RU2778514C2 - Complement activity modulation - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: present invention relates to polypeptides, which are complement activity modulators. Polypeptides show C5-inhibitory activity.

EFFECT: obtaining polypeptides for complement activity modulation.

11 cl, 7 dwg, 18 tbl, 22 ex

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority of U.S. Provisional Application No. 62/011368, filed June 12, 2014, entitled "Modulation of Complement Activity", U.S. Provisional Application No. 62/077460, filed November 10, 2014, entitled "Modulation Complement Activity" and U.S. Interim Application No. 62/108772, filed January 28, 2015, entitled "Modulation of Complement Activity", the contents of each of which are incorporated herein by reference in their entirety.

SEQUENCE LIST

[0002] This application contains a sequence listing that has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. The specified ASCII copy, created on June 11, 2015, is named 20111005PCT_SL.txt and has a size of 130110 bytes.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0003] The present invention relates to compounds, including polypeptides, which are useful as inhibitors and/or antagonists of complement activity. The invention also relates to methods for using inhibitors as therapeutic agents.

BACKGROUND OF THE INVENTION

[0004] The immune response of vertebrates consists of adaptive and innate components of immunity. While the adaptive immune response is selective for specific pathogens and responds slowly, components of the innate immune response recognize a wide range of pathogens and respond quickly to infection. One such component of the innate immune response is the complement system.

[0005] The complement system includes about 20 circulating proteins synthesized mainly by the liver. The components of this specific immune response were first called "complement" because of the observation that they complemented the humoral response in killing bacteria. These proteins remain in an inactive form until activated in response to infection. Activation occurs via a proteolytic cleavage pathway initiated by pathogen recognition and leading to destruction of the pathogen. Three such pathways are known in the complement system, which are called the classical pathway, the lectin pathway, and the alternative pathway. The classical pathway is activated when an IgG or IgM molecule binds to the surface of a pathogen. The lectin pathway is initiated by the mannan-binding protein lectin, which recognizes sugar residues in the bacterial cell wall. The alternative pathway remains active at a low level in the absence of any specific incentives. Although all three pathways differ in their initiation, they converge on the cleavage of the C3 component of the complement system. C3 is split into two products called C3a and C3b. Of these, C3b becomes covalently bound to the surface of the pathogen, while C3a acts as a diffusing signal, increasing inflammation and promoting the recruitment of circulating immune cells. Surface-bound C3b forms a complex with other components, initiating a cascade of reactions of later components of the complement system. Due to the need for surface attachment, complement activity remains localized and minimizes the destruction of non-target cells.

[0006] Pathogen-associated C3b contributes to the destruction of pathogens in two ways. In one pathway, C3b is directly recognized by phagocytes and results in the ingestion of the pathogen. In the second pathway, pathogen-bound C3b initiates the formation of a membrane attack complex (MAC). In the first step, C3b forms a complex with other complement components to form the C5-convertase complex. Depending on the initial pathway of complement activation, the components of this complex may differ. The C5 convertase resulting from the classical complement pathway includes C4B and C2a in addition to C3b. When formed along an alternative pathway, C5 convertase consists of two C3b subunits, as well as one Bb component.

[0007] The C5 complement component is cleaved by any C5 convertase complex into C5a and C5b. C5a, like C3a, diffuses into the bloodstream and increases inflammation by acting as a chemoattractant for inflammatory cells. C5b remains attached to the cell surface where it induces MAC formation through interaction with C6, C7, C8 and C9. MAC is a hydrophilic pore that passes through the membrane and promotes the free flow of fluid into and out of cells, thereby destroying it.

[0008] An important component of all immune activity is the ability of the immune system to distinguish between self and non-self cells. Pathology occurs when the immune system is unable to do so. In the case of the complement system, vertebrate cells express proteins that protect them from the activity of the complement cascade. This ensures that the targets of the complement system are restricted to pathogenic cells. Many complement-related disorders and diseases are associated with the abnormal destruction of their cells by the complement cascade. In one example, patients suffering from paroxysmal nocturnal hemoglobinuria (PNH) are unable to synthesize functional versions of the complement regulatory proteins, CD55 and CD59, on hematopoietic stem cells. This leads to complement-mediated hemolysis and various subsequent complications. Other complement related disorders and diseases include, but are not limited to, autoimmune diseases and disorders, neurological diseases and disorders, hematological diseases and disorders, and infectious diseases and disorders. Experimental evidence suggests that many complement-related disorders are attenuated by inhibition of complement activity. Therefore, there is a need to develop compounds capable of selectively blocking complement-mediated cell destruction.

SUMMARY OF THE INVENTION

[0009] The present invention relates to compounds, including polypeptides (for example, peptidomimetics, cyclic polypeptides and cyclic peptidomimetics), small molecule compounds, antibodies, antibody fragments and aptamers, as well as methods of using these compounds for complement modulation. According to the present invention, the polypeptides may have the sequences indicated in SEQ ID NO: 1-201 or 211. They may be linear or cyclic and may contain a cyclic loop formed by a bridge element between two amino acids. Bridge elements may include a feature selected from the group consisting of a disulfide bond, an amide bond (lactam), a thioether bond, an aromatic ring, an unsaturated aliphatic hydrocarbon chain, a saturated aliphatic hydrocarbon chain, a triazole ring, or a combination thereof. In addition, the cyclic loop can vary in length and can be 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids, 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids , 14 amino acids, 15 amino acids, 16 amino acids or more amino acids.

[0010] The bridge element may include a disulfide between two cysteine residues or an aromatic ring obtained by reaction with poly(bromomethyl)benzene, and such poly(bromomethyl)benzene may be selected from the group consisting of 1,2-bis(bromomethyl)benzene , 1,3-bis(bromomethyl)benzene and 1,4-bis(bromomethyl)benzene.

[0011] The bridging element may also include an aromatic ring obtained by reaction with a compound selected from the group consisting of 2,6-bis(bromomethyl)pyridine, (E)-1,4-dibromobut-2-ene and 1,2 -bis(bromomethyl)-4-alkylbenzene.

[0012] The bridging element may also include an amide bond formed by reaction of the side chains of the following pairs of amino acids: lysine and glutamic acid, lysine and aspartate, ornithine and glutamate, ornithine and aspartate, homolysine and glutamic acid, homolysine and aspartic acid, other combinations of amino acids , non-natural amino acids or non-amino acid groups, which include a primary amine and a carboxylic acid.

[0013] According to the present invention, the polypeptides are useful in that they can exhibit C5 inhibitory activity. In some instances, such activity may range from half maximum inhibitory concentration (IC ₅₀ ) of about 50 nM to about 200 nM, or may be less than 50 nM.

[0014] In some embodiments, the present invention provides polypeptides having tryptophan or one or more tryptophan analogs selected from the group consisting of 5-fluorotryptophan, 5-methyl-O-tryptophan, 1-methyltryptophan, D-tryptophan, and 7- azatryptophan present in the amino acid sequence. Such compounds include, among others, the compounds of SEQ ID NOS: 3, 9, 11, 19, 45, 46, 50 and 59.

[0015] In some embodiments, the implementation of the polypeptides of the present invention can contact the region on C5, where the specified region is distal to the cleavage site C5a-C5b. In some cases, the polypeptides of the present invention can inhibit the cleavage of C5 to cleavage products of C5a and C5b.

[0016] In some cases, the polypeptides of the present invention may be part of an antibody.

[0017] The polypeptides of the present invention may be contained in compositions. Such compositions may include one or more acceptable carriers or excipients. Such polypeptides may be further conjugated to another non-polypeptide element, such as, for example, a water-soluble polymer. These polymers may be hydrophilic or hydrophobic. In some embodiments, the hydrophilic polymer is selected from the group consisting of polyalkylene oxide homopolymers, polypropylene glycols, polyoxyethylated polyhydric alcohols, and copolymers thereof. It may also include polyethylene glycol (PEG). The compositions may further include polypeptides conjugated to an albumin-binding polypeptide selected from the group consisting of SEQ ID NOs: 202-204. In some instances, the compositions may include polypeptides conjugated to a cell-penetrating polypeptide selected from the group consisting of SEQ ID NOs: 205-210. The compositions may further include polypeptides conjugated to a lipid element. Lipid elements may include, but are not limited to, fatty acids, phospholipids, and sterols. In some embodiments, lipid elements may be directly conjugated to the polypeptides of the invention, or linked to a polypeptide-PEG conjugate. Some compositions may include a pharmaceutically acceptable excipient.

[0018] In some embodiments, the present invention provides a method for inhibiting C5 cleavage in a cellular system, comprising using a composition of the present invention, such as those described above. Some of these methods can reduce C5a levels. Other methods may reduce the formation of the membrane attack complex (MAC).

[0019] Some methods of the invention can provide inhibition of C5 cleavage with an IC ₅₀ of about 50 nM to about 200 nM. In some cases, the methods of the present invention may include inhibition of C5 cleavage with an IC _{50 of} less than 50 nM.

[0020] Some of the methods of the present invention can be applied to cell systems that are selected from an in vitro system, an in vivo system, and an ex vivo system. Some in vivo systems may include patients, such as a human. In some instances, the polypeptides and polypeptide compositions may be used in the treatment or prevention of a complement related disease, disorder and/or condition in a patient. Administration to a patient may be selected from the group consisting of buccal, intranasal, oral, intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, and intravitreal. In some cases, the compositions may be used to treat paroxysmal nocturnal hemoglobinuria and/or atypical hemolytic uremic syndrome. In some instances, the compositions of the present invention may be used to treat one or more of an inflammatory disease, wound, trauma, autoimmune disease, vascular disease, neurological disease, kidney disease, and eye disease.

[0021] In some embodiments, the present invention relates to methods for inhibiting thrombin-induced complement activation in cellular systems, comprising contacting such systems with the polypeptides of the present invention. Additionally, methods for treating hemolysis in patients are provided, comprising administering a polypeptide described herein. According to some such methods, the hemolysis to be treated is caused by thrombin-induced complement activation.

[0022] In some embodiments, kits are provided for the diagnosis, prognosis, prevention, or treatment of a disease, disorder, and/or condition in a mammal, including a human. Such kits will contain one or more polypeptides or polypeptide compositions of the present invention and, optionally, reagents and/or instructions for use. In such kits, the polypeptides may contain a detectable label or may be capable of binding to a detectable label to form a detectable complex. According to one embodiment, the tag contains a BODIPY-TMR tag.

DESCRIPTION OF FIGURES

[0023] The foregoing and other objects, features and advantages will be apparent from the following description of specific embodiments of the invention illustrated in the accompanying drawings, in which similar conventions are used to refer to the same parts throughout the drawings. The drawings are not necessarily drawn to scale, on the contrary, particular attention is directed to illustrating the principles of various embodiments of the present invention.

[0024] Figure 1 is a graph showing the results of an enzyme-linked immunosorbent assay (ELISA) for the detection of C5a in the supernatant from a human erythrocyte hemolysis assay with increasing concentrations of inhibitors R3002 (SEQ ID NO: 3) and R3008 (SEQ ID NO: 9). C5a levels correlate with complement activity and are therefore indicative of the ability of test compounds to inhibit the activity of the complement system. The supernatant from the hemolysis assay was diluted 1:50 and analyzed for C5a content. C5a levels decreased in supernatant samples from the human erythrocyte hemolysis assay with increasing levels of any inhibitor tested. R3002 (SEQ ID NO: 3) had an IC _{50 of} 5.4 nM, while R3008 (SEQ ID NO: 9) had an IC _{50 of} 54.5 nM. Used in the present description, the term "IC ₅₀ "refers to half the maximum inhibitory concentration - a value used to indicate the amount of inhibitor needed to reduce a given reaction or process by half.

[0025] Figure 2 is a graph showing the results of an ELISA for the detection of membrane attack complex (MAC) in the supernatant from a human erythrocyte hemolysis assay with increasing concentrations of R3008 (SEQ ID NO: 9). MAC levels correlate with complement activity and are therefore indicative of the ability of R3008 (SEQ ID NO: 9) to inhibit the activity of the complement system. The supernatant from the hemolysis assay was diluted 1:5 and analyzed for MAC content. MAC levels decreased in the supernatant samples from the hemolysis assay with increasing levels of analyte inhibitor with an IC _{50 of} 33 nM.

[0026] Figure 3 is a graph showing competitive fluorescence polarization (FP) data for test compounds R3003 (SEQ ID NO: 4), R3011 (SEQ ID NO: 31), R3014 (SEQ ID NO: 55), R3023 (SEQ ID NO: 104), R3043 (SEQ ID NO: 50) and R3050 (SEQ ID NO: 23). FP allows measurement of binding events in a homogeneous solution. A competition binding assay was performed where a 25 nM solution of compound R3076 (SEQ ID NO: 40), which has a fluorescent label, was mixed with an increasing amount of test compounds and changes in FP (millipolarization units, mP) were measured. The decrease in the mP level correlates with successful competition for C5 of the studied compounds. The average of two independent experiments performed in triplicates (+/- standard deviation) is shown. Of the compounds tested, R3003 (SEQ ID NO: 4) was the most potent, while R3023 (SEQ ID NO: 104, control polypeptide) was not active even at the highest concentration tested.

[0027] Figure 4 shows the results of a study on cynomolgus monkeys. Changes in plasma concentrations of R3152 (SEQ ID NO: 153) (circles) are shown after a single dose of 3 mg/kg intravenously administered to cynomolgus monkeys. Changes in hemolytic activity (squares) at the same time points are also shown.

[0028] Figure 5 shows the results of plasma monitoring following intravenous (IV; squares) or subcutaneous (SC, circles) administration of 2 mg/kg of compound R3152 (SEQ ID NO: 153) to male Sprague-Dawley rats. Monitoring included the determination of pooled plasma concentrations of R3152 (SEQ ID NO: 153) as well as its C-terminally deamidated metabolite, R3201 (SEQ ID NO: 211), having equal activity.

[0029] Figure 6 shows the pharmacokinetics of the compounds of the present invention in rats. Left: Male Sprague-Dawley rats (n=3) were treated intravenously at a single dose of 2 mg/kg. Blood samples were collected at the indicated time points, plasma was isolated and analyzed for the content of the specified compound using LC-MS. Black circles: R3176 (SEQ ID NO: 177) (non-lipidated compound); open circles: R3183 (SEQ ID NO: 184) (C16 lipidated compound). Right: Male Sprague-Dawley rats (n=3) were administered the compound subcutaneously at a single dose of 15 mg/kg. Blood samples were collected at the indicated time points, plasma was isolated and analyzed for the content of the specified compound using LC-MS. Black circles: R3176 (SEQ ID NO: 177) (non-lipidated compound); open circles: R3183 (SEQ ID NO: 184) (C16 lipidated compound).

[0030] Figure 7 is a graph showing the effect of R3183 (SEQ ID NO: 184) (C16-lipidated compound) or an anti-C5 monoclonal antibody similar to ECULIZUMAB® on inhibition of hemolysis via the thrombin-induced complement pathway.

DETAILED DESCRIPTION OF THE INVENTION

[0031] The present invention relates to the discovery of new modulating C5 compounds. Such compounds may include, but are not limited to, polypeptides (eg, cyclic polypeptides, peptidomimetics and cyclic peptidomimetics, small molecule compounds, antibodies, antibody fragments, and aptamers). In some instances, C5 modulating compounds are polypeptides, such as cyclic polypeptides, peptidomimetics, and cyclic peptidomimetics, which are suitable for the diagnosis and/or treatment of diseases in which inhibition of complement activation is desired. In some embodiments, the polypeptides of the invention bind specifically to the C5 component of complement. in other embodiments, the polypeptides of the invention reduce complement-mediated cell-to-cell lysis by preventing C5 cleavage to C5a and C5b fragments.

[0032] As used herein, "mimetic" refers to a molecule that exhibits some of the properties or features of another molecule. A "peptidomimetic" or "polypeptidomimetic" is a mimetic in which the molecule contains structural elements that are not found in natural polypeptides (ie, polypeptides consisting of only 20 proteinogenic amino acids). In a preferred embodiment, peptidomimetics are capable of replicating or mimicking the biological action of a natural peptide. The peptidomimetic may differ in many ways from natural polypeptides, including, but not limited to, changes in the backbone structure and the presence of amino acids that do not occur naturally. In some cases, peptidomimetics may include amino acids with side chains that are not found among the known 20 proteinogenic amino acids, non-polypeptide bridge elements used to effect cyclization between the ends or internal regions of the molecule, replacement of the hydrogen element of the amide bond with methyl groups (N-methylation) or other alkyl groups, replacement of a peptide bond with a chemical group or bond that is resistant to chemical or enzymatic processing, N- and C-terminal modifications, and conjugation to non-peptide extension molecules (e.g., polyethylene glycol, lipids, carbohydrates, nucleosides, nucleotides, nucleoside bases , various low molecular weight compounds or phosphate or sulfate groups).

[0033] Some polypeptides of the invention may be cyclic. Cyclic polypeptides include any polypeptides that have as part of their structure one or more features of the presence of a cycle, such as a loop, a bridging element, and/or an internal link. As used herein, the term "bridge" refers to one or more components of a bridge formed between two adjacent or non-adjacent amino acids, non-natural amino acids, or non-amino acid groups in a polypeptide. Bridge elements can be of any size and composition. In some embodiments, bridging elements may comprise one or more chemical bonds between two adjacent or non-adjacent amino acids, non-natural amino acids, non-amino acid groups, or combinations thereof. In some embodiments, such chemical bonds may be between one or more functional groups on contiguous or non-contiguous amino acids, non-natural amino acids, non-amino acid groups, or combinations thereof. Bridge elements may contain one or more features, including, but not limited to, an amide bond (lactam), a disulfide bond, a thioether bond, an aromatic ring, a triazole ring, and a hydrocarbon chain. In some embodiments, the bridging elements comprise an amide bond between an amino group and a carboxy group that are present on the side chain of an amino acid, a non-natural amino acid, or a non-amino acid group. In some embodiments, the amino or carboxy groups are part of a non-amino acid group or a non-natural amino acid residue. In some cases, bridging elements may contain bonds formed between residues, which may include, but are not limited to, (S)-2-amino-5-azidovaleric acid (also referred to herein as "X02"), (S)-2 -aminohept-6-enoic acid (also referred to herein as "X30"), (S)-2-aminopent-4-oic acid (also referred to herein as "X31") and (S)-2-aminopent-4 -enoic acid (also referred to herein as "X12"). Bridge elements can be formed through a cyclization reaction using an olefin exchange reaction. In some cases, such bridge elements can be formed between the residues X12 and X30. In some embodiments, the implementation of the bridge element contains a disulfide bond formed between two thiol-containing residues. In some embodiments, the bridging element contains one or more thioether linkages. Such thioether linkages may include those present in cyclo-thioalkyl compounds. These bonds are formed during a chemical cyclization reaction between N-terminally modified chloroacetic acid groups (also referred to herein as "X35") and cysteine. In some cases, the bridge elements contain one or more triazole rings. Such triazole rings may include, but are not limited to, rings formed by a cyclization reaction between X02 and X31. In some embodiments, the bridging elements comprise non-protein or non-polypeptide groups including, but not limited to, cyclic rings (including, but not limited to, aromatic ring structures (eg, xylyls)). Such bridging elements can be introduced by reaction with reagents containing many reactive halides, including, but not limited to, poly(bromomethyl)benzenes, poly(bromomethyl)pyridines, poly(bromomethyl)alkylbenzenes and/or (E)-1 ,4-dibromobut-2-ene. In some embodiments, the implementation of the bridge elements of the present invention include, but are not limited to, the following structures:

where each X is independently H or CH such that no ring contains more than 2 nitrogen atoms; each Z is independently absent or selected from a bond, NR, O, S, CH ₂ , C(O)NR, NRC(O), S(O) _v NR and NRS(O) _v ; each m is independently selected from 0, 1, 2, and 3; each v is independently selected from 1 and 2; each R is independently selected from H and C ₁ -C ₆ ; and each bridge element is connected to the polypeptide by an independently selected bond or C ₁ -C ₆ spacer.

[0034] In some embodiments, the implementation of the polypeptides become macrocyclic due to the formation of covalent bonds between the atoms present in the linear polypeptide, and the atoms of the bridge element. This bridge element serves to chemically link two reactive sites on a linear polypeptide in such a way as to obtain a cyclic polypeptide product. Embodiments of the present invention include polypeptides cyclized as above and containing a bridge element containing an aromatic 6-membered ring. In these embodiments, the linear polypeptide atoms that form direct chemical bonds to the bridging element can be heteroatoms (including but not limited to nitrogen, oxygen, and sulfur) or saturated or unsaturated carbon atoms. In each of these embodiments, the side chain atoms of the polypeptide can be connected directly to a carbon atom in the aromatic ring of the bridging element. In alternative forms, atoms of the polypeptide side chain may be linked to a saturated -CH2- group, which in turn is directly linked to a carbon atom in the aromatic ring of the bridging element. In some cases, the aromatic 6-membered ring in the bridging element is benzene, as in the following structures, where Z can be selected from NH, S, O and (CH) ₂ :

[0035] In alternative forms of the present invention, the aromatic 6-membered ring that contains the bridge element is a heterocycle and contains one or more nitrogen atoms. In these embodiments, the aromatic heterocycle can be a pyridine containing one nitrogen atom in the aromatic ring (eg, any of the structures below, where Z can be selected from NH, S, O, and (CH) ₂ ):

[0036] Aromatic heterocycles may alternatively be pyridazine containing two adjacent nitrogen atoms in the 1,2 orientation in the aromatic ring (e.g., any of the structures below, where Z can be selected from NH, S, O and (CH) ₂ ):

[0037] In other embodiments, the aromatic heterocycle can be a pyrimidine containing two nitrogen atoms in the 1,3 orientation in the aromatic ring (e.g., any of the structures below, where Z can be selected from NH, S, O, and ( CH) ₂ ):

[0038] Alternatively, the aromatic heterocycle may be a pyrazine containing two nitrogen atoms in the 1,4 orientation in the aromatic ring (e.g., any of the structures below, where Z can be selected from NH, S, O, and ( CH) ₂ ):

[0039] In alternative forms of implementation of the present invention, the polypeptides become macrocyclic as a result of the formation of covalent bonds between the atoms of the linear polypeptide and the atoms of the bridge element, consisting of a heterocyclic aromatic 5-membered ring. In these embodiments, the linear polypeptide atoms that form direct chemical bonds to the bridging element can be heteroatoms (including but not limited to nitrogen, oxygen, and sulfur) or saturated or unsaturated carbon atoms. In each of these embodiments, the side chain atoms of the polypeptide may be attached directly to a carbon or nitrogen atom in the aromatic ring of the bridging element. In alternative forms, the side chain atoms of the polypeptide may be attached to a saturated -CH2- group, which in turn is directly attached to a carbon or nitrogen atom in the aromatic ring of the bridging element. In some cases, the heterocyclic aromatic 5-membered ring in the bridging element is 1,2,3-triazole. In these embodiments, the aromatic ring may be substituted at positions 1 and 4 with reactive groups on the linear polypeptide to be linked. Alternatively, the 1,2,3-triazole backbone may be substituted at positions 1 and 4 with -CH2- groups that are directly linked to the atoms of the linear polypeptide to be linked (e.g., any of the structures below, where Z can be selected from NH, S, O and (CH) ₂ ):

[0040] In other embodiments, the implementation of heterocyclic aromatic 5-membered ring, which contains a bridge element, is a pyrazole. In these embodiments, the aromatic ring may be substituted either at positions 1 and 3 or at positions 1 and 4 with the reactive groups of the linear polypeptide to be linked. Alternatively, the pyrazole backbone may be substituted either at positions 1 and 3 or at positions 1 and 4 with -CH2- groups that are directly bonded to atoms of the linear polypeptide to be linked (e.g., any of the structures below, where Z may be selected from NH, S, O and (CH) ₂ ):

[0041] Unless otherwise indicated, all technical and scientific terms used in the present description have the same meaning as usually understood by the average person skilled in the art to which the present invention belongs. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the cyclic polypeptides and methods of the invention, suitable methods and materials are described below.

Polypeptides as drugs

[0042] Because of their size and structural complexity, polypeptides are able to form multiple, highly specific contacts with their biological targets and may exhibit a high level of selectivity for the “correct” or desired target over a closely related target within the same family. Off-target effects (also known as side effects) often prevent high potency drugs from being approved by regulatory authorities due to safety.

