156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 730

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Lys Arg Ala Lys Glu Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 731 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;

MOD RES(1)..(1) Xaa is DMIA

MOD RES (16)..(16) Xaa is AIB MISC.FEATT/RH (16)..(20) Salt Bridge MISC.FEATURE (17)7.(21) Salt Bridge MOD RES (24)..(24 PEGylated MOD RES (29)..(29) C-terminal amide hydration &lt;400&gt; 731 Xaa Ser Gin Gly Thr Phe

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt; 012 3 2 2 VV &lt;&lt; 732 29 PRT Artificial Sequence &lt;220> 156004 - Sequence Listing.doc • 328. 201143790 &lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;222&gt; (17 ) (21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Lys Arg Ala Lys Glu Phe Val Gin Trp Leu Met Asn Thr

&lt;210&gt; 733 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2). (2) &lt;223&gt; D-serine, D_alanine, valine, aminobutyric acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via dipeptide spacer chemistry &lt;220&gt;

&lt;223&gt; MOD RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 734 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-329-156004 - Sequence Listing.doc 201143790 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is XlB &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) &lt;223&gt; is acidified with an acidic amino acid spacer at &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; 297..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 734

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 735 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; WC16 fat thiol is oxidized via acidic amino acid spacer &lt;220&gt;;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; 0-terminal amidation &lt;400&gt; 735

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 736 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide 330-

156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; M0D_RES (2): (2) Parent aa is ΑΪΒ MOD.RES(101..(10) via C16 fat thiol Acid Amino Acid Spacer Deuteration M0D-RES (24).. (24) PEGylated MOD RES (29).. (29) C-terminal amide hydration &lt;400&gt; 736 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21

737 30 PRT Human Process 歹 1J &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;M0D.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via acidic amino acid spacer thiolation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (307..(30) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD^RES &lt;222&gt; (30)..(30) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 737 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Gin Trp Leu Leu Asp Thr Cys 20 25 30 &lt;210&gt; 738 &lt;21)&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt; 156004-Sequence List.doc • 331 · 201143790 &lt;223&gt;Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1〇Τ..(10) &lt;223&gt; with (:16 fat thiol via acidic amino acid spacer Basicization &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD^RES &lt;222&gt; 29)..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 738 His Ala Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

ArS Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp &lt;2I0&gt; 739 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;;&lt;222&gt;&lt;223&gt; MOD RES(2)..(2) D-serine, D-alanine, guanidinium methylamine, amino-aminobutyric acid Acid, glycine &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat brewing base via acidic amino acid spacers &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; 0-terminal amidation &lt;400&gt; 739 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 740 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2) 156004-sequence, doc-332-201143790 &lt;223&gt; D_serine, D·alanine, valine , Amino-n-butyric acid, glycine, N-methylserine, Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via acid amino acid spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 740

His Xaa Gin Gly Thr Phe Thr Scr Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Leu Asp Thr 20 25

&lt;210&gt; 741 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-serine, D_alanine, valine, aminobutyric acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; 醯16 fat thiol via acidic amino acid spacer thiolation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (291..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 741

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr

10

Leu Asp Glu 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 742 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2) 7. (2) &lt;223&gt; D-serine, D-alanine, valine, amino-n-butyric acid, glycine, N_ Thiolsic acid, aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) -333 - 156004 - Sequence Listing.doc 201143790 &lt;223&gt;Chemical amino acid spacers with &lt;400&gt; 742

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 743 &lt;211&gt; 31 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D·alanine, valine, amino-n-butyric acid, glycine, N-methyl Serine, Aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; 〇: 16 fat thiol via acidic amino acid spacer Purification &lt;220&gt;&lt;221&gt; MOD RHS &lt;222> (31)..(31) &lt;223&gt; C-terminal amidation &lt;400&gt; 743

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Gly Glu 20 25 30 &lt;210&gt; 744 &lt;211&gt; 31 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;223&gt;;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D_alanine, valine, amino-n-butyric acid, glycine , N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with 016 fat thiol via acidic amino acid Spacerization &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu •334·

156004-sequence table.doc 201143790 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Gly Gly 20 25 30 &lt;210&gt; 745 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D•serine, D-alanine, valine, amino-n-butyric acid, glycine, N-mercaptosine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10)

&lt;223&gt; 醯16 fat thiol via acidic amino acid spacer hydration &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 745

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 746 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D „RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D_alanine, valine, amino-n-butyric acid, glycine, N_ Thiolsic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat sulfhydryl group via acidic amino acid spacer Basicization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (30 )..(30) 335 - 156004-sequence table.doc 201143790 &lt;223&gt; terminal amination &lt;400&gt; 746

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Ala Ala Gin Asp Phe Val Gin Trp Leu Leu Asp Thr Cys 20 25 30 &lt;210&gt; 747 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D•serine, D-alanine, valine, aminobutyric acid, glycine, N _Methyl-silic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via acidic amino acid Spacerization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; )..(30) &lt;223&gt; C-terminal amidation &lt;400&gt; 747

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Glu 20 25 30 &lt;210&gt; 748 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminic acid, D-alanine, proline, amino-n-butyric acid, glycine, N-methyl Serine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (10)..(10) &lt;223&gt; 匚16 fat thiol via acidic amino acid spacer 醯&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) -336·

156004-sequence table.doc 201143790 &lt;223&gt; PEGylation &lt;400&gt; 748

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr Cys 20 25 30 &lt;210&gt; 749 &lt;2U&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (1)..(1)

&lt;223&gt; Xaa is DMIA &lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10) &lt;223&gt; oxidized by acidic amino acid spacer at 016 fat thiol &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; (: terminal amination &lt;400&gt; 749

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 750 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2Π&gt;

&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt;Deamino-His &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;220&gt;&lt;221> MOD RES &lt;222&gt; by (:16 fat sulfhydryl group via acidic amino acid spacer) 29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 750

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 1 5 10 15 -337 - 156004 · Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Leu Asp Thr 20 25

&gt;&gt;&gt;&gt; 012 3 2 2 2 &lt;&lt; VV 751 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (1) ..(1) &lt;223&gt; Ac-His &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via acidic amino acid spacer Basicization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; )..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 751 His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr 1 5 10

Gin Ala Ala Lys Glu Phe He Cys Trp Leu Leu Asp Thr 20 25 &lt;210&gt; 752 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt; 0:16 Fatty sulfhydryl group is converted via acidic amino acid spacer &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29).. (29) &lt;223&gt; C-terminal amide hydration &lt;400&gt; His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr 1 5 10 31u Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25 156004 · Sequence Listing. doc .338 · 201143790 &lt;210&gt; 753 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D• Serine, D-alanine, valine, aminobutyric acid, glycine, N-mercapto-silicic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD R ES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide amination

&lt;400&gt; 753

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 754 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence Synthetic Peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, valine, amino-n-butyric acid, glycine, N· Thiolsic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; 0 terminal amidation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Glu Trp Leu Met Asn Thr 20 25 &lt;210&gt; 755 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide-339- 156004 · Sequence Listing.doc 201143790 &lt;220〉

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D·alanine, valine, amino-n-butyric acid, glycine, N· Methyl serine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (297..(29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe lie Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 756 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;220&gt;&lt;221&gt; MOD-RES &lt; 221 &lt;221&gt;;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 756

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Glu Ala Val Arg Leu Phe He Glu Trp Leu Met Asn Thr 20 25 &lt;210&gt; 757 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminic acid, D. alanine, valine, aminobutyric acid, glycine, N-mercaptosine Acid, Aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (17)..(21) &lt;223&gt; Salt Bridge 340-

.156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amide &lt;400&gt; 757

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr 10

Leu Asp Glu 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 758 &lt;211&gt; 29 &lt;212&gt; PRT · &lt;213&gt;

&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D·serine, D_alanine, valine Amino-n-butyric acid, glycine acid, N-mercapto-silicic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16)

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 17).. (21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24).. (24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D-RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Lys Arg Ala Lys Glu Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 759 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence -341 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2).. (2) &lt;223&gt; D-serine, D-alanine, valine, amine N-butyric acid, glycine acid, N-mercapto-silicic acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; salt bridge &lt;;220&gt;&lt;221&gt; M[SC FEATURE &lt;222&gt; (17)..(21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29 ) &lt;223&gt; 〇: terminal amination &lt;400&gt; 759

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Lys Are Ala Lys Glu Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 760 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, valine, amino-n-butyric acid, glycine, N-A Baseline acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10..(10) &lt;223&gt; 匚16 fat thiol via acidic amino acid spacer 醯&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (15)..(20) &lt;223&gt;Salt Bridge&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16 )

&lt;223&gt; Xaa is AIB &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (21) &lt;223&gt; Salt Bridge &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; 29)..(29) &lt;223&gt; (: terminal amidation 342-156004-sequence table.doc 201143790 &lt;400&gt; 760

His Ser Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Lys Arg Ala Lys Glu Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 761 &lt;400&gt; 761 000 &lt;210&gt; 762 &lt;400&gt; 762 000 &lt;210&gt; 763 &lt;400&gt;

&lt;210&gt; 764 &lt;400&gt; 764 000 &lt;210&gt; 765 &lt;400&gt; 765 000 &lt;210&gt; 766 &lt;400&gt; 766 000 &lt;210&gt; 767 &lt;400&gt; 767 000 &lt;210&gt; 768 &lt;;400&gt; 768 000 &lt;210&gt; 769 &lt;400&gt; 769 000 &lt;210&gt; 770 &lt;400&gt; 770 000 &lt;210&gt; 771 &lt;400&gt; 771 000 &lt;210&gt; 772 &lt;400&gt; 772 000 &lt;;210&gt; 773 &lt;400&gt; 773 000 -343 · 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 774 &lt;4〇〇&gt; 774 000 &lt;210&gt; 775 &lt;400&gt; 775 000 &lt;210&gt;&lt;400&gt; 776 000 &lt;210&gt; 777 &lt;400&gt; 777 000 &lt;210&gt; 778 &lt;40〇&gt; 778 000 &lt;210&gt; 779 &lt;400&gt; 779 000 &lt;210&gt; 780 &lt;400&gt; 780 000 &lt;210&gt; 781 &lt;400&gt; 781 000 &lt;210&gt; 782 &lt;400&gt; 782 000 &lt;210&gt; 783 &lt;400&gt; 783 000 &lt;210&gt; 784 &lt;400&gt; 784 000 &lt;210&gt; 785 &lt;400&gt; 785 000 &lt;210&gt; 786 &lt;400&gt; 786 000 &lt;210> 787 &lt;400&gt; 787 000 &lt;210&gt; 788 &lt;400&gt; 788 000 • 344 156004 · Sequence Listing.doc 201143790 &lt ;210&gt; 789 &lt;400&gt; 789 000 &lt;210&gt; 790 &lt;400&gt; 790 000 &lt;210&gt; 791 &lt;400&gt; 791 000 &lt;210&gt; 792 &lt;400&gt; 792 000 &lt;210&gt; 793 &lt;400&gt;&lt;210&gt; 794

&lt;400&gt; 794 000 &lt;210&gt; 795 &lt;400&gt; 795 000 &lt;210&gt; 796 &lt;400&gt; 796 000 &lt;210&gt; 797 &lt;400> 797 000 &lt;210&gt; 798 &lt;400&gt; 798 000 &lt;210&gt; 799 &lt;400&gt; 799 000 &lt;210&gt; 800 &lt;400&gt; 800 000 &lt;210&gt; 801 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Homo sapiens &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 156004-Sequence Listing.doc 345

s &lt;210&gt (16)..(16) &lt;223&gt; Xaa is Ser, Cys, Om, homocysteine or acetylalanine &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27).. (27) &lt;223&gt; Xaa is Met, Leu or Nle &lt;400&gt; 802

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 803 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (17T..(17) &lt;223&gt; Xaa is Arg, Cys, Om, homocysteine or acetylalanine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; kaa is Klet, Leu or Nle &lt;400&gt; 803

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Xaa Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 804 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (21)..(21) &lt;223&gt; Xaa is Asp, Cys, Om, homocysteine or acetylalanine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) •346- 156004·sequence table.doc 201143790 &lt;223&gt; Xaa is Met, Leu or Nle &lt;400&gt; 804

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Xaa Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 805 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; xaa is (3111, (^3, 〇111, homocysteine or acetyl phenylalanine)

&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is I^Iet, Leu or Nle &lt;400&gt; 805

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Xaa Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 806 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (21)..(21) &lt;223&gt; Xaa is Asp, Cys, Om, homocysteine or acetylated amphetamine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa is 〇111, (^5, 〇01, homocysteine or acetylalanine &lt;220&gt;&lt;221&gt; MOD .RES &lt;222&gt; (27)..(27) &lt;223&gt; j{aa is Ivlet, Leu or Nle &lt;400&gt; 806

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Xaa Phe Val Xaa Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 807 156004 · Sequence Listing.doc •347-

i;: itliV 201143790 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Glycoside analogue &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; 27)..(27) &lt;223&gt; Xaa is ^let, Leu or Nle &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (28)..(28) &lt;223&gt; Xaa is dead ys, Arg, His, Asp, Glu, resveratrol or high sulfoalanine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Xaai^Thr, Lys, Aig, His, Asp, Glu, sulfoalanine or high sulfoalanine &lt;400&gt; 807

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Xaa Xaa 20 25 &lt;210&gt; 808 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Glycoside analogue &lt;223&gt;;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt; kaa is li/Iet, Leu or Nle &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 28).. (28) &lt;223&gt; Xaa is Asp or Glu &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Xaa is Thr, Asp or Glu &lt;;400&gt; 808

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Xaa Xaa 20 25 &lt;210&gt; 809 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glycoglycan Analog - 348 -

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Met, Leu or Nle &lt;220&gt;&lt;221&gt; MOD. RES &lt;222&gt; (29)..(29) &lt;2M&gt; 3 (aa is Asp or Glu &lt;400&gt; 809

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asn Xaa 20 25 012 3 &lt;21&lt;21&lt;21&lt;21 810 29

PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; iCaa is Iviet, Leu or Nle &lt;400&gt; 810

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 811 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;400&gt; 811

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp·Thr 20 25 &lt;210&gt; 812 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glucagon Analog &lt;220&gt;

&lt;221&gt; MOD RES 349- 156004. Sequence Listing.doc 201143790 &lt;222&gt; (29)..(29) &lt;223&gt; kaa is Lys, Arg or His &lt;400&gt; 812 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Xaa 20 25 &lt;210&gt; 813 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Glycoside analogue &lt;223&gt;;400&gt; 813 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Glu Ser 15 10 15 Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &gt;&gt;&gt;&gt; 012 3 2 2&lt ; &lt;vv 814 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ]^过, 1^11 or &gt;^ &lt;400&gt; 814 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Cys I 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 815 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (17)..(17) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD.RES 156004-sequence table.doc -350 - 201143790 &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ^let, Leu or Nle &lt;400&gt; 815

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 816 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (21)..(21) &lt;223&gt; PEGylation

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27j..(27) &lt;223&gt; 3 (aa is iClet, Leu or Nle &lt;400&gt; 816

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15

Arg Arg Ala Gin Cys Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 817 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Met, Leu or Nle &lt;400&gt; 817

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 818 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence -351 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt; Glycosin analogue &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (21)..(21) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (27)..(27) &lt;;223&gt; Xaa is I^let, Leu or Nle &lt;400&gt; 818

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Lys Phe Val Gin Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 819 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. (27 ) &lt;223&gt; kaa is, Leu or Nle &lt;400&gt; 819

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Arg Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Lys Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 820 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; A peptide fragment representing 10 amino acids of the carboxy terminal of the intestinal vasopressin analog _4 &lt;400&gt;