[0043] Numerous polypeptides (including but not limited to peptidomimetics) have been developed into effective drugs. These include, without limitation, insulin, glucagon-like peptide 1 (GLP-1), somatostatin, vasopressin, cyclosporin A, and the like. The therapeutic polypeptide may be identical to a naturally occurring molecule (ie, one that circulates in the human body and is considered "wild type" in the human population). In many other cases, this polypeptide is unsuitable or sub-optimal for therapeutic use due to its short circulating half-life, often due to metabolic instability in the body. In these cases, a modified form or variant of the polypeptide (peptidomimetic) is used, resulting in improved pharmacokinetic and pharmacodynamic characteristics. Alternatively, a polypeptide derived from a natural source has an equivalent mechanism of action and a preferred pharmaceutical profile and can be used as a therapeutic agent. For example, exenatide, a synthetic variant of exendin-4, has similar biological properties to human glucagon-like peptide-1 (GLP-1) but improved pharmacokinetic properties and has been approved by the FDA for the treatment of type II diabetes mellitus. In another example, salmon calcitonin (calcitonin isolated from salmon ultimobranchial glands) resembles human calcitonin but is more potent than human calcitonin and can be used to treat postmenopausal osteoporosis, hypercalcemia, Paget's disease, bone metastases, and phantom limb pain.

[0044] Polypeptides are generally limited to non-oral routes of administration. In almost all cases, the polypeptides must be delivered by injection, since even very short polypeptides (eg, polypeptides with 4-10 amino acid residues) are unable or poorly able to pass through the cell membranes lining the gastrointestinal tract. For effective oral availability of drugs, it is generally necessary to pass through both the luminal and basolateral membranes of the intestinal epithelial cells in order to enter the systemic circulation. Poor membrane permeability and the lack of oral bioavailability of polypeptides significantly limits their therapeutic use.

[0045] The effectiveness of a polypeptide as a drug may depend on its proteolytic stability. In the body, polypeptides can be modified or degraded by enzymes, which can limit their effectiveness in relation to interaction with a given target.

[0046] The metabolic stability of polypeptides is important because it is related to their overall flexibility, intramolecular fluctuations, various internal dynamic processes, as well as many biological functions. The metabolic stability of polypeptides can be of critical importance in the development of pharmaceuticals, influencing parameters such as, but not limited to, clearance, half-life, and bioavailability of drug compounds.

[0047] Maintenance of a given level of a therapeutic polypeptide in the body or bloodstream can be difficult due to its excretion. The rate of clearance of a polypeptide from the body may vary and should be controlled when considering administration of therapeutic polypeptides.

[0048] There remains a strong need in medicine for complement activation inhibitors or complement activity inhibitors and inhibitor preparations that are highly active and highly specific.

Search for peptidomimetics

[0049] Peptidomimetics can be identified by various means. In some cases, a natural peptide or sequence found in a natural protein is used as a starting point. In these cases, the original peptide sequence was chosen because it is known to physically interact with the desired target molecule. A natural peptide may be selected because it is an agonist or antagonist for the receptor, inhibits an enzyme, or modulates a channel. A sequence found in a natural protein may be chosen because it contains a domain involved in interaction with another protein or some other molecule in a human or animal. In many cases, structural data on interacting proteins can be obtained from public databases (for example, RCSB Protein Data Bank; H.M. Berman, J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H. Weissig, I.N. Shindyalov, P.E. Bourne ( 2000) The Protein Data Bank Nucleic Acids Research, 28: 235-242) and the specific region of the protein that interacts with the target can be identified based on the crystallographic data of the protein complex. In other cases, polypeptides corresponding to different regions of the protein can be generated and tested for binding to the target of interest. Once identified, chemical modifications are introduced to increase its stability and potency, and the resulting peptidomimetic has improved pharmacokinetic or pharmacodynamic parameters.

[0050] In other instances, a polypeptide is isolated by one of several methods for isolating polypeptide sequences from polypeptide libraries based on their affinity for specific target proteins, nucleic acids, carbohydrates, lipids, or whole cells. Such methods include phage display, mRNA display, ribosomal display, DNA display, DNA-encoded assembly, and two-hybrid screening, as well as modifications thereof (see, e.g., Takashashi, T.T et al. (2003). Trends in Biochem. Sci 28(3):159-165 Kay, B. K. et al (2001) Methods 24:240-246 He, M and Taussig, M (2002) Briefs in Functional Genomics and Proteomics 1(2) : 204-212 Rothe, A. et al (2006) The FASEB Journal 20(10):1599-1610, all of which are incorporated herein by reference in their entirety).

[0051] Polypeptides can take on three-dimensional structures that are able to bind to other biological molecules with a certain degree of affinity and specificity. Some of them will bind with very high affinity and specificity. The library of random polypeptide sequences will include molecules with a wide range of different three-dimensional structures. In order to isolate a polypeptide with a conformation that interacts with a particular target protein, individual sequences from a library can be obtained and tested or screened for their affinity for the target. However, for very large libraries (>10 ⁶ members), screening for individual sequences by binding affinity is not possible. To overcome this limitation, a number of methods have been developed to select new polypeptides from extremely large and complex mixtures by virtue of their binding affinity to the target. Because high binding affinity polypeptides are expected to occur in a population at very low frequency, these selection methods rely on maintaining a physical link between the polypeptide and the genetic material (usually a nucleic acid such as DNA or RNA) encoding the polypeptide so that the selection of the polypeptide automatically triggers the isolation of the nucleic acid encoding it. The nucleic acid encoding the selected polypeptide can be amplified and sequenced to reveal the sequence of both the nucleic acid and the polypeptide. In one phage display approach (see Cwirla, SE et al. (1990). Proc. Natl. Acad. Sci. USA 87:6378-6382; Dower WJ and Cwirla SE US Pat. Nos. 5,427,908 and 5,580,717) each random member of a polypeptide The library is displayed on the surface of a bacteriophage particle as part of a fusion protein between the polypeptide and one of the phage coat proteins. The phage particle provides a link between the polypeptide and the coding DNA by colocalizing them within one physical unit, and the coding DNA can be subsequently amplified by infecting bacteria with the selected phage. In another ribosome display approach (see Kawasaki, GHUS Patents Nos. 5658754 and 5643768), a mixture of messenger RNA (mRNA) molecules is translated in vitro in a manner that produces, for each mRNA in the mixture, a stabilized complex of ribosome, mRNA, and a newly synthesized polypeptide acting as from the ribosome. Stabilization of the complex allows it to remain intact while the polypeptides are screened for binding to the target of interest. mRNAs encoding selected polypeptides can be amplified by polymerase chain reaction (PCR) and then characterized, for example, by sequencing.

[0052] In yet another mRNA display approach (see Szostak JW and Roberts RW, US Pat. No. 6,258,558, the contents of which are hereby incorporated by reference in their entirety), each mRNA molecule in the library is modified by covalently adding a puromycin-like moiety at its 3 '-end. The puromycin-like fragment is an analogue of the aminoacyl-tRNA acceptor stem that functions as a peptidyl acceptor and can be added to the growing polypeptide chain by the peptidyl transferase activity of the mRNA-translating ribosome. During in vitro translation, the mRNA and the encoded polypeptide become covalently linked through a puromycin-like fragment, creating an RNA-peptide fusion. After selecting the fusion molecule by binding its polypeptide component to the target, the RNA component of the selected fusion molecule can be amplified by PCR and then characterized. Several other methods have been developed to create a physical link between a polypeptide and its encoding nucleic acid to facilitate selection and amplification (see Yanagawa, H., Nemoto, N., Miyamoto, E., and Husimi, Y., US patent No. 6361943 ; Nemoto, H., Miyamoto-Sato, E., Husimi, H., and Yanagawa, H. (1997) FEBS Lett. 414:405-408; Gold, L., Tuerk, C., Pribnow, D. , and Smith, JD, U.S. Patent Nos. 5,843,701 and 6,194,550; Williams, RB, U.S. Patent No. 6,962,781; Baskerville, S. and Bartel, DP (2002) Proc. Natl. Acad. Sci. USA 99:9154-9159; Baskerville, DS and Bartel, DP, U.S. Patent No. 6,716,973 Sergeeva, A. et al (2006) Adv Drug Deliv Rev 58:1622-1654, the contents of which are incorporated herein by reference in their entirety).

[0053] mRNA display is a particularly useful way to create large libraries of polypeptides. Accordingly, provided herein are methods for selecting a polypeptide (or mRNA encoding a polypeptide) that interacts with the C5 complement protein. The library typically contains at least 10 ² members, more preferably at least 10 ⁶ members, and more preferably at least 10 ⁹ members (eg, any mRNA-polypeptide complexes). In some embodiments, the implementation of the library will include at least 10 ¹² members or at least 10 ¹⁴ members. In general, the members will differ from one another, however, it is expected that there will be some degree of degeneracy in any library. The library may exist as a single mixture of all members, or may be divided into multiple pools contained in separate containers or wells, each containing a subset of the library, or a library may be a collection of containers or wells on a plate, each container or well containing only one or more library members.

[0054] Each mRNA in the library preferably includes a translation initiation sequence, a start codon, and a variable region encoding a polypeptide (e.g., protein or short peptide) that is generated, for example, by random or semi-random nucleotide assembly, and varies from mRNA to the mRNA in the library (although it is possible that there will be some degree of degeneracy in the library). The translation initiation sequence, the start codon and the variable region encoding the polypeptide may be flanked by known fixed sequences, which may be used for PCR amplification of the mRNA, eg after selection. Other fixed sequences that may be present include those corresponding to sequences that code for amino acids that can be involved in chemical or enzymatic cross-linking reactions so that the resulting polypeptide can be modified or derivatized after translation, or that code for a fixed C-terminal extension, such as a polypeptide tag, which can facilitate purification of the fused peptide and mRNA.

[0055] Once a puromycin-derivatized mRNA library has been created, the library can be translated. The resulting polypeptides (eg, presenting polypeptides) will be linked to their respective mRNAs as described herein (eg, as an mRNA-polypeptide complex).

[0056] Numerous in vitro translation systems have been described in the literature. The most common systems use rabbit reticulocyte lysates, wheat germ extracts, or E. coli extracts, which are available from a variety of commercial sources in kit form (e.g., from Ambion, Austin, TX; Promega, Madison, WI; Novagen/EMD Chemicals, Gibbstown, NJ; Qiagen, Valencia, CA).

[0057] Unlike phage display or other systems that rely on cellular translation, mRNA display can be adapted to directly generate peptidomimetic libraries by performing in vitro translation with non-natural or non-standard amino acids. The 20 naturally occurring proteinogenic amino acids have been identified and are referred to in this specification with one-letter or three-letter designations: aspartic acid (Asp: D), isoleucine (Ile: I), threonine (Thr: T), leucine (Leu: L), serine (Ser: S), tyrosine (Tyr:Y), glutamic acid (Glu:E), phenylalanine (Phe:F), proline (Pro:P), histidine (His:H), glycine (Gly:G), lysine (Lys: K), alanine (Ala: A), arginine (Arg: R), cysteine (Cys, C), tryptophan (Trp: W), valine (Val: V), glutamine (Gln: Q) methionine (Met: M) , asparagine (Asn: N). Naturally occurring amino acids exist in their levorotatory (L) stereoisomeric form. The amino acids mentioned in the present description are L-stereoisomers, unless otherwise indicated.

[0058] Non-natural amino acids have side chains or other features not present in the 20 naturally occurring amino acids listed above and include, but are not limited to: N-methyl-amino acids, N-alkyl-amino acids MINO acids, alpha,alpha-substituted amino acids, beta-amino acids, alpha-hydroxy amino acids, D-amino acids, and other non-natural amino acids known in the art (see, for example, Josephson et al., (2005) J. Am. Chem. Soc. 127: 11727-11735; Forster, A. C. et al. (2003) Proc. Natl. Acad. Sci. USA 100: 6353-6357 Subtelny et al. (2008) J. Am. Chem. Soc. 130: 6131-6136 Hartman, M. C. T. et al (2007) PLoS ONE 2:e972 and Hartman et al., (2006) Proc Natl Acad Sci USA 103:4356-4361).

[0059] Essentially, any amino acid can be used which, when attached to the appropriate tRNA, can be assembled into a polymer by natural or mutated ribosomes (see Sando, S. et al., (2007) J. Am. Chem. Soc.129:6180-6186; Dedkova, L. et al. (2003) J. Am. Chem. Soc. 125: 6616-6617; Josephson, K., Hartman, M.C.T., and Szostak, J.W. (2005) J. Am. Chem. Soc. 127:11727-11735; Forster, A. C. et al. (2003) Proc. Natl. Acad. Sci. USA 100:6353-6357; Subtelny, A. O., Hartman, M. C. T., and Szostak, J. W. (2008 ) J. Am. Chem. Soc. 130:6131-6136 and Hartman, M.C.T. et al. (2007) PLoS ONE 2:e972).

[0060] When it is desired to use non-natural amino acids, it may be preferable to use a purified translational system that lacks endogenous aminoacylated tRNAs (Shimizu, Y. et al. (2001) Nat. Biotech. 19:751-755; Josephson, K., Hartman , MCT, and Szostak, JW (2005) J. Am. Chem. Soc. 127: 11727-11735; Forster, AC et al. (2003) Proc. Natl. Acad. Sci. USA 100: 6353-6357). If non-natural amino acids are used in an in vitro translation system based on a lysate or extract, it may be desirable to deplete the extract for endogenous tRNAs, as previously described (see Jackson, RJ, Napthine, S., and Brierley, I. (2001) RNA 7 :765-773). A system based on purified translational factors from E. coli (PUREXPRESS™, New England Biolabs, Ipswich, MA) is commercially available. These systems are especially useful in translation with non-natural amino acids for the production of peptidomimetics.

[0061] When using natural amino acids with an in vitro translation system based on a lysate or extract, translation depends on the enzymatic transfer of amino acids to tRNA by tRNA synthetases, which are all components of the extracts. Alternatively, in vitro translation systems that use purified translation factors and ribosomes or tRNA-depleted extracts require the addition of aminoacylated tRNAs. In these cases, purified or in vitro synthesized tRNAs can be coupled to amino acids using chemical (see Frankel, A., Millward, SW, and Roberts, RW (2003) Chem. Biol. 10:1043-1050) or enzymatic procedures. (Josephson, K., Hartman, MCT, and Szostak, JW (2005) J. Am. Chem. Soc. 127: 11727-11735; Murakami, H. et al. (2006) Nat. Methods 3:357-359) .

[0062] Numerous publications describe the isolation of mRNA-presented polypeptides from translational complexes and are suitable for use with the methods described herein (Liu, R. et al. (2000). Methods Enzymol. 318:268-293; Baggio, R. et al (2002) J. Mol Recognit 15:126-134, U.S. Patent No. 6,261,804). The isolation of mRNA-presented polypeptides can be facilitated by the use of various "tags" which are incorporated into the polypeptide by translation of fixed sequences of the polypeptide coding sequence and which bind to specific substrates or molecules. Numerous reagents for capturing such tags are commercially available, including His tag, FLAG tag, glutathione S-transferase (GST tag), streptococcal tag, HSV tag, T7 tag, S tag, DsbA tag, DsbC tag, Nus tag, Myc tag, hemagglutinin tag (HA tag), or Trx tag (Novagen, Gibbstown, NJ; Pierce, Rockford, IL). Presented on mRNA polypeptides can also be isolated by linking the polyA tail on the mRNA to a polydT resin or using a combination of a polyA tail and a His tag.

[0063] After performing the in vitro translation reaction and prior to the selection step, the mRNA portion of the functionalized RNA is typically reverse transcribed to produce a hybrid RNA-DNA molecule. This serves to protect the RNA from degradation and also prevents the formation of an RNA secondary structure that can bind to the target used for selection, which would result in the selection of inappropriate products (eg selection of RNA aptamers rather than polypeptide aptamers).

[0064] After in vitro translation and isolation of the fused polypeptide and mRNA, the polypeptide element can be modified by intramolecular or intermolecular crosslinking, chemical conjugation, enzymatic cleavage, truncation, or extension using additional amino acid monomers. One way to achieve this goal is to include unnatural amino acids with reactive side chains in the polypeptides that make up the library. After translation, newly synthesized polypeptides can interact with molecules that specifically interact with the reactive side chain of the included amino acid. For example, an amino acid with an alkyne side chain terminal can be included in a polypeptide library and then reacted with an azido sugar to create a library of presentable polypeptides with sugars attached to alkynyl side chains (Josephson, K., Hartman, MCT, and Szostak, JW (2005 ) J. Am. Chem. Soc. 127: 11727-11735). A variety of reactive side chains can be used for such post-translational conjugation, including amines, carboxyl groups, azides, terminal alkynes, alkenes, and thiols.

[0065] One particularly useful modification is based on the crosslinking of amino acids to form cyclic structures. The cyclic regions in the polypeptide contain a rigid domain that reduces conformational flexibility and rotational freedom, resulting in very high binding affinity for target proteins. A number of methods for cyclizing a polypeptide are available to those skilled in the art and are incorporated herein by reference. As a rule, to obtain a cyclic molecule, the chemical reactivity of individual amino acid side chains and/or carboxy or amino ends of the polypeptide is used to crosslink two sections of the polypeptide. In one method, a thiol group of a cysteine residue is linked to another cysteine residue to form a disulfide bond. In some embodiments, thiol groups of cysteine residues react with bromomethyl groups of poly(bromomethyl)benzene molecules to form stable bonds (see Timmerman, P. et al., (2005) ChemBioChem 6:821-824, the content of which is incorporated herein by references in their entirety). The poly(bromomethyl)benzene molecules of the present invention may include, but are not limited to, 1,2-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene, and 1,4-bis(bromomethyl)benzene. Bis, tris, and tetrakis(bromomethyl)benzene molecules, for example, can be used to create bridging elements to produce polypeptides with one, two, or three loops, respectively. The bromomethyl groups of a poly(bromomethyl)benzene molecule can be located on the benzene ring on adjacent ring carbons (ortho- or o-position), with a ring carbon atom separating the two groups (meta- or m-position), or on opposite ring carbons (para- or p-position). In some embodiments, m-bis(bromomethyl)benzene (also referred to herein as m-dibromoxylene) is used to form cyclic polypeptides. In some embodiments, o-bis(bromomethyl)benzene (also referred to herein as o-dibromoxylene) or p-bis(bromomethyl)benzene (also referred to herein as p-dibromoxylene) is used to form cyclic polypeptides. In some embodiments, thiol groups of cysteine residues react with other reagents containing one or more bromo functional groups to form stable bonds. Such reagents may include, but are not limited to, poly(bromomethyl)pyridine (including but not limited to 2,6-bis(bromomethyl)pyridine), poly(bromomethyl)alkylbenzene (including but not limited to 1 ,2-bis(bromomethyl)-4-alkylbenzene) and/or (E)-1,4-dibromobut-2-ene).

[0066] In yet another exemplary method, the amino side chain and the amino terminal group are fused to disuccinimidyl glutarate (see Millward, S.W. et al., J. Am. Chem. Soc. 127:14142-14143, 2005). In other approaches, cyclization is accomplished by forming a thioether bond between two sites on the polypeptide (see Timmerman, P. et al., (2005) ChemBioChem 6:821-824; incorporated herein by reference in its entirety). The enzymatic method is based on the reaction between (1) cysteine and (2) a dehydroalanine or dehydrobutyrine group catalyzed by lantibiotic synthetase to form a thioether bond (see Levengood, M. R. and Van der Donk, W. A., Bioorg. and Med. Chem. Lett. 18: 3025-3028, 2008). A dehydro-functional group can also be created chemically by oxidation of selenium-containing amino acid side chains incorporated during translation (see Seebeck, F.P. and Szostak, J.W. J. Am. Chem. Soc. 2006).

[0067] In order to isolate complexes representing the desired polypeptides, a batch selection step can be carried out using a mRNA polypeptide fusion library (also referred to herein as an mRNA display library), which is generated using the methods described above, and which can be subjected to ( or not) post-translational modification (eg, polypeptide cyclization as described above).

[0068] Typically, C5 is conjugated to a solid substrate such as agarose or synthetic polymer beads. There are many ways to immobilize C5 on a solid support. In one particularly preferred method, C5 is conjugated to biotin and streptavidin beads are used to immobilize the protein. Beads containing immobilized C5 are mixed with the mRNA display library and incubated under specific conditions (eg, temperature, ionic strength, divalent cation content, and competing binding molecules) that allow certain members of the library to bind to the target. Alternatively, the biotinylated enzyme may be present free in solution and, after binding to the appropriate polypeptide, mRNA and polypeptide fusion molecules bound to C5 are captured by suitably modified beads.

[0069] The conditions of binding can be varied in order to change the stringency of the selection. For example, low concentrations of competitive binding agent may be added to ensure that the selected polypeptides have a relatively higher affinity. Alternatively, a very short incubation time can be chosen so that only polypeptides with high k _on (rate of association) values are selected. Thus, the incubation conditions play an important role in determining the properties of the selected polypeptides. Negative selection can also be used. In this case, selection is made to remove polypeptides with affinity for the substrate to which the target is bound (eg Sepharose) by reacting the library with substrate beads without the target protein. This step can remove mRNAs and the polypeptides they encode that are not specific to the target protein. Numerous references are available describing how to conduct selection experiments. (See, for example, US Pat. No. 6,258,558, Smith, GP and Petrenko, VA, (1997) Chem. Rev. 97:391-410; Keefe, AD and Szostak, JW (2001) Nature 15:715-718; Baggio , R. et al. (2002) J. Mol. Recog. 15:126-134 and Sergeeva, A. et al. (2006) Adv. Drug Deliv. Rev. 58:1622-1654, the contents of which are incorporated herein in their entirety. document by reference).

[0070] The frequency with which binding molecules are present in the random sequence library is expected to be very low. Thus, at the initial stage of selection, very few polypeptides that meet the selection criteria (and their associated mRNAs) need to be isolated. Typically, the selection is repeated with the mRNAs selected in the first round of selection. This is done using PCR to amplify the mRNA or corresponding cDNAs selected in the first round followed by in vitro transcription to generate a new mRNA library. Use PCR primers corresponding to the 5' and 3' ends of the mRNA in the library. Typically, the 5' primer will extend 5' from the end of the mRNA so that a bacterial promoter such as the T7 promoter will be added to the 5' end of each amplified molecule. After amplification, double-stranded DNA can be used in an in vitro transcription reaction to generate mRNA for a subsequent selection round.

[0071] The selection process typically includes a series of rounds or cycles in which the pool of selected molecules is enriched step by step for a specific set of sequences at the end of each round. The selection conditions may be the same for each round, or the conditions may change, for example, in order to increase the rigidity of the selection in subsequent rounds. The progress of selection can be monitored using isotopically labeled amino acids such as ³⁵ S-methionine. The amount of radiolabeled polypeptide bound to the target is measured in each round, and the gradual accumulation of isolated radiolabel indicates progressive enrichment in RNA molecules encoding polypeptides with affinity for the target. After any round, PCR products can be cloned and sequenced. Typically, cloning and sequencing is performed after a round in which an appreciable (eg, >2% relative to background for beads lacking immobilized C5) amount of radiolabeled polypeptide is released in the target-bound pool. Sequences that are present in multiple isolated samples potentially encode polypeptides that specifically bind to the target. Alternatively, high-throughput sequencing of thousands of clones can be performed after the first or subsequent rounds. Sequences that increase in frequency between rounds, such as rounds three and four, are potentially coding for polypeptides that specifically bind to the target. A polypeptide encoded by any sequence can be translated or synthesized and tested for binding affinity to the original target protein used in selection.

[0072] The libraries and methods of the present invention can be used to optimize the function or properties of a polypeptide. One approach uses mutagenic PCR (Keefe, AD and Szostak, JW (2001). Nature 15:715-718) to introduce sequence variation into a library after a population has been enriched for polypeptides with a certain level of binding affinity. Alternatively, a single RNA sequence encoding a polypeptide with certain binding properties can be replicated but with a certain level of mutations, or mutagenic PCR can be performed to generate a pool of mutant molecules. After in vitro translation, the resulting mixture of mRNA molecules from such a pool is expected to encode polypeptides with improved, similar, or reduced affinity compared to the original sequence, and selection performed on mRNA from such a pool can be expected to identify polypeptides with improved affinity. , if the appropriate selection severity mode is used during selection.