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 &lt;210&gt; 821 &lt;211&gt; 8 352 - 156004 - Sequence Listing.doc 201143790 &lt;212&gt; PRT &lt;213&gt; Manual Sequence &lt;220&gt;&lt;223&gt;; synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; represents a peptide fragment of 8 amino acids at the carboxy terminus of nascent acid &lt;400&gt;

Lys Arg Asn Arg Asn Asn He Ala &lt;210&gt; 822 &lt;2il&gt; 4 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;

&lt;221&gt; MISC-FEATURE &lt;223&gt; A peptide fragment representing an amino group of 4 amino acids of the carboxy terminal of phytic acid SEQ ID NO: 21 &lt;400&gt; 822 Lys Arg Asn Arg &lt;210&gt; 823 &lt;;211&gt; 10 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; represents a peptide fragment of 10 amino acids at the carboxy terminus of insulinotropic analog-4

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt;mysylated &lt;400&gt; 823

Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 &lt;210&gt; 824 &lt;211&gt; 39 &lt;212&gt; PRT &lt;2Π&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;400&gt;; 824

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15 -353 - 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 825 &lt;211&gt; 37 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;glycoside analogue &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr Lys Arg Asn 20 25 30

Arg Asn Asn lie Ala 35 &lt;210&gt; 826 &lt;211&gt; 33 &lt;212&gt; PRT &lt;2丨3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Glycoside analogue &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr Lys Arg Asn 20 25 30

Arg &lt;210&gt; 827 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; artificial sequence &lt;220&gt;&lt;223&gt;glycoside analogue &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Cys Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 828 &lt;211&gt; 39 &lt;2ί2&gt; PRT &lt;213&gt; Artificial Sequence -354 - 156004 Sequence Listing, doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;400&gt; 828

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 829 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;glycoside analogue &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (24T (24) &lt;223&gt; 2-butyrolactone bonded via thiol group &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 830 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Several thiol groups bound by i Cys thiol group &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 831 &lt;211&gt; 39 &lt;212&gt; PRT &lt;2Π&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;;400&gt; 831 355 - 156004 - Sequence Listing.doc 201143790

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 832 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Glycosin Analog &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (30)..(30) &lt;223&gt; kaa is into sp, Glu, Lys, Arg or His &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg AlaGln Asp Phe Va, G, n Trp Leu Met Asp Thr Xaa &lt;210&gt; 833 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;&lt;220>&lt;221&gt; M0D.RES &lt;222&gt; (15)..(15) &lt;223&gt; Xaa is Asp, Glu, sulfoalanine, glutamic acid or high sulfoalanine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Met, Leu or Nle &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (281..(28) &lt;223&gt; Xaa is into sn, Lys, Arg, His, Asp, or Glu &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 29)..(29) &lt;223&gt; Xaa'Thr, Lys, Arg, His, Asp or Glu &lt;400&gt; 833

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Xaa Xaa 20 25 •356-

156004-Sequence List.doc 201143790 &lt;210&gt; 834 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Glycoside Analog &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (15)..(15) &lt;223&gt; Xaa is Asp, Glu, resveryl alanine, homoglycosyl or homo-acrylic acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ivlet, Leu or Nle &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (28)..(28) &lt;223&gt; Xaa is Asn Or acidic amino acid &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; Xaa is Thr or acidic amino acid &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Xaa Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Xaa Xaa Xaa 20 25 &lt;210&gt; 835 &lt;211&gt; 39 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;400&gt; 835

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Glu Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 836 &lt;211&gt; 37 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;glycoside analogue &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15 357- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Glu Thr Lys Arg Asn 20 25 30

Arg Asn Asn He Ala 35 &lt;210&gt; 837 &lt;211&gt; 33 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;glycoside analogue &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Glu Thr Lys Arg Asn 20 25 30

Arg &lt;210&gt; 838 &lt;211&gt; 29 &lt;212&gt; PR Ding &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Glycoside analogue &lt;400&gt; 838

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 】 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Glu Thr 20 25 &lt;210&gt; 839 &lt;211&gt; 27 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is any amino acid &lt;220&gt;&lt;221&gt; MOD RES (0\ (〇) &lt;223&gt; Xaai Any amino acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222> (27)..(27)

&lt;223&gt; Met contains Z &lt;400&gt; 839

Xaa Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser •358· 156004 - Sequence Listing.doc 201143790 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met 20 25 &lt;210&gt; 840 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;221&gt; MOD.RES &lt;222&gt; (1)..(1) &lt;223&gt; xaa is o^cc•dimercaptoimidazoleacetic acid (DMA) &lt;220&gt;&lt;223&gt; MISC FEATURE &lt;222&gt; 16)..(20)

&lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;400&gt; 840

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 841 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; 乂 is %~dimercaptoimidyacetic acid (DMIA) &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Mutation of glutamic acid to alanine &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; PEGylation &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 359- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Lys Asp Phe Val Ala Trp Leu Met Asn Cys 20 25

^ &gt;&gt;&gt; 0123 1L n I n 842 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is ο^α•dimethylimidazole Acetic acid (DMIA) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; PEGylation &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle or Leu &lt;400&gt; 842

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp GIu 15 10 15

Arg Arg Ala Lys Asp Phe Val Cys Trp Leu Xaa Asn Thr 20 25 &lt;210&gt; 843 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; is suppressed to seven hearts dimethyl misoacetic acid (DMA) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;;223&gt; mutation of glutamic acid to alanine &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (27)..(27) &lt;22 3&gt; i (aa is l^le or Leu &lt;;220&gt;

&lt;221&gt; M0D.RES • 360. 156004· Sequence Listing.doc 201143790 &lt;222&gt; (29)..(29) &lt;223&gt; PEGylation &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Ala Trp Leu Xaa Asn Cys 20 25 &lt;210&gt; 844 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE

&lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. (27) &lt;223&gt; Xaa having further la 20, Ala 24, Nle 27 and Asp 28 For Nle &lt;4〇〇&gt; 844

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser ] 5 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Xaa Asp Thr 20 25 &lt;210&gt; 845 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC_FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; W)D RES &lt;m&gt; (27) having Ala 20, Ala 24, Nle 27, Asp 28 and Glu 29 (27). .(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 845

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 846 &lt;211&gt; 30 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence&lt;220&gt; 156004-Sequence List.doc -361 - 201143790 &lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27).. (with Ala 20, Ala 24, Nle 27, Asp 28, and Glu 30) 27) &lt;223&gt; Xaa is Nle &lt;400&gt; 846

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Ala Trp Leu Xaa Asp Glu &lt;210&gt; 847 &lt;211&gt; 29 &lt

&lt;221&gt; MISC FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27) with Ala 20, Ala 24, Nle 27, Glu 28 and Glu 29 (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 847

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 1 5 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Xaa Glu Glu 20 25 012 3 2 ΛΖ 2 &lt;vv &lt;

84S 30

PRT artificial sequence synthetic peptide

&lt;220&gt;&lt;223〉&lt;220〉

&lt;221&gt; MISC FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27) having human la 20, Ala 24, Nle 27, Glu 28 and Glu 30. (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 848

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Xaa Glu Thr Glu 156004. Sequence Listing. doc -362- 25 201143790 &lt;210&gt; 849 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (27).. (27) &lt;223&gt; SEQ ID NO: 1 &lt;400&gt; 849 having Xla 20, Ala 24, Nle 27, Glu 29 and Glu 30

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Xaa Asn GIu Glu 20 25 30 &lt;210&gt; 850 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220> &lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES having Ala 20, Glu 21, Ala 24, Nle 27 and Asp 28 (27)..(27) Xaa is Nle &lt;400&gt; 850

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Thr 20 25 012 3 11 li 11 li 2 2 2 &lt; V &lt;&lt; Column 1 T 8529 booker &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt; having Ala 20, Glu 21, Ala 24, Nle 27, Asp 28 and Glu 29

&lt;221&gt; MOD RES 363-156004-sequence table.doc 201143790 &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 852 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC_FEATTJRE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (271..) having Ala 20, Glu 21, Ala 24, Nle 27, Asp 28, and Glu 30 (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 852

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 853 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; SEQ ID NO: ! &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27) having Ala 20, Glu 21, Ala 24, Nle 27, Glu 28, and Glu 29 ..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 853

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Glu Glu 20 25 &lt;210&gt; 854 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence • 364 - 156004 · Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; SEQEDNO: 1 &lt;400&gt; 854 having Ala 20, Glu 2 Bu Ala 24, Nle 27, Glu 28, and Glu 30

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 855 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; SEQDDNO: 1 &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (27) having Ala 20, Glu 21, Ala 24, Nle 27, Glu 29, and Glu 30 ..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 855

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asn Glu Glu 20 25 30

&lt;210&gt; 856 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; SEQ ID NO: 1 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; having 16, Ala 20, Glu 2 Bu Ala 24, Nle 27, Asp 28 and Glu 29 ; (27)..(27) &lt;223&gt; Xaa^Nle &lt;400&gt; 856

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 - 365 - 156004 · Sequence Listing.doc 201143790 7 T people 7 8531 is wisdom 85 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;400&gt;

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin AJa Ala Lys Glu Phe He Ala Trp Leu Val Lys Gly Arg Gly 20 25 30 &gt;&gt;&gt;&gt; 012 3 2 2 2 &lt; V &lt;&lt; 8 T 人 50R ΟΪ 83P智&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) Alanine &lt;400&gt; 858

His Ala Glu Gly Thr Phe TTir Ser Asp Val Ser Ser Tyr Leu Glu Gly 15 10 15

Gin 20 25 30 &lt;210&gt; 859 &lt;211&gt;&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is branamine analog &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 859

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 860 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide•366· 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is branamine analog &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 860

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp GIu 20 25 &lt;210&gt; 861 &lt;21]&gt; 29 &lt;212&gt; PRT &lt;213&gt;

&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;Add &gt; Xaa is Nle &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 862 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamido-mercapto-cysteine &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; 27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 862

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 863 &lt;211&gt; 29 156004-sequence table.doc -367- 201143790 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is heart &lt;400> 863

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg A,a Ala Glu Phe Va, A,a Trp Leu Xaa Asp G!u &lt;210&gt; 864 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is amine-mercaptodiaminopropionic acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 864

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 865 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is decyl branide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (27).. (27) &lt;223&gt; Xaa is Nle 368 -

156004-sequence table.doc 201143790 &lt;400&gt; 865

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu λβρ Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 866 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is hydrazine sulfoxide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 866

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 867 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;22]&gt; MOD-RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetaminophen&lt;220&gt;&lt;221> MOD RES &lt;222&gt; (27). .(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 867

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thi 1 5 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 868 &lt;21]&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide 156004- Sequence Listing.doc -369- 201143790 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (161..(16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 868

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 869 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16). (16) &lt;223&gt; Xaa is aminoisobutyric acid &lt;400&gt; 869

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 870 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is methyl glutamic acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16).. (16) &lt;223&gt; Xaa is Aib &lt;400&gt; 870

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 -370- 156004 · Sequence Listing.doc 201143790 &lt;210&gt; 871 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa' is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 871

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 872 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (16).. (16) &lt;223&gt; amine tomb isobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (39)..(39) &lt;223&gt; amides &lt;400&gt;

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 873 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide 371 - 156004 · Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 16)..(16) &lt;223&gt; Xaa is amine tomb isobutyric acid &lt;400&gt; 873

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ser Asp Phe Val Ser Trp Leu Leu Asp GIu 20 25 &lt;210&gt; 874 &lt;21l&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16) ..(16) &lt;223&gt; Xaa is amine tomb isobutyric acid &lt;400&gt; 874

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Thr Asp Phe Val Thr Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 875 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;400&gt; 875

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Glu 20 25 &lt;210&gt; 876 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide•372· 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 876

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Glu 20 25 &lt;210&gt; 877 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; misc^feature &lt;222&gt; (3)..(3) &lt;223&gt; Xaa can be any naturally occurring amino acid &lt;400&gt;

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 878 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;400&gt; S78

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 879 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; jCaa is d-Ser &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (30)..(30) 373 · 156004-sequence table.doc 201143790 &lt;223&gt; with (:14 fat-based hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt;&lt;400&gt; 879

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 880 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOOES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:14 fat base conversion &lt;220&gt;&lt;221&gt; MOD.RHS &lt;222&gt; (29)..(29) &lt;223&gt; amide &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 881 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is d-Ser &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (30)..(30) &lt;;223&gt; with (:16 fat base hydrogenation &lt;220&gt;&lt;22l&gt; M0D_RES &lt;222&gt; (30)..(30) &lt;223&gt; alanine 374. 156004-sequence table.doc 201143790 &lt;400&gt; 881

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 882 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt; 220>

&lt;221&gt; MOD RES &lt;222&gt; (2),. (2) &lt;223&gt; 3 (aa is d-Ser &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat thiol based &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (29). (29) &lt;223&gt; Alanine &lt;400&gt; 882

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 883 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD^RES &lt;222&gt; (2), (2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;18 fat base based &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (24).. (twenty four)

&lt;223&gt; C^s-PEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amylation &lt;400&gt; 883

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu -375 - 156004 · Sequence Listing.doc 201143790 5 10 15

Gin Ala Ala Lys Glu Phe Ie Cys Trp Leu Met Asn &lt;210&gt; 884 &lt;211&gt; 30 &lt;212&gt; FRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Aminoisobutyric acid &lt;220&gt;&lt;221>MODJRES&lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (30)..(30) &lt;223&gt; Based on 〇8 fat 醯 &&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt; amide &lt;400&gt; 884

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 885 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Ser or 双^disubstituted amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20).. (20) &lt;223&gt; Xaa is Gin or substituted amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (21)..(21) &lt;223&gt; Xaa is Asp Or 双^disubstituted amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa is Gin or hydrazine disubstituted amino acid 376-156004 · Sequence Listing.doc 201143790 &lt;400&gt; 885 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Xaa Phe Val Xaa Trp Leu Met Asn Thr 20 25 &lt;210&gt; 886 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;22i&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; 3Caa is AiG &lt;400&gt; 886 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thi 20 25 &lt;210&gt; 887 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt;- MOD.RES &lt;222&gt; (19)..(19) &lt;223&gt; Xaa is Aib &lt;400&gt; 887 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Xaa Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21 888 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;;&lt;221&gt;MOD.RES&lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;400&gt; 888 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 156004- List .doc -377 · 201143790 1 5 Arg Arg Ala Xaa Asp Phe 20 10 15

Val Gin Trp Leu Met Asn Thr 25

&gt;&gt;&gt;&gt; 0 12 3 &lt; V &lt; V 889 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (21). (21) &lt;223&gt; Xaa is Aib &lt;400&gt; 889 His Ser Gin Gly Thr Phe

Arg Arg Ala Gin Xaa Phe 20

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15 Val Gin Trp Leu Met Asn Thr 25 &lt;210&gt; 890 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa is Aib &lt;400&gt; 890 His Ser Gin Gly Thr Phe

Arg Arg Ala Gin Asp Phe 20

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 10 15 Vai Xaa Trp Leu Met Asn Thr 25 &lt;210&gt; 891 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES ( 20)..(20) Xaa is Aib &lt;400&gt; 891 His Ser Gin Gly Hir Phe

Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 156004-Sequence Listing.doc -378- 201143790 10 15

Arg Arg Ala Xaa Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 892 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D„RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa is Aib &lt;400&gt; 892 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Xaa Trp Leu Met Asn Thr 20 25 &gt;&gt;&gt;&gt;, 77 012 3 Q 3 lull 22 ^&lt;2&lt;2 893 29 PRT Artificial Sequence Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa Aib &lt;400&gt; 893 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Asn Thr 20 25 &lt;210&gt; 894 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt; 156004-Sequence List.doc .379· 201143790 &lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221>MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Xaa is Aib &lt;400&gt;