[0073] In the second approach, directional optimization is performed. A sequence encoding a polypeptide with established binding or functional properties is subjected to site-directed mutagenesis, resulting in a set of sequences, with each sequence having one codon replaced by, for example, an alanine codon. The number of sequences in the set is equal to the number of amino acid residues to be mutated. Following in vitro translation, the polypeptide product of each alanine-scanning mutant is tested for binding or functional properties. The sites where an alanine substitution affects the binding or function of the polypeptide are considered critical residues. Similarly, an N-methyl scan can be performed such that each residue is replaced by an N-methyl derivative and positions in the polypeptide chain allowing N-methyl substitutions can be identified.

[0074] Alternatively, the sequences can be combined, subjected to one or more rounds of high stringency selection, and a pool of sequences representing polypeptides with high binding affinity is isolated. Critical residues are defined after sequencing of the isolated DNA as those that cannot be replaced by an alanine residue without loss of activity. After identification of critical residues, a pool of mRNA molecules is obtained that encodes a wide range of natural (or non-natural) amino acids at each of the critical positions. The resulting pool is subjected to one or more rounds of high stringency selection (with an appropriate mixture of tRNAs bearing natural or non-natural amino acids) and sequences representing high binding affinity polypeptides are isolated after in vitro translation. Thus, the optimal polypeptide can be identified. Since the optimal sequence may not necessarily be identified by combining optimal residues at separate sites, it is useful to test mutations at multiple sites in combination with each other.

[0075] Both alanine and N-methyl scanning can also be performed using chemical synthesis approaches such as solid phase polypeptide synthesis (see, for example, Coin, I et al. (2007); Nature Protocols 2(12):3247-56 , the contents of which are incorporated herein by reference in their entirety).

[0076] Once a pool, population, or subset of polypeptides has been identified, they can be evaluated for therapeutic or diagnostic applications, including improved pharmacokinetic and/or pharmacodynamic properties.

[0077] In one embodiment, the polypeptides are evaluated for one or more of target binding affinity, activity in biochemical or cellular assays, resistance to proteases, in vitro or in vivo passage into cells, properties related to suitability for use as a pharmaceutical agents such as plasma protein binding, metabolism (in microsomes, hepatocytes or plasma), inhibition of P-glycoprotein (PGP) and inhibition of cytochrome P450. The polypeptides of the present invention can also be tested for oral bioavailability, toxicity, inhibition of the human Ether-a-go-go-related gene (HERG) product, blood half-life, other pharmacokinetic and pharmacodynamic parameters, and efficacy in animal models of disease.

Polypeptides of the invention

[0078] In accordance with the present invention, once a single polypeptide or pool of potential polypeptide molecules has been identified, they can go through one or more rounds of structure activity ratio (SAR) optimization using standard chemistry and polypeptide synthesis techniques. Such optimization may include the exclusion of charged polar side chains (Asp, Glu, Arg, Lys) that can interfere with cell entry, the exclusion of side chains that accelerate peptide metabolism (Tyr, Met, Trp, Cys), improved solubility, reduction unnecessary molecular weight, exclusion of rotating bonds and change in lipophilicity.

[0079] In one embodiment, it is an object of the present invention to provide cyclic peptidomimetics designed to be metabolically stable, cell-penetrating and/or orally available.

Amino acid variants

[0080] As used herein, the term "amino acid" includes natural amino acid residues as well as non-natural amino acids. The term also includes amino acids bearing a conventional amino protecting group (e.g., acetyl or benzyloxycarbonyl) as well as natural and non-natural amino acids protected at the carboxy terminus (e.g., as a (C1-C6) alkyl, phenyl, or benzyl ester or amide, or as alpha-methylbenzylamide). Other suitable amino and carboxy protecting groups are known to those skilled in the art (see, e.g., Greene, T. W.; Wutz, P. G. M., Protecting Groups In Organic Synthesis; second edition, 1991, New York, John Wiley & sons, Inc. , and the documents cited in them). The polypeptides and/or polypeptide compositions of the present invention may also include modified amino acids.

[0081] Non-natural amino acids useful for optimizing the polypeptides and/or polypeptide compositions of the present invention include, but are not limited to, 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid, 1-amino-2,3-hydro -1H-inden-1-carboxylic acid, homolysin, homoarginine, homoserine, 2-aminoadipic acid, 3-aminoadipic acid, beta-alanine, aminopropionic acid, 2-aminobutyric acid, 4-aminobutyric acid, 5-aminovaleric acid, 5- aminocaproic acid, 6-aminocaproic acid, 2-aminoheptanoic acid, 2-aminoisobutyric acid, 3-aminoisobutyric acid, 2-aminopimelic acid, desmosine, 2,3-diaminopropionic acid, N-ethylglycine, N-ethylasparagine, homoproline, hydroxylysine, allo -hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, isodesmosine, allo-isoleucine, N-methylpentylglycine, naphthylalanine, ornithine, pentylglycine, thioproline, norvaline, tert-butylglycine, phenylglycine, azatryptophan, 5-azatryptophan, 7-azatryptophan, 4-fluorophenylalanine , pen icillamine, sarcosine, homocysteine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 4-aminotetrahydro-2H-pyran-4-carboxylic acid, ( S )-2-amino-3-( 1 H -tetrazol-5-yl) propionic acid, cyclopentylglycine, cyclohexylglycine, cyclopropylglycine, η-ω-methylarginine, 4-chlorophenylalanine, 3-chlorotyrosine, 3-fluorotyrosine, 5-fluorotryptophan, 5-chlorotryptophan, citrulline, 4-chloro- homophenylalanine, homophenylalanine, 4-aminomethyl-phenylalanine, 3-aminomethyl-phenylalanine, octylglycine, norleucine, tranexamic acid, 2-aminovaleric acid, 2-aminocaproic acid, 2-aminoheptanoic acid, 2-aminocaprylic acid, 2-aminopelargonic acid, 2- aminocapric acid, 2-aminoundecanoic acid, 2-aminolauric acid, aminovaleric acid and 2-(2-aminoethoxy)acetic acid, pipecolic acid, 2-carboxyazetidine, hexafluoroleucine, 3-fluorovaline, 2-amino-4,4-difluoro-3 -methylbutanecarboxylic acid acid, 3-fluoroisoleucine, 4-fluoroisoleucine, 5-fluoroisoleucine, 4-methylphenylglycine, 4-ethylphenylglycine, 4-isopropylphenylglycine, ( S )-2-amino-5-azidovaleric acid (also referred to herein as “X02”), ( S )-2-aminohept-6-enoic acid (also referred to herein as "X30"), ( S )-2-aminopent-4-oic acid (also referred to herein as "X31"), ( S )-2 -aminopent-4-enoic acid (also referred to herein as "X12"), ( S )-2-amino-5-(3-methylguanidino)valeric acid, ( S )-2-amino-3-(4-( aminomethyl)phenyl)propionic acid, ( S )-2-amino-3-(3-(aminomethyl)phenyl)propionic acid, ( S )-2-amino-4-(2-aminobenzo[ d ]oxazol-5-yl )butyric acid, ( S )-leucinol, ( S )-valinol, ( S )-tert-leucinol, ( R )-3-methylbutan-2-amine, ( S )-2-methyl-1-phenylpropan-1- amine and ( S ) -N ,2-dimethyl-1-(pyridin-2-yl)propan-1-amine, ( S )-2-amino-3-(oxazol-2-yl)propionic acid, ( S ) -2-amino-3-(oxazol-5-yl)propionic acid, ( S )-2-amino-3-(1,3,4-oxadiazol-2-i l) propionic acid, (S)-2-amino-3-(1,2,4-oxadiazol-3-yl)propionic acid, ( S )-2-amino-3-(5-fluoro-1H-indazol- 3-yl)propionic acid and ( S )-2-amino-3-( 1H -indazol-3-yl)propionic acid, ( S )-2-amino-3-(oxazol-2-yl)butyric acid, ( S )-2-amino-3-(oxazol-5-yl)butyric acid, ( S )-2-amino-3-(1,3,4-oxadiazol-2-yl)butyric acid, ( S )- 2-amino-3-(1,2,4-oxadiazol-3-yl)butyric acid, ( S )-2-amino-3-(5-fluoro-1H- indazol -3-yl)butyric acid and ( S )-2-amino-3-( 1H -indazol-3-yl)butyric acid, 2-(2'-methoxyphenyl)-2-aminoacetic acid, tetrahydro-3-isoquinolinecarboxylic acid and their stereoisomers (including but not limited to D and L isomers).

[0082] Additional non-natural amino acids that are useful in optimizing the polypeptides or polypeptide compositions of the invention include, but are not limited to, fluorinated amino acids in which one or more of the associated carbon hydrogens has been replaced by fluorine. The number of fluorine atoms included may range from 1 to all hydrogen atoms, inclusive. Examples of such amino acids include, but are not limited to, 3-fluoroproline, 3,3-difluoroproline, 4-fluoroproline, 4,4-difluoroproline, 3,4-difluoroproline, 3,3,4,4-tetrafluoroproline, 4-fluorotryptophan, 5-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan and their stereoisomers.

[0083] Additional non-natural amino acids that are useful in optimizing the polypeptides or polypeptide compositions of the present invention include, but are not limited to those that are disubstituted at the α-carbon. These include amino acids in which two substituents on the α-carbon are the same, such as α-aminoisobutyric acid and 2-amino-2-ethylbutyric acid, as well as those in which the substituents are different, such as α-methylphenylglycine and α-methylproline . In addition, substituents on the α-carbon can be combined to form a ring, e.g. 4-aminotetrahydropyran-4-carboxylic acid, 3-aminopyrrolidine-3-carboxylic acid, 3-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-4-carboxylic acid and their stereoisomers.

[0084] Additional non-natural amino acids that are useful in optimizing the polypeptides or polypeptide compositions of the present invention include, but are not limited to, tryptophan analogs in which the indole system is replaced by another 9- or 10-membered bicyclic system containing 0, 1, 2 , 3, or 4 heteroatoms independently selected from N, O, or S. Each ring system may be saturated, partially unsaturated, or fully unsaturated. The ring system may be substituted with 0, 1, 2, 3 or 4 substituents on any substitutable atom. Each substituent is independently selected from H, F, Cl, Br, CN, COOR, CONRR', oxo, OR, NRR'. Each R and R' are independently selected from H, C1-C20 alkyl, C1-C20 alkyl-O-C1-20 alkyl.

[0085] In some embodiments, tryptophan analogs (also referred to herein as "tryptophan analogs") that can be used in optimizing polypeptides or polypeptide compositions of the invention include, but are not limited to, 5-fluorotryptophan [(5-F )W], 5-methyl-O-tryptophan [(5-MeO)W], 1-methyltryptophan [(1-Me-W) or (1-Me),W], D-tryptophan (D-Trp), azatryptophan (including, but not limited to, 4-azatryptophan, 7-azatryptophan and 5-azatryptophan) 5-chlorotryptophan, 4-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan and their stereoisomers. Except where otherwise noted, the term "azatryptophan" and its abbreviation "azaTrp" as used herein refer to 7-azatryptophan.

[0086] Modified amino acid residues useful in optimizing the polypeptides and/or polypeptide compositions of the present invention include, but are not limited to, those that are chemically blocked, reversibly or irreversibly, or chemically modified at their N-terminal amino group or side chain group. , or chemically modified on the amide backbone, for example, N-methylated; stereoisomers or residues of D (non-natural amino acids) and L (natural amino acids), in which the functional groups of the side chain are chemically modified into another functional group. For example, modified amino acids include, without limitation, methionine sulfoxide; methionine sulfone; aspartic acid beta-methyl ester, modified aspartic acid; N-ethylglycine, modified glycine; or alanine carboxamide and modified alanine. Non-natural amino acids can be purchased from Sigma-Aldrich (St. Louis, MO), Bachem (Torrance, CA) or other suppliers. Non-natural amino acids may further include any of those listed in Table 2 of US Patent Publication US 2011/0172126, the contents of which are incorporated herein by reference in their entirety.

[0087] In some embodiments, the implementation of the amino acid sequence of the polypeptides and/or polypeptide compositions of the present invention may contain only naturally occurring amino acids. Although it is known in the art that the terms peptides, polypeptides and/or fragments thereof imply relative size, these terms in the context of the present invention should not be construed as limiting the size of the various polypeptide-based molecules described in the present description and which are covered by this invention. , unless otherwise specified. In some embodiments, the implementation of the polypeptides may contain both naturally occurring and non-naturally occurring and/or modified amino acids, or may exclusively consist of non-naturally occurring amino acids.

Polypeptide variants

[0088] According to the present invention, any amino acid-based molecule (natural or non-natural) may be referred to as a "polypeptide", and this term includes "peptides", "peptidomimetics" and "proteins". Polypeptides are also included in the category of proteins and are traditionally considered to be from about 4 to about 50 amino acids in size. Dipeptides having two amino acid residues are categorized as polypeptides, as are tripeptides (polypeptides containing three amino acids). Polypeptides greater than about 50 amino acids are commonly referred to as "proteins". Polypeptide sequences may be linear or cyclic. For example, a cyclic polypeptide may be formed by or may result from the formation of disulfide bonds between two cysteine residues in the sequence. The polypeptide may be cyclized through the carboxy-terminus, amino-terminus, or any other convenient point of attachment, such as, for example, sulfur in a cysteine or any side chain of an amino acid residue or other bond, including, but not limited to, a maleimide bond, an amide bond, an ester bond, an ether bond, a thioether bond, a hydrazone bond, or an acetamide bond. In some embodiments, cyclic polypeptides are formed when a molecule acts as a bridge to connect two or more regions of a polypeptide.

[0089] The term "amino acid sequence variant" refers to polypeptides with some differences in their amino acid sequences compared to the original, reference or native sequence. Amino acid sequence variants may have substitutions, deletions and/or insertions at certain positions within the amino acid sequence. Typically, variants will have at least about 70% homology with the native or parent sequence, and preferably they will be at least about 80%, more preferably at least about 90% homologous to the native or parent sequence.

[0090] "Homology" in relation to amino acid sequences is defined as the percentage of residues in a candidate amino acid sequence that are identical to residues in a second amino acid sequence after sequence alignment and gaps are introduced, if necessary to achieve the maximum percent homology. Methods and computer programs for alignment are well known in the art. It is clear that the homology depends on the calculation of percent identity, but may vary in magnitude due to discontinuities and penalties taken into account in the calculations.

[0091] By "homologues" with respect to amino acid sequences is meant a corresponding sequence from another species that has a significant identity with a second sequence of the second species.

[0092] "Analogs" means the inclusion of variants of amino acid sequences that differ in one or more amino acid changes, such as substitution, addition or deletion of amino acid residues, that still retain one or more of the properties of the parent or parent polypeptide.

[0093] The present invention provides several types of compositions that include polypeptides, including variants and derivatives. These include substituted, insertion, deletion and covalent variants and derivatives. The term "derivative" is used as a synonym for the term "variant" and refers to a molecule that has been modified or altered in any way from a reference or parent molecule.

[0094] Thus, included in the present invention are polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications. For example, tag sequences or amino acids, such as one or more lysines, can be added to the polypeptide sequences of the invention (eg, at the N- or C-terminus). Tag sequences can be used to purify or locate a polypeptide. Lysines can be used to increase the solubility of a polypeptide or to provide site-specific modifications such as, but not limited to, biotinylation or PEGylation. In some cases, the polypeptides may be dethiobiotinylated. As used herein, a polypeptide that is dethiobiotinylated may comprise a dethiobiotin (Dtb) molecule conjugated to the epsilon-amino group of a lysine residue. Such lysine residues may, in some cases, be C-terminal residues. Alternatively, amino acid residues located at the carboxy- and amino-terminal portions of the amino acid sequence of the polypeptide may optionally be deleted, resulting in truncated sequences. Some amino acids (eg, C-terminal or N-terminal residues) may alternatively be deleted depending on the intended use of the sequence, such as expressing the sequence as part of a larger sequence that is soluble or bound to a solid support.

[0095] "Substituted variants" in relation to polypeptides are those in which at least one amino acid residue in the native or parent sequence is deleted and another amino acid is inserted in its place. These substitutions may be single, when only one amino acid in a molecule is substituted, or they may be multiple, when two or more amino acids are substituted in one molecule.

[0096] As used herein, the term "conservative amino acid substitution" refers to the replacement of an amino acid that is normally present in a sequence with another amino acid having a similar size, charge, or polarity. Examples of conservative substitutions include replacing a non-polar (hydrophobic) moiety such as isoleucine, valine, and leucine with another non-polar moiety. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another, such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. In addition, substitution of a basic residue such as lysine, arginine or histidine with another, or substitution of one acidic residue such as aspartic acid or glutamic acid with another acidic residue are further examples of conservative substitutions. Examples of non-conservative substitutions include replacing a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine with a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid, or lysine, and/or replacing a polar residue with a non-polar remainder.

[0097] "Isosteres" are two or more molecules that exhibit some similarity in biological properties as a result of having the same number of shared or valence electrons in the same arrangement, and which are composed of different atoms, optionally with the same number of atoms. There are two classes of isosteres - classical and non-classical. Classical isosteres have the same number of atoms and/or the same number of valence electrons, while non-classical isosteres are molecules that give a similar biological effect in vivo , but do not have the same number of atoms and/or valence electrons.

[0098] According to the present invention, "peptide bond isosteres" are defined as isosteres having properties resembling a peptide bond. Peptide bond isosteres may be of the linear type, including at least one peptide bond substitution, or may be cyclic and include carboxylic acid and amine function. Such a substitution may be any moiety that improves the physicochemical, structural or functional properties of the molecule. Peptide bond replacement can increase the metabolic stability of polypeptides and decrease or increase flexibility. Peptide bond isosteres described herein may be mono-, di-, tri-, tetra-, penta-, sexta-, septa-, octa-, nona- or deca-peptide bond isosteres, which means that at least at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 peptide bonds can be replaced. Non-limiting examples of linear dipeptide bond isosteres for amide (peptide) bonds include thioamide, sulfanilamide, sulfonate, phosphonamide, phosphonate, phosphothioate, phosphinate, alkane, 1- or 2-hydroxyethylene, dihydroxyethylene, C-C single bond (alkane), C-C double bond (alkene ), C-C triple bond (alkyne), C-O bond (methylene oxide), O-N or N-O bond, (methyleneamino), triazole, hydrazide, urea, ketone, urethane bond, (di) haloalkene, methylene mercapto, methyleneamino, trifluoroethylamino, hydrazide, amide oxide and others known to those skilled in the art.

[0099] Peptide bond isosteres can also be cyclic molecules that carry an amino group and a carboxy group. Non-limiting examples of cyclic peptide bond isosteres with various ring sizes include carbacycles, azacycles, and oxacycles. Azacycles can be based on an alkaloid nucleus that forms an isostere with a bicyclic structure. An example of an azacyclic isostere includes an isostere based on a triazole ring resulting from a copper-catalyzed azide-alkyne cycloaddition. The cyclic isosteres of the peptide bond described herein may be the cyclic isosteres of bi-, tri-, tetra-, penta-, sexta-, septa, octa-, nona-, deca-peptides.

[00100] "Insertional variants" in relation to polypeptides are variants with one or more amino acids inserted in close proximity to an amino acid at a specific position in the native or parent sequence. "In close proximity" to an amino acid means linked to the alpha-carboxy or alpha-amino functional group of the amino acid.

[00101] "Deletion variants" in relation to polypeptides, are variants with one or more amino acids deleted in the native or original amino acid sequence. Typically, deletion variants will have one or more amino acids deleted in a specific region of the molecule.

[00102] "Shortened variants" in relation to polypeptides are variants with one or more amino acids in the native or original amino acid sequence removed from either end of the polypeptide.

[00103] According to the present invention, the polypeptides can be modified by adding one or more connecting groups. In some embodiments, the polypeptides may be administered in combination with one or more additional molecules.

[00104] Used in the present description, the term "conjugate" refers to any molecule or fragment connected to another molecule. In the present invention, the conjugates may or may not be polypeptide (amino acid) based. Conjugates may contain lipids, small molecules, RNA, DNA, polypeptides, polymers, or combinations thereof. Functionally, the conjugates may serve as guide molecules or may serve as a payload to be delivered to a cell, organ, or tissue. Conjugates are typically covalent modifications made by reacting target amino acid residues or ends of a polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or end residues. Such modifications are known to those of ordinary skill in the art and are performed without undue experimentation.

[00105] The conjugation process may include PEGylation, lipidation, addition of albumin, biotinylation, dethiobiotinylation, addition of other polypeptide tails, or grafting onto antibody Fc domains, intact antibody CDR regions, or antibody domains generated in any way. The conjugate may include anchor molecules ("anchors") including a cholesterol oleate group, a cholesterol laurate group, an α-tocopherol group, a phytol group, an oleate group, or an unsaturated cholesterol ester group, or a lipophilic compound selected from acetanilides, anilides, aminoquinolines, benzhydryl compounds, benzodiazepines , benzofurans, cannabinoids, cyclic polypeptides, dibenzazepines, digitalis glycosides, ergot alkaloids, flavonoids, imidazoles, quinoline, macrolides, naphthalenes, opiates (such as, but not limited to, morphines or other psychoactive substances), oxazines, oxazoles, phenylalkylamines, piperidines , polycyclic aromatic hydrocarbons, pyrrolidines, pyrrolidinones, stilbenes, sulfonylureas, sulfones, triazoles, tropanes and vinca alkaloids.

[00106] As used herein, the term "covalent derivative" in relation to a polypeptide includes modification of a native or parent polypeptide with an organic proteinaceous or non-proteinaceous derivatizing agent and/or post-translational modification. Covalent modifications are traditionally added by reacting the target amino acid residues of the polypeptide with an organic derivatizing agent that is capable of reacting with selected side chains or terminal residues, or by using post-translational modification mechanisms that function in selected recombinant host cells. The obtained covalent derivatives can be used in programs aimed at identifying residues important for biological activity, for immunological analysis, or for obtaining antibodies to the protein for immunoaffinity purification of the recombinant protein. Such modifications are known to those of ordinary skill in the art and are performed without undue experimentation.

[00107] Some post-translational modifications result from the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues can be deamidated to form the corresponding glutamyl and aspartyl residues. Alternatively, these residues can be deamidated under mildly acidic conditions. Any form of these residues may be present in the polypeptides obtained in accordance with the present invention.

[00108] Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of tyrosinyl, seryl, or threonyl residues, methylation of alpha-amino groups of lysine, arginine, and histidine side chains (Creighton, T. E. Proteins: Structure and Molecular Properties, W. H. Freeman & Co. , San Francisco, 1983, pp. 79-86).

[00109] Covalent modifications specifically include the connection of non-protein polymers with the polypeptides of the present invention. Non-protein polymers may include a hydrophilic synthetic polymer, ie the polymer is not otherwise found in nature. However, polymers that exist in nature and are produced by recombinant or in vitro methods are useful because they are polymers that are isolated from the natural environment. Hydrophilic polyvinyl polymers are within the scope of the present invention, such as polyvinyl alcohol and polyvinylpyrrolidone. These polypeptides can be linked to various non-protein polymers such as polyethylene glycol, polypropylene glycol, or polyoxyalkylenes by the method described in US Pat.

[00110] "Features" in relation to polypeptides are defined as the components of a molecule based on individual amino acid sequences. Features of the polypeptide of the present invention include surface shape, local conformational shapes, folds, loops, half-loops, domains, half-domains, sites, ends, or any combination thereof.

[00111] When used herein in relation to polypeptides, the term "fold" refers to the resulting conformation of the amino acid sequence after energy minimization. The fold may occur at a secondary or tertiary level in the polypeptide folding process. Examples of secondary level folds include beta sheets and alpha helices. Examples of tertiary folds include domains and regions formed by aggregation or separation of physico-chemically distinct regions. The regions thus formed include hydrophobic and hydrophilic pockets and the like.

[00112] As used herein, the term "kink" in relation to protein conformation means a kink that changes the direction of a polypeptide chain and may include one, two, three or more amino acid residues.

[00113] As used herein, when referring to polypeptides, the term "loop" refers to a structural feature of a polypeptide that can serve to reverse the direction of the polypeptide backbone. If the loop is in the polypeptide and only changes the direction of the main chain, it may include four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (Oliva, B. et al., J Mol Biol. 1997 Mar 7;266(4):814-30; the contents of which are incorporated herein by reference in their entirety). Loops can be open or closed. Closed or "cyclic" loops can form when two amino acids are linked by a bridge. The cyclic loop includes the amino acids in the polypeptide between the bridging amino acids. Cyclic loops may include 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids.