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Xaa Asp Phe Val Xaa Trp Leu Met Asn Thr 20 25 &lt;210&gt; 895 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;mysylated &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 896 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is person ib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (161..(16) 380- 156004 - Sequence Listing.doc 201143790 &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 896 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 b&gt; Λ &gt; ^12 3 &lt;21&lt;21&lt;21&lt;21 897 29 PRT Human Process 歹&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is A* &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;;223&gt; with (:16 fat base conversion &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Αΐύ &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Alanine &lt;400&gt; 897 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 898 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES&lt;m&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (10)..(10) &lt;223&gt;匚16 fat thiol group is oxidized via Ala-Ala spacer 156004 - Sequence Listing. doc 381 · 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;imidization &lt;400&gt; 898 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser 1 5 10

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met 20 25

Lys Asn

Tyr Leu Asp Xaa 15 Thr 0 12 3 &lt;21&lt;21&lt;21&lt;21 899 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) .. (2) &lt;223&gt; iCaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; with (:16 fat thiol via dipeptide spacer Purification &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29). (29) &lt;223&gt; Alanine &lt;400&gt; 899 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser l 5 10

Arg Arg Ala Gin Asp Phe Va】Gin Trp Leu Met 20 25

Lys Asn

Tyr Leu Asp Xaa 15 Thr &lt;210&gt; 900 &lt;211&gt; 29 &lt;212&gt; FRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (10)..(10) 156004. Sequence Listing.doc -382- 201143790 &lt; 223 &gt; 016 fat thiol via P-Ala-P-Ala spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt;mysylated &lt;400&gt; 900

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25

&lt;210&gt; 901 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; 3Caa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; 〇: 16 fat thiol via 6-aminocaproic acid Spacerization &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; )..(29) &lt;223&gt; Alanine &lt;400&gt; 901

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15 ·

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 902 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib 383 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;

&lt;221&gt; MOD-RES &lt;222&gt; (10)..(10) &lt;223&gt; by (:16 fat sulfhydryl group via Leu-Leu spacer chemistry &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 902

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 903 &lt;211> 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;22l&gt; MOD„RHS &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is A* &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;;223&gt; (:16 fat thiol via Pro-Pro spacer chemistry &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; MOD^RES &lt;222&gt; (29)..(29) &lt;223&gt;mysylated &lt;400&gt; 903

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 904 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide &lt;220&gt;

&lt;221&gt; MOD.RES 384·

156004· Sequence Listing.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (107..(10) &lt;223&gt;(:14 fat base conversion &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; Amylation &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 905 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; (: 14 fat thiol via dipeptide spacer hydrogenation &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;; M0D_RES &lt;222&gt; (24)..(24)

&lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; Amylation &lt;400&gt;

His Xaa Glri Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 -385- 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 906 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; kaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 10).. (10) &lt;223&gt; Purification via a dipeptide spacer by a C14 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 906

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 907 &lt;211&gt; 29 &lt;2I2&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xm is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Purification by Ala-Ala spacer based on C14 fat thiol &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; j(aa is Aib &lt;220&gt;&lt;;221&gt; MOD RES &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (29)..(29) &lt;223&gt; Amidoxime-386-

156004· Sequence Listing.doc 201143790 &lt;400&gt; 907

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 908 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (101..(10) &lt;223&gt; via Ala-Ala spacer modification &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 909 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; is (&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt;; (16)..(16) &lt;223&gt; 3Caa is Aib &lt;220&gt;

&lt;221&gt; M0D.RES 387-156004-sequence table.doc 201143790 &lt;222&gt; (24)..(24) &lt;223&gt; Cys-PEG &lt;220&gt;&lt;221&gt; M0D RES &lt;222&gt; (29)..(29) &lt;223&gt; amidation &lt;400&gt; 909 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 910 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2丨3&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; mD_RES &lt;222&gt; (10)..(10) &lt;;223&gt; via the dipeptide spacer for &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;;&lt;221&gt;&lt;222&gt;&lt;223&gt; MOD RES (16)..(16) Xaa is Aib RES (24)..(24) Cys-PEG M0D_RES (297..(29) amide &lt;400&gt; 910 His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15 ^rg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&gt;&gt;&gt;&gt; 012 3 V v &lt; V 911 29 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2 &lt;223> Xaa is Aib 156004 - Sequence Listing. doc 388 · 201143790 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to C14 fat sulfhydryl &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 911

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25

&lt;210&gt; 912 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;

&lt;221&gt; MOD.RHS &lt;222&gt; (2)..(2) &lt;223&gt; kaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C14 fat thiol via a dipeptide spacer &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29).. (29) &lt;223&gt; Amination &lt;400&gt; 912

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 1 5 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 913 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt; -389· 156004 - Sequence Listing.doc 201143790 &lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10).. (10) &lt;223&gt; Covalently bonded to C14 fat sulfhydryl group via Ala-Ala spacer&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (167..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (29)..(29) &lt;223&gt;imidization &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 914 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221> MOD RES &lt;222&gt; (2)..(2) &lt;223>Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (l〇T..(l〇) &lt;223&gt; covalently bonded to C16 fat thiol via a dipeptide spacer &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt; 914

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210&gt; 915 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide -390·

156004 Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; M0D „RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to C16 fat sulfhydryl group via Ala-Ala spacer&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; Amination &lt;400&gt;

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Gin Asp Phe Val Cys Trp Leu Met Asn Thr 20 25 &lt;210> 916 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;22]&gt; MOD-RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D·alanine, valine, amino-n-butyric acid, glycine, N-mercaptosine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (30)..(30) &lt;223&gt;&lt;220&gt;;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt;Amination &lt;400&gt; 916

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 917 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide 391 156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D-serine, D-alanine, valine, amine Butyric acid, glycine, N-methylserine, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt;醯基化化&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;mysylated &lt;400&gt; 917

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 918 &lt;211&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; D•serine, D·alanine, valine, amino-n-butyric acid, glycine, N-A Baseline acid, aminoisobutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt;&lt;&quot;&quot;;221&gt; MOD RES &lt;222&gt; (30)..(30) &lt;223&gt;mysylated &lt;400&gt; 918

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr Lys 20 25 30 &lt;210&gt; 919 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;SyntheticPeptide&gt;&gt;&gt;&gt; Q 1 2 3 2 2 2 2 2 2 ΛΥ 2 V &lt;v&lt;

MOD RES (2)..(2) D-serine, D-alanine, valine, aminobutyric acid, glycine, N-methylserine, aminoisobutyric acid-392 - 156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (10)..(10) &lt;223&gt; Conversion to 0:16 fat base &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;imidization &lt;400&gt; 919

His Xaa Gin Gly Thr Phe Thr Ser Asp Lys Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 920 &lt;400&gt; 920 000 &lt;210&gt; 921

&lt;400&gt; 921 000 &lt;210&gt; 922 &lt;400&gt; 922 000 &lt;210&gt; 923 &lt;400&gt; 923 000 &lt;210&gt; 924 &lt;400&gt; 924 000 &lt;210&gt; 925 &lt;400&gt;&lt;210&gt; 926 &lt;400&gt; 926 000 &lt;210&gt; 927 &lt;400&gt; 927 000 &lt;210&gt; 928 &lt;400&gt; 928 000 &lt;210&gt; 929 &lt;400&gt; 929 000 &lt;210&gt; 930 &lt;;400&gt; 930 000 -393 - 156004-sequence table.doc 201143790 &lt;210&gt; 931 &lt;400&gt; 931 000 &lt;210&gt; 932 &lt;400&gt; 932 000 &lt;210&gt; 933 &lt;400&gt; 933 000 &lt;210&gt; 934 &lt;400&gt; 934 000 &lt;210&gt; 935 &lt;400&gt; 935 000 &lt;210&gt; 936 &lt;400&gt; 936 000 &lt;210&gt; 937 &lt;400&gt; 937 000 &lt;210&gt; 938 &lt;400&gt ; 938 000 &lt;210&gt; 939 &lt;400&gt; 939 000 &lt;210&gt; 940 &lt;400&gt; 940 000 &lt;210&gt; 941 &lt;400&gt; 941 000 &lt;210&gt; 942 &lt;400&gt; 942 000 &lt;210&gt ; 943 &lt;400&gt; 943 000 &lt;210&gt; 944 &lt;400&gt; 944 000 &lt;210&gt; 945 &lt;400&gt; 945 000 -394 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 946 &lt;400&gt; 946 000 &lt;21 0&gt; 947 &lt;4〇〇&gt; 947 000 &lt;210&gt; 948 &lt;400&gt; 948 000 &lt;210&gt; 949 &lt;400&gt; 949 000 &lt;210&gt; 950 &lt;400&gt; 950 000

&lt;210&gt; 951 &lt;400&gt; 951 000 &lt;210&gt; 952 &lt;400&gt; 952 000 &lt;2]0&gt; 953 &lt;400&gt; 953 000 &lt;210&gt; 954 &lt;400&gt; 954 000 &lt;210&gt; 955 &lt;400&gt; 955 000 &lt;210&gt; 956 &lt;400&gt; 956 000 &lt;210&gt; 957 &lt;400&gt; 957 000 &lt;210&gt; 958 &lt;400&gt; 958 000 &lt;210&gt; 959 &lt;400&gt; 000 &lt;210&gt; 960 &lt;400&gt; 960 000 156004. Sequence Listing.doc 201143790 &lt;210&gt; 961 &lt;400> 961 000 &lt;210&gt; 962 &lt;400&gt; 962 000 &lt;210&gt; 963 &lt;400&gt; 963 000 &lt;210&gt; 964 &lt;400&gt; 964 000 &lt;210&gt; 965 &lt;400&gt; 965 000 &lt;210&gt; 966 &lt;400&gt; 966 000 &lt;210&gt; 967 &lt;400&gt; 967 000 &lt;210&gt; 968 &lt;400> 968 000 &lt;210&gt; 969 &lt;400&gt; 969 000 &lt;210&gt; 970 &lt;400&gt; 970 000 &lt;210&gt; 971 &lt;400&gt; 971 000 &lt;210&gt; 972 &lt;400&gt; 000 &lt;210&gt; 973 &lt;400&gt; 973 000 &lt;210&gt; 974 &lt;400&gt; 974 000 &lt;210&gt; 975 &lt;400&gt; 975 000 -396 156004 - Sequence Listing.doc 201143790 &lt;210&gt; 976 &lt;400&gt; 976 00 0 &lt;210&gt; 977 &lt;400&gt; 97.7 000 &lt;210&gt; 978 &lt;400&gt; 978 000 &lt;210&gt; 979 &lt;400&gt; 979 000 &lt;210&gt; 980 &lt;400&gt; 980 000

&lt;210&gt; 981 &lt;400&gt; 981 000 &lt;210&gt; 982 &lt;400&gt; 982 000 &lt;210&gt; 983 &lt;400&gt; 983 000 &lt;210&gt; 984 &lt;400&gt; 984 000 &lt;210&gt; 985 &lt;;400&gt; 985 000 &lt;210&gt; 986 &lt;400&gt; 986 000 &lt;210&gt; 987 &lt;400&gt; 987 000 &lt;210&gt; 988 &lt;400&gt; 988 000 &lt;210&gt; 989 &lt;400&gt; 989 000 &lt;;210&gt; 990 &lt;400&gt; 990 000 -397- 156004-sequence table.doc 201143790 &lt;210&gt; 991 &lt;400&gt; 991 000 &lt;210&gt; 992 &lt;400&gt; 992 000 &lt;210&gt; 993 &lt;400&gt ; 993 000 &lt;210&gt; 994 &lt;400&gt; 994 000 &lt;210&gt; 995 &lt;400&gt; 995 000 &lt;210&gt; 996 &lt;400&gt; 996 000 &lt;210&gt; 997 &lt;400&gt; 997 000 &lt;210&gt ; 998 &lt;400&gt; 998 000 &lt;210&gt; 999 &lt;400&gt; 999 000 &lt;210&gt; 1000 &lt;400&gt; 1000 000 &lt;210&gt; 1001 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Person &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;223&gt; Wild Type Glucagon &lt;400&gt; 1001

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1002 &lt;2U&gt; 31 &lt;212&gt; PRT &lt;213&gt; Homo sapiens -398·

156004· Sequence Listing.doc 201 143790 '&gt;&gt;&gt;&gt; o 164 3 2222 &lt;400&gt; MI SC FEATURE (1).7(31) GLP-l(7-37) 1002

His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 1 5 10

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys 20 25

Tyr Gly

Leu Glu 15

Arg Gly 30

Gly &lt;210&gt; 1003 &lt;211&gt; 30 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (1) .7(30) &lt;223&gt; Amineralized GLP-1 (7-36) &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;222&gt; (30)..(30) &lt;223&gt; Terminal amidation &lt;400&gt; 1003 His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser 1 5 10

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Val Lys 20 25

Tyr Gly

Leu Glu 15

Gly

Arg 30 0&gt;1&gt;2&gt;3&gt; 1 1 11 11 &lt;2&lt;2&lt;2&lt;2

&lt;220&gt;&lt;221&gt; mat_peptide &lt;222&gt; (1) 7. (42) &lt;223&gt; Suppressive polypeptide &lt;400&gt; 1004 Tyr Ala Glu Gly Thr Phe lie Ser Asp Tyr Ser lie 1 5 10 lie His Gin Gin Asp Phe Val Asn Trp Leu Leu Ala 20 25

Ala Gin

Met Asp 15

Lys Gly 30

Lys Lys

Lys Asn Asp Trp Lys His Asn lie Thr Gin 35 40 012 3 &lt;vv &lt;&lt;2i77!7170&gt; 1005 29 PRT Artificial Sequence 156004 · Sequence Listing. doc 399 · 201143790 &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 61 &lt;220&gt;&lt;221&gt; M]SC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Residue 16 and Residue 20 The indoleamine bridge. &lt;400&gt; 1005

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15 lie His Gin Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1006 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC_FEAT\JRE &lt;223&gt; Analog 62 &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (16) (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20. &lt;400&gt; 1006

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1007 &lt;211&gt; 29 &lt;212&gt; PRT &lt;;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; similar to 63 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (12). (16) &lt;223&gt; The intrinsic amine bridge between residue 12 and residue 16. &lt;400&gt; 1007

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 • 400- 156004 · Sequence Listing.doc 201143790 &lt;210&gt; 1008 &lt;; 211 &gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt; 223 &gt; Similar 砀 66 &lt; 400 &gt; 1008

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe He Ala Trp Leu Leu Ala Gin 20 25

&lt;210&gt; 1009 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Similar to Yang 68 &lt;;400&gt; 1009

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15 lie His Gin Glu Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1010 &lt;211&gt; 29 &lt;212&gt; PRT &lt;;213&gt;Artificialsequence&lt;220&gt;&lt;223&gt;Syntheticpolypeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; similar ulcer 69 &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; an intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1010

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 15 10 15 I]e His Gin Glu Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 -401 · 156004 Sequence Listing.doc 201143790 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21 1011 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220> &lt;221&gt; MISC.FEATURE &lt;223&gt; analogue 84 &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (16).. (20) Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt; 1011 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe lie Cys Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1012 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like Yang &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; covalently linked to cysteine PEG (20kDa) &lt;400&gt; 1012 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

He His Gin Lys Glu Phe lie Cys Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1013 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to 92 156004. Sequence Listing. doc • 402· 201143790 &lt;400&gt; 1013