[00114] As used herein, when referring to polypeptides, the term "half-loop" refers to the portion of an identified loop containing at least half the number of amino acids in the loop from which it is formed. It is understood that the loops may not always contain an even number of amino acid residues. Therefore, in cases where a loop contains or is identified as containing an odd number of amino acids, a half-loop from a loop with an odd number of amino acids will contain an integer amino acid part or a next integer amino acid part (number of amino acids in the loop/2 +/- 0 .5 amino acids). For example, a loop identified as a 7-amino acid loop may give rise to half-loops of 3 or 4 amino acids (7/2=3.5 +/- 0.5 may be 3 or 4).

[00115] As used herein, when referring to proteins, the term "region" refers to a zone or a general region. In some embodiments, when referring to a protein, the region may include the linear amino acid sequence of the protein, or may contain a particular secondary or tertiary structure and/or one or more features or protein domains.

[00116] As used herein, the term "domain" when referring to proteins refers to a polypeptide motif having one or more identifiable structural (such as secondary or tertiary structures) or functional characteristics or properties (such as binding ability acting in site for protein-protein interactions).

[00117] As used herein, the term "semi-domain" when referring to proteins refers to a portion of an identified domain containing at least half the number of amino acids in the domain from which it is derived. It is understood that domains may not always contain an even number of amino acid residues. Therefore, in cases where a domain contains or is identified as containing an odd number of amino acids, a half-domain from a domain with an odd number of amino acids will contain an integer amino acid part or a part with the following integer amino acid number (number of amino acids in the loop / 2 +/- 0 .5 amino acids). For example, a domain identified as a 7-amino acid domain may give rise to 3 or 4 amino acid half-domains (7/2=3.5 +/- 0.5 may be 3 or 4). It should also be understood that subdomains can be identified within domains or half-domains, and these subdomains do not have all of the structural or functional properties defined in the domains or half-domains from which they were derived. It should also be understood that the amino acids that make up any of the types of domains in this invention need not necessarily be located sequentially in the backbone of the polypeptide (i.e., non-sequential amino acids may fold into the structure to form a domain, half-domain, or subdomain).

[00118] As used herein in relation to polypeptides, the term "site" when referring to amino acid variants is used in parallel with "amino acid residue" and "amino acid side chain". A site is a position in a polypeptide that can be modified, manipulated, altered, derivatized, or varied in the polypeptide-based molecules of the present invention.

[00119] In the present description, the terms "ends" or "end" in relation to polypeptides refer to the terminal part of the polypeptide. Such a terminus is not limited to the first or last site of the polypeptide, but may include additional amino acids in the terminal regions. The polypeptide-based molecules of the present invention can be characterized as having both N- and C-terminus. The polypeptides and/or polypeptide compositions of the present invention in some cases consist of several polypeptide chains linked by disulfide bonds or non-covalent forces (multimers, oligomers). These kinds of proteins will have multiple N- and C-terminals. Alternatively, the ends of the polypeptides may be modified such that they begin or end (as the case may be) with a non-polypeptide molecule, such as an organic conjugate.

[00120] In one embodiment, the polypeptides of the present invention may include a terminal region. In the present description, the term "terminal region" is the terminal region of the amino acids, which may include cysteine. The end region may be N- and/or C-terminal. In some embodiments, the implementation of the end regions can be connected to the parent polypeptides using a bridge element. Used in the present description, the term "parent polypeptide" refers to the part of the polypeptide, which does not include the terminal region. The terminal region may be separated from the parent polypeptide by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues. The added residues can be selected from, but are not limited to, any natural or artificial amino acid, the N-methylated form of any natural or artificial amino acid, the D-stereoisomer of any natural or artificial amino acid, norvaline, t-butylglycine, phenylglycine, azatryptophan, 7-azatryptophan , 4-fluorophenylalanine, penicillamine, sarcosine, homocysteine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 4-aminetetrahydro-2H-pyran-4-carboxylic acid, aminoisobutyric acid, ( S ) -2-amino-3-(1 H -tetrazol-5-yl) propionic acid, cyclopentylglycine, cyclohexylglycine, cyclopropylglycine, η-ω-methylarginine, 4-chlorophenylalanine, 3-chlorotyrosine, 3-fluorotyrosine, 5-fluorotryptophan, 5- chlorotryptophan, citrulline, 4-chloro-homophenylalanine, homophenylalanine, 4-aminomethylphenylalanine, 3-aminomethylphenylalanine, octylglycine, norleucine, tranexamic acid, 2-aminoval eric acid, 2-aminocaproic acid, 2-aminoheptanoic acid, 2-aminocaprylic acid, 2-aminopelargonic acid, 2-aminocapric acid, 2-aminoundecanoic acid, 2-aminolauric acid, aminovaleric acid and 2-(2-aminoethoxy)acetic acid , pipecolic acid, 2-carboxyazetidine, hexafluoroleucine, 3-fluorovaline, 2-amino-4,4-difluoro-3-methylbutanecarboxylic acid, 3-fluoroisoleucine, 4-fluoroisoleucine, 5-fluoroisoleucine, 4-methylphenylglycine, 4-ethylphenylglycine, 4 -isopropylphenylglycine, ( S )-2-amino-5-(3-methylguanidino)valeric acid, ( S )-2-amino-3-(4-(aminomethyl)phenyl)propionic acid, ( S )-2-amino- 3-(3-(aminomethyl)phenyl)propionic acid, ( S )-2-amino-4-(2-aminobenzo[ d ]oxazol-5-yl)butyric acid, ( S )-leucinol, ( S )-valinol , ( S )-tert-leucinol, ( R )-3-methylbutan-2-amine, ( S )-2-methyl-1-phenylpropan-1-amine, and ( S ) -N ,2-dimethyl-1-( pyridin-2-yl)propan-1-amine, ( S )-2-amino-3-(oxazol-2-yl)propionic acid, ( S )-2-amino-3-(o xazol-5-yl)propionic acid, ( S )-2-amino-3-(1,3,4-oxadiazol-2-yl)propionic acid, (S)-2-amino-3-(1,2, 4-oxadiazol-3-yl)propionic acid, ( S )-2-amino-3-(5-fluoro-1H-indazol-3-yl)propionic acid and ( S )-2-amino-3-( 1H -indazol-3-yl)propionic acid.

[00121] Additional non-natural amino acids that are useful in optimizing the polypeptides of the present invention include, but are not limited to, fluorinated amino acids, where one or more hydrogen carbon atoms are replaced by fluorine atoms. The number of fluorine atoms included may vary from 1 to all inclusive hydrogen atoms. Examples of such amino acids include, but are not limited to, 3-fluoroproline, 3,3-difluoroproline, 4-fluoroproline, 4,4-difluoroproline, 3,4-difluoroproline, 3,3,4,4-tetrafluoroproline, 4-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan and their stereoisomers.

[00122] Additional non-natural amino acids that are useful in optimizing the polypeptides of the invention include, but are not limited to, α-carbon disubstituted amino acids. These include amino acids where two substituents on the α-carbon are the same, such as α-aminoisobutyric acid and 2-amino-2-ethylbutyric acid, and those where the substituents differ, such as α-methylphenylglycine and α-methylproline. In addition, substituents on the α-carbon can be linked to form a ring, e.g. 4-aminotetrahydropyran-4-carboxylic acid, 3-aminopyrrolidine-3-carboxylic acid, 3-aminopiperidine-3-carboxylic acid, 4-aminopiperidine-4-carboxylic acid, and their stereoisomers.

[00123] Additional non-natural amino acids that are useful in optimizing the polypeptides of the present invention include, but are not limited to, tryptophan analogs in which the indole system is replaced by another 9 or 10-membered bicyclic ring system containing 0, 1, 2, 3 or 4 heteroatoms independently selected from N, O, or S. Each ring system may be saturated, partially unsaturated, or fully unsaturated. The ring system may be substituted with 0, 1, 2, 3 or 4 substituents on any substitutable atom. Each substituent is independently selected from H, F, Cl, Br, CN, oxo, COOR, CONRR', OR, NRR'. Each R and R' is independently selected from H, C1-C20 alkyl, C1-C20 alkyl-O-C1-20 alkyl.

[00124] In some embodiments, tryptophan analogs (also referred to herein as "tryptophan analogs") that can be used in optimizing the polypeptides of the present invention include, but are not limited to, 5-fluorotryptophan [(5-F)W ], 5-methyl-O-tryptophan [(5-MeO)W], 1-methyltryptophan [(1-Me-W) or (1-Me)W], D-tryptophan (D-Trp), 7-azatryptophan (including, but not limited to, 4-azatryptophan, 7-azatryptophan, and 5-azatryptophan) 5-chlorotryptophan, 4-fluorotryptophan, 6-fluorotryptophan, 7-fluorotryptophan, and their stereoisomers. Except where otherwise noted, the term "azatryptophan" and its abbreviation "azaTrp" as used herein refer to 7-azatryptophan

[00125] In one embodiment, the polypeptides of the present invention may include a terminal modification at the N- or C-terminus with the addition of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more residues and /or cysteines in the terminal region. The added residues can be selected from, but are not limited to, any natural or artificial amino acid, the N-methylated form of any natural or artificial amino acid, the D-stereoisomer of any amino acid, norvaline, t-butylglycine, phenylglycine, azatryptophan, 7-azatryptophan, 4- fluorophenylalanine, penicillamine, sarcosine, homocysteine, 1-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 4-aminetetrahydro-2H-pyran-4-carboxylic acid, aminoisobutyric acid, ( S )-2- amino-3-( 1H -tetrazol-5-yl)propionic acid, cyclopentylglycine, cyclohexylglycine, cyclopropylglycine, η-ω-methylarginine, 4-chlorophenylalanine, 3-chlorotyrosine, 3-fluorotyrosine, 5-fluorotryptophan, 5-chlorotryptophan, citrulline , 4-chloro-homophenylalanine, homophenylalanine, 4-aminomethylphenylalanine, 3-aminomethylphenylalanine, octylglycine, norleucine, tranexamic acid, 2-aminovaleric acid, 2-a minocaproic acid, 2-aminoheptanoic acid, 2-aminocaprylic acid, 2-aminopelargonic acid, 2-aminocapric acid, 2-aminoundecanoic acid, 2-aminolauric acid, aminovaleric acid and 2-(2-aminoethoxy)acetic acid, pipecolic acid, 2 -carboxyazetidine, hexafluoroleucine, 3-fluorovaline, 2-amino-4,4-difluoro-3-methylbutanecarboxylic acid, 3-fluoroisoleucine, 4-fluoroisoleucine, 5-fluoroisoleucine, 4-methylphenylglycine, 4-ethylphenylglycine, 4-isopropylphenylglycine, ( S )-2-amino-5-(3-methylguanidino)valeric acid, ( S )-2-amino-3-(4-(aminomethyl)phenyl)propionic acid, ( S )-2-amino-3-(3- (aminomethyl)phenyl)propionic acid, ( S )-2-amino-4-(2-aminobenzo[ d ]oxazol-5-yl)butyric acid, ( S )-leucinol, ( S )-valinol, ( S )- tert-leucinol, ( R )-3-methylbutan-2-amine, ( S )-2-methyl-1-phenylpropan-1-amine and ( S ) -N ,2-dimethyl-1-(pyridin-2-yl )propan-1-amine, ( S )-2-amino-3-(oxazol-2-yl)propionic acid, ( S )-2-amino-3-(oxazol-5-yl)propionic th acid, ( S )-2-amino-3-(1,3,4-oxadiazol-2-yl)propionic acid, (S)-2-amino-3-(1,2,4-oxadiazol-3- yl)propionic acid, ( S )-2-amino-3-(5-fluoro-1H-indazol-3-yl)propionic acid and ( S )-2-amino-3-( 1H -indazol-3-yl ) propionic acid.

[00126] The polypeptides of the present invention can be conjugated to a polypeptide that increases or decreases plasma protein binding, including but not limited to those described in Dennis, M.S. et al., Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem. 2002 Sep 20; 277(38):35035-43; Nguyen, A. et al., The pharmacokinetics of an albumin-binding Fab (AB Fab) can be modulated as a function of affinity for albumin. Protein Eng Des Sel. 2006 Jul;19(7):291-7 and Langerheim, J.F. et al., Improving the pharmacokinetics/pharmacodynamics of prolactin, GH, and their antagonists by fusion to a synthetic albumin-binding polypeptide. J Endocrinol. 2009 Dec;203(3):375-87. In some embodiments, such polypeptides bind serum albumin (referred to herein as "albumin-binding polypeptides"). In some embodiments, albumin-binding polypeptides undergo cyclization by forming a disulfide bond between cysteine residues present in their polypeptide sequences. In some embodiments, albumin-binding polypeptides are conjugated through their N- or C-termini. In some embodiments, the implementation of conjugation with albumin-binding polypeptide changes the time during which the polypeptide of the present invention remains intact in the patient. In a preferred embodiment, conjugation to an albumin-binding polypeptide increases the time that the polypeptide of the present invention remains in the patient's blood. The polypeptides of the present invention can be conjugated to polypeptides that have cell-penetrating properties (referred to herein as "cell-penetrating polypeptides"), including, but not limited to, those disclosed in Milletti, F., Cell-penetrating peptides: classes , origin, and current landscape. Drug Disc Today. 2012 Aug;17(15-16):850-60. Additional cell-penetrating polypeptides are known to those skilled in the art. The polypeptides of the present invention can be conjugated with any of the polypeptide conjugates described, for example, in US patent publications US20110172126 or US20030040472, the contents of which are herein fully incorporated by reference. The polypeptides of the present invention may be conjugated to a lipophilic molecule that enhances plasma protein binding, such as lipophilic substituents as described, for example, in US Pat. No. 6,268,343 or US Pat. .

[00127] Once any features have been identified or determined to be a desired component of a polypeptide, any of several manipulations and/or modifications of those features can be performed by transposition, replacement, inversion, deletion, randomization, or duplication. In addition, it should be understood that the manipulation of features can give the same result as the modification of the molecules according to the invention. For example, a manipulation that involves removing a domain can result in a change in the length of the molecule, as can a nucleic acid modification that shortens the coding region relative to the full length of the molecule.

[00128] Modifications and manipulations can be performed using methods known in the art, such as, but not limited to, site-directed mutagenesis. The resulting modified molecules can then be tested for activity using in vitro or in vivo assay methods such as those described herein, or using any other suitable screening method known in the art.

[00129] According to the present invention, the polypeptides may include a consensus sequence, which is found after a series of experiments. As used herein, a "consensus" sequence is a single sequence that represents a cumulative population of sequences while allowing variability at one or more sites.

[00130] The term "identity", known in this field, refers to the relationship between the sequences of two or more polypeptides, determined by comparing the sequences. In this area, identity also means the degree of similarity of sequences between polypeptides, determined by the number of matches between chains of two or more amino acid residues. Identity measures the percentage of identical matches between the smaller of two or more sequences with discontinuities in the alignment (if any) inserted by a particular mathematical model or computer program (i.e., "algorithm"). The identity of related polypeptides can be easily calculated by known methods. Such methods include, but are not limited to, those previously described by others (Lesk, A. M., ed., Computational Molecular Biology, Oxford University Press, New York, 1988; Smith, D. W., ed., Biocomputing: Informatics and Genome Projects, Academic Press, New York, 1993; Griffin, A. M. et al., ed., Computer Analysis of Sequence Data, Part 1, Humana Press, New Jersey, 1994; von Heinje, G., Sequence Analysis in Molecular Biology, Academic Press, 1987; Gribskov, M. et al., ed., Sequence Analysis Primer, M. Stockton Press, New York, 1991; and Carillo et al., Applied Math, SIAM J, 1988, 48, 1073).

[00131] In some embodiments, a variant polypeptide may have the same or similar activity as a reference polypeptide. Alternatively, the variant may have an altered activity (eg, increased or decreased) compared to the reference polypeptide. In general, variants of a particular polypeptide of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 100% sequence identity compared to a specific reference polypeptide as determined by the sequence and parameter alignment programs described in the present description, and known to specialists in this field. Such alignment tools include the BLAST package (Altschul, S.F. et al., Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Res. 1997, 25:3389-3402). Other tools are described in this document, in particular in the definition of "identity".

[00132] The default parameters in the BLAST algorithm include, for example, expected threshold 10, word length 28, Pass/Miss score 1, -2, linear gap cost. Any filter can be used, as well as selection for species-specific repeats, such as Homo sapiens .

Abbreviations used in polypeptides

[00133] As used herein, the abbreviations have the following meanings: "Ac" and "NH2" denote the acetyl and amidated ends, respectively, "Nvl" denotes norvaline; "Phg" refers to phenylglycine; "Tbg" refers to tert-butylglycine; "Chg" means cyclohexylglycine; "(N-Me)X" means the N-methylated form of an amino acid indicated by a one-letter or three-letter amino acid code instead of the variable "X", written as N-methyl-X [e.g., (N-Me)A or (N-Me )Ala is the N-methylated form of alanine or N-methylalanine]; "azaTrp" means azatryptophan; "(4-F)Phe" means 4-fluorophenylalanine; "Tyr(OMe)" means O-methyl-tyrosine, "Aib" means aminoisobutyric acid; "(homo)F" or "(homo)Phe" means homophenylalanine; "(2-OMe)Phg" means 2-O-methylphenylglycine; "(5-F)W" means 5-fluorotryptophan; "DX" refers to the D-stereoisomer of a given amino acid "X" [eg, (D-Chg) is D-cyclohexylglycine]; "(5-MeO)W" means 5-methyl-O-tryptophan; "homoC" means homocysteine; "(1-Me-W)" or "(1-Me)W" means 1-methyltryptophan; "Nle" means norleucine; "Tiq" denotes a tetrahydroisoquinoline residue; "Asp(T)" refers to ( S )-2-amino-3-(1 H -tetrazol-5-yl)propionic acid; "(3-Cl-Phe)" means 3-chlorophenylalanine; "[(N-Me-4-F)Phe]" or "(N-Me-4-F)Phe" means N-methyl-4-fluorophenylalanine; "(m-Cl-homo)Phe" means meta-chlorohomophenylalanine; "(desamino)C" means 3-thiopropionic acid; "(alpha-methyl)D" refers to alpha-methyl-L-aspartic acid; "2Nal" means 2-naphthylalanine; "(3-aminomethyl)Phe" means 3-aminomethyl-L-phenylalanine; "Cle" means cycloleucine; "A-pyran" means 4-amino-tetrahydropyran-4-carboxylic acid; "(Lys-C16)" refers to N-ε-palmitoyllysin; "(Lys-C12)" refers to N-ε-lauryllysin; "(Lys-C10)" refers to N-ε-capryllisin; "(Lys-C8)" refers to N-ε-capryllisin; "[ x -xylyl( y , z )]" denotes a xylyl bridge between two thiol-containing amino acids, where x can be m, p or o indicating the use of meta-, para- or ortho-dibromoxylenes (respectively) to create the bridge , and the numeric identifiers, y and z , indicate the amino acid positions in the polypeptide for the amino acids involved in the cyclization process; "[cyclo( y , z )]" refers to the formation of a bond between two amino acid residues, where the numerical identifiers, y and z , indicate the positions of the residues involved in the formation of the bond; "[cyclo-olefinyl( y , z )]" refers to the formation of a bond between two amino acid residues using an olefin exchange reaction, where the numerical identifiers, y and z , indicate the positions of the residues involved in the formation of the bond; "[cyclo-thioalkyl( y , z )]" refers to the formation of a thioether bond between two amino acid residues, where the numeric identifiers, y and z , indicate the positions of the residues involved in the formation of the bond; "[cyclo-triazolyl( y , z )]" refers to the formation of a triazole ring between two amino acid residues, where the numerical identifiers, y and z , indicate the positions of the residues involved in the formation of the connection. "B20" stands for N-ε-(PEG2-γ-glutamic acid-N-α-octodecanedioic acid) lysine [also known as (1 S ,28 S )-1-amino-7,16,25,30-tetraoxo- 9,12,18,21-tetraoxa-6,15,24,29-tetraazahexatetracontane-1,28,46-tricarboxylic acid]

B20

"B28" refers to N-ε-(PEG24-gammaglutamic acid-N-α-hexadecanoyl)lysine.

B28

"K14" refers to N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-lysine. All other characters refer to the standard single letter amino acid code.

Antibodies

[00134] In some embodiments, the compounds and/or compositions of the present invention may contain antibodies or fragments thereof. As used herein, the term "antibody" is used in its broadest sense and specifically encompasses various variations including, but not limited to, monoclonal antibodies, polyclonal antibodies, polyspecific antibodies (e.g., bispecific antibodies formed from at least two intact antibodies), as well as fragments of antibodies, such as diabodies, provided that they exhibit the desired biological activity. The antibodies of the present invention may also include human antibodies or humanized antibodies. Antibodies are molecules primarily composed of amino acids, but may also include one or more modifications (including but not limited to the addition of sugar molecules, fluorescent residues, chemical tags, etc.)

[00135] As used herein, the term "antibody fragment" refers to any portion of an intact antibody. In some embodiments, the antibody fragments include antigen-binding regions from intact antibodies. Examples of antibody fragments may include, but are not limited to, Fab-, Fab', F(ab') ₂ -, and Fv fragments; diantibodies; linear antibodies; single chain antibody molecules; and polyspecific antibodies formed from antibody fragments. Cleavage of antibodies with papain produces two identical antigen-binding fragments, referred to as "Fab" fragments, each with one antigen-binding site. A residual "Fc" fragment is also produced, the name of which reflects its ability to easily crystallize. Pepsin treatment produces an F(ab') ₂ fragment which has two antigen binding sites and is still capable of antigen crosslinking. The compounds and/or compositions of the present invention may contain one or more of these moieties. In the context of the present invention, the term "antibody" may include the variable domains of the heavy and light chains, as well as in the Fc region.

[00136] As used herein, the term "native antibody" refers to a typically heterotetrameric glycoprotein of about 150,000 daltons, consisting of two identical light (L) chains and two identical heavy (H) chains. Each light chain is linked to the heavy chain by a single covalent disulfide bond, while the number of disulfide bonds between heavy chains varies between immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (V _H ) followed by a number of constant domains. Each light chain has a variable domain (V _L ) at one end and a constant domain at the other end; the light chain constant domain is located along the first heavy chain constant domain, and the light chain variable domain is located along the heavy chain variable domain.

[00137] As used herein, the term "variable domain" refers to certain antibody domains that differ significantly in sequence between antibodies and are used in the binding and specificity of each particular antibody for its particular antigen.

As used herein, the term "Fv" refers to antibody fragments containing complete antigen recognition and antigen binding sites. These regions consist of a dimer of one heavy chain and one light chain variable domains in tight, non-covalent association.

[00138] As used herein, the term "light chain" refers to an antibody component from any vertebrate species assigned to one of two distinct types, called kappa and lambda, based on the amino acid sequences of the constant domains.

[00139] Depending on the amino acid sequence of the constant domain of their heavy chains, antibodies can be assigned to different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further subdivided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA, and IgA2.

[00140] As used herein, the term "single chain Fv" or "scFv" refers to a fusion protein of the V _H and V _L domains of an antibody, where these domains are joined together in a single polypeptide chain. In some embodiments, the Fv polypeptide linker allows the scFv to form the desired structure for antigen binding.

[00141] As used herein, the term "dianbody" refers to a small fragment of an antibody with two antigen-binding sites. The diantibodies comprise a V _H heavy chain variable domain coupled to a V _L light chain variable domain in a single polypeptide chain. When using a linker that is too short to allow pairing between two domains on the same strand, the domains are forced to pair with complementary domains on the other strand and create two antigen-binding sites. Diabodies are described in more detail, for example, in EP 404097; WO 93/11161; and Hollinger et al. (Hollinger, P. et al., "Diabodies": Small bivalent and bispecific antibody fragments. PNAS. 1993. 90:6444-8), the contents of which are hereby incorporated by reference in their entirety.

[00142] As used herein, the term "monoclonal antibody" refers to an antibody derived from a population of substantially homogeneous cells (clones), i. the individual antibodies that make up the population are identical and/or bind the same epitope, except for possible variations that may arise during the production of monoclonal antibodies, and such variants are usually present in small quantities. Unlike polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.