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Lys His Gin Lys Glu Phe lie Ala Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1014 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like Yang 93 &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (17) 7. (21) &lt;223&gt; The intrinsic amine bridge between residue 17 and residue 21 &lt;400&gt; 1014

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Lys His Gin Lys Glu Phe lie Ala Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1015 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to ^95 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; between residue 16 and residue 20 Indole bridge key &lt;400> 1015

His Ala Glu Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1016 &lt;211&gt; 29 &lt;212&gt; PRT &lt;; 213 &gt; artificial sequence • 403· 156004 - Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 96 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1016 Tyr Ala Glu Gly Thr Phe lie Ser Asp Tyr Ser lie 1 5 10

Ala

Met

Asp Glu 15

He His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala 20 25

Gin 10123 &lt;21&lt;21&lt;21&lt;21 1017 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATVRE &lt;223&gt; similar to 97 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1017 His Ala Glu Gly Thr Phe Thr Ser Asp Ding yr Ser lie 1 5 10

Tyr

Met

Asp Glu 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala 20 25

Gin &lt;210&gt; 1018 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to Yang 98 &lt;;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1018 Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie 1 5 10

Tyr

Met

Asp Glu 15 156004-sequence list.doc 404·201143790 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1019 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt; Artificial sequence&lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 99 &lt;400&gt; 1019

Tyr Ala Glu Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Asn Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1020 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt;; MISC.FEATURE &lt;223&gt; is similar to 100 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;400&gt; 1020

Tyr Xaa Glu Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Asn Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1021 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE 405 - 156004 - Sequence Listing.doc 201143790 &lt;223&gt; Analog 101 &lt;400&gt; 1021

Tyr Ala Pro Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Asn Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1022 &lt;211&gt; 42 &lt;2I2&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 102 &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Cys Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1023 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt;; MiSC FEATURE &lt;223&gt;similar to Le 104 &lt;400&gt; 1023

Tyr Ala Pro Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Cys Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1024 •406· 156004 Sequence Listing.doc 201143790 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like Yang 105 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)7.(24) &lt;223&gt; Amino acid PEG (40kDa) &lt;400&gt; 1024

Tyr Ala Pro Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Cys Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1025 &lt;2H&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MISC.FEATURE &lt;223&gt; similar to 106 &lt;40O&gt; 1025

Tyr Ala Glu Gly Thr Phe He Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1026 &lt;211&gt; 29 &lt;212&gt; PRT &lt;;213&gt;ArtificialSequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to ^107 &lt;220> &lt;221&gt; MISC.FEATURE &lt;222&gt; (16) .. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1026

His Ser Gin Gly Thr Phe He Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 -407- 156004 - Sequence Listing.doc 201143790 lie His Gin Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1027 &lt ;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to %108 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1027

His Ser Gin Gly Thr Phe lie Ser Asp Tyr Ser Lys Ala Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe lie Ala Trp Leu Met Asn Thr 20 25 &lt;210&gt; 1028 &lt;211&gt; 29 &lt;212&gt; PRT &lt;; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;22i&gt; M1SC FEATURE &lt;223&gt; similar to 109 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16). (20) &lt;223&gt; an intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1028

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1029 &lt;211&gt; 29 &lt;212&gt; PRT &lt;;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; Analog 110-408-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt; 1029 Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &gt;&gt;&gt;&gt; 012 3 ζΝ 2 2 VV &lt;&lt; 1030 29 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 111 &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;;222> (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1030 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 0&gt;1&gt;2&gt;3&gt; n 11 ϋ .1 2 ΛΖ 2 2 &lt; V &lt;&lt; 1031 24 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; synthetic peptide

&lt;221&gt; MISC.FEATURE &lt;223&gt;Like 113 &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (1) 7. (1) &lt;223&gt; Xaa is 3-phenyllactate &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (11)..(15) &lt;223&gt; The intrinsic amine bridge between residue 11 and residue &lt;400&gt; 1031 Xaa lie Ser Asp Tyr Ser lie Ala Met Asp Glu lie His Gin Lys Asp 15 10 15

He 409 409- 201143790 &lt;210&gt; Peptide &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;223&gt; Analog 114 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is 3-phenyl Lactic acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (11)..(]5) &lt;223&gt; Intrinsic amine bridge between residue 11 and residue &lt;400&gt; 1032

Xaa Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu I]e His Gin Lys Asp 15 10 15

Phe Val Asn Trp Leu Leu Ala Gin 20 &lt;210&gt; 1033 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like 115 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1033

His Ser Gin Cly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1034 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide 410·

156004· Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Similar to Yang 116 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt;; intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1034

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 1035 &lt;211&gt; 29 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1035

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Glu Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1036 &lt;211&gt; 39 &lt;212&gt; PRT &lt;;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;221&gt; MISC FEATURE &lt;223&gt;Like Yang 120 &lt;220&gt;&lt;221&gt; MISC FHATORE &lt;222&gt; (16). (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1036

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 411 - 156004 · Sequence Listing.doc 201143790 20 25 30

Ser Giy Ala Pro Pro Pro Ser 35 &lt;210&gt; 1037 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Similar to 刼124 &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1037

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Met Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1038 &lt;211&gt; 29 &lt;212&gt; PRT &lt;;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; M1SC FEATURE &lt;223&gt; similarly as 125 &lt;220&gt;&lt;221&gt; Ml SC FEATURE &lt;222&gt; (16) .. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1038

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Met Asp Glu 15 10 15 lie His Gin Lys Asp Phe Val Asn Trp Leu Leu Ala Gin 20 25 &lt;210&gt; 1039 &lt;211&gt; 39 &lt;212&gt; PRT &lt;;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Similar to Yang 127 -4) 2-

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt; 1039

Tyr Scr Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1040 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like 128 &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic Amine Bridge between 16 and Residue 20 &lt;400&gt; 1040

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 lie His Gin Lys Asp Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1041 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 129 &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt;; 1041

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15 413· 156004 - Sequence Listing.doc 201143790 lie His Gin Lys Asp Phe lie Ala Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1042 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 139 &lt;220&gt;&lt;221&gt; M1SC_FEATME &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1042

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe He Ala Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1043 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;22i&gt; MISC FEATURE &lt;;223&gt; Analog 140 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt;; 1043

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 1044 &lt;211&gt; 39 &lt;212&gt; PRT 414-

156004· Sequence Listing.doc 201143790 &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like Yang 141 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;4〇〇&gt; 3044

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Met Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;2]〇&gt; 1045 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt; 223 &gt; similar to Yang 142 &lt; 220 &lt; 221 &gt; MISC FEATURE &lt; 222 &gt; (16) .. (20) &lt; 223 &gt; 醯 醯 之间 bridge between residue 16 and residue 20 &lt;400&gt; 1045

Tyr Ala Glu Gly Thr Phe Tht Sex Asp Tyr Ser lie Tyr Met Asp Glu

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1046 &lt;211&gt; 39 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;223&gt; analogue 143 &lt;220&gt; 415-156004-sequence table.doc 201143790 &lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Residue 16 and residue醯 醯 桥 bridge between 20 &lt;400&gt; 1046

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Arg Arg Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1047 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 144 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic amine bridge between residue 16 and residue &lt;400&gt;; 1047

Tyr Ala Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Met Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1048 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 145 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Internal guanamine bridge between residue 16 and residue &lt;400&gt; 1048

Tyr Ala Gin Gly Thr Phe lie Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser •416-

156004· Sequence Listing.doc 201143790 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1049 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence&lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;221&gt; MISC FEATURE &lt;;223&gt;Like Yang 146 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20)

&lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1049

Tyr Ala Gin Gly Thr Phe lie Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1050 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;223&gt; similarly as 147 &lt;220&gt;&lt;221&gt; MISC FEATTfRB &lt;222&gt; (16)..(20) &lt;223&gt; Indole Bridge &lt;400&gt; 1050

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1051 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; artificial sequence 156004-sequence table _doc 417·

Cl: 201143790 &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 148 &lt;220&gt;&lt;221&gt; MISC.FEATTIRE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1051 Tyr Ser GIu Gly Thr Phe Thr Ser Asp Tyr Ser lie 1 5 10

Tyr Leu Asp Glu 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Leu Ala 20 25

Gly Gly Pro Ser 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1052 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 149 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1052 Tyr Ala Glu Gly Thr Phe Thr Ser Asp Tyr Ser Me 1 5 10

Tyr Leu Asp Glu 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala 20 25 Ser Gly Ala Pro Pro Pro Ser 35

Gly Gly Pro Ser 30 0 12 3 V &lt;v 1053 39 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 150 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) 156004 - Sequence Listing.doc 418·201143790 &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt;; 1053

Tyr Ser Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1054 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 151 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Residue 16 and residue醯 醯 桥 bridge between 20 &lt;400&gt; 1054

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Ala Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1055 &lt;213&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt;Like Yang 152 &lt;220&gt;

&lt;22 】&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1055

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15 419- 156004 · Sequence Listing.doc 201143790

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1056 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt;Like 154 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (1).. (1) &lt;223&gt; xaa is hippuric acid &lt;220&gt;&lt;22i&gt; MISC.FEATURE &lt;;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt;

Xaa Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1057 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 155 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (12)..(16) &lt;223&gt; The intrinsic amine bridge between residue 12 and residue &lt;400&gt; 1057

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 420-

156004-sequence table.doc 201143790

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1058 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 156 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (20).. (24) &lt;223&gt; The intrinsic amine bridge between residue 20 and residue &lt;400&gt; 1058 Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1059 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; Analog 157 &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (24).. (28) &lt;223&gt; The intrinsic amine bridge between residue 24 and residue 28 &lt;400&gt; 1059 Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Glu Trp Leu Leu Lys Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro 35 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 1060 39 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide 156004 - Sequence Listing.doc 421 - 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; is similar as 158 &lt;220> &lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1061 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATORE &lt;;223&gt; Analog 162 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220> &lt;221&gt; MISC FEATURE &lt;222&gt; 16) 7. (20) &lt;223&gt; an intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1061

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Tyr Tyr Leu Asp Glu 1 5 10 15

Gin Ala Val Lys Glu Phe Val Asn Trp Leu lie Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1062 &lt;211&gt; 29 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide 422-

156004-Sequence table_doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; similarly as 163 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt; 1062

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1063 &lt;21l&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; is similar to 164 &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt; 1063

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 Column 64T 1040PR Human 0&gt;1&gt;2&gt;3&gt;&lt;21&lt;21&lt;21&lt;21&lt;220&gt;&lt;223&gt; Synthetic polypeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; similar to first 165 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7, (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 - 423 - 156004 · Sequence Listing.doc 201143790 &lt;400&gt ; 1064

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leii Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1065 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; analogue 166 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is d-alanine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Endo-amine bridge between residue 16 and residue &lt;400&gt; 1065

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1066 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 167 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (17)..(20) &lt;223&gt; The intrinsic amine bridge between residue 17 and residue &lt;;400&gt; 1066

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15 424- 156004 · Sequence Listing.doc 201143790 GIu Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1067 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt;similar to Le 168

&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;

MISC FEATURE 8^’1&amp;] Intrinsic amine bridge between 4 bases 21 &lt;400&gt; 1067

Tyr Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 】5

Gin Lys Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1068 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MISC-FEATURE &lt;223&gt; similar to 169 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (16)..(20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt; 1068

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1069 &lt;211&gt; 40 156004 · Sequence Listing.doc .425 - h 201143790 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to $7170 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220> &lt;221&gt; MISC FEATURE &lt;222> (16)..(20) &lt;223&gt The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently linked to cysteine PEG (40kDa) &lt;400&gt; 1069

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1070 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;223&gt; Analog 172 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISCJFEAIURE &lt;222&gt; (24)..(24) &lt;;223&gt; PEG (40 kDa) &lt;400&gt; 1070 covalently linked to cysteine

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly • 426-

156004-Sequence List.doc 201143790 20 25 &lt;210&gt; 1071 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;;223&gt; Analog 174 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 16)..(20)

&lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1071

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1072 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;223&gt; is similar to 175 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu l 5 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 427- 156004 - Sequence Listing.doc 201143790 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1073 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt; similar to 176 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt;; intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1073

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser He Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1074 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; is similar to 177 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 •428· 156004 Sequence Listing.doc 201143790 &lt;210&gt; 1075 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC-FEATURE &lt;223&gt;Like Yang 178 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1076 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC .FEATURH &lt;223&gt; is similar to 179 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; PEG (40 kDa) &lt;400&gt; 1076 covalently linked to cysteine

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Glu -429· 156004 - Sequence Listing.doc 201143790 5 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1077 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar uncle 182 &lt;220&gt;&lt;22&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; 40)..(40) &lt;223&gt; PEG (40kDa) &lt;400&gt; 1077 covalently linked to cysteine

Tyr

Xaa GlnG.yThrPhelleSer Asp Tyr Ser Ile Tyr Leu Asp Glu

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1078 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Analog 186 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) 156004-sequence table.doc -430-

201143790 &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;400&gt; 1078

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Cys Trp Leu Met Asn Gly 20 25 &lt;210&gt; 1079 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;similar to Yang 191

&lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;400&gt; 1079

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1080 &lt;211&gt; 34 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC.FEATOE &lt;223&gt; similar to 192 &lt;400&gt; 1080

Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu Gin Ala Ala Lys Glu 15 10 15

Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser Gly Ala Pro Pro 20 25 30

Pro Ser &lt;210&gt; 1081 &lt;211&gt; 38 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence • 431 - 156004 - Sequence Listing. doc 201143790 &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt;similar to Le 194 &lt;220&gt;

&lt;221> MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Aib &lt;400&gt; 1081

Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu Glu 15 10 15

Ala Val Arg Leu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser Ser 20 25 30

Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1082 &lt;211&gt; 26 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt; 223> similar as 197 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (13)..(17) &lt;223&gt; The intrinsic amine bridge between residue 13 and residue &lt;400&gt; 1082

Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu Gin Ala Ala 1 5 10 15

Lys Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1083 &lt;211&gt; 28 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MISC.FEATURE &lt;223&gt; Analog 198 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Aib &lt;220&gt; 156004. Sequence Listing.doc 432-

201143790 &lt;221&gt; MISC FEATURE &lt;222&gt; (15) 7. (19) &lt;223&gt; Intrinsic amine bridge between residue 15 and residue 19 &lt;400&gt; 1083

Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu Gin 15 10 15

Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1084 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;;221&gt; MISC FEATURE &lt;223&gt; Similar to &lt;220〉

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt; 1084

Tyr Xaa Gin Gly Thr Phe Val Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40

&lt;210&gt; 1085 &lt;211&gt; 40 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (16).. (20 &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;22〇&gt; -433 - 156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (27). (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1085 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &gt;&gt;&gt;&gt; 012 3 2 2 ofc 2 &lt;&lt;v&lt; 1086 39 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;223&gt;Similar 刼201 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;400&gt; 1086 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Glu Ala Va] Arg Leu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1087 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223> Similar to %202 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC FEATTJRE 156004-preface List .doc 434. 201143790 &lt;222&gt; (40)..(40) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Val Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1088 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide

&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; Similar to ^203 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently linked to cysteamine Acid PEG (40kDa) &lt;400&gt; 1088

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1089 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; is similar to 204.435 · 156004 Sequence Listing. doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; M1SC.FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu l 5 10 15

Gin Ala Ala Lys Glu Phe Va) Asn Trp Leu Leu Ala Gly Arg Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40

&lt;210&gt; 1090 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;223&gt; Analog 205 &lt;;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently linked to cysteine PEG (40kDa)

&lt;400&gt; 1090

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Arg Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1091 &lt;21l&gt; 43 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide 156004 - Sequence Listing.doc -436- 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;Like 206 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (16) 7. (20) &lt;223> Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin Cys

&lt;210&gt; 1092 &lt;211&gt; 43 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20)

&lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin Cys 35 40 &lt;210&gt; 1093 &lt;211&gt; 43 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Polypeptide.437·156004-Preface List .doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; Analog 208 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;222&gt; (16) 7. (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (43)..(43) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 IS

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin Cys 35 40 &lt;210&gt; 1094 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;221&gt; MISC.FEATURE &lt;223&gt; similar to 209 &lt;220&gt;&lt;22]&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223> Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (9).. (12) &lt;223&gt; The intrinsic amine bridge between residue 9 and residue &lt;220&gt;&lt;221&gt;&lt;222&gt;;223>

MISC.FEATURE The intrinsic amine bridge between bases 20 &lt;400&gt; 1094

Tyr Xaa Gin Gly Thr Phe Thr Ser Glu Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1095 156004 - Sequence Listing.doc -438 - 201143790 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; CEX &lt;400&gt; 1095 Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 &gt;&gt;&gt;&gt;&gt; ^12 3 i 1 lx 1 V &lt; V &lt; 1096 11 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE0)..0) Xaa is 4 amine Acid &lt;400&gt; 1096 Xaa Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser 1 5 10 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt; 1097 8 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;400&gt; 1097 Lys Arg Asti Arg Asn Asn lie Ala &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt; 1098 4 PRT artificial sequence synthesis polypeptide &lt;400&gt;&lt;210&gt 04-Sequence List.doc •439· 201143790

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 1099 covalently linked to cysteine

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1100 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; 〇: terminal amination &lt;400&gt; 1100

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 -440·

156004-Sequence List.doc 201143790 &lt;210&gt; 1101 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24).. (24) &lt;223&gt; PEG (40 kDa) &lt;220&gt; covalently linked to cysteine

&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Covalently linked to a 16-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; 0: terminal amidation &lt;400&gt; 1101

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1102 &lt;211&gt; 40 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MOD RES &lt;m&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24): (24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;22]&gt; MISC FEATURE &lt;222&gt; (40)..(40) 156004-Sequence List.doc 441 ·

S 201143790 &lt;223&gt; covalently linked to 14-carbon fat sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; 〇:醯Amination &lt;400> 1102

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Vai Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1103 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;22&gt;; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently attached to the 18-carbon fatty sulfhydryl group of the lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40). (40) &lt;223&gt; C-terminal amide &lt;400&gt; 1103

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1104 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt; -442-

156004-Sequence List.doc 201143790 &lt;223&gt;Synthetic Peptide&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa^Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)7.(40) &lt;223&gt; The valence is linked to the 14-carbon fatty sulfhydryl group of the amine acid &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys l 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1105 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Xib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) ' &lt;223&gt; covalently linked to the 16-carbon fatty sulfhydryl group of the lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1105

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 -443 - 156004 - Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 '&gt;&gt; Λ &gt; 0123 2 2 2 &lt;&lt; V &lt; 1106 40 PRT Artificial Sequence &lt;220&gt;&lt;223> Synthetic Peptide &lt;220&gt;&lt;221&gt;M0D.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221> M0D-RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)., (40) &lt;223&gt; covalently linked to 18-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400> 1106 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt;&lt;211&gt;&lt;212&gt;&lt;213&gt;&lt;220&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; 1107 40 PRT artificial sequence synthesis polypeptide MOD RES (2).. (2) Xaa Aib MOD RES (20)..(20) Xaa is Aib MISC.FEATTJRE (40).. (40) C-terminal amide hydration &lt;400&gt; 1107 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15 156004 · Sequence Listing.doc -444- 201143790

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1108 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20)

&lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MI SC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; PEG (40 kDa) &lt;220&gt; linked to cysteine ;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1108

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1109 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2〇T..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MI SC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amide 445-156004-sequence table.doc 201143790 &lt;400&gt; 1109

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1110 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222> (29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 1110

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1111 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;22 3&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2〇T._(20) &lt;;223&gt; Xaa is ib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amide &lt;400&gt; 1111

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys -446-

156004-sequence table.doc 201143790 15 10

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1112 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (20)..(20) &lt;223&gt; xaa is Aib &lt;400&gt; 1112

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Ding rp Leu Leu Ala Gly 20 25 &lt;210&gt; 1113 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;;

&lt;221&gt; MOD RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24).. (24) &lt;223&gt; Covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;221&gt; MISC FEATURE &lt;222&gt; (39)..(39) &lt;223&gt; C-terminal amidation &lt;400&gt; 1113

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser 447· 156004· Sequence Listing.doc 201143790 20 25 30

Ser Gly Ala Pro Pro Pro Ser &lt;210&gt; 35 1114 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; MI SC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently linked to a 16-carbon fat sulfhydryl group of lysine &lt;220&gt;&lt;221> MISC FEATURE &lt;222&gt; (39)..(39) &lt;223&gt; C-terminal amidation &lt;400&gt; 1114

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser

&lt;210&gt; 35 1115 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2): (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; 18-carbon fat sulfhydryl group covalently linked to lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE 156004-sequence table.doc 448·

201143790 &lt;222&gt; (39)..(39) &lt;223&gt; 〇: terminal amidation &lt;400&gt; 1115

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1116 &lt;2I1&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (39)..(39) &lt;223&gt; terminal amination &lt;400&gt; 1116

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Lys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1117 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; covalently attached to lysine 14 carbon fat thiol &lt;220&gt; 449-156004. Sequence Listing.doc 201143790 &lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (39)7.(39) &lt;223&gt; C-terminal amidation &lt;400&gt; 1117

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1118 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATORB &lt;222&gt; (10)..(10) &lt;223&gt; covalently connected to &lt;220&gt 222&gt; (39)..(39) &lt;223&gt; C-terminal amide &lt;400&gt; 1118

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1119 &lt;211&gt; 39 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Polypeptide 450 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC.FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; covalently attached to the 18-carbon fatty sulfhydryl group of the lysine &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (39) 7. (39) &lt;223&gt; C-terminal amide &lt;400&gt; 1119

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1120 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (39)..(39) &lt;223&gt;; C-terminal amides &lt;400&gt; 1120

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1121 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence 451 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic Polypeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;;223&gt; Xaa is 0m &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide &lt;400&gt; 1121

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1122 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is 2,4-diaminobutyric acid &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (201..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt;; terminal amination &lt;400&gt; 1122

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Me Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser -452- 156004-sequence table.doc 201143790 25 CV40 Γ eso pr 0 pr r0 pr cQ 1 5 A 3 ,y Γ es column 23T::milk Booker &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;222&gt; (40)..(40) &lt;223&gt; Covalently linked to 14-carbon fatty sulfhydryl groups of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) ) &lt;223&gt; C-terminal amide &lt;400&gt; 1123

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1124 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to a 16-carbon fat sulfhydryl group of lysine &lt;220&gt;

&lt;221&gt; MISC FEATURE • 453 · 156004 - Sequence Listing.doc 201143790 &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1124

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1125 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Covalently linked to 18-carbon fatty sulfhydryl groups of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;222&gt; (40)7.(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1125

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1126 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt; -454-156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (201..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

&lt;210&gt; 1127 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt;; PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (29).. (29) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Trp Leu Leu Ala Gly 25 455-

Gin Ala Ala Xaa Glu Phe Val Cys 20 &lt;210&gt; 1128 &lt;211&gt; 29 &lt;212> PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib 156004-sequence table.doc 201143790 &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (10) 7. (10) &lt;223&gt; covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;221&gt; MISC FEATURE &lt;222&gt; (29)..(29) &lt;223&gt; 〇: terminal amination &lt;400&gt; 1128

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1129 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; Covalently linked to a 16-carbon fat sulfhydryl group of amine acid &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURB &lt;222&gt; (29)..(29) &lt;;223&gt; Extremely aminated &lt;400&gt; 1129

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1130 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt; -456- 156004 - Sequence Listing.doc 201143790

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (10)..(10) &lt;223&gt;; 18-carbon fat sulfhydryl group covalently linked to lysine &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;; MISC.FEATURE &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 1130

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1131 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (207..(20) &lt;223&gt; Xaa is ib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (29)..(29) &lt;223&gt;; C-terminal amides &lt;400&gt; 1131

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1132 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MODJES &lt;222&gt; (2)..(2) -457- 156004-sequence table.doc 201143790 &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently attached to 14 carbons of lysine Fat base &&lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 1132 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &gt;&gt;&gt;&gt; 012 3 2 2 ζΜ ζΜ &lt;&lt;vv 1133 40 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently attached to the 16-carbon fatty sulfhydryl group of the lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1133 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gy Ala Pro Pro Pro Ser Lys &lt;210&gt; 1134 156004 - Sequence Listing.doc -458-201143790 &lt;211&gt; 40 &lt;212&gt; PRT &lt;2]3&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;

&lt;221&gt; MOD_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; covalently linked to 18-carbon fatty sulfhydryl groups of lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40)

&lt;223&gt; C-terminal amide &lt;400&gt; 1134

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210> 1135 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MODJES &lt;222> (2)..(2) &lt;223&gt; X^a is Xib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;;223&gt; C-terminal amide &lt;400&gt; 1135

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 -459- 156004 - Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1136 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; xaa is Aib &lt;;220&gt;&lt;221&gt; M1SC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;221&gt; covalently linked to cysteine 222&gt; (40)..(40) &lt;223&gt; covalently attached to the 14-carbon fatty sulfhydryl group of the lysine

&lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; 0-terminal amidation &lt;400&gt; 1136 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu 1 5 10

Gin Ala Ala Xaa Glu Phe Val Cys 20

Trp Leu Leu Ala Gly Gly 25 30

Asp Lys 15 Pro Ser

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1137 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;

&lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;22&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; 3 (aa is Aib &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;

MISC.FEAmE &lt;222&gt; (24)..(24) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine 156004. Sequence Listing. doc 460- 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to a 16-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. 40) &lt;223&gt; terminal amidation &lt;400&gt; 1137 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1138 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; M0D.RES (2)7. (2) Xaa is Aib MOD RES (20)..(20) Xaa is Aib ^ &gt;&gt;&gt; Q1 &lt;Si 3 2222 &lt;2&lt;2&lt;2&lt;2 MISC FEATURE (24)7.(24) , PEG (40kDa) covalently linked to cysteine &lt;220 〉 &lt;221&gt;&lt;222&gt;&lt;223&gt;&lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (40)7. (40) Covalently attached to 18-carbon fat of lysine醯基&lt;400&gt; MISC.FEAHJRE (40) 7. (40) C-terminal amide amide 1138

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

&lt;210&gt; 1139 &lt;211&gt; 40 &lt;212&gt; PRT 156004. Sequence Listing.doc • 461 · 201143790 &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Xib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; XaaAAib &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1139

TyrXaa Gin Oly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1140 &lt;21i&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amide &lt;&gt;1140

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15 •462·

156004-sequence table.doc 201143790

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1141 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;

&lt;221>MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20)

&lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Covalently linked to the 16-carbon fatty sulfhydryl group of the lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1141

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Scr lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1142 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Co-linked to a 16-carbon fatty sulfhydryl group of lysine &lt;220> 463-156004-sequence table.doc 201143790 &lt;221&gt; MISC_FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; *imidization &lt;400&gt; 1142

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1143 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220> &lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..( 20) &lt;223>Xaa is Aib &lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to the 16-carbon fat sulfhydryl group of the lysine &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation

&lt;400〉 1143

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1144 &lt;211&gt; 40 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide 464 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt; 223 &gt; covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;; 1144

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys ] 5 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1145 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently linked to 18-carbon fatty sulfhydryl groups of lysine &lt;220> &lt;221&gt; MISC_FEATORE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 156004-Sequence List.doc -465-201143790 &lt;210&gt; 1146 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (20).. (20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Oy Ala Pro Pro Pro Ser Lys &lt;210&gt; 1147 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; MISC.FEATORE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to the 3-SH-propionyl group of the lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; 〇: terminal amidation &lt;400&gt; 1147

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15 466 ·

156004-sequence table.doc 201143790

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu 20 25

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; Π48 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is A* &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20)

Ala Gly Gly Pro Ser 30 &lt;223&gt; Xaa is Alb &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently attached to 8 carbon fat of lysine醯基&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1148

Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser 5 10 lie Tyr Leu Asp Lys 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu 20 25

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

Ala Gly Gly Pro Ser 30 &lt;210&gt; 1149 &lt;211&gt; 40 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1149 -467- 156004 · Sequence Listing.doc 30 201143790

Tyr Xaa Gin Gly Thr Phe Ser Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa GIu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1150 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (7)..(7) &lt;223&gt; Xaa is 2 - Aminobutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223>Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223>C-terminal amidation &lt;400&gt; 1150

Tyr Xaa Gin Gly Thr Phe Xaa Ser Asp Tyr Ser He Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1151 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (20)..(20) &lt;223&gt; Xaa is Aib 156004· Sequence Listing.doc 468-

201143790 &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently linked to 8 carbon aliphatic bases of lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1151

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

&lt;210&gt; 1152 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEAHJRE &lt;222&gt; (40)..(40) &lt; 223 &gt; covalently linked to 8-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1153 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide 469-156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MOD^RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Xib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..( 20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;

MISC-FEATORE

PEG of cysteine (40 kDa) &lt;220&gt;&lt;221&gt; MlSC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; (: terminal amination &lt;400&gt; 1153

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1154 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (4〇T..(40) &lt;;223&gt; Xaa is d-lysine &lt;220&gt;&lt;22i&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to 14-carbon fat d of d-lysine Base &lt;220&gt;&lt;221&gt; MISCJEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1154

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 470-

156004· Sequence Listing.doc 201143790 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1155 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib

&lt;221&gt; M0D_RES &lt;222&gt; (40)..(40) &lt;223&gt; Xaa is d_aluric acid &lt;220&gt;&lt;221&gt; MISC.FEAHJRE &lt;222&gt; (40).. (40 ) &lt;223&gt; C-terminal amidation &lt;400> 1]55

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1156 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; PEG (40 kDa) covalently linked to cysteine &lt;220&gt; 471 - 156004 - Sequence Listing.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; Xaa is d-lysine &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..( 40) &lt;223&gt; covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide amination &lt;400&gt; 1156

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1157 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;222&gt; (40)..(40) &lt;223&gt; Xaa is d-lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Alanine &lt;400&gt; 1157

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 472·

156004 Sequence Listing.doc 201143790 &lt;210&gt; 1158 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Polypeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; covalently attached to lysine 14 carbon fat thiol &lt;220&gt;&lt;221&gt; » RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1158

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1159 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; M0D RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Kaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt;; C-terminal amides &lt;400&gt; 1159

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 -473· 156004 - Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1160 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently linked to 14-carbon fat sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41)..(41) &lt;223&gt; C-terminal amidation &lt;400&gt; 1160

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 &lt;210&gt; 1161 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41)..(41) &lt;223&gt; 〇: terminal amination &lt;400&gt; 1161

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys -474·

156004·List of contents _doc 201143790 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 &gt;&gt;&gt;&gt; 012 3 · · »1 · &lt;2&lt;2&lt;2&lt;2 1162 39 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;M0D.RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10) 7. (10) &lt;223&gt; Covalently linked to 14-carbon fat sulfhydryl group of lysine &lt;220&gt;&lt;221&gt;MOD.RES&lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;221&gt;223&gt; MISC_FEVnjRE (39)..(39) C-terminal amide hydration &lt;400&gt; 1162 Tyr Xaa Glu Gly Thr Phe Thr Set Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15 Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; Π63 &lt;211&gt; 41 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2) 7. (2) &lt;223&gt; iiaa is Aib &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (20)..(20) 156004-sequence table.doc •475 · 201143790 &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;221&gt; MISC.FEATTJRE &lt;222&gt; (41)..(41) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (co-linked to cysteine) 41)..(41) &lt;223&gt; C-terminal amidation &lt;400&gt; 1163