[00143] The modifier "monoclonal" indicates the nature of the antibody derived from a substantially homogeneous population of antibodies and should not be construed as requiring the production of the antibody by any particular method. Monoclonal antibodies as used herein include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibodies, while the remainder of the chain ( chains) is identical or homologous to corresponding sequences in antibodies derived from a different species or belonging to a different class or subclass of antibodies, and also includes fragments of such antibodies.

[00144] As used herein, the term "humanized antibody" refers to a chimeric antibody containing a minimum portion from one or more animal antibody (e.g., murine) sources and the remainder derived from one or more human immunoglobulin sources. For the most part, humanized antibodies are human (recipient) immunoglobulins in which residues from the hypervariable region of the recipient antibody are replaced by residues from the hypervariable region of antibodies from animal species (donor antibodies) such as mouse, rat, rabbit, or non-human primate, having the desired specificity, affinity and/or binding.

[00145] As used herein, the term "hypervariable region" refers to regions in the antigen-binding domain of an antibody containing amino acid residues responsible for antigen binding. The amino acids present in the hypervariable regions determine the structure of the complementarity determining region (CDR). As used herein, the term "CDR" refers to antibody regions containing a structure that is complementary to its target antigen or epitope.

[00146] In some embodiments, the compounds and/or compositions of the present invention may be or contain antibody mimetics. As used herein, the term "antibody mimetic" refers to any molecule that mimics the function or action of an antibody and that binds specifically and with high affinity to its molecular targets. In some embodiments, the antibody mimetics may be monoantibodies designed to include a type III fibronectin (Fn3) domain as a protein backbone (US 6,673,901 and US 6,348,584, the contents of which are incorporated herein by reference in their entirety). In some embodiments, antibody mimetics may include those known in the art, including, but not limited to, affiantibody molecules, affilins, affytins, anticalins, avimers, Centirins, DARPin™, Fynomer, Adnectin, and peptides from the Kunitz domain. In other embodiments, antibody mimetics may include one or more non-peptide regions.

[00147] As used herein, the term "antibody variant" refers to a biomolecule that resembles an antibody in structure and/or function, containing some differences in its amino acid sequence, composition, or structure compared to a native antibody.

[00148] Obtaining antibodies, monoclonal or polyclonal, is known in the art. Techniques for producing antibodies are well known in the art and are described, for example, in Harlow and Lane "Antibodies, A Laboratory Manual", Cold Spring Harbor Laboratory Press, 1988 and Harlow and Lane "Using Antibodies: A Laboratory Manual" Cold Spring Harbor Laboratory Press, 1999.

[00149] In some embodiments, the implementation of the polypeptide sequences described in the present description, can be used to obtain one or more antibodies. In some cases, such polypeptide sequences may be included in the variable domains of antibodies. Such variable domains may be included in antibodies, antibody mimetics, or antibody variants.

Low molecular weight compounds

[00150] In some embodiments, the compounds of the present invention may be small molecule compounds. Such compounds can range in size from about 100 to about 2000 daltons (e.g., from about 100 to about 200, to about 300, to about 400, to about 500, to about 600, to about 700, to about 800, to about 900, to up to about 1000, up to about 1100, up to about 1200, up to about 1300, up to about 1400, up to about 1500, up to about 1600, up to about 1700, up to about 1800, up to 1900, or up to about 2000 daltons). Small molecule compounds can be non-peptidic or have some or more of the characteristics of polypeptides and cyclic polypeptides, including amide bonds, cyclic structures, and amino acid-like substituents.

Aptamers

[00151] In some embodiments, the compounds of the present invention may include aptamers (Keefe, AD, Pai, S. and Ellington, A. (2010). Nat. Rev. Drug Discovery 9 :537-550). Used in the present description, the term "aptamers" refers to oligonucleotide or polypeptide molecules that are able to bind certain target molecules. Some aptamers can adopt a three-dimensional conformation capable of binding such target molecules with high affinity and specificity.

Isotopic variants

[00152] The polypeptides of the present invention may contain one or more atoms that are isotopes. Used in the present description, the term "isotope" refers to a chemical element that has one or more additional neutrons. In one embodiment, the polypeptides of the present invention may be deuterated. As used herein, the term "deuterated" refers to a substance in which one or more hydrogen atoms have been replaced by isotopes of deuterium. Isotopes of deuterium are isotopes of hydrogen. A hydrogen nucleus contains one proton, whereas deuterium nuclei contain both a proton and a neutron. The compounds and pharmaceutical compositions of the present invention may be deuterated in order to change physical properties such as stability or to be useful in diagnostic or experimental work.

Recipes and delivery

[00153] The term "pharmaceutical composition" refers to a composition containing at least one active ingredient (eg, such as a polypeptide) in a form and in an amount that allows the active ingredient to be therapeutically effective.

[00154] The polypeptide formulations of the present invention include duodenal controlled release formulations, time controlled release formulations, osmotically controlled release delivery systems, microemulsions, microspheres, liposomes, nanoparticles, patches, pumps, drug depots, and the like. Specifically included in the present invention are solid oral dosage forms such as powders, soft gelatin capsules, capsules, pills and tablets.

[00155] The pharmaceutical compositions of the present invention may be administered by any route that results in a therapeutically effective result. These include, but are not limited to, enteral, gastroenteric, epidural, oral, epidural, intracerebral (to the brain), intratrachial (into the airways for delivery to the lungs), intracerebroventricular (into the ventricles of the brain), dermal (applied to the skin), intradermal (into the skin itself), subcutaneous (under the skin), nasal (through the nose), intravenous (into a vein), intra-arterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous (into the bone marrow) infusion, intrathecal (into the spinal canal), intraperitoneal or peritoneal infusion, intravesicular infusion, intravitreal (into the back chamber of the eye), intracavernous (at the base of the penis) injection, intravaginal, intrauterine, extra-amniotic, transdermal (diffusion through intact skin for systemic distribution), transmucosal (diffusion through the mucous membrane) administration, insufflation (blowing), buccal, subling oral, sublabial administration, enemas, eye drops (on the conjunctiva) or ear drops.

[00156] In some embodiments, the implementation of the polypeptides of the present invention are presented in the form of a sterile aqueous solution. In some embodiments, the implementation of the polypeptides of the present invention are presented in lipid or non-lipid composition. In another embodiment, the polypeptides of the present invention are provided in a cationic or non-cationic lipid formulation. In any embodiment, the sterile aqueous solution may contain additional active or inactive components. Inactive ingredients, also referred to herein as "auxiliaries", may include, but are not limited to, physiologically compatible salts, sugars, fillers, surfactants, or buffers.

[00157] The polypeptides and/or polypeptide compositions of the present invention may contain or may be formulated or delivered in combination with one or more carrier agents. Used in the present description, the term "carrier" refers to a substance that helps in the delivery or enhances the effectiveness of the polypeptides and/or polypeptide compositions of the present invention. The carrier agent may be a naturally occurring substance such as a protein (for example, human serum albumin (HSA), low density lipoprotein (LDL) or globulin), a carbohydrate (for example, dextran, pullulan, chitin, chitosan, inulin, cyclodextrin, or hyaluronic acid) or lipid. The carrier molecule may also be a recombinant or synthetic molecule such as a synthetic polymer, eg a synthetic polyamino acid. Examples of polyamino acids include poly-L-lysine (PLL), poly-L-aspartic acid and poly-L-glutamic acid, as well as polymers containing D-stereoisomers of these amino acids. Other carriers include poly(L-lactide-glycolide) copolymer, polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(2-ethylacrylic acid) and N-isopropylacrylamide polymers. Other useful carrier molecules can be identified by routine means.

[00158] In some embodiments, the compounds of the present invention may be combined with one or more pharmaceutically acceptable excipients to form a pharmaceutical composition. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are medically suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, or other problem, or complications in accordance with a reasonable ratio of benefits and risks. The term "pharmaceutically acceptable excipient" as used herein refers to any ingredient other than the compounds of the invention described herein (e.g., a carrier capable of suspending or dissolving the active ingredient) and that is substantially non-toxic and non-inflammatory. at the patient. Excipients may include, for example: release agents, antioxidants, binders, casings, compression aids, disintegrants, colorants, emollients, emulsifiers, fillers (diluents), film or casing formers, fragrances, slippery fragrances agents (flow aids), lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners and water of crystallization. Examples of excipients include, but are not limited to: butylhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, stearate Magnesium, Maltitol, Mannitol, Methionine, Methylcellulose, Methylparaben, Microcrystalline Cellulose, Polyethylene Glycol, Polyvinylpyrrolidone, Povidone, Pregelatinized Starch, Propylparaben, Retinyl Palmitate, Shellac, Silicon Dioxide, Sodium Carboxymethylcellulose, Sodium Citrate, Sodium Starch Glycolate, Sorbitol, Starch (Corn) , stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and xylitol. In some embodiments, the pharmaceutical compositions contain one or more active polypeptide ingredients along with ethanol, corn oil mono-di-triglycerides, hydrogenated castor oil, DL-tocopherol, propylene glycol, gelatin, glycerin, colors, flavors, and sweeteners.

[00159] In other embodiments, the pharmaceutical compositions comprise one or more active polypeptide ingredients together with a delivery agent such as 4-(2-hydroxy-4-methoxybenzamido)butyric acid (or any of the delivery agents described in US Patent No. 7744910B2, the contents of which are incorporated herein by reference in their entirety), a pharmaceutically acceptable buffer, a disintegrating agent, a detergent, hydroxypropyl methylcellulose, colors, flavors, and sweeteners.

[00160] In other embodiments, the pharmaceutical compositions comprise one or more active polypeptide ingredients together with ethanol, soy phosphatidylcholine, glycerol diolate, administered in excess saline as described in US Patent Application 2008/0146490A1, the content of which is incorporated herein in its entirety. description by reference.

[00161] Delivery of one or more polypeptides to a patient in need thereof can be accomplished in several different ways. In vivo delivery can be carried out directly by administering to the patient a composition containing one or more polypeptides. Alternatively, delivery can be accomplished indirectly by introducing one or more vectors that encode and drive the expression of the polypeptides.

[00162] Local delivery avoids intestinal absorption and systemic exposure. For example, the polypeptides and/or polypeptide compositions of the present invention can be used in the eye as drops or in the back of the eye by direct injection. They can be used in the intestine to target the enzyme. They can be used topically in dermatology (eg, creams, ointments, transdermal patches)

[00163] The polypeptides and/or polypeptide compositions of the present invention may contain or may be formulated with one or more fusion agents. Used in the present description, the term "fusion agent" refers to an agent that responds to changes, such as, for example, changes in pH in the environment. When exposed to an endosome pH environment, the fusion agent can cause a physical change, such as a change in osmotic properties, that impairs or increases the permeability of the endosome membrane. Preferably, the fusion agent changes charge, eg becomes protonated at a pH below the physiological range. For example, the fusion agent may be protonated at pH 4.5-6.5. The fusion agent may serve to release the polypeptide into the cytoplasm of the cell after the composition has been taken up by the cell, for example by endocytosis, thereby increasing the concentration of the polypeptide in the cell.

[00164] In some embodiments, the implementation of the fusion agents may contain a moiety, for example, an amino group, which, when exposed to a certain pH range, undergoes changes, for example, in charge, for example, is protonated. Changing the charge of fusion agents can trigger changes, eg osmotic changes, in vesicles, eg endocytic vesicles, eg endosomes. For example, a fusion agent at the pH of the endosome provides a dissolution or osmotic change sufficient to increase the porosity (preferably leading to rupture) of the endosomal membrane.

[00165] Fusion agents can be polymers, preferably polyamine chains, such as polyethyleneimine (PEI). PEI can be linear, branched, synthetic or natural. PEI may be, for example, alkyl-substituted PEI or lipid-substituted PEI.

[00166] In other embodiments, the fusion agents may be polyhistidine, polyimidazole, polypyridine, polypropyleneimine, mellitin, or polyacetal compounds, for example, cationic polyacetals. In some embodiments, the fusion agents may have an alpha helical structure. Fusion agents can be membrane rupturing agents such as mellitin. Other suitable fusion agents can be tested and determined by a person skilled in the art.

[00167] The polypeptides and/or polypeptide compositions of the present invention may contain or may be formulated with one or more condensing agents. Condensing agents of the compositions described herein can interact with (e.g., attract, retain, or bind to) polypeptides and act to cause (a) condensation, for example, to reduce the size or charge of the polypeptides and/or (b) to protect the polypeptides , for example, protecting polypeptides from degradation. Condensing agents may include a moiety, such as a charged moiety, that can interact with polypeptides through ionic interactions. The condensing agents are preferably charged polymers, eg polycationic chains. The condensing agents can be polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide polyamine, polyamine peptidomimetic, dendrimeric polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, polyamine quaternary salt, or alpha helical peptide.

[00168] In some embodiments, the implementation of the polypeptides of the present invention may be bicyclic polypeptides. Used in the present description, the term "bicyclic polypeptide" means a polypeptide with two loops. As a non-limiting example, bicyclic C5 polypeptide inhibitors can be obtained from combinatorial libraries. Bicyclic polypeptides may have 2, 3, 4, 5, 6 or more amino acids in one loop.

[00169] In some embodiments, the polypeptides and/or polypeptide compositions of the present invention may be provided as prodrugs. As used herein, the term "prodrug" refers to a compound that is present in an inactive form that becomes active at some point in time after administration. In some embodiments in which the polypeptides are administered in the form of a prodrug, the amino acids critical to the inhibitory activity of the polypeptide are not available for interaction with the target due to a reversible chemical bond, such as an ester bond. Once administered, such prodrugs can be reversibly cleaved, for example, by enzymatic or acid hydrolysis in the stomach, blood, and/or cells of the target tissue.

C5 inhibitors

[00170] Certain polypeptides and/or polypeptide compositions of the present invention inhibit complement activation at the level of the C5 component of the complement system and are referred to herein as "C5 inhibitors". Some C5 inhibitors act to prevent the cleavage of C5 to the cleavage products, C5a and C5b, such inhibitors are referred to herein as "C5 cleavage inhibitors". in some embodiments, the methods of the present invention may include inhibition of C5 cleavage in the system. As used herein, the term "system" refers to a group of related parts that work together. Such systems include those containing C5 and are referred to herein as "C5 systems". C5 systems may include, but are not limited to, solutions, matrices, cells, tissues, organs, and body fluids (including, but not limited to, blood). In some cases, C5 systems may be cellular systems. As used herein, the term "cell system" refers to a system that includes one or more cells, or one or more components or products of a cell. In some instances, C5 systems may include in vivo systems, in vitro systems, and ex vivo systems. In vivo C5 systems may or may be contained in a patient. Used in the present description, the term "patient" refers to any organism to which the compound of the present invention can be entered, for example, experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical patients include animals (eg, mammals such as mice, rats, rabbits, non-human primates, and humans).

[00171] In some cases, the C5 inhibitors of the present invention may include any of the polypeptides listed in Table 1.

Table 1. Compounds of the present invention

Connection number Subsequence SEQID NO. R3000 Ac-Nvl-C-Y-K-N-Y-H-azaTrp-E-Y-P-Tbg-Y-NH2 one R3001 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 2 R3002 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 3 R3003 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-P-NH2 four R3004 Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-Y-P-Phg-Tbg-NH2 5 R3005 Ac-Nvl-C-Y-azaTrp-(N-Me)G-Tbg-Nvl-azaTrp-E-Y-P-Phg-P-NH2 6 R3006 Ac-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 7 R3007 [m-xylyl(2,7)]Ac-Nvl-C-K-E-Phg-Y-C-(N-Me)S-Tbg-K-azaTrp-E-Y-NH2 eight R3008 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 9 R3020 [m-xylyl(2,7)]M-C-S-E-R-Y-C-E-V-R-W-E-Y-NH2 ten R3021 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 eleven R3079 Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 12 R3055 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 13 R3120 Ac-Nvl-Nvl-Y-E-(N-Me)N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 fourteen R3057 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 fifteen R3056 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 16 R3054 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 17 R3029 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-NH2 eighteen R3048 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 19 R3072 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-NH2 twenty R3024 Ac-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 21 R3114 Ac-Nvl-Nvl-(N-Me)Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 22 R3050 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 23 R3025 Ac-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 24 R3061 Ac-Nvl-S-Y-E-A-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 25 R3041 Ac-Y-E-N-Tbg-Y-W-E-Y-P-Phg-Nvl-NH2 26 R3077 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-(PEG2000)NH2 27 R3030 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-NH2 28 R3062 Ac-Nvl-S-Y-E-N-A-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 29 R3066 Ac-Nvl-S-Y-E-N-Tbg-A-azaTrp-E-Y-P-Chg-Nvl-NH2 thirty R3011 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-NH2 31 R3070 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-A-Chg-Nvl-NH2 32 R3071 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-P-A-Nvl-NH2 33 R3033 [m-xylyl(2,10)]Ac-Nvl-C-Phg-A-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 34 R3038 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 35 R3012 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 36 R3060 Ac-Nvl-S-Y-A-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 37 R3039 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-A-NH2 38 R3037 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)A-H-C-Nvl-NH2 39 R3076 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-(BODIPY-TMR-X)NH2 40 R3074 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Tyr(OMe)-(N-Me)S-H-C-Nvl-NH2 41 R3013 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-NH2 42 R3065 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-P-H-C-Nvl-NH2 43 R3073 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Phe(4-F)-(N-Me)S-H-C-Nvl-NH2 44 R3116 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-(N-Me)W-E-Y-P-Chg-Nvl-NH2 45 R3091 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-E-Y-(N-Me)S-A-C-Nvl-NH2 46 R3078 PEG2000-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 47 R3100 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-F-(N-Me)S-A-C-Nvl-NH2 48 R3121 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-(N-Me)Phg-Nvl-NH2 49 R3043 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-NH2 fifty R3102 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-P-H-C-Nvl-NH2 51 R3026 Ac-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 52 R3031 [m-xylyl(2,10)]Ac-A-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 53 R3019 [m-xylyl(2,14)]Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-C-NH2 54 R3014 [m-xylyl(1,9)]Ac-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 55 R3104 [p-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 56 R3059 Ac-Nvl-S-A-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 57 R3115 Ac-Nvl-Nvl-Y-(N-Me)E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 58 R3110 Ac-Y-E-N-Tbg-Y-(1-Me)W-E-Y-P-Phg-Nvl-NH2 59 R3126 Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-C-P-Phg-Tbg-NH2 60 R3049 [o-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 61 R3069 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-A-P-Chg-Nvl-NH2 62 R3015 [m-xylyl(1,9)]Ac-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-NH2 63 R3068 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-A-Y-P-Chg-Nvl-NH2 64 R3105 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 65 R3106 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 66 R3111 [m-xylyl(4,10)]Ac-Nvl-T-Phg-C-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 67 R3112 [m-xylyl(2,10)]Ac-Nle-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 68 R3113 [m-xylyl(3,11)]Ac-Y-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 69 R3134 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-(3-Cl-Phe)-(N-Me)S-A-C-Nvl-NH2 70 R3018 [m-xylyl(2,10)]Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-C-P-Phg-Nvl-NH2 71 R3027 Ac-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 72 R3028 Ac-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 73 R3032 [m-xylyl(2,10)]Ac-Nvl-C-A-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 74 R3058 [p-xylyl(2,10)]Ac-Nvl-C-Chg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 75 R3067 Ac-Nvl-S-Y-E-N-Tbg-Y-A-E-Y-P-Chg-Nvl-NH2 76 R3117 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-(N-Me)Y-P-Chg-Nvl-NH2 77 R3022 Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 78 R3016 [m-xylyl(1,9)]Ac-C-Tbg-Y-azaTrp-E-Y-(N-Me)S-H-C-NH2 79 R3089 [m-xylyl(2,10)]Ac-Chg-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 80 R3083 [m-xylyl(2,10)]Ac-V-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 81 R3087 [m-xylyl(2,10)]Ac-Nvl-C-(2-OMe)Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 82 R3103 [m-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 83 R3135 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-(D-Ala)-C-Nvl-NH2 84 R3034 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-A-E-Y-(N-Me)S-H-C-Nvl-NH2 85 R3035 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-A-Y-(N-Me)S-H-C-Nvl-NH2 86 R3036 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-A-(N-Me)S-H-C-Nvl-NH2 87 R3044 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-NH2 88 R3080 [m-xylyl(2,9)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-C-Nvl-NH2 89 R3085 [m-xylyl(2,10)]heptanoyl-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 90 R3086 [m-xylyl(5,13)]Ac-Nvl-S-Y-E-C-Tbg-Y-azaTrp-E-Y-P-Chg-C-Nvl-NH2 91 R3092 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-F-E-Y-(N-Me)S-A-C-Nvl-NH2 92 R3095 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-(homo)F-(N-Me)S-A-C-Nvl-NH2 93 R3096 [m-xylyl(2,10)]Ac-Nvl-C-Phg-Aib-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 94 R3122 [m-xylyl(2,10)]Ac-Nvl-C-Tiq-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 95 R3075 [m-xylyl(2,11)]Nvl-C-Y-(N-Me)S-Phg-(N-Me-4-F)Phe-(N-Me)S-H-(N-Me-4-F) Phe-G-C-NH2 96 R3107 [m-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 97 R3108 [p-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 98 R3127 [m-xylyl(2,10)]Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-C-P-Phg-Tbg-NH2 99 R3133 [m-xylyl(2,10)]Ac-Nvl-C-Phg-(D-Ala)-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 100 R3009 [m-xylyl(2,10)]Ac-Nvl-C-Y-E-(N-Me)G-Tbg-Y-azaTrp-E-C-Nvl-P-Nvl-NH2 101 R3010 [m-xylyl(2,13)]Ac-Nvl-C-Y-E-(N-Me)G-Tbg-Y-azaTrp-E-Nvl-Nvl-P-C-NH2 102 R3017 [m-xylyl(2,8)]Ac-Nvl-C-Y-E-N-Tbg-Y-C-E-Y-P-Phg-Nvl-NH2 103 R3023 Ac-Y-P-Y-C-Phg-azaTrp-Tbg-E-Nvl-N-Y-Nvl-E-NH2 104 R3040 [cyclo(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl 105 R3042 [cyclo(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 106 R3045 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-NH2 107 R3046 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-NH2 108 R3047 [m-xylyl(2,7)]M-C-V-E-R-F-C-NH2 109 R3051 [m-xylyl(2,11)]Nvl-C-Y-(N-Me)S-Phg-(N-Me-4-F)Phe-(N-Me)S-H-(N-Me-4-F) Phe-(N-Me)G-C-NH2 110 R3052 [m-xylyl(2,9)]Nvl-C-Y-Tbg-Phg-N-(N-Me)G-L-C-Phg-(N-Me)A-NH2 111 R3053 [m-xylyl-bicyclo]Nvl-C-C-N-Tbg-Phg-C-Tbg-(N-Me)S-C-Tbg-NH2 112 R3063 Ac-Tbg-Y-azaTrp-E-Y-NH2 113 R3064 Ac-Y-azaTrp-E-Y-P-NH2 114 R3081 Ac-Y-E-N-Tbg-Y-azaTrp-(N-Me)E-Y-P-Phg-Nvl-NH2 115 R3082 [m-xylyl(1,9)]heptanoyl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 116 R3084 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-S-A-C-Nvl-NH2 117 R3088 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(5-F)W-E-Y-(N-Me)S-A-C-Nvl-NH2 118 R3090 [m-xylyl(2,10)]Ac-Nvl-C-F-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 119 R3093 [m-xylyl(2,10)]Ac-Nvl-C-(D-Chg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 120 R3094 Ac-Y-E-N-Tbg-Y-(5-MeO)W-E-Y-P-Phg-Nvl-NH2 121 R3097 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-D-Y-(N-Me)S-A-C-Nvl-NH2 122 R3098 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-Q-Y-(N-Me)S-A-C-Nvl-NH2 123 R3099 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-N-Y-(N-Me)S-A-C-Nvl-NH2 124 R3101 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-G-C-Nvl-NH2 125 R3109 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(1-Me-W)-E-Y-(N-Me)S-A-C-Nvl-NH2 126 R3118 Ac-Y-E-N-Tbg-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 127 R3119 Ac-Y-E-N-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 128 R3123 Ac-Y-E-N-Tbg-Y-azaTrp-(D-Glu)-Y-P-Phg-Nvl-NH2 129 R3124 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-V-Y-W-E-F-NH2 130 R3125 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-W-E-F-NH2 131 R3128 Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 132 R3129 [m-xylyl(2,8)]Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 133 R3130 Ac-Nvl-Nvl-Y-E-N-Tbg-(N-Me)Y-azaTrp-E-Y-P-Chg-Nvl-NH2 134 R3131 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-Asp(T)-Y-(N-Me)S-H-C-Nvl-NH2 135 R3132 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(D-Trp)-E-Y-(N-Me)S-H-C-Nvl-NH2 136 R3136 [m-xylyl(2,10)]heptanoyl-Nvl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 137 R3137 [m-xylyl(1,9)]heptanoyl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 138 R3138 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-W-E-F-NH2 139 R3139 [m-xylyl(1,6)]Ac-C-Tbg-E-R-F-C-D-Tbg-Y-W-E-F-NH2 140 R3140 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-Y-P-NH2 141 R3141 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-P-NH2 142 R3142 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-azaTrp-E-Y-P-NH2 143 R3143 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-W-E-Y-P-NH2 144 R3144 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 145 R3145 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 146 R3146 [m-xylyl(1,6)]Ac-C-Tbg-E-R-F-C-D-V-Y-W-E-F-NH2 147 R3147 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-propargyl-Gly-NH2 148 R3148 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-W-E-Y-P-Phg-Nvl-NH2 149 R3149 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-W-E-Y-P-(D-Phg)-Nvl-NH2 150 R3150 [m-xylyl(1,6)]Ac-C-V-A-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 151 R3151 [m-xylyl(1,6)]Ac-C-V-A-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 152 R3152 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 153 R3153 [m-xylyl(1,6)]Ac-C-V-E-A-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 154 R3154 [m-xylyl(1,6)]Ac-C-V-E-A-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 155 R3155 [m-xylyl(1,6)]Ac-C-V-E-R-A-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 156 R3156 [m-xylyl(1,6)]Ac-C-V-E-R-A-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 157 R3157 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-A-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 158 R3158 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-A-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 159 R3159 [m-xylyl(1,6)](desamino)C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 160 R3160 [m-xylyl(1,6)](desamino)C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 161 R3161 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-K-NH2 162 R3162 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-K-NH2 163 R3163 [cyclo(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 164 R3164 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C12)-NH2 165 R3165 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C10)-NH2 166 R3166 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C8)-NH2 167 R3167 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(alpha-methyl)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 168 R3168 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-Asp(T)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 169 R3169 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 170 R3170 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-K 171 R3171 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C12) 172 R3172 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 173 R3173 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 174 R3174 [cyclo(1,6)]Ac-K-V-E-R-F-D-Asp(T)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 175 R3175 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-B20 176 R3176 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 177 R3177 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-W-P-Chg-Nvl 178 R3178 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(homo)Phe-P-Chg-Nvl 179 R3179 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(m-Cl-homo)Phe-P-Chg-Nvl 180 R3180 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-2Nal-P-Chg-Nvl 181 R3181 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-(3-aminomethyl)Phe-E-Y-P-Chg-Nvl 182 R3182 [cyclo-triazolyl(1,6)]Ac-X02-V-E-R-F-X31-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 183 R3183 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 184 R3184 [cyclo-thioalkyl(1,5)]V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 185 R3185 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-Cle-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 186 R3186 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(Ac-pyran)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 187 R3187 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(3-aminomethyl)Phe-P-Chg-Nvl 188 R3188 [cyclo-olefinyl(1,6)]Ac-X30-V-E-R-F-X12-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 189 R3189 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C16) 190 R3190 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B20 191 R3191 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-K 192 R3192 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-K-NH2 193 R3193 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B28 194 R3194 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16)-NH2 195 R3195 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-(Lys-C16) 196 R3196 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-K 197 R3197 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-K14 198 R3198 [cyclo(1,6)](desamino)C-V-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 199 R3199 [cyclo(1,6)](desamino)C-(D-Ala)-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 200 R3200 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Aib-(Lys-C16) 201 R3201 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 211