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 &lt;210&gt; 1164 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC^FEATTJRE &lt;222&gt; (41)..(41) &lt;223&gt; PEG (4〇kDa) covalently linked to cysteine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41) 7. (41) &lt;223&gt; C-terminal amidation &lt;400&gt; 1164

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 &lt;210&gt; 1165 156004. Sequence Listing.doc -476· 201143790 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Manual Sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40):. (40) &lt;223&gt; Covalently linked to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal guanamine &lt;400&gt; 1165

His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1166 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24) (24) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;22i&gt; MISC_FEATORE &lt;222&gt; (40).. (40) &lt;223&gt; covalently linked to the cysteine acid 14-carbon fatty acid covalently linked to the lysine Base &lt;220&gt;&lt;22l&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15 477- 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1167 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Alb &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)7.(40) &lt;223&gt; (: terminal amination &lt;400&gt; 1167 yn G1 oa xa Γ Tyl 6 s Γ yo T1 p As Γ 6 s Γ Th e ph ps A 1 u Le Γ Ty

G na A, u Le u Le p Γ 5 T2 n s va e ph u G1 s yo L2 oa M 6 s o pr y n G3 se

G yo C4 Γ 6 so Γ po pr r0 F na 15 A 3 column 8 c 6 TJ 1140PR person ^ &gt;&gt;&gt; Q 1 2 3 VV &lt;&lt;&lt; 220 &lt; 223 &gt;&lt; 223 &gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MODEES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; terminal amidation &lt;400&gt; 1168

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15 478- 156004 · Sequence Listing.doc 201143790

Gin Ala Ala Gin Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1169 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (12)..(16)

&lt;223&gt; The intrinsic amine bridge between the residue 12 and the residue 16 &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amide &lt;400&gt; 1169

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Glu 1 5 10 15 '

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1170 &lt;211&gt; 10 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;400&gt;

Gly Pro Ser Ser Gly Ala Pro Pro Pro Lys 1 5 10 &lt;210&gt; 1171 &lt;211&gt; 11 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Polypeptide &lt;220&gt;

&lt;221&gt; M0D.RES -479· 156004. Sequence Listing.doc 201143790 &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Gly or a small aliphatic or non-polar or slightly polar amine group Acid &lt;400&gt; 1171

1aa &lt;211&gt; 12 &lt MOD RES &lt;222&gt; (1)..(1) &lt;223&gt; Xaa is Gly or a small aliphatic or non-polar or slightly polar amino acid &lt;400&gt;

Xaa Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser Lys 1 5 10 &lt;210&gt; 1173 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; 3Caa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (167..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1174 •480·

156004. Sequence Listing.doc 201143790 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently linked to cysteine PEG (40 kDa) &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1174

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Gin Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1175 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)7. 40) &lt;223&gt; C-terminal amide &lt;400&gt; 1175

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 1 5 10 15 481 · 156004 - Sequence Listing.doc 201143790

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1176 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Oig amide &lt;400&gt; 1176

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1177 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (29)7.(29) &lt;;223&gt; 0: terminal amidation &lt;400&gt; 1177

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15 482-

156004· Sequence Listing.doc 201143790

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1178 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MISC FEATURE &lt;223&gt; 0 terminal amidation &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20)

&lt;223&gt; Xaa is into ib &lt;400&gt; 1178

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Ser 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1179 &lt;21]&gt; 30 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Polypeptide&lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently linked to cysteine PEG (40kDa) &lt;400&gt; 1179

His Xaa Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly Arg 20 25 30 &lt;210&gt; 1180 &lt;211&gt; 42 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide - 483 · 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATORE &lt;222&gt; (24).. (24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt; 1180

Tyr Ala Pro Gly Thr Phe lie Ser Asp Tyr Ser lie Ala Met Asp Lys 15 10 15 lie His Gin Gin Asp Phe Val Xaa Trp Leu Leu Ala Gin Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin 35 40 &lt;210&gt; 1181 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt;; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC FEATTJRE &lt;222&gt; (40)..(40) &lt;223&gt; covalently bonded to the hydrophilic group Substituted amino acid &lt;400&gt; 1181

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1182 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MODJ ^ES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC_FEATURE -484-

156004. Sequence Listing.doc 201143790 &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24).. (24) &lt;223&gt; conjugated amino acid bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; misc_feature &lt;222&gt; (29).. (29) &lt;223&gt; The harshness of any of the naturally occurring amino acids &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 1 5 10 15

Gin Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Xaa 20 25

&lt;210&gt; 1183 &lt;21l&gt; 39 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic amine between residue 16 and residue 20 Bridge key &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24) 7. (24) &lt;2 of 3&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1184 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; M0D RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib 156004-sequence table.doc -485 - t;: 201143790 &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16). (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue 20 &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (40)..(40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt; 1184

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa &gt;&gt;&gt;&gt;&gt;&gt; 012 3 03 li 1 1i 1 Ti d^^&lt;2&lt;2 1185 29

PRT

Artificial sequence synthesis polypeptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16 (20) &lt;223&gt; The intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISCFEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt; 1185

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Xaa Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1186 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (16)..(20) - 486-156004-Sequence Listing.doc 201143790 &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40 &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1187 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial sequence

&lt;220> &lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; an intrinsic amine bridge between residue 16 and residue &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24) (24) &lt;223&gt; covalently bonded to a hydrophilic group Substituted amino acid &lt;400&gt; 1187

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Xaa Trp Leu Met Asn Gly &lt;210&gt; 1188 &lt;211&gt; 40 &lt;212&gt; PRT &lt;2]3&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D.RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16).. (20) &lt;223&gt; intrinsic amine bridge between residue 16 and residue &lt;220&gt;

&lt;221&gt; MISC.FEATURE 487- 156004-sequence table.doc 201143790 &lt;222&gt; (40)..(40) &lt;223&gt; Substituted amino acid bonded to a hydrophilic group &lt;400&gt; 1188

Tyr Xaa Gin Gly Thr Phe Val Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1189 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222> (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220> &lt;221&gt; MISC FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; The intrinsic amine bridge between the residue and the residue 20 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223>Xaa is Nle &lt;220&gt;&lt;221&gt; FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt;

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Xaa Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1190 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223:&gt; Xaa is Aib &lt;220&gt; •488·

156004-Sequence List.doc 201143790 &lt;221&gt; MISC.FEATURE &lt;222&gt; (16) 7. (20) &lt;223&gt; Intrinsic Amine Bridge between Residue 16 and Residue 20 &lt;220&gt;;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to the hydrophilic base map &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Arg Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40

&lt;210&gt; 1191 &lt;211&gt; 43 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2). (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (16)..(20) &lt;223&gt; guilt between residue 16 and residue 20. Amine bridge &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (43) 7. (43) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Lys Gly Lys 20 25 30

Lys Asn Trp Leu Lys His Asn lie Thr Gin Xaa 35 40 &lt;210&gt; 1192 &lt;211&gt; 40 &lt;2)2&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt; 489-156004-sequence table.doc 201143790 &lt;221&gt; MOD RES &lt;222&gt; (20 (20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURB &lt;222&gt; (40)..(40) &lt;223&gt; Covalently bonded to the substitution of a hydrophilic group Amino acid &lt;220&gt;&lt;221&gt; MISC_FEATORE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1193 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221> MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24) (24) &lt;223&gt; Covalent & coupled to hydrophilic group of substituted amino acid &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222> (40): (40) &lt;223&gt; C-terminal ameliation &lt;400&gt; 1193

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1194 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence • 490·

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;223&gt;Synthetic polypeptide

&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; kaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20).. (20 &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (24) 7. (24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40): (40) &lt;223&gt; C-terminal amide &lt;400&gt; 1194

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr 1 5 10

Ser lie Tyr Leu Asp Lys 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu 20 25

Leu Ala Gly Gly Pro Ser 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1195 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;

&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D „RES &lt;222&gt; (207..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently bonded to a mercapto or alkyl substituted amino acid &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1195 156004-sequence, doc 491-201143790

Tyr Xaa GIu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1196 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222> (40): (40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1196 Tyr Xaa Gin Giy Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 ^ &gt;&gt;&gt; 012 3 2 2 2 2 &lt;&lt;&lt; 1197 39 PRT Artificial Sequence &lt;220〉 &lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib 156004. Sequence Listing. doc - 492 · 201143790 &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Covalently bonded to sulfhydryl or alkane Substituted amino acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (39)..(39) &lt;223&gt; C-terminal amide hydration &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35

&lt;210&gt; 1198 &lt;211&gt; 39 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to a mercapto or alkyl substituted amine group Acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (39)..( 39) &lt;223&gt; C-terminal amidation &lt;400&gt; 1198

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1199 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt;Synthetic Peptide 493 · 156004 · Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222> (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently bonded to a mercapto or alkyl substituted amino acid &lt;220&gt;;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; 0: terminal amidation &lt;400&gt; 1199

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1200 &lt;2U&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Substituted amino acid covalently bonded to the pro-long group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (29)..(29) &lt;223&gt; terminal amination &lt;400&gt; 1200

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1201 •494-

156004-Sequence List.doc 201143790 &lt;2ll&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2) ..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M1SC_FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; Covalently bonded to a mercapto or alkyl substituted amine Base acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (29) 7. (29) &lt;223&gt; C-terminal amidation &lt;400&gt; 1201

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1202 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; And X; ;221&gt; MISC FEAmE &lt;222&gt; (40)7, (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1202

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 495 - 156004 - Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1203 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; A substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; covalently bonded to a mercapto or alkyl group Substituted amino acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; 0 terminal amidation &lt;400&gt; 1203

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1204 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;

&lt;221&gt; MISC.FEATURE 156004 - Sequence Listing.doc 496-

201143790 &lt;222&gt; (24)..(24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC_FEATIJRE &lt;222&gt; (40).. (40 ) &lt;223&gt; C-terminal amide &lt;400&gt; 1204

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40

&lt;210&gt; 1205 &lt;211&gt; 40 &lt;212&gt; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; 0: terminal amination &&lt;400&gt; 1205

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1206 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D.RES • 497- 156004-sequence table.doc 201143790 &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto group or an alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 1206

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1207 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD A RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;

&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; 0: terminal amidation &lt;400&gt; 1207

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 156004-Sequence Listing.doc -498-

201143790 &lt;210&gt; 1208 &lt;211&gt; 40 &lt;2)2&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;2M&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; 2) 7. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)7 (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto group or an alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; : Terminal amination &lt;400&gt; 1208

Tyr Xaa Gin Gly Thr Phe Thr Ser

Asp Tyr 10

Ser lie Tyr Leu Asp Lys 15

Gin Ala Ala Xaa Glu Phe Val Xaa 20

Trp Leu 25

Met Asn Gly Gly Pro Ser 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40

&lt;210&gt; 1209 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (2)7 (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC^ FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40). (40) -499· 156004-sequence table.doc 201143790 &lt;223&gt; C-terminal amidation &lt;400&gt; 1209

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Cly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1210 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D__RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;22i&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; A substituted amino acid covalently bonded to a mercapto group or an alkyl group &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 1210

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Va) Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1211 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES -500 - 156004 - Sequence Listing.doc 201143790 &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40 (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto group or an alkyl group &lt;220> &lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt;; 0: terminal amidation &lt;400&gt; 1211

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40

&lt;210&gt; 1212 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223>Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; (: terminal amination &lt;400&gt; 1212

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1213 &lt;21l&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt; 501 - 156004. Sequence Listing.doc 201143790 &lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20).. (20 &lt;223&gt; Xaa is Aib &lt;220> &lt;221&gt; Ml SC FEATURE &lt;222&gt; (24): (24) &lt;223&gt; Covalently bonded to the hydrophilic group of the substituted amino acid &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1213

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1214 &lt;211&gt; 40 &lt;212&gt; PRT &lt;2U&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (201..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1214

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Va'l Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30 502- 156004 · Sequence Listing.doc 201143790

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1215 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24) 7. (24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;&lt;221&gt; MISC.FEATIJRE &lt;;222&gt; (40)..(40) &lt;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (40 ) (40) C-terminal amide hydration &lt;400&gt; 1215 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 b&gt; Λ 012 012 3 &lt;21&lt;21&lt;21&lt;21 1216 40 PRT artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2): (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (24):, (24) 156004 - Sequence Listing _doc - 503 - 201143790 &lt;223&gt; Substituted Amino Acid Covalently Bonded to Hydrophilic Group &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; 〇: terminal amidation &lt;400&gt; 1216 Tyr Xaa Glu Gly Thr Phc Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1.5 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1217 &lt;21l&gt; 39 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD A RES&lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE&lt;222&gt; (10)..(10) &lt;223&gt; covalently bonded to Mercapto or alkyl substituted amino acid &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt; MISC FEATURE (40).. (40) C-terminal amide hydration &lt;400&gt; 1217 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Cys Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &gt;&gt;&gt;&gt; 012 3 2 2 2 &lt;v &lt; v 1218 41 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide

&lt;220&gt;&lt;221&gt; M0D.RES 156004· Sequence Listing.doc -504-201 143790 &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD .RES&lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalent Bonding Substituted amino acid to mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC.FEATTJRE &lt;222&gt; (41) 7. (41) &lt;223&gt; C-terminal amide hydration &lt;400&gt; 1218 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie 1 5 10

Tyr Leu Asp Lys 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala 20 25

Gly Gly Pro Ser 30

Ser Gly Ala Pro Pro Pro Ser Xaa Cys 35 40 !&gt;&gt;&gt;&gt;&gt;&gt;&gt; 0123 03 n 11 1* 1 2 1219 39 PRT Artificial Sequence Synthesis Polypeptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10)..(10) &lt;223&gt; covalent bond Substituted amino acid to thiol or alkyl group &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC .FEATURE &lt;222&gt; (24) (24) &lt;223&gt; Covalently sutured to the hydrophilic group of substituted amino acids &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (39)..( 39) &lt;223&gt; 0-terminal amidation &lt;400&gt; 1219 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Xaa Ser lie 1 5 10 Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala 20 25

Tyr Leu Asp Lys 15 Gly Gly Pro Ser 30 156004 - Sequence Listing.doc • 505 · 201143790

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1220 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC„FEAT\JRE &lt;222&gt; (40)7.(40) &lt;;223&gt; Substituted amino acid covalently bonded to a mercapto or alkyl group &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (41)..(41) &lt;223&gt; covalently bonded to Substituted amino acid of hydrophilic group &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (41)..(41) &lt;223&gt; 0 terminal amidation &lt;400&gt; 1220

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa Xaa 35 40 &lt;210&gt; 1221 &lt;211&gt; 41 &lt;212> PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Ib

MISC.FEATURE &lt;220&gt;&lt;222&gt; (41)..(41) &lt;223&gt; conjugated amino acid 506-linked to a hydrophilic group 】 56004 - Sequence Listing. doc 201 143790 &lt; 220 &gt ; &lt;221&gt; MISC FEATURE &lt;222&gt; (41)7.(41) &lt;223&gt; C-terminal amidation &lt;400&gt; 1221 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser 1 5 10

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu 20 25 lie Tyr Leu Ala Gly Gly 30

Asp Lys 15 Pro Ser

Ser Gly Ala Pro Pro Pro Ser Lys Xaa 35 40 012 3 11 1 11 V &lt; V &lt; Column 22T Worker 1240PR Person &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Covalently bonded to thiol or alkane Substituted amino acid &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (40) 7. (40) &lt;223&gt; (: terminal amidation &lt;400&gt; 1222 His Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser 1 5 10