[00172] In C5 systems, C5 and other components of the system may be in solution or may be fixed, for example, in the assay well. C5 systems may additionally contain other complement components, and in some cases, may include all components necessary for the formation of the membrane attack complex (MAC). In some cases, the polypeptides and/or polypeptide compositions of the present invention can be used to inhibit C5 cleavage in humans. Such polypeptides and/or polypeptide compositions may find use in the treatment of various complement system-related disorders and/or diseases, as well as their accompanying inflammatory diseases. Some C5 inhibitors are known in the art and are described in US Pat. Nos. 7,348,401 and 6,355,245, which are incorporated herein by reference in their entirety.

[00173] C5 cleavage gives the proteolytic products C5a and C5b. The C5 cleavage site that yields these products when cleaved is referred to herein as the C5a-C5b cleavage site. C5b promotes the formation of the membrane attack complex (MAC), while C5a stimulates the immune system and inflammatory responses. In some embodiments, the polypeptides and/or polypeptide compositions of the present invention prevent C5 cleavage and therefore may be useful in the treatment of inflammation by inhibiting inflammatory responses, including, but not limited to, chemotaxis and activation of inflammatory cells (e.g., macrophages, mast cells). cells, neutrophils and platelets), endothelial cell proliferation and edema.

[00174] Many of the components of the complement system, including but not limited to C3, C4, and C5, are functionally inactive in the native state prior to targeted cleavage into multiple active components. Cleavage of C3 or C4 causes a conformational change that exposes the internal thioether domain. In this domain, the internal thioether bond between the side chains of cysteine and glutamine residues is a chemically labile bond that confers the ability of C3 and C4 to bind to cell surfaces and/or biological molecules. Cleavage of C3 and C4 also yields C5 convertase components, C3bC4bC2a or (C3b)2Bb. (Law, S.K., et al. (1997). Protein Science. 6:263-274; van den Elsen, J.M.H., (2002). J. Mol. Biol. 322:1103-1115, the contents of which are incorporated herein in their entirety. by reference).

[00175] The multi-domain structure of C5 is similar to C3 and C4. C5 convertase cleaves C5 into components C5a and C5b. C5 cleavage induces a conformational change that exposes the C5b thioether-like domain involved in the binding of C5 to C6, followed by interaction with C7 and C8 to form a cytolytic MAC. The C5 domain structures contain regulatory functions that are critical for the action and subsequent activity of complement. ((Fredslund, F. et al. (2008). Nature. 9:753-760; Hadders, M.A. et al. (2012). Cell Reports. 1:200-207).

[00176] In some embodiments, the compounds of the present invention can bind C5 and prevent C5 cleavage to C5a and C5b cleavage products.

[00177] Recently, a new complement activation paradigm has been proposed based on the discovery that thrombin generates previously unidentified C5 products that support the terminal complement activation pathway (Krisinger, et al., (2014). Blood. 120(8) :1717-1725).

[00178] Thrombin acts in the coagulation cascade, a second process occurring in the circulation, by which organisms, in response to injury, can limit bleeding, restore vascular integrity, and enhance healing. After damage to the vessel, tissue factor enters the bloodstream, triggering a cascade of proteolytic reactions, which leads to the formation of the central coagulation enzyme thrombin, which converts fibrinogen into a fibrin thrombus.

[00179] Historically, the complement activation pathway has been considered separate from the coagulation cascade; however, the interaction of these two systems deserves re-examination. In response to common pathophysiological stimuli, coagulation and complement are activated in a coordinated manner with overlap in space and time to maintain homeostasis, and disease occurs when the innate immune and coagulation responses are not properly activated, as evidenced by, for example, atherosclerosis, stroke, coronary heart disease, diabetes, ischemia-reperfusion injury, trauma, paroxysmal nocturnal hemoglobinuria, age-related macular degeneration and atypical hemolytic uremic syndrome. Indeed, the administration of complement inhibitors has been found to simultaneously treat the inflammatory and thrombotic disorders associated with some of these diseases.

[00180] As noted above, the complement system is activated in three main pathways that all converge on the proteolytic activation of the C3 central complement component. The subsequent formation of C5 convertases leads to the cleavage of C5 at 751 arginine (R751), releasing the chemotactic and anaphylactic C5a fragment and generating C5b. C5b is the initiator for the assembly of the C5b-dependent lytic membrane attack complex (MAC; also known as C5b-9), which is responsible for the destruction of damaged cells and pathogens.

[00181] Several molecular links between complement and coagulation have been identified. Most importantly, what has been described as a new pathway for complement activation has been found that thrombin is able to directly promote complement activation by cleaving C5, presumably at R751, thereby releasing C5a in the absence of C3 (Huber-Lang, et al., 2006. Nature Med 12(6):682-687). However, these studies did not rigorously compare thrombin and C5 convertase, only limited biochemical analyzes were performed; thus, the physiological significance of the signaling pathway has not been analyzed.

[00182] Using purified and plasma systems, the effects of thrombin and C5 convertase on C5 were evaluated by measuring the release of C5a anaphylatoxin and the generation of C5b, a component of MAC. It has been found that although thrombin cleaves C5 poorly at R751, producing minimal amounts of C5a and C5b, it efficiently cleaves C5 at the newly identified, highly conserved R947 site, generating previously undescribed _C5T and _C5bT intermediates. Tissue factor-induced plasma coagulation resulted in C5 proteolysis at a thrombin-responsive site corresponding to this new R947 site, rather than R751. Combined treatment of C5 with thrombin and C5 convertase gave C5a and C5b _T , the latter forming a C5b _T -9 membrane attack complex with significantly higher lytic activity than C5b-9. Thus, a new complement activation paradigm has been proposed in which thrombin is the invariant and critical partner of C5 convertase in initiating the formation of a more active MAC through the formation of previously unknown C5 products that are generated by combined proteolysis by the two enzymes. These discoveries provide new insights into the regulation of innate immunity in the context of coagulation activation occurring in many diseases. (Krisinger, et al., (2014). Blood. 120(8):1717-1725).

[00183] In some embodiments, the polypeptides and/or polypeptide compositions of the invention can inhibit thrombin-induced complement activation. Therefore, such polypeptides and/or polypeptide compositions can be used to treat hemolysis resulting from thrombin-induced complement activation.

[00184] In view of the molecular links found between the complement and coagulation pathways, it is believed that complement may be activated by additional components of the coagulation and/or inflammatory cascades. For example, other serine proteases with slightly different substrate specificities may act in a similar manner. Huber-Lang et al. (2006) showed that thrombin not only cleaved C5 but also generated C3a in vitro when incubated with native C3 (Huber-Lang, et al., 2006. Nature Med. 12(6):682- 687; the contents of which are incorporated herein by reference in their entirety). Similarly, other components of the coagulation pathway, such as FXa, FXIa and plasmin, have been found to cleave both C5 and C3.

[00185] In particular, plasmin, FXa, FIXa, and FXIa have been found to be able to cleave C5, generating C5a and C5b, in a mechanism similar to that seen with thrombin activation (Amara, et al., (2010). J. Immunol 185:5628-5636 Amara, et al., (2008) "Interaction Between the Coagulation and Complement System" in Current Topics in Complement II , JD Lambris (ed.), pp. 71-79). The anaphylatoxins produced were found to be biologically active, as shown by the dose-dependent chemotaxis response of neutrophils and HMC-1 cells, respectively. Plasmin-induced cleavage activity can be dose-dependently blocked by serine protease inhibitors, aprotinin and leupeptin. These data indicate that various serine proteases belonging to the coagulation system are able to activate the complement cascade independently of known pathways. In addition, functional C5a and C3a are generated (detected by immunoblotting and ELISA), both of which are known to be important participants in the inflammatory response.

[00186] In some embodiments, the implementation of the polypeptides and/or polypeptide compositions of the present invention can inhibit the activation of C5 by plasmin, FXa, FIXa, FXIa and other coagulation pathway proteases.

[00187] It has long been known that human leukocyte elastase (HLE), an enzyme secreted by neutrophils and macrophages during inflammatory processes, also releases a chemotaxis C5a-like fragment from C5. However, this C5a-like fragment is not identical to C5a, and HLE does not cleave peptide bonds at the cleavage site at which C5 is normally cleaved into C5a and C5b upon contact with complement convertases. In contrast, cleavage of complement component C5 by elastane HLE has been found to generate a functionally active C5b-like molecule that is capable of participating in MAC formation (Vogt, (1999). Immunobiology. 201:470-477).

[00188] In some embodiments, the implementation of the polypeptides and/or polypeptide compositions of the present invention can inhibit the activation of C5 by HLE and other proteases of the inflammatory cascade.

[00189] In some embodiments, the implementation of the polypeptides and/or polypeptide compositions of the present invention may be useful in the treatment of diseases, disorders and/or conditions, where C5 cleavage leads to the development of the disease, disorder and/or condition. Such diseases, disorders and/or conditions may include, but are not limited to, immune and autoimmune, neurological, cardiovascular, pulmonary and ocular diseases, disorders and/or conditions. Immune and autoimmune diseases and/or disorders may include, but are not limited to, acute disseminated encephalomyelitis (ADEM), acute necrotizing hemorrhagic leukoencephalitis, Addison's disease, agammaglobulinemia, alopecia areata, amyloidosis, ankylosing spondylitis, acute antibody-mediated organ rejection after transplantation, анти-GBM/анти-ТВМ нефрит, антифосфолипидный синдром (APS), аутоиммунную ангиоэдему, аутоиммунную апластическую анемию, аутоиммунную дизавтономию, аутоиммунный гепатит, аутоиммунную гиперлипидемию, аутоиммунный иммунодефицит, аутоиммунные заболевания внутреннего уха (AIED), аутоиммунный миокардит, аутоиммунный панкреатит, аутоиммунную ретинопатию , autoimmune thrombocytopenic purpura (ATP), autoimmune thyroid disease, autoimmune urticaria, axonal and neuronal neuropathies, bacterial sepsis and septic shock, Balo's disease, Behçet's disease, bullous pemphigoid, cardiomyopathy, Castleman's disease, celiac disease, Chagas disease, chronic fatigue syndrome, chronic inflammatory demyelinating polyneuropathies (CIDP), chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome, cicatricial pemphigoid/benign mucosal pemphigoid, Crohn's disease, Cogan's syndrome, cold agglutinin disease, congenital block heart disease, Coxsackie's myocarditis, CREST syndrome, essential mixed cryoglobulinemia, demyelinating neuropathies, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), type I diabetes, discoid lupus, Dressler's syndrome, endometriosis, eosinophilic esophagitis, eosinophilic fasciitis, experimental erythema nodosum encephalomyelitis, Evans syndrome, fibromyalgia, fibrosing alveolitis, giant cell arteritis (temporal arteritis), glomerulonephritis, Goodpasture's syndrome, granulomatosis with polyangiitis (GPA) see Wegener's granulomatosis, Graves' disease, Guillain-Barré syndrome, Hashimoto's encephalitis, thyroid Hashimoto'sitis, hemolytic anemia (including atypical hemolytic uremic syndrome and plasma therapy-resistant atypical hemolytic uremic syndrome), Henoch-Schonlein purpura, gestational herpes, hypogammaglobulinemia, idiopathic thrombocytopenic purpura (ITP), IgA nephropathy, IgG4-related sclerosing disease, immunoregulatory lipoproteins, inclusion body myositis, insulin-dependent diabetes (type 1), interstitial cystitis, juvenile arthritis, juvenile diabetes, Kawasaki syndrome, Lambert-Eaton syndrome, large vessel vasculopathy, leukocytoclastic vasculitis, lichen planus, lichen sclerosus, ligneous conjunctivitis, IgA-linear disease (LAD), lupus (SLE), Lyme disease, Meniere's disease, microscopic polyangiitis, mixed connective tissue disease (MCTD), corneal ulcer, Fly-Habermann disease, multiple endocrine neoplasia syndrome, multiple sclerosis, multifocal motor neuropathy, myositis , myasthenia gravis, narcolepsy, neuromyelitis optica (Devic's disease), neutropenia, ocular cicatricial pemphigoid, optic neuritis, osteoarthritis, palindromic rheumatism, PANDAS (children's autoimmune neuropsychiatric disorders associated with streptococcal infection), paraneoplastic degeneration of the cerebellum, paroxysmal nocturnal hemoglobinuria (PNH), Parry-Romberg syndrome, Parsonage-Turner syndrome, parsplanitis (peripheral uveitis), pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia, POEMS syndrome, nodular polyarthritis, autoimmune polyglandular syndromes I, II and III, polyendocrinopathy, polymyalgia rheumatica, polymyositis, postinfarction syndrome, postpericardiotomy syndrome, progesterone dermatitis, primary dermatitis biliary cirrhosis, primary sclerosing cholangitis, psoriasis, psoriatic arthritis, idiopathic pulmonary fibrosis, pyoderma gangrenosum, aplasia vera, Raynaud's syndrome, reactive arthritis, reflex sympathetic dystrophy, Reiter's syndrome, relapsing polychondritis, restless legs syndrome, retroperitoneal fibrosis, rheumatism, rheumatoid arthritis arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma caused by Shigatoxin-producingEscherichia coli hemolytic uremic syndrome (STEC-HUS), Sjogren's syndrome, small vessel vasculopathy, autoimmune infertility, muscle stiffness syndrome, subacute bacterial endocarditis (SBE), Susak's syndrome, sympathetic ophthalmia, Takayasu's arteritis, temporal arteritis/giant cell arteritis, thrombocytopenic purpura (TTP) ), Toloz-Hunt syndrome, transverse myelitis, autoimmune tubular disease, ulcerative colitis, undifferentiated connective tissue disease (UCTD), uveitis, vesiculobullous dermatosis, vasculitis, Vitiligo, and Wegener's granulomatosis (also known as granulomatosis with polyangiitis (GPA)). Neurological diseases, disorders and/or conditions may include, but are not limited to, Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, and multiple sclerosis. Cardiovascular diseases, disorders and/or conditions may include, but are not limited to, atherosclerosis, myocardial infarction, stroke, vasculitis, trauma, and conditions following cardiovascular interventions (including, but not limited to, cardiac bypass, arterial transplantation and angioplasty). Pulmonary diseases, disorders and/or conditions may include, but are not limited to, asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), and adult respiratory distress syndrome. Eye diseases, disorders, and/or conditions may include, but are not limited to, age-related macular degeneration, allergic and giant papillary conjunctivitis, Behcet's disease, choroidal inflammation, complications associated with intraocular surgery, corneal transplant rejection, corneal ulcers, cytomegalovirus retinitis, syndrome dry eye, endophthalmitis, Fuchs' disease, glaucoma, immune complex vasculitis, inflammatory conjunctivitis, ischemic retinal disease, keratitis, macular edema, ocular parasitic infestation/migration, retinitis pigmentosa, scleritis, Stargardt's disease, subretinal fibrosis, uveitis, vitreoretinal inflammation, and Vogt's disease -Koyanagi-Harada.

[00190] The polypeptides and/or polypeptide compositions of the present invention may be particularly useful in the treatment of patients with PNH who exhibit poor response to monoclonal antibody therapy, such as ECULIZUMAB® therapy, due to mutations in the C5 gene that prevent antibody binding to C5 (Nishimura, JI. (2012). 54th ^ASH Annual Meeting, Abstract 3197).

[00191] The polypeptides and/or polypeptide compositions of the present invention may be useful in the treatment of infectious diseases, disorders and/or conditions, for example, in a patient having an infection. In some preferred embodiments, the implementation of the patient has an infection, and there is a risk of developing sepsis or septic syndrome. The polypeptides and/or polypeptide compositions of the present invention are particularly useful in the treatment of sepsis.

[00192] The polypeptides and/or polypeptide compositions of the present invention may also be administered to improve the results of clinical procedures in which complement inhibition is desired. Such procedures may include, but are not limited to, bypass surgery, transplantation, implantation, catheterization, intubation, and the like. In some embodiments, the implementation of the polypeptides and/or polypeptide compositions of the present invention are used to coat products, materials and/or biomaterials used in such procedures. In some embodiments of the present invention, the inner surface of the tube may be coated with polypeptides and/or polypeptide compositions to prevent complement activation in the body fluid that passes through the tube, in vivo or ex vivo , such as in extracorporeal shunting, such as dialysis and cardiac bypass.

[00193]

Methods of application

Indications for use

[00194] The invention relates in particular to the use of a polypeptide (eg, peptidomimetics and cyclic polypeptides) and compositions containing at least one polypeptide for the treatment of a disorder, condition or disease. In some cases, the compounds and compositions of the present invention can be used to treat patients suffering from paroxysmal nocturnal hemoglobinuria (PNH). Patients with PNH are unable to synthesize functional versions of the regulatory proteins of the complement system, CD55 and CD59, on hematopoietic stem cells. This leads to complement-mediated hemolysis and various subsequent complications. Other complement related disorders and diseases include, but are not limited to, autoimmune diseases and disorders, neurological diseases and disorders, gemological diseases and disorders, and infectious diseases and disorders. Experimental evidence suggests that many complement-related disorders are ameliorated by inhibition of complement activity.

[00195] An acquired mutation in the phosphatidylinositol glycan anchor biosynthesis gene, class A (PIG-A), which is derived from multipotent hematopoietic stem cells, results in a rare disease known as paroxysmal nocturnal hemoglobinuria (PNH) (Pu, J.J. et al., Paroxysmal nocturnal hemoglobinuria from bench to bedside Clin Transl Sci 2011 Jun;4(3):219-24). PNH is characterized by bone marrow dysfunction, hemolytic anemia, and thrombosis. The PIG-A gene product is required to produce the glycolipid anchor, glycosylphosphatidylinositol (GPI), used to anchor proteins to the plasma membrane. Two proteins regulating the complement system, CD55 and CD59, become non-functional in the absence of GPI. This leads to complement-mediated destruction of these cells. The polypeptides and/or polypeptide compositions of the present invention are particularly useful in the treatment of PNH. As used herein, the terms "treat", "treat", etc. refer to the weakening or alleviation of pathological processes. In the context of the present invention, if they refer to any other condition listed below in the present description, the terms "treat", "treatment", etc. means reducing or alleviating at least one symptom associated with such a condition, or slowing or reversing the development or expected development of such a condition, for example, slowing the growth of a malignant tumor or cancer, or accelerating the clearance of an infectious organism in order to alleviate/reduce the symptoms caused by an infection, for example hepatitis caused by hepatitis virus infection, or reduced red blood cell destruction (measured by reduced need for blood transfusions or increased hematocrit or hemoglobin levels) resulting from paroxysmal nocturnal hemoglobinuria.

[00196] The term "reduce" or "decrease" in the context of a marker or symptom of a disease means a statistically significant reduction in its level. The reduction may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably up to a level corresponding to the normal range for a person without such a disease.

[00197] The term "increase" or "increase" in the context of a marker or symptom of a disease means a statistically significant increase in its level. The increase may be, for example, at least 10%, at least 20%, at least 30%, at least 40% or more, and preferably up to a level corresponding to the normal range for a person without such a disease.

[00198] As used herein, the phrases "therapeutically effective amount" and "prophylactically effective amount" refer to an amount that provides a therapeutic effect in the treatment, prevention or control of pathological processes or a significant symptom of one or more pathological processes. The specific amount that is therapeutically effective can be readily determined by the ordinary practitioner, and may vary depending on factors known to those skilled in the art, such as, for example, the type of pathological processes, the patient's medical history and age, the stage of the pathological processes, as well as the introduction of other agents that inhibit pathological processes.

[00199] As used herein, the term "pharmaceutical composition" includes a pharmacologically effective amount of a polypeptide and a pharmaceutically acceptable carrier. As used herein, the terms "pharmacologically effective amount", "therapeutically effective amount", or simply "effective amount" refer to that amount of a polypeptide that is effective to produce the intended pharmacological, therapeutic, or prophylactic result. For example, if a given clinical treatment is considered effective when there is at least a 10% change (increase or decrease) in a measurable parameter associated with a disease or disorder, then a therapeutically effective amount of a drug intended to treat that disease or disorder is the amount required to make at least a 10% change in this parameter. For example, a therapeutically effective amount of a polypeptide may be an amount that alters the target's binding to its natural binding partner by at least 10%.

[00200] The term "pharmaceutically acceptable carrier" refers to a carrier for administering a therapeutic agent. Such carriers include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The term specifically excludes cell culture medium. For orally administered preparations, their pharmaceutically acceptable carriers include, but are not limited to, pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweeteners, flavoring agents, coloring agents, and preservatives. Suitable inert diluents are calcium carbonate, sodium and calcium phosphate, and lactose, while cornstarch and alginic acid are suitable disintegrating agents. Binders may include starch and gelatin, while the lubricant, if present, will typically be magnesium stearate, stearic acid, or talc. If desired, tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract. The agents included in dosage forms are further described herein below.

[00201] The effectiveness of treating or alleviating a disease can be assessed, for example, by measuring disease progression, disease remission, symptom severity, pain reduction, quality of life, the dose of drug compound required to maintain a therapeutic effect, the level of a disease marker, or any other measurable parameter, appropriate for the disease to be treated or to be prevented. It is within the skill of the art to monitor the effectiveness of treatment or prevention by measuring any of these parameters or any combination of parameters. With respect to the administration of a polypeptide or a pharmaceutical composition thereof, "effective against" a disease or disorder indicates that administration in a clinically appropriate manner provides a beneficial effect in at least a subset of patients, such as amelioration of the symptoms of the disease, cure, reduction in the severity of the disease, reduction in tumor volume. or cell count, prolongation of life, improvement in quality of life, reduction in the need for blood transfusions, or other effect generally recognized as beneficial by physicians familiar with the treatment of a particular type of disease or disorder.

[00202] A treatment or prophylactic effect occurs when there is a statistically significant improvement in one or more parameters of the disease state, or in the absence of deterioration or development of symptoms otherwise expected. By way of example, a positive change of at least 10% in a measured disease score, and preferably at least 20%, 30%, 40%, 50%, or more, may be an indication of treatment success. Efficacy for a given polypeptide drug or formulation of that drug can also be evaluated using an animal model for a given disease known in the art. When using an experimental animal model, the effectiveness of the treatment is confirmed when there is a statistically significant modulation for the marker or symptom.

[00203] The polypeptide and the additional therapeutic agent may be administered together in the same composition, for example parenterally, or the additional therapeutic agent may be administered as part of a separate composition or in another manner described herein.

Inflammatory diseases

[00204] In some embodiments, the compounds and compositions of the present invention can be used to treat patients with diseases, disorders and/or conditions associated with inflammation. Inflammation may increase during the development of the proteolytic cascade of the complement system. Although inflammation may have a beneficial effect, excessive inflammation can lead to various pathologies (Markiewski et al. 2007. Am J Pathol. 17: 715-27). Accordingly, the compounds and compositions of the present invention can be used to reduce or eliminate inflammation associated with complement activation.

Sterile inflammation

[00205] In some embodiments, the compounds and compositions of the present invention can be used to treat, prevent, or slow the development of sterile inflammation. Sterile inflammation is inflammation that occurs in response to any stimulus other than infection. Sterile inflammation may be a common response to stress such as genomic stress, hypoxic stress, nutritional stress, or endoplasmic reticulum stress caused by physical, chemical, or metabolic noxious stimuli. Sterile inflammation can contribute to the pathogenesis of many diseases, such as, but not limited to, ischemia-induced injury, rheumatoid arthritis, acute lung injury, drug-induced liver injury, inflammatory bowel disease, and/or other diseases, disorders, or conditions. The mechanism of sterile inflammation, as well as methods and compositions for treating, preventing and/or delaying the onset of symptoms of sterile inflammation, may include any of those given by Rubartelli et al. in Frontiers in Immunology, 2013, 4:398-99, Rock et al. in Annu Rev Immunol. 2010, 28:321-342 or in US patent No. 8101586, the contents of which are fully incorporated into this description by reference.

Systemic inflammatory response syndrome (SIRS) and sepsis

[00206] In some embodiments, the compounds and compositions of the present invention may be used to treat and/or prevent systemic inflammatory response syndrome (SIRS). SIRS is an inflammation that affects the entire body. If SIRS is caused by an infection, then it is called sepsis. SIRS can also be caused by non-infectious events such as trauma, injury, burns, ischemia, hemorrhage, and/or other conditions. During sepsis and SIRS, complement activation leads to excessive generation of complement activation products, which can lead to multiple organ failure (MOF) in patients. The compounds and compositions of the present invention can be used to control and/or balance complement activation for the prevention and treatment of SIRS, sepsis and/or MOF. Methods of using complement inhibitors for the treatment of SIRS and sepsis may include those set forth by Rittirsch et al. in Clin Dev Immunol, 2012, 962927, US Pat. links.

Acute Respiratory Distress Syndrome (ARDS)

[00207] In some embodiments, the compounds and compositions of the present invention can be used to treat and/or prevent the development of acute respiratory distress syndrome (ARDS). ARDS is a widespread inflammation of the lungs and can be caused by trauma, infection (eg, sepsis), severe pneumonia, and/or inhalation of harmful substances. ARDS is usually a severe, life-threatening complication. Studies show that neutrophils may contribute to the development of ARDS by influencing the accumulation of polymorphic cells in damaged lung alveoli and interstitial lung tissue. Accordingly, the compounds and compositions of the present invention may be administered to reduce and/or prevent neutrophil production of tissue factor in the alveoli. The compounds and compositions of the present invention may furthermore be used to treat, prevent and/or delay the onset of ARDS, in some cases in accordance with any of the methods set forth in International Publication No. WO2009/014633, the contents of which are incorporated herein in their entirety. by reference.

Periodontitis

[00208] In some embodiments, the compounds and compositions of the present invention can be used to treat or prevent the development of periodontitis and/or related conditions. Periodontitis is a widespread chronic inflammation resulting in the destruction of periodontal tissue, which is the tissue that supports and surrounds teeth. The condition also includes loss of alveolar bone (the bone that holds the teeth). Periodontitis can be caused by poor oral hygiene resulting in a buildup of bacteria on the gum line, also known as plaque. Certain health conditions such as diabetes or malnutrition and/or habits such as smoking may increase the risk of periodontitis. Periodontitis can increase the risk of stroke, myocardial infarction, atherosclerosis, diabetes, osteoporosis, premature birth, and other health problems. Studies show a correlation between periodontitis and local complement activity. Periodontal bacteria can inhibit or activate certain components of the complement cascade. Accordingly, the compounds and compositions of the present invention can be used to prevent and/or treat periodontitis and related diseases and conditions. Complement activation inhibitors and treatments may include any of those set forth by Hajishengallis in Biochem Pharmacol. 2010, 15; 80(12): 1 or Lambris in US Publication No. US2013/0344082, the contents of which are incorporated herein by reference in their entirety.

Wounds and injuries

[00209] the Compounds and compositions of the present invention can be used to treat and/or promote healing of various types of wounds and/or lesions. As used herein, the term "injury" generally refers to physical injury, but may include local infectious or disease processes. Injury can be characterized as harm, damage or destruction caused by external events affecting parts and/or organs of the body. Wounds are associated with cuts, blows, burns, and/or other exposures to the skin that leave the skin torn or damaged. Wounds and injuries are often acute events, but if not properly healed, they can lead to chronic complications and/or inflammation.

Wounds and burn wounds

[00210] In some embodiments, the compounds and compositions of the present invention may be used to treat and/or promote wound healing. Healthy skin provides a waterproof, protective barrier to pathogens and other environmental influences. The skin also regulates body temperature and fluid evaporation. When the skin is injured, these functions are impaired, making it difficult for the skin to heal. Injury initiates a number of physiological processes associated with the immune system, which heals and regenerates tissues. Complement activation is one of these processes. Complement activation studies have identified several components of complement associated with wound healing as outlined by van de Goot et al. in J Burn Care Res 2009, 30:274-280 and Cazander et al. in Clin Dev Immunol, 2012, 2012:534291 , the contents of which are fully incorporated into the present description by reference. In some cases, complement activation can be excessive, causing cell death and increased inflammation (resulting in impaired wound healing and chronic wounds). In some cases, the compounds and compositions of the present invention can be used to reduce or eliminate such complement activation to promote wound healing. Treatment with the compounds and compositions of the present invention may be carried out in accordance with any of the methods for treating wounds disclosed in International Publication No. WO2012/174055, the contents of which are hereby incorporated by reference in their entirety.

Head injury

[00211] In some embodiments, the compounds and compositions of the present invention can be used to treat and/or enhance healing of a head injury. Head injuries include injuries to the head, skull, or brain. Examples of head injuries include, but are not limited to, concussions, bruises, skull fractures, traumatic brain injuries, and/or other injuries. Head injuries can be mild or severe. In some cases, head trauma can lead to long-term physical and/or mental complications or death. Research indicates that head trauma can induce abnormal intracranial complement activation, which can lead to local inflammatory responses that promote secondary brain injury through brain edema and/or neuronal death (Stahel et al. in Brain Research Reviews, 1998, 27: 243-56, the contents of which are fully incorporated into the present description by reference). The compounds and compositions of the present invention may be used to treat head injury and/or to reduce or prevent associated secondary complications. Methods for using the compounds and compositions of the present invention to control complement cascade activation in head trauma may include any of those set forth by Holers et al. in US Pat. No. 8,911,733, the contents of which are incorporated herein by reference in their entirety.

Tissue crush injury

[00212] In some embodiments, the compounds and compositions of the present invention can be used to treat and/or enhance the healing of crush injuries. Crush injuries are injuries caused by applying force or pressure to the body causing bleeding, bruising, fractures, nerve damage, wounds, and/or other damage to the body. The compounds and compositions of the present invention may be used to reduce complement activation following crush injury, thereby promoting healing from crush injury (e.g., by promoting nerve regeneration, promoting fracture healing, preventing or treating inflammation, and/or other related complications with them). Compounds and compositions of the present invention can be used to promote healing in accordance with any of the methods described in US patent No. 8703136; International Publication Nos. WO2012/162215, WO2012/174055 or US Patent Publication US2006/0270590, the contents of which are incorporated herein by reference in their entirety.

Autoimmune diseases

[00213] The compounds and compositions of the present invention can be used to treat patients with autoimmune diseases and/or disorders. The immune system can be divided into innate and adaptive systems, corresponding to non-specific immediate defense mechanisms and more complex antigen-specific systems, respectively. The complement system is part of the innate immune system that recognizes and eliminates pathogens. In addition, complement proteins can modulate adaptive immunity by linking innate and adaptive responses. Autoimmune diseases and disorders are immunological disorders in which the system becomes the target of its own tissues and substances. Autoimmune diseases can affect certain tissues or organs in the body. Compounds and compositions of the present invention can be used for complement modulation in the treatment and/or prevention of autoimmune diseases. In some cases, such compounds and compositions can be used in accordance with the methods presented in Ballanti et al. Immunol Res (2013) 56:477-491, the contents of which are incorporated herein by reference in their entirety.

Antiphospholipid syndrome (APS) and catastrophic antiphospholipid syndrome (CAPS)

[00214] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat antiphospholipid syndrome (APS) by controlling complement activation. APS is an autoimmune condition caused by antiphospholipid antibodies that cause blood to clot. APS can lead to recurrent venous or arterial thrombosis in organs, as well as placental circulation complications, causing pregnancy complications such as miscarriage, stillbirth, preeclampsia, preterm birth and/or other complications. Catastrophic antiphospholipid syndrome (CAPS) is a severe and acute case of a similar condition leading to blockage of veins in several organs at the same time. Research indicates that complement activation may contribute to APS-related complications, including pregnancy complications, thrombotic complications (formation of blood clots), and vascular complications. The compound and compositions of the present invention can be used to treat APS-related conditions by reducing or stopping complement activation. In some cases, the compounds and compositions of the present invention can be used to treat APS and/or APS-related complications in accordance with the methods set forth in Salmon et al. Ann Rheum Dis 2002;61(Suppl II):ii46-ii50 and Mackworth-Young in Clin Exp Immunol 2004, 136:393-401, the contents of which are incorporated herein by reference in their entirety.

Cold agglutinin disease

[00215] In some embodiments, the compounds and compositions of the present invention can be used to treat cold agglutinin disease (CAD), also referred to as cold agglutin mediated hemolysis. CAD is an autoimmune disease resulting from a high concentration of IgM antibodies interacting with red blood cells at low body temperatures (Engelhardt et al. Blood, 2002, 100(5):1922-23). CAD can lead to conditions such as anemia, fatigue, dyspnea, hemoglobinuria, and/or acrocyanosis. CAD is associated with strong complement activation, and studies have shown that CAD can be treated with complement inhibitors. Accordingly, the present invention relates to methods for the treatment of CAD using the compounds and compositions of the present invention. In some instances, the compounds and compositions of the present invention may be used to treat CAD according to the methods set forth in Blood, 2009, 113:3885-86, Roth et al. the present description by reference.

Vascular diseases

[00216] In some embodiments, the compounds and compositions of the present invention can be used to treat vascular diseases affecting the blood vessels (eg, arteries, veins, and capillaries). Such diseases can affect circulation, blood pressure, blood flow, organ function, and/or other bodily functions.

Thrombotic microangiopathies (TMA)

[00217] In some embodiments, the compounds and compositions of the present invention can be used to treat and/or prevent thrombotic microangiopathy (TMA) and related diseases. Microangiopathies affect the small blood vessels (capillaries) of the body, causing the capillary walls to become thick, weak, and prone to bleeding and slowing blood circulation. Typically, TMA leads to vascular thrombosis, endothelial cell damage, thrombocytopenia, and hemolysis. Organs such as the brain, kidneys, muscles, gastrointestinal tract, skin, and lungs may be affected. TMAs may result from medical operations and/or conditions that include, but are not limited to, hematopoietic stem cell transplantation (HSCT), kidney disease, diabetes, and/or other conditions. TMA may be caused by an underlying dysfunction of the complement system, as described by Meri et al. in European Journal of Internal Medicine, 2013, 24: 496-502, the contents of which are incorporated herein by reference in their entirety. In general, elevated levels of some complement components can lead to TMA, leading to thrombosis. In some cases, this may be caused by mutations in complement proteins or related enzymes. The resulting complement dysfunction can cause endothelial cells and platelets to become targets of complement, leading to increased thrombosis. In some embodiments, TMA can be prevented and/or treated with the compounds and compositions of the present invention. In some instances, the methods for treating TMA with the compounds and compositions of the present invention may be carried out as described in US Patent Publication Nos. US2012/0225056 or US2013/0246083, the contents of which are incorporated herein by reference in their entirety.

Disseminated intravascular coagulation ( DIC )

[00218] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat disseminated intravascular coagulation (DIC) by controlling complement activation. DIC is a pathological condition in which the coagulation cascade in the blood is highly activated and leads to the formation of blood clots, especially in the capillaries. DIC can lead to obstruction of blood flow to tissues and can eventually lead to organ damage. In addition, DIC affects the normal blood clotting process, which can lead to heavy bleeding. The compounds and compositions of the present invention can be used to treat, prevent, or reduce the severity of DIC by modulating complement activity. In some instances, the compounds and compositions of this invention may be used in accordance with any of the methods for treating DIC described in US Pat. No. 8,652,477, the contents of which are incorporated herein by reference in their entirety.

Vasculitis

[00219] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat vasculitis. In general, vasculitis is a disorder associated with inflammation of blood vessels, including veins and arteries, characterized by leukocytes attacking tissue and causing blood vessels to swell. Vasculitis may be associated with an infection, such as Rocky Mountain spotted fever, or an autoimmune disease. An example of an autoimmune-associated vasculitis is vasculitis with neutrophil cytoplasmic autantibodies (ANCA). ANCA vasculitis is caused by abnormal antibodies attacking the body's own cells and tissues. ANCA antibodies attack the cytoplasm of certain white blood cells and neutrophils, causing them to attack the walls of blood vessels in certain organs and tissues of the body. ANCA vasculitis can involve the skin, lungs, eyes, and/or kidneys. Studies show that in ANCA vasculitis, the alternative complement pathway is activated and certain complement components are generated that create a cycle of increased inflammation, leading to vascular injury (Jennette et al. 2013, Semin Nephrol. 33(6): 557-64, the content of which incorporated herein by reference in its entirety). In some cases, the compounds and compositions of the present invention can be used to prevent and/or treat ANCA vasculitis by inhibiting complement activation.

Neurological diseases

[00220] The compounds and compositions of the present invention can be used to prevent, treat, and/or relieve symptoms of neurological diseases, including, but not limited to, neurodegenerative diseases and related disorders. Neurodegeneration generally refers to the loss of neuronal structure or function, including neuronal death. These disorders can be treated by inhibiting the action of complement on neuronal cells using the compounds and compositions of the present invention. Neurodegeneration-associated disorders include, but are not limited to, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Parkinson's disease, and Alzheimer's disease.

Amyotrophic lateral sclerosis (ALS)

[00221] In some embodiments, the compounds and compositions of the present invention can be used to prevent, treat and/or alleviate the symptoms of ALS. ALS is a fatal motor neuron disease characterized by degeneration of neurons in the spinal cord, brainstem, and motor cortex. ALS results in a loss of muscle strength, eventually leading to respiratory failure. Complement dysfunction may contribute to ALS, and therefore ALS may be prevented, may respond to treatment, and/or its symptoms may be alleviated by therapy with the compounds and compositions of the present invention that target complement activity. In some cases, the compounds and compositions of the present invention can be used to enhance nerve regeneration. In some instances, the compounds and compositions of the present invention may be used as complement inhibitors in accordance with any of the methods set forth in US Patent Publication Nos. US2014/0234275 or US2010/0143344, the contents of which are incorporated herein by reference in their entirety.

Alzheimer's disease

[00222] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat Alzheimer's disease by controlling complement activity. Alzheimer's disease is a chronic neurodegenerative disease, with symptoms that can include confusion, memory loss, mood swings, behavioral problems, and eventually loss of bodily functions. Alzheimer's disease is believed to be caused by extracellular deposits of amyloid in the brain that are associated with inflammation associated with proteins such as complement proteins (Sjoberg et al. 2009. Trends in Immunology. 30(2): 83-90, the content of which is included in full to the present description by reference). In some instances, the compounds and compositions of the present invention may be used as complement inhibitors in accordance with any of the treatments for Alzheimer's disease set forth in US Patent Publication US2014/0234275, the contents of which are incorporated herein by reference in their entirety.

kidney disease

[00223] Compounds and compositions of the present invention can be used to treat certain diseases, disorders and/or conditions associated with the kidneys, in some cases, by inhibiting complement activity. The kidneys are the organs responsible for removing metabolic products from the bloodstream. The kidneys regulate blood pressure, the urinary system, and homeostatic functions and are therefore essential for various bodily functions. The kidneys can be more severely affected by inflammation (compared to other organs) due to their unique structural features and exposure to blood. The kidneys also produce their own complement proteins, which can be activated during infection, kidney disease, and kidney transplants. In some cases, the compounds and compositions of the present invention can be used as complement inhibitors in the treatment of certain renal diseases, conditions and/or disorders in accordance with the methods set forth in Quigg, J Immunol 2003; 171:3319-24, the contents of which are incorporated herein by reference in their entirety.

Lupus nephritis

[00224] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat lupus nephritis by inhibiting complement activity. Lupus nephritis is an inflammation of the kidneys caused by an autoimmune disease called systemic lupus erythematosus (SLE). Symptoms of lupus nephritis include high blood pressure, foamy urine, swelling of the legs, feet, hands, or face, joint pain, muscle pain, fever, and rash. Lupus nephritis can be treated with inhibitors that control the activity of the complement system, including the compounds and compositions of the present invention. Methods and compositions for the prevention and/or treatment of lupus nephritis by complement inhibition may include any of those proposed in US Pat. No. US2013/0345257 or US Pat.

Membrane glomerulonephritis (MGN)

[00225] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat membranous glomerulonephritis (MGN) by inhibiting the activation of certain complement components. MGN is a disorder of kidney function that can lead to inflammation and structural changes. MGN is caused by antibodies that bind to soluble antigen in the glomerular capillaries (glomeruli). MGN can affect kidney functions such as filtering fluids and can lead to kidney failure. The compounds and compositions of the present invention may be used in accordance with the methods for preventing and/or treating MGN by complement inhibition as set forth in US Patent Publication No. US2010/0015139 or International Patent Publication No. WO2000/021559, the contents of which are incorporated herein in their entirety by links.

Complications after hemodialysis

[00226] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat complications associated with hemodialysis by inhibiting complement activation. Hemodialysis is a medical procedure used to maintain kidney function in patients with kidney failure. In hemodialysis, the removal of waste products such as creatinine, urea and free water from the blood is carried out extracorporeally. A common complication of the hemodialysis procedure is chronic inflammation caused by contact between the blood and the dialysis membrane. Another common complication is thrombosis, which is the formation of blood clots that impede blood circulation. Studies have shown that these complications are related to complement activation. Hemodialysis may be combined with complement inhibitor therapy to allow control of inflammatory responses and pathologies, and/or to prevent or treat thrombosis in patients undergoing hemodialysis due to renal insufficiency. Methods for using the compounds and compositions of the present invention to treat complications of hemodialysis can be carried out in accordance with any of the methods set forth in DeAngelis et al. in Immunobiology, 2012, 217(11): 1097-1105 or in Kourtzelis et al. Blood, 2010, 116(4):631-639, the contents of which are incorporated herein by reference in their entirety.

Eye diseases

[00227] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat certain ocular diseases, disorders and/or conditions. In a healthy eye, the complement system is activated at a low level and is constantly regulated by membrane-bound and soluble intraocular proteins that protect against pathogens. Therefore, complement activation plays an important role in several ocular complications, and control of complement activation can be used to treat such diseases. The compounds and compositions of the present invention may be used as complement inhibitors in the treatment of ophthalmic disorders according to any of the methods set forth by Jha et al. in Mol Immunol. 2007; 44 (16): 3901-3908, or in US patent No. 8753625, the contents of which are fully incorporated into the present description by reference.

Age-Related Macular Degeneration (AMD)

[00228] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat age-related macular degeneration (AMD) by inhibiting complement activation in the eye. AMD is a chronic eye disease that causes blurred central vision, blind spots in central vision, and/or possible loss of central vision. Central vision affects the ability to read, drive and/or recognize faces. AMD is broadly classified into two types - non-exudative (dry) and exudative (wet). Dry AMD refers to the deterioration of the macula, which is the tissue in the center of the retina. Wet AMD refers to damage to the blood vessels under the retina, leading to leakage of blood and fluid. Several human and animal studies have identified complement proteins that are associated with AMD, and novel therapeutic strategies include control of complement activation pathways as described by Jha et al. in Mol Immunol. 2007; 44(16): 3901-8. Methods of the invention involving the use of the compounds and compositions of the present invention for the prevention and/or treatment of AMD may include any of those set forth in US Patent Publication Nos. US2011/0269807 or US2008/0269318, the contents of which are incorporated herein by reference in their entirety. .

Corneal diseases

[00229] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat diseases of the cornea by inhibiting complement activation in the eye. The complement system plays an important role in protecting the cornea from pathogenic particles and/or inflammatory antigens. The cornea is the outer anterior part of the eye, covering and protecting the iris, pupil, and anterior chamber, and is therefore exposed to external factors. Corneal diseases include, but are not limited to, keratoconus, keratitis, ocular herpes, and/or other diseases. Corneal diseases can cause pain, blurred vision, tearing, redness, sensitivity to light, and/or scarring of the cornea. The complement system is critical for protecting the cornea, but complement activation can lead to damage to corneal tissue after the infection has cleared because some complement components are overexpressed. Methods of the present invention for modulating complement activity in the treatment of corneal disorders may include any of those set forth by Jha et al. in Mol Immunol. 2007; 44 (16): 3901-8, the contents of which are fully incorporated into the present description by reference.

Autoimmune uveitis

[00230] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat uveitis, which is inflammation of the uveal layer (choroid) of the eye. The choroid of the eyeball is a pigmented area of the eye containing the choroid, iris and ciliary body of the eye. Uveitis causes redness, blurred vision, pain, adhesions, and can eventually lead to blindness. Studies have shown that complement activation products are present in the eyes of patients with autoimmune uveitis, and complement plays an important role in the development of the disease. In some instances, the compounds and compositions of the present invention may be used to treat and/or prevent uveitis, in accordance with any of the methods set forth by Jha et al. in Mol Immunol. 2007. 44 (16): 3901-8, the contents of which are hereby incorporated by reference in their entirety.

diabetic retinopathy

[00231] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat diabetic retinopathy, which is a disease caused by changes in the retinal blood vessels in diabetic patients. Retinopathy can cause blood vessels to swell and leak fluid and/or abnormal blood vessels to grow. Diabetic retinopathy affects vision and can eventually lead to blindness. Studies have shown that complement activation plays an important role in the development of diabetic retinopathy. In some cases, the compounds and compositions of the present invention can be used in accordance with the methods of treatment of diabetic retinopathy described in Jha et al. Mol Immunol. 2007; 44(16): 3901-8, the contents of which are incorporated herein by reference in their entirety.