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Met 20 25

Lys Tyr Leu Asn Gly Gly 30

Asp. Glu 15 Pro Ser

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1223 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES&lt;222&gt; (20)..(20) 156004-sequence list.doc 507- 201143790 &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATORE &lt;222&gt; (24) 7. (24) &lt;223&gt; A substituted amino acid covalently bonded to a hydrophilic group circle &lt;220&gt;&lt;221&gt; MISC.FEATDRE &lt;222&gt; (40).. (40) &lt;223&gt; A substituted amino acid covalently bonded to a brewing group or an alkyl group &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; (: terminal amination &lt;400&gt; 1223

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Xaa Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1224 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;220&gt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; terminal amination &lt;400&gt; 1224

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Lys Glu Phe Vai Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &lt;210&gt; 1225 &lt;211&gt; 40 156004. Sequence Listing. doc -508· 201143790 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220&gt;&lt;221&gt; MOD RES . &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16).. (16) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;223 ;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Extremely aminated &lt;400&gt; 1225

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Gin Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Xaa 35 40 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21&lt;21 1226 30

PRT artificial sequence &lt;220&gt;&lt;223&gt; synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt;; MISC FEATURE &lt;222&gt; (24)..(24) &lt;223&gt; Substituted amino acid covalently bonded to a hydrophilic group &lt;400&gt; 1226

His Xaa GIu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Glu 15 10 15

Gin Ala Ala Lys Glu Phe lie Cys Trp Leu Val Lys Gly Arg 20 25 30 &lt;210&gt; 1227 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence - 509 - 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (29)7.(29) &lt;223&gt; C-terminal amidation &lt;400&gt;; 1227

Tyr Xaa Gin Gly Thr Phe Thr Ser 1 5

Asp Tyr Ser lie Tyr Leu Asp Lys 10 15

Trp Leu Leu Ala Gly 25

Gin Ala Ala Xaa Glu Fhe Val Asn 20 &lt;210&gt; 1228 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is D-Ser, D-Ala, Val, Gly, N-methyl Ser, N-methyl Ala or Aib &lt;220&gt;&lt;221&gt;; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; kaa is ilys, Glu, Ser, Om, Dab, Aib or any ctjCt disubstituted amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is any 双^disubstituted amino acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. (27 &lt;223&gt; Xaa is lie, Leu or Nle &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (28)..(28) &lt;223&gt; Xaa is Ala or Gly &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt;XaaSThr, Ala4Gly &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (29)..(29) &lt;223&gt; Terminal amidation &lt;400&gt; 1228 510- 156004-sequence table.doc 201143790

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Xaa 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Xaa Xaa Xaa 20 25 &lt;210&gt; 1229 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MODJRES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (207..(20)

&lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (29)..(29) &lt;223&gt; Amylation &lt;400&gt; 1229

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Lys 1 5 10 15

Arg Arg Ala Xaa Asp Phe Val Gin Trp Leu Leu Ala Gly 20 25 &lt;210&gt; 1230 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt;Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD.RES &lt;222&gt; (2)., (2) &lt;223&gt; Xaa^D-Ser, DAla, Val, Gly, N-methyl Ser, N-mercapto Ala or Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Lys, Glu, Ser, Om, Dab, Aib or any (^disubstituted amino acid &lt;220&gt;;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is any 双^disubstituted amino acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (27) ..(27) &lt;223&gt; Xaa is lie, Leu or Nle &lt;220&gt;&lt;221&gt; M0D_RBS &lt;222&gt; (28)..(28) &lt;223&gt; Xaa is human la or Gly 511 · 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (29)..(29) &lt;223&gt; Xaa is Thr, Ala or Gly &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (29)..(29) &lt;223&gt; C-terminal amidation &lt;400&gt; 1230

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Xaa Asp Phe Val Gin Trp Leu Xaa Xaa Xaa 20 25 &lt;210&gt; 1231 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt; Artificial sequence &lt;220&gt;

&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;223&gt; homodimer &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (2).. (2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD^RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC_FEATURE &lt;222&gt; (40) &lt;223&gt; Covalently bonded to 14-carbon fatty sulfhydryl group of lysine &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (40).. (40)

&lt;223&gt; terminal amidation &lt;220&gt;&lt;221&gt; DISULFID &lt;222&gt; (41)..(41) &lt;223&gt; Disulfide formed with Cys residue of the second peptide having the same structure Key &lt;400&gt; 1231

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 &lt;210&gt; 1232 156004 - Sequence Listing.doc -512- 201143790 &lt;211&gt; 40 &lt;2I2&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;

&lt;221&gt; MOD^RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;

&lt;221&gt; M0D „RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;;223&gt; C-terminal amide &lt;400&gt; 1232

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Met Asn Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210> 1233 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib

&lt;220&gt;

&lt;221&gt; M0D_RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; (40)..(40) &lt;223&gt;; C-terminal amides &lt;400&gt; 1233

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 •513- 156004-sequence table.doc 201143790 &lt;210&gt; 1234 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthesis Peptide &lt;220> &lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; jCaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2〇T.. (20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; Covalently bonded to the 16-carbon fat sulfhydryl group of the amine acid ;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1234

Tyr Xaa Gin Gly Thr Phe lie Ser Asp Tyr Ser lie Tyr Leu Asp Lys 1 5 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser L,s &lt;210&gt; 1235 &lt;211&gt; 40 &lt;2I2&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MOD .RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40).. (40) &lt;223&gt; Covalently bonded to the 16-carbon fatty sulfhydryl group of the lysine via the dipeptide spacer &lt;220&gt;221&gt; MISC_FEATTJRE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1235 514-

156004· Sequence Listing.doc 201143790

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1236 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;SyntheticPolypeptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib

&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)7. 40) &lt;223&gt; Covalently bonded to the 16-carbon fatty sulfhydryl group of the lysine via the dipeptide spacer &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; C-terminal amides &lt;400&gt; 1236

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 10 15

Gin Ala Ala Xaa Glu Phe Va) Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1237 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D .RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (10) 7. (10) &lt;223&gt; via dipeptide The spacer is covalently bonded to the 16-carbon fatty sulfhydryl group of the lysine 515- 156004-sequence table. doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; C-terminal amidation &lt;400&gt; 1237

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Lys Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Va! Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1238 &lt;211&gt; 41 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt; 223 &gt; suffix &lt; 220 &lt; 221 &gt; MOD RES &lt; 222 &gt; (2) 7. (2) &lt; 223 > Xaa is Aib &lt; 220 &gt;&lt; 221 &gt; MOD RES &lt;222&gt; (20)..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40)..(40) &lt;223&gt; covalently bonded to lysine 14 carbon fat thiol &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41) 7. (41) &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41).. (41) &lt;223&gt; covalently linked to a Cys residue of 20 kDa PEG, which is in turn covalently linked to a Cys residue of the second peptide having the same structure &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 516-

156004-Sequence List.doc 201143790 35 &lt;210&gt; 1239 &lt;211&gt; 41 &lt;212&gt; PRT &lt; 213 &gt; Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;;223&gt;Equivalent__Poly&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (201..(20) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (40) 7. (40) &lt;223&gt; covalently bonded to lysine 14 carbon fat thiol &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41) 7. (41) &lt;223&gt; PEG (5 kDa) &lt;220&gt; covalently bonded to cysteine; &lt;220&gt;221&gt; MISC FEATURE &lt;222&gt; (41)7.(41) &lt;223&gt; (: terminal amination &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (41) 7. (41) &lt;223&gt; covalently linked to a Cys residue of 5 kDaPEG, which is in turn covalently linked to a Cys residue of the second peptide of the same structure &lt;400&gt;

Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser He Tyr Leu Asp Lys 15 10 15

Gin Ala Ala Xaa Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys Cys 35 40 012 3 li n 1· n &lt;2&lt;2&lt;2&lt;2 &lt;220&gt;&lt;223&gt; 1240 29

PRT artificial sequence synthetic peptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is branamine analog 156004 - Sequence Listing. doc -517- 201143790 &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1240

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1241 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is branamine analog &lt;220&gt;&lt;22l&gt; MOD RES &lt;222&gt; (16)..( 16) &lt;223&gt; Xaa is Aib &lt;400&gt; 1241

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210> 1242 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle · &lt;400&gt; 1242

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1243 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide•518- 156004 - Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt;&lt;222&gt;&lt;223&gt;

MOD-RES B>醯aminomethyl·cystein J is acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1243

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp G)u 20 25 &lt;210&gt; 1244 &lt;211&gt; 29 &lt;2i2&gt; PRT &lt;213&gt; Artificial Sequence &lt;220&gt;

&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is Nle &lt;4〇〇&gt; 1244

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1245 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is amine-mercaptodiaminopropionic acid &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (27) ..(27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1245

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 1 5 10 15 519- 156004 - Sequence Listing.doc 201143790

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1246 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is thioglycolic acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1246

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1247 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is arsenic amide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27).. (27) &lt;223&gt; Xaa is Nle &lt;400&gt; 1247

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210> 1248 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidine 520·

156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (27)..(27) &lt;223&gt; Xaa is ^Ile &lt;400&gt; 1248 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Thr 15 10 15

Arg Arg Ala Ala Glu Phe Val Ala Trp Leu Xaa Asp Glu 20 25 &lt;210&gt; 1249 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 1249 His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &gt;&gt;&gt;&gt; 012 3 &lt;21&lt;21&lt;21«^1 &lt;220&gt;&lt;223&gt; 1250 29 PRT Artificial Sequence Synthesis of Polypeptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 1250 His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 1251 &lt;211> 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt; 156004-Sequence List.doc -521 - 201143790 &lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; MOD_RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is methyl-proline lysine &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 1251

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Met Asp Glu 20 25 &lt;210&gt; 1252 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;400&gt; 1252

His Ser Gin Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser 15 10 15

Arg Arg Ala Gin Asp Phe Val Gin Trp Leu Met Asp Thr 20 25 &lt;210&gt; 1253 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial sequence &lt;220&gt;&lt;223&gt; Synthetic polypeptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD.RES &lt;222&gt; (16). .(16) &lt;223&gt; Xaa is Aib &lt;400&gt; 1253

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 1254 &lt;211&gt; 39 &lt;212&gt; PRT &lt;213&gt; Artificial sequence • 522·

ϊ 56004 - Sequence Listing. doc 201143790 &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiamine Butyric acid &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (16)..(16) &lt;22 3&gt; Xaa^Aib &lt;220&gt;&lt;221&gt; MISC.FEATURE &lt;222&gt; ) 7.(39) &lt;223&gt; C-terminal amidation &lt;400&gt; 1254

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Ala Asp Phe Val Ala Trp Leu Leu Asp Thr Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser 35 &lt;210&gt; 1255 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt; Synthetic Peptide&lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (3) 7. (3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid &lt;220&gt;&lt;221&gt; MOD-RES &lt;222&gt; (16)..(16) &lt;223&gt;; Xaa is Aib &lt;400&gt; 1255

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 1 5 10 . 15

Arg Arg Ala Ser Asp Phe Val Ser Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 1256 &lt;211&gt; 29 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220&gt;&lt;221&gt; M0D.RES &lt;222&gt; (3)..(3) &lt;223&gt; Xaa is acetamidodiaminebutyric acid-523 - 156004. Sequence Listing.doc 201143790 &lt;220&gt;&lt;221&gt;; MOD RES &lt;222&gt; (16)..(16) &lt;223&gt; Xaa is into ib &lt;400&gt; 1256

His Ser Xaa Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Xaa 15 10 15

Arg Arg Ala Thr Asp Phe Val Thr Trp Leu Leu Asp Glu 20 25 &lt;210&gt; 1257 &lt;400&gt; 1257 000 &lt;210&gt; 1258 &lt;400&gt; 1258 000 &lt;210&gt; 1259 &lt;211&gt; 40 &lt;212&gt ; PRT &lt; 213 &gt; artificial sequence &lt;220&gt;&lt;223&gt; synthetic peptide &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is Aib &lt;220&gt;;&lt;221&gt; MISC.FEATURE &lt;222&gt; (16)..(20) &lt;223&gt; Linking the indole bridge of Glul6 and Lys20&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; 40).. (40) &lt;223&gt; The epsilon amine of Lys is linked to Ala-Ac-Cys (PEG), wherein Ac-Cys (PEG) is an alpha amine group comprising a thiol group (CH3CO) and comprises Dys residue of 40kDaPEG covalently linked to the side chain &lt;400&gt; 1259

Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Lys 35 40 &lt;210&gt; 1260 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt;Artificial Sequence&lt;220&gt;&lt;223&gt;Synthetic Peptide•524- 156004-Sequence List.doc 201143790 &lt;220&gt;&lt;221&gt; M0D_RES &lt;222&gt; (2)..(2) &lt;223&gt; Xaa is A* &lt;220&gt;&lt;221&gt; MISC FEATURE &lt;222&gt; (16)..( 20) &lt;223&gt; linkage between Glul6 and Lys20 guanamine bridge &lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; Lys ε amine is attached to Aig -Ac-Cys (PEG), wherein Ac-Cys (PEG) is a Cys residue comprising an alpha-amino group terminated with an ethyl thiol (CH3CO) and comprising a 40 kDa PEG covalently linked to a side chain &lt;400&gt; 1260 Tyr Xaa Gin Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ly Lys 35 40 &gt;&gt;&gt;&gt; 0123 11 11 1* 2 ΟΛ οώ 2 &lt; VV &lt; 1261 40 PRT Artificial Sequence &lt;220&gt;&lt;223&gt; Synthetic Peptide &lt;220 〉 &lt;221&gt; MOD RES &lt;222&gt; (2)7.(2) &lt;223&gt; Xaa is Aib &lt;220&gt;&lt;221&gt; MISC.FEATliRE &lt;222&gt; (16)..(20) &lt;;223&gt; Linking Glul6 to Lysin's indole bridge (&lt;220&gt;&lt;221&gt; MOD RES &lt;222&gt; (40)..(40) &lt;223&gt; Cys covalently bonded via a thioether bond -PEG &lt;400&gt; 1261 Tyr Xaa Glu Gly Thr Phe Thr Ser Asp Tyr Ser lie Tyr Leu Asp Glu 15 10 15

Gin Ala Ala Lys Glu Phe Val Asn Trp Leu Leu Ala Gly Gly Pro Ser 20 25 30

Ser Gly Ala Pro Pro Pro Ser Cys 35 40 &lt;210&gt; 1262 &lt;211&gt; 40 &lt;212&gt; PRT &lt;213&gt; Artificial Sequence 156004-Sequence List.doc •525·

Claims (1)

201143790 VII. Application for Patent Park: 1 _ A compound containing the structure QL-Υ, where Q is a superfamily peptide; Y is an activated nuclear hormone with EC5〇 of about 1 μΜ or less An NHR ligand having a molecular weight of up to about 1 Dalton; and L is a linking group or a bond. 2. The compound of claim 1, wherein the activity exhibited by Q on the GLP-1 receptor is at least 〇. 1 〇/〇 of the activity of the native GLP-1. 3. The compound of claim 1 or 2, wherein the activity exhibited by Q on the glycemic receptor is at least 0.1 °/〇 of the activity of the native glycein. 4. The compound of any one of claims 1, 2 or 3, wherein the activity exhibited by Q on the GIP receptor is at least 〇. 1 〇/0 of the activity of the native GIP. 5. A compound according to any of the preceding claims, wherein q has an ECm of gamma-1 receptor within 10 times ec5 of the nuclear hormone receptor. 6. The compound according to any of the preceding claims, wherein q is an oxime of the glycoside-accepting EC" is 〇 within 1〇 of the EC5〇 of the nuclear hormone receptor. 7. As in the preceding claim A compound of any one, wherein the ECso of q for the GIp receptor is Y within 1 〇 of the nuclear hormone receptor. 8. A compound according to any one of the preceding claims, wherein γ is An NHR ligand which acts on a type 1 nuclear hormone receptor or a type II nuclear hormone receptor. 9. The compound of claim 8, wherein γ is a nhr ligand, the effect of which is selected from the group consisting of Group of nuclear hormone receptors: estrogen receptor, glucocorticoid receptor, mineralocorticoid receptor, progesterone receptor, androgen receptor 156004.doc 201143790 thyroid hormone receptor, retinoic acid receptor, peroxidation Body proliferator-activated receptor, liver X receptor, farnesic acid 受体 receptor, vitamin D receptor, RAR-related orphan receptor, and pregnane receptor. ίο. 11. 12. 13 14. 15. 16. 17. 18. 19. The compound of claim 9 wherein Y is a NHR ligand, which activates the estrogen A compound, such as a compound of claim 10, wherein γ is activating an estrogen receptor 2Nhr ligand. A compound according to any one of the preceding claims. Wherein γ is selected from the group consisting of fatty acids and derivatives thereof, bile acids and derivatives thereof, cholesterol and derivatives thereof, and steroids and derivatives thereof. The compound of claim 12, wherein γ is selected from the group consisting of a group consisting of: an estradiol and a derivative thereof, an estrone and a derivative thereof, a testosterone and a derivative thereof, and a cortisol and a derivative thereof. The compound according to any one of the preceding items, wherein L is in vivo The compound of any one of the preceding claims, wherein the compound of any one of the preceding claims, wherein L is in an octet in vivo. Wherein L comprises an ether moiety or a guanamine moiety. The compound of claim 15 wherein l comprises an ester moiety. The compound of claim 16, wherein L comprises an acid labile moiety, reducing 156004.doc 201143790 The compound of claim 19, wherein L comprises a guanidine moiety, a disulfide moiety or a cathepsin cleavable moiety. 21. A compound according to any of the preceding claims, wherein Q Containing an amino acid sequence that is at least 50% identical to native glycosidic acid, which retains the alpha helix of the amino acid corresponding to the amino acid 12 to 29 of the native glucagon (SEQ ID NO: 1601) The compound of any one of the preceding claims, wherein Q comprises at least 50°/ of the native GLP-1. A homologous amino acid sequence which retains the alpha helix configuration of the amino acid corresponding to the amino acid 12 to 29 of native GLP-1 (SEQ ID NO: 1603). The compound according to any of the preceding claims, wherein Q comprises the following amino acid sequence: Xi-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu- Asp-Ser-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met-Z (SEQ ID NO: 839) having 1 to 3 amino acid modifications, (a) wherein also! And/or X2 is a non-native amino acid (relative to SEQ ID NO: 1601) which reduces the possibility of dipeptidyl peptidase IV (DPP-IV) cleavage of the glycosidic peptide, (b) wherein Z is selected from a group consisting of -COOH, -Asn-COOH, Asn-Thr-COOH, and W-COOH, wherein W is 1 to 2 amino acids or GPSSGAPPPS, (c) wherein Q comprises a modification selected from the group consisting of : (1) an intrinsic amine bridge between the amino acid side chain at position i and the amino acid side chain at position i+4 156004.doc 201143790, where i is 12, 16, 20 or 24, and (ii) One, two, three or all of the amino acids at positions 16, 20, 21 and 24 of the glycosidic peptide are substituted with an alpha, alpha disubstituted amino acid; wherein Q exhibits a glycoside Agonist activity. 24. The compound of claim 23, wherein Q comprises the amino acid sequence SEq id NO: 1601 and comprises: (a) at least one amino acid modification selected from the group consisting of: (1) Thr at position 29 Substituted by a charged amino acid; said (ii) Thr at position 29 is substituted with a charged amino acid selected from the group consisting of Lys, Arg, His, Asp, Glu, apo-alanine, and a south base. (iii) substituted with Asp, Glu or Lys at position 29; (iv) substituted with Glu at position 29; (v) 1 to 3 charged amino acids after position 29; (vi) Insert Glu or Lys after position 29; (vii) Insert Gly-Lys or Lys-Lys after position 29; Gin at position 3 of Lu (viii) is substituted with an amino acid containing a side chain of structure I, II or III : • 卜r1-ch2-x 丄R2 Structure IY j-R1-CH2-*L Structure II 156004.doc 201143790 ο ^-r1-ch2-s-ch2-r4 Structure III wherein R1 is C0-3 alkyl or C 〇_3 heteroalkyl; R2 is NHR4*^^alkyl; ... is 匕^alkyl; R4 is 11 or (:1.3 alkyl; X is NH, hydrazine or S; and Y is NHR4, SR3 or OR3; And (ix) its combination; (b) the Ser of the position 16 Thr, Glu or Aib substitution; and at least one amino acid modification selected from the group consisting of: (1) His position at position 1 reduces the possibility of cleaving the glyce peptide by dipeptidyl peptidase IV (DPP-IV) a non-primary amino acid substitution, (ii) a non-native amino acid substitution at position 2 in which Ser is reduced by the possibility of cleaving the glycosidic peptide by dipeptidyl peptidase IV (DPP-IV), (iii) The Thr at position 7 is substituted by lie, Abu or Val; (iv) the Gin at position 20 is replaced by Ser, Thr, Ala, Aib, Arg or Lys; (v) Met at position 27 is replaced by Leu or Nle; Vi) deletion of the amino acid at positions 28 to 29; (vii) deletion of the amino acid at position 29; (viii) addition of the amino acid sequence GPSSGAPPPS to the C-terminus; and (ix) addition of the amino acid sequence GPSSGAPPPSX To the C-terminus, wherein X is any amino acid; and (X) a combination thereof; wherein Q exhibits a glycosidic agonist activity. 25. A compound according to any one of claims 1 to 22, wherein Q comprises a glycoside Prime phase 156004.doc S 201143790 Guan peptide SEQ ID NO: 1601, which has the following modifications: (a) Amino acid modification imparting GIP agonist activity at position 1, (b) The modification of the group consisting of: (1) the amino acid side chain at position i and the amino acid side chain at position i+4 or the amino acid side chain at position j and position j + 3 An intrinsic amine bridge between amino acid side bonds wherein hydrazine is 12, 13, 16, 17, 2 or 24' and wherein j is 17, and (ii) the position of the analog 16, 20, 21 And one or two, or all or all of the amino acids on the 24 and the α,α disubstituted amino acid are substituted, (c) 1 to 1 〇 at the other amino acid modification; wherein Q pairs This GIP receptor exhibits activity. 26. The compound of claim 25, wherein the 1 to 10 other amino acid modifications are selected from the group consisting of: (1) the serine at position 2 via D-Ser, Ala, D-Ala, Gly, Ν-Methyl-Ser, Aib, Val or ε-amino-N-butyric acid substitution; (ii) Phosphine at position 16 via Glu, Gin, glutamic acid, high sulfoalanine, Thr, Replace with Gly or Aib; (iii) the glutamic acid at position 20 is substituted with Ser, Thr, Ala, Lys, citrulline, Arg, Orn or Aib; (iv) methionine at position 27 is replaced by Leu (v) arginine at position 28 is substituted with Ala; (vi) threonine at position 29 is replaced by Gly; (vii) positions 2, 5, 9, 10, 11, 12, 13, 14, 15 , 16, 156004.doc. a. 201143790 Conservative substitution on any of 17, 18, 20, 21, 24, 27, 28, and 29; (viii) Adding 1 to 21 amino acids to C (ix) Adding the amino acid sequence GPSSGAPPPS to the C-terminus; (X) adding the amino acid sequence GPSSGAPPPSX to the C-terminus, where X is any amino acid; (xi) C-terminal carboxyl group via decylamine or carboxylic acid Ester substitution; and (xii) combinations thereof. The compound according to any one of claims 1 to 22, wherein Q comprises the following amino acid sequence: Xi-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X3-Ser-X4-Tyr -Leu-X5-X6-X7~X8-Ala-X9-Xi〇-Phe-Xii-Xi2_Trp-L6u-Xj3-X14-X15 (SEQ ID NO: 55), or an analogue thereof, wherein the analog and SEQ ID NO: 55 differs in that it is selected from the group consisting of positions 1, 2, 3, 5, 7, 10, 11, 13, 14, 17, 18, 19, 21, and 25 to 1 to 3 amino acid modification, wherein : (a) X丨 is His, D-His, (de-amino) His, hydroxy-His, acetyl-His, high-His or α, α-dimethylimidazoliumacetic acid (DMIA), N- Mercapto-His, α-methyl His or taste. Sitting on acetic acid; (b) X2 is Ser, D-Ser, Ala, D-Ala, Val, Gly, N-mercapto Ser, aminoisobutyric acid (Aib) or N-methyl Ala; (c) x3, X4, x5, x1Q, 乂丨丨 and "individually any amino acid; (d) X6 is Ser, Glu, Gin, homofacial acid or homo-alanine; 156004.doc 201143790 (e) X7 is Arg , Gin, Lys, Cys, Orn, homocysteine or acetopheniric acid; (f) fork 8 is Arg, Ala, Lys, Cys, Orn, homocysteine or acetyl phenylalanine; g) X9 is Gin, Lys, Arg, Orn or citrulline; (h) X12 is Ala, Gin, Glu, Lys, Cys, Orn, homocysteine or acetyl phenylalanine; (i) X丨3 is Met, Leu or Nle; (j) X15 is Thr, Gly, Lys, Cys, Orn, homocysteine or acetamino albendine; and one of the following modifications is optionally included: (a) Deletion of the amino acid at positions 28 to 29; (b) deletion of the amino acid at position 29; (c) addition of the amino acid sequence GPSSGAPPPS to the C-terminus; and (d) addition of the amino acid sequence GPSSGAPPPSX to C Terminal, wherein X is any amino acid; and (e) a combination thereof. The compound of any one of claims 1 to 22, wherein Q comprises an amino acid sequence which differs from SEQ ID NO: 1601 by at most 10 amino acid modifications, comprising: (a) positions 16, 20, 21 And/or 24 one or more amino acids substituted by Aib, and (b) amino acid modification at position 1 and/or 2 to reduce the possibility of cleavage by dipeptidyl peptidase IV and 156004.doc 201143790 Depending on the situation, one or more of the following modifications are included: (a) deletion of amino acids at positions 28 and 29, (b) deletion of amino acid at position 29, (c) addition of amino acid sequence GPSSGAPPPS to C (d) Adding the amino acid sequence GPSSGAPPPSX to the C-terminus, wherein X is any amino acid, (e) the C-terminal carboxyl group is substituted with a decylamine or a carboxylic acid ester, and wherein Q exhibits GLP-1 agonist activity And a compound of any one of the preceding claims, wherein LY is covalently bonded to the N-terminus, C-terminus or amino acid side chain of q. a compound wherein LY binds to an amine group of Q corresponding to position 10, 30, 37, 38, 39, 40, 41, 42 or 43 of the native glucagon (SEQ ID NO: 1601) Side chain. 31. The compound of claim 27, wherein L-Y binds to the amino acid side chain of Q corresponding to the position of the sequence comprising the native glucagon (SEQ ID NO-1601) of 1 〇 and/or 4 。. 32. A prodrug of a compound according to any of the preceding claims, which comprises the structure AB wherein A is an amino acid or a hydroxy acid; B is a guanamine bond between the carboxyl moiety of B and the amine of Q An N-alkylated amino acid bonded to q; an amino acid of A, B or Q bonded to aB is a non-coding amino acid, further wherein the half-life of AB chemical cleavage from AB in PBS under physiological conditions (ti/: 2) is at least about 1 hour to about 1 week. 156004.doc -9· 201143790 3 3. The compound of claim 32 wherein a-B comprises the following structure: Ο R4 Rs (a) R1, R2, R4 and R8 are independently selected from the group consisting of H, C1-C18 alkyl, C2-C18 alkenyl, (C1-C18 alkyl) 〇H, (C1- C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC (NH2+)NH2, (C0-C4 alkyl) (C3_C6 cycloalkyl), (COCA alkyl) (C2-C5 heterocyclic), (C0-C4 alkyl) (C6-C10 aryl) R7, ( (: 1-€4 alkyl) (〇3-€9 heteroaryl) and (: 1-(:12 alkyl(\^1)(:1-(:12 alkyl'' tWl is selected from N a hetero atom of the group consisting of S, and 〇, or (II) R1 and R2 together with the atom to which they are attached form a C3_c 12 ring or an aryl group; or (III) R and R8 together with the atom to which they are attached匸3{6 cycloalkyl; (b) R3 is selected from the group consisting of C1_C18 alkyl, (C1C18 alkyl) OH, (C1-C18 alkyl) NH2, (C1-C18 alkyl) SH, ( C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (c〇·C4 alkyl)(C6-C10 aryl)R7 and (ci_C4) Burning base) (C3-C9 heteroaryl a group of 4, 5 or 6 membered heterocyclic rings together with R3 and R3; (c) R5 is NHR6 or OH; 156004.doc -10- 201143790 (d) R6 is H, C1 a C8 alkyl group, or R6 and R2 together with the atom to which they are attached form a 4-, 5- or 6-membered heterocyclic ring; and (e) R7 is selected from the group consisting of η and 〇H. A compound according to any one of the preceding claims, which further comprises an amino acid side chain which is covalently bonded to a mercapto or alkyl group via an alkylamine bond, a guanamine bond, an ether bond, an ester bond, a thioether bond or a thioester bond. The mercapto or alkyl group is non-native to the naturally occurring amino acid. 3 5. The compound of claim 34 wherein the amino acid attached to the mercapto or alkyl group is located corresponding to the native glycoside The position of the sequence is 丨〇, 2〇, 24, 30, 37, 38, 39, 40, 41, 32 or 43 or C-terminal amino acid. 36. The compound of claim 35: wherein the The amino acid of the thiol or alkyl group is located at a position corresponding to the position 10 and/or 40 of the sequence comprising the native glucosin. 37. The compound of claim 36, wherein Group or the alkyl group is connected to the side chain of the amino acid via a spacer group. 38. The compound of claim 37, wherein the spacer is an acidic amino acid or an acid dimorph. A compound according to any one of the preceding claims, wherein q is covalently linked to one or more heterologous moieties. 40. The compound of claim 39, wherein the one or more heterologous moieties are selected from the group consisting of peptides, polypeptides, nucleic acid molecules, antibodies or fragments thereof, polymers, quantum dots, small molecules, toxins, diagnostics And a combination of any of the above. 41. The compound of any one of the preceding claims, wherein q is selected from the group consisting of SEQ ID NOs: 1-564, 566-570, 573-575, 577, 579- 580, 585-612, 616, 618-632, 634-642, 647, 657-692, 694-695, 715-718, 722, 724-725, 729, 731-760, 801-878, 883-919, 1001-1275, 1301-1371, 1401-1518, and 1601-1650. 42. A dimer or multimer comprising a compound according to any one of the preceding claims, a pharmaceutical composition comprising a compound according to any one of the preceding claims, such as s blue A mono- or multimer or combination thereof, and a pharmaceutically acceptable carrier. 44. A method of treating a disease or medical condition in a patient, wherein the disease bite medical condition is selected from the group consisting of metabolic syndrome, diabetes, obesity, hepatic steatosis, and neurodegenerative diseases, the method comprising administering A pharmaceutical composition such as Jingyi 43 in an amount effective to treat the disease or medical condition. 156004.doc 12-