Preeclampsia and HELLP Syndrome

[00232] In some embodiments, the compounds and compositions of the present invention can be used to prevent and/or treat pre-eclampsia and/or HELLP syndrome (an abbreviation of syndrome features: 1) hemolysis, 2) elevated liver enzymes, and 3) low platelet count ) with complement inhibitor therapy. Preeclampsia is a pregnancy disorder with symptoms including high blood pressure, edema, shortness of breath, impaired kidney function, impaired liver function, and/or low blood platelets. Preeclampsia is usually diagnosed by high levels of protein in the urine and high blood pressure. HELLP syndrome is a combination of hemolysis, elevated liver enzymes, and low platelets. Hemolysis is a disorder involving the destruction of red blood cells, resulting in the release of hemoglobin from them. Elevated liver enzymes may indicate pregnancy-induced liver disease. Low platelet levels lead to a decrease in the ability of the blood to clot, which raises the risk of excessive bleeding. HELLP is associated with preeclampsia and liver disease. HELLP syndrome usually occurs late in pregnancy or after childbirth. It is usually diagnosed by a blood test indicating the presence of the three components that it includes. Treat HELLP by inducing labor.

[00233] Studies show that complement activation occurs in HELLP syndrome and preeclampsia, and that some complement components are present in increased amounts in HELLP and preeclampsia. Complement inhibitors can be used as therapeutic agents to prevent and/or treat these conditions. The compounds and compositions of the present invention may be used in accordance with the methods for the prevention and/or treatment of HELLP and preeclampsia set forth by Heager et al. in Obstetrics & Gynecology, 1992, 79(1):19-26 or International Patent Publication No. WO201/ 078622, the contents of which are fully incorporated into the present description by reference.

Dosages and Administration

[00234] For use in human therapy, the polypeptides can be formulated into pharmaceutical compositions. Depending on the patient to be treated, the route of administration, and the type of treatment desired (eg, prevention, prophylaxis, or therapy), polypeptides are formulated to meet these parameters. A summary of such methods can be found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Williams & Wilkins, (2005); and in Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-1999, Marcel Dekker, New York, which are incorporated herein by reference.

[00235] The compositions of the present invention are preferably formulated in a therapeutically effective amount, which may be, for example, a daily amount of from about 0.1 mg to about 100 mg, from about 0.5 mg to about 200 mg, from about 1 mg to about 300 mg, about 5 mg to about 500 mg, about 10 mg to about 750 mg, about 50 mg to about 1000 mg, or at least 1000 mg. In one embodiment, the pharmaceutical composition includes a capsule, for example in unit dosage form.

Standard dosage forms

[00236] The polypeptides of the invention may be present in amounts generally ranging from 0.1-95% by weight of the total weight of the composition. The composition may be presented in a dosage form suitable for oral administration. Thus, the pharmaceutical composition may be in the form of, for example, hard capsules (e.g., hard gelatin capsules or hard hydroxypropyl methylcellulose capsules), soft gelatin capsules, tablets, caplets, enteric-coated tablets, chewable tablets, enteric-coated hard gelatin capsules. , enteric-coated soft gelatin capsules, minicapsules, lozenges, cachets, strips, softgels, dragees, solutions, emulsions, suspensions, syrups or aerosols.

[00237] Patients may be administered a therapeutic amount of the polypeptide, such as 0.01 mg/kg, 1.0 mg/kg, or 15 mg/kg. For human administration, the dosage of the polypeptides of the present invention is typically 0.01 to 15 mg/kg, more preferably 3 to 5 mg/kg. However, dosage levels may vary greatly depending on the nature of the disease, the efficacy of the drug, the condition of the patient, the judgment of the practitioner, and the frequency and route of administration.

[00238] In other embodiments, the polypeptides are administered at a frequency such as every 4 hours, every 6 hours, every 12 hours, every 18 hours, every 24 hours, every 36 hours, every 72 hours, every 84 hours, every 96 hours, every 5 days, every 7 days, every 10 days, every 14 days, every 3 weeks or more. The compositions can be administered once a day, or the polypeptide can be administered in two, three or more divided doses at regular intervals throughout the day, or by delivery using a controlled release formulation. In this case, the content of the polypeptide in each fractional dose should be correspondingly lower in order to reach the total daily dose. Unit dosage forms can also be designed for delivery over several days, for example using a conventional extended release formulation that provides sustained release of the polypeptide over several days.

[00239] Sustained release formulations are well known in the art and are particularly useful for delivering agents to a specific site so that they can be used with the polypeptide compositions of the present invention. The effect of a single dose may be prolonged, so that subsequent doses are administered no more frequently than at 3-, 4-, or 5-day intervals, or no more than 1-, 2-, 3-, or 4-week intervals.

[00240] The polypeptide can be administered by intravenous infusion over a period of time, such as 5 minutes, 10 minutes, 15 minutes, 20 minutes, or 25 minutes. The administration may be repeated, for example, on a regular basis, for example, biweekly (ie, every two weeks) for one month, two months, three months, four months or more. After the initial treatment regimen, the introduction can be done less frequently. For example, after administration every two weeks for three months, administration may be repeated once a month for six months or a year or more. Administration of a polypeptide or composition may decrease, decrease, increase, or alter binding or any physiologically detrimental process, for example, in a cell, tissue, blood, urine, or other patient fluid, by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% or more.

[00241] Before administering a full dose of a polypeptide and/or a polypeptide composition, patients may be given smaller doses, such as 5% of the total dose, and monitored for side effects such as allergic or infusion reactions, or elevated lipid levels or elevated blood pressure. pressure. In another example, the patient can be monitored for undesirable immunostimulatory effects, such as increased levels of cytokines (eg, TNF-alpha, Il-1, Il-6, or Il-10).

[00242] Genetic predisposition plays a role in the development of certain diseases or disorders. Thus, a patient in need of treatment with a polypeptide and/or a polypeptide composition may be identified by family history or, for example, by screening for one or more genetic markers or variants. A healthcare professional, such as a physician or nurse, or a family member, may consider family history prior to prescribing or administering a therapeutic composition of the present invention.

Sets

[00243] Any of the compositions described herein may be included in a kit. As a non-limiting example, polypeptides can be included in a kit for treating a disease. The kit may include a vial of sterile dry powder of the polypeptide, a sterile solution for dissolving the dry powder, and an infusion syringe for administering the polypeptide.

[00244] When polypeptides are presented as a dry powder, it is assumed that from 10 μg to 1000 mg of the polypeptide (at least or at most) are provided in the kits of the invention.

[00245] Containers typically include at least one vial, test tube, flask, bottle, syringe, and/or other containers into which polypeptide formulations are placed, preferably suitably dispensed. The kits may also include a second container containing a sterile, pharmaceutically acceptable buffer and/or other diluent.

[00246] The kit may include instructions for using the components of the kit, as well as for using any other reagent not included in the kit. The instructions may include changes that may be implemented.

[00247] While various embodiments of the present invention have been shown and described in detail, those skilled in the art will appreciate that various changes in form and detail may be made to the invention without departing from the spirit and scope of the present invention, which are defined by the appended the claims of the invention.

EQUIVALENTS AND SCOPE OF THE INVENTION

[00248] Those skilled in the art will recognize, or be able to determine using no more than routine experimentation, many equivalents of the specific embodiments in accordance with the present invention described herein. The scope of the present invention is not intended to be limited by the above description, but rather as set forth in the appended claims.

[00249] In the claims, singular forms may mean one or more than one, unless otherwise indicated or otherwise apparent from the context. A claim or description that includes the conjunction "or" between one or more members of a group is deemed to be satisfied if one, more than one, or all of the members of the group are present, used, or otherwise related to the product or process, unless otherwise stated. or otherwise not obvious from the context. The present invention includes embodiments in which one member of the group is present, used, or otherwise related to a given product or process. The invention includes embodiments in which more than one or all of the members of the group are present, used, or otherwise related to a given product or process.

[00250] It should also be noted that the term "comprising" is intended to be open-ended and permits, but does not require, the inclusion of additional elements or steps. When the term "comprising" is used in the present description, the terms "consisting of" and "or including", thus, are also covered and disclosed.

[00251] If ranges are given, endpoints are included. In addition, it should be understood that, unless otherwise indicated, or otherwise obvious from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges may imply any particular value or lesser range within the specified ranges in various embodiments of the present invention, up to a tenth of the unit lower limit of the range, unless the context clearly dictates otherwise.

[00252] In addition, it should be understood that any particular embodiment of the present invention that relates to the prior art may be expressly excluded from any one or more paragraphs. invention formulas. Since such variants are considered to be known to those of ordinary skill in the art, they may be excluded, even if the exclusion is not explicitly stated in the present description. Any particular embodiment of the composition of the present invention (eg, any nucleic acid or protein so encoded, any method of preparation, any method of use, etc.) may be excluded from any one or more paragraphs. claims for any reason, whether or not related to the existence of a prototype.

[00253] All cited sources, such as references, publications, databases, database entries, and techniques in the art, cited herein are incorporated into this application by reference, even if not indicated in the citation. In the event of conflicting statements between the cited source and this application, the statement in this application shall prevail.

[00254] Section and table headings are not intended to limit the invention.

EXAMPLES

Example 1 Preparation of Biotinylated C5

[00255] For preparative biotinylation, an effective 1:4 final molar ratio of C5 and biotin was used. A 10 mM solution of EZ-Link Sulfo-NHS-LC Biotin (Thermo Scientific, Billerica, MA) was prepared according to the manufacturer's instructions. To 1 mg C5 from a 1 mg/ml solution (Complement Tech, Tyler TX) was added 2.1 μl of a 10 mM biotin solution and incubated on ice for 2 hours. The reaction was stopped for 30 minutes at 4°C after the addition of 100 μl of 1 M Tris-HCl, pH 7.5. The reaction mixture was dialyzed overnight against cold PBST (phosphate buffered saline (PBS)+0.1% Tween 80). Biotinylated C5 was aliquoted and stored at -80°C. Biotinylated C5 was characterized by SDS-PAGE under reducing and non-reducing conditions, and activity was characterized by erythrocyte hemolysis assay. Biotinylated C5 was also tested for release on streptavidin beads (Invitrogen, Grand Island, NY). The capture was carried out using the conditions recommended by the manufacturer. For capture, 4 μg of a 100 nM biotinylated C5 solution and 40 μl of bead suspension were used and incubated at 4°C for 1 hour. The concentration of captured biotinylated C5 was calculated by running a known amount of C5 on a NuPAGE 4-12% Bis-Tris gel (Invitrogen, Grand Island, NY).

Example 2 Human Hemolysis Assay for Biotinylated C5 QC

[00256] Hemolysis assays were performed with C5-poor sera and biotinylated C5 and non-biotinylated C5 to compare C5 lysis activity before and after biotinylation. Antibody-sensitized sheep erythrocytes (Complement Technology, Tyler TX) in a solution at a concentration of 5×10 ⁸ cells/ml were centrifuged at 2090g for 3 minutes and resuspended in GVB++ buffer (Complement Technology, Tyler TX). C5-poor human sera (Complement Technology, Tyler TX) were rapidly thawed at 37° C. and placed on ice with water until diluted in GVB++. Non-biotinylated C5 protein (Complement Technology, Tyler TX) and biotinylated C5 protein (biotinylated by the authors) were rapidly thawed at 37° C. and placed on ice and water until diluted in GVB++. 100 µl of cells (at a final concentration of 2.5×10 ⁷ cells/ml) were mixed with C5-poor human sera and 50 µl of biotinylated or non-biotinylated C5 (at a final concentration of 10 µg/ml, 3 µg/ml or 1 µg/ml) in a tissue culture treated 96-well microtiter plate (USA Scientific, Ocala, FL). The tablet was incubated for 1 h at 37°C. After incubation, the plates were centrifuged at 2090g for 2 minutes before transferring 100 μl of the supernatant to a new microtiter plate. Optical density was read at 412 nm and the percent lysing activity of non-biotinylated and biotinylated C5 was compared.

Example 3 Selection of C5 Binding Polypeptides

[00257] C5 inhibitors have been identified in several rounds of mRNA display screening. mRNA display was carried out essentially as described (Roberts, RW, and Szostak, JW (1997). Proc. Natl. Acad. Sci. USA 94, 12297-12302; WO2009067191, which are incorporated herein by reference in their entirety. ) with the modifications described in this document. RNA pools were generated by in vitro transcription using DNA synthesized with fixed N-terminal methionine and cysteine codons followed by three positions from a sixteen-codon phosphoramidite mixture followed by eight positions from a second codon mixture also containing a cysteine codon. The resulting mRNA library has a fixed initiator methionine followed by a cysteine residue, and then three positions lacking cysteine, and then eight positions where cysteine occurs at a frequency of 12.5%. In selection, the first round of enrichment included a first step in which RNA pools containing a 3' UV-linked oligonucleotide containing puromycin were translated in vitro with the purified translational components listed in Table 2. Translation was performed in two versions to create two unique libraries based on amino acid variation. In the first variant, only 20 natural amino acids were used, while in the second variant, natural amino acids (0.1 mM histidine, threonine, proline, lysine, asparagine, tyrosine, glutamic acid and cysteine), non-natural amino acids (2 mM tert-glycine (Tbg), 0.8 mM 7-azatryptophan (abbreviation "azaTrp" in this example) and 1 mM norvaline (Nvl), azaleucin and phenyl-glycine (Phg)) and N-methyl amino acids (450 μM mixture of N-methylated serine [(N-Me)S], alanine [(N-Me)A], glycine [(N-Me)G], and 4-fluoro-N-methylphenylalanine [(N-Me-4-F)Phe]). ³⁵ S-labeled cysteine residues were included in both variants to allow monitoring of polypeptide enrichment per round.

Table 2. Translation components in vitro

Component Conc. Creatinine Phosphate 20 mM MeTHF, pH 7.6 15 µg/ml HEPES-KOH, pH 7.6 51 mm KCl 101 mm spermidine 2 mM DTT 1 mM Creatinine kinase 4 mM Myokinase 3 mM Nucleotide diphosphate kinase 1 mM Pyrophosphate 1 mM ATP+GTP' 2 mM each EF Tu 50 µM Ribosomes 1 µM MTF 0.56 µM 1F1 0.96 µM IF2 0.40 µM IF3 0.44 µM EF-G 0.64 µM EF-Ts 1.58 µM RF1 0.24 µM RF3 0.17 µM RRF 0.46 µM mg 17.46 mM

[00258] The tRNAs were enzymatically linked to their respective amino acids using tRNA synthetases. Four N-methylated tRNAs were pre-linked, while all other tRNAs were enzymatically linked during the in vitro translation reaction. tRNA synthetases were added on a volume basis regardless of their concentration. 0.1 μl of each tRNA synthetase (except methionine tRNA synthetase, which was added at 0.4 μl per 25 μl translation reaction) was added for in-situ crosslinking during translation per 25 μl translation reaction. The crosslinked mRNA was added at a final concentration of 0.75 μM. The translation reaction was incubated at 37°C for 1 hour. After translation, fusion of the translated polypeptides and their respective mRNAs was carried out by adding a large amount of salt to the translation mixture and incubating at 37° C. for 1.5 hours. The natural polypeptide selection library was generated from eight separate libraries with a fixed cysteine codon at positions 5-11. Random positions in these libraries, with all possible 20 amino acids, were generated combinatorially using repeated NNS codon units (N is A, G, C or T, S is G or C) (Devlin, JJ, et. al., (1990) Science 249, 404-406). Translation of these libraries into native polypeptides was performed using an in vitro translation kit from rabbit reticulocytes rather than the reengineered system described above.

[00259] Isolation of mRNA-presented polypeptides was performed using oligo-dT and Ni-NTA affinity isolation to isolate fusion molecules containing both polyA-mRNA and His-tagged polypeptides. Oligo-dT bead-bound polypeptides are then cyclized with dibromoxylene as described in the literature (J. Am. Chem. Soc. 127:1 1727 (2005)).

[00260] Direct selection of polypeptides by affinity to the target was then performed. The polypeptides displayed on the mRNA were allowed to bind for 1 hour at 4° C. to biotinylated C5 in a 100 nM solution of biotinylated C5 in PBST. RNA corresponding to the affinity-selected polypeptides was subjected to reverse transcription and PCR amplification to create a double-stranded DNA pool. The DNA pool was transcribed in vitro to create mRNA, and the resulting mRNA was fused as before at its 3' end with a puromycin-containing oligonucleotide. Puromycin-fused mRNAs were translated in vitro to give a second round of the library, which was now enriched in C5 complement binding polypeptides. The qualifying round was repeated in six rounds. After the sixth round, a DNA pool representing the selected polypeptides was cloned and sequenced, and the amino acid sequences of potential C5 inhibitors were determined based on the DNA sequences. These identified polypeptide sequences are shown in Table 3.

[00261] As used in all of the following tables, as well as in the sequence listing, the abbreviations have the following meanings: "Ac" and "NH2" denote the acetyl and amidated ends, respectively; "Nvl" means norvaline; "Phg" refers to phenylglycine; "Sar" stands for sarcosine; "Tbg" refers to tert-butylglycine; "Trt" means trityl or triphenylmethyl; "Chg" refers to cyclohexylglycine; "(N-Me)X" means the N-methylated form of an amino acid, denoted by the letter or three-letter abbreviation for that amino acid instead of the variable "X", written as N-methyl-X [e.g., (N-Me)A and (N-Me )Ala - both refer to the N-methylated form of alanine or N-methyl-alanine]; 7-azatryptophan is included where "azaTrp" is indicated; "(4-F)Phe" means 4-fluorophenylalanine; "Tyr(OMe)" refers to O-methyl-tyrosine; "Aib" refers to amino-isobutyric acid; "(homo)F" or "(homo)Phe" means homophenylalanine; "(2-OMe)Phg" means 2-O-methylphenylglycine; "propargyl-Gly" refers to propargyl-glycine; "(5-F)W" or "(5-F)Trp" means 5-fluorotryptophan; "DX" refers to the D-stereoisomer of a given amino acid "X", where the amino acid may be abbreviated using a one- or three-letter code [eg, (D-Chg) is D-cyclohexylglycine and (DW) is D-tryptophan]; "(5-MeO)W" or "(5-MeO)Trp" means 5-methyl-O-tryptophan; "homoC" refers to homocysteine; "(1-Me-W)" or "(1-Me)W" or "(1-Me-Trp)" or "(1-Me)Trp" refers to 1-methyltryptophan; "Nle" means norleucine; 1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid is included where "Tiq" is indicated; "Asp(T)" refers to (S)-2-amino-3-(1H-tetrazol-5-yl)propionic acid; "(3-Cl-Phe)" means 3-chlorophenylalanine; "[(N-Me-4-F)Phe]" or "(N-Me-4-F)Phe" refers to N-methyl-4-fluorophenylalanine; "Boc" is a tert-butyloxycarbonyl protecting group; "[ x -xylyl( y,z )]" refers to a xylyl bridge between two cysteines, where x can be m-, p-, or o-, indicating the use of meta-, para-, or ortho-dibromoxylenes (respectively), to obtain bridging groups, and the numerical identifiers, y and z , indicate the amino acid positions in the polypeptide for the cysteines involved in the cyclization process; "[cyclo( y , z )]" refers to the formation of a bond between two amino acid residues, where the numerical identifiers, y and z , indicate the positions of the residues involved in the formation of the bond; "[m-xylyl-bicyclo]" indicates that the polypeptide contains two cyclic loops and that the bridging group is formed by reaction with meta-dibromoxylene. All other symbols refer to the standard single-letter amino acid code. In addition, polypeptides containing PEG2000 or the sequence tag, BODIPY-TMR-X, are indicated.

Table 3. Polypeptide sequences

Connection number Subsequence SEQID NO R3000 Ac-Nvl-C-Y-K-N-Y-H-azaTrp-E-Y-P-Tbg-Y-NH2 one R3001 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 2 R3002 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 3 R3003 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-P-NH2 four R3004 Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-Y-P-Phg-Tbg-NH2 5 R3005 Ac-Nvl-C-Y-azaTrp-(N-Me)G-Tbg-Nvl-azaTrp-E-Y-P-Phg-P-NH2 6 R3006 Ac-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 7 R3007 [m-xylyl(2,7)]Ac-Nvl-C-K-E-Phg-Y-C-(N-Me)S-Tbg-K-azaTrp-E-Y-NH2 eight R3008 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 9 R3020 [m-xylyl(2,7)]M-C-S-E-R-Y-C-E-V-R-W-E-Y-NH2 ten R3021 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 eleven

Example 4 Synthesis of polypeptides

[00262] Polypeptides were synthesized using standard Fmoc/tBu solid phase methods. Synthesis was typically performed on a Liberty automated microwave peptide synthesizer (CEM, Matthews NC) using standard Rink amide resin protocols, although other automated synthesizers without the microwave option can also be used. All amino acids are from commercial sources unless otherwise noted. The coupling reagent is 2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3,-tetramethylaminium hexafluorophosphate (HCTU) and the base is diisopropylethylamine (DIEA). The polypeptides are cleaved from the resin using 95% TFA, 2.5% TIS and 2.5% water for 3 hours and isolated by ether precipitation. The crude polypeptides are purified by reverse phase preparative HPLC using a C18 column in acetonitrile/water, 0.1% TFA with a 20%-50% gradient over 30 minutes. Fractions containing pure polypeptide are collected and lyophilized and all polypeptides are analyzed by LC-MS.

Example 5 Formation of Disulfide Cyclized Polypeptides

[00263] To obtain disulfide-cyclized polypeptides, a linear polypeptide is dissolved in a mixture of water and DMSO, and the resulting solution is vigorously stirred in air for 12 hours.

Example 6 Cyclization of Polypeptides with Dibromoxylene

[00264] Acetonitrile (12 ml) and water (24 ml) are added to a 100 ml flask and degassed with argon for approximately 5 minutes. The linear polypeptide (0.01 mmol) and 200 mM ammonium bicarbonate (6 ml) are then added, followed by the addition of 0.012 mmol or 1,3-bis(bromomethyl)benzene, 1,2-bis(bromomethyl)benzene, 1,4-bis (bromomethyl)benzene, 2,6-bis(bromomethyl)pyridine or (E)-1,4-dibromobut-2-ene. The reaction mixture is stirred under argon at room temperature for approximately 2 hours and monitored by LC-MS. After completion of the reaction, the reaction solution is frozen and lyophilized. HPLC purification of the crude lyophilized product followed by lyophilization of the fractions containing the purified polypeptide gave the final cyclized product as a white powder.

Example 7 Lactam Cyclization of Polypeptides

[00265] The cyclization of polypeptides using the lactam group was performed on the solid phase. The polypeptide was first synthesized on a Wang solid resin carrier using the standard Fmoc method. Fmoc-ASP(allyl)-OH and Fmoc-LYS(Alloc)-OH were included in the polypeptide at the indicated positions as two lactam bridge precursor monomers. After completion of elongation, the resin was washed with dry dichloromethane (3 times) and purged with dry nitrogen gas for 10 minutes. To remove the allyl and Alloc protecting groups, the resin was treated with a 5-fold molar excess of phenylsilane and purged with nitrogen for 10 minutes. A catalytic amount of tetrakis-Pd(0) was dissolved in dry dichloromethane and added to the resin slurry. After one hour, the resin was washed successively with dichloromethane (3 times), dimethylformamide (3 times), sodium diethyldithiocarbamate trihydrate (3 times), dimethylformamide (3 times) and dichloromethane (3 times). Lactam cyclization in dimethylformamide (DMF) was obtained by treating the resin containing the unprotected polypeptide with PyAOP phosphorus) and diisopropylethylamine and left to pass the reaction overnight. The resin was washed with DMF and treated with fresh PyAOP and diisopropylethylamine for another 60 minutes at 45°C. The resin was aged and washed with dimethylformamide five times. The polypeptide was digested and purified as described in Example 4.

Example 8 Triazole Cyclization of Polypeptides

[00266] The cyclization of polypeptides containing azide and alkyne groups was carried out on the solid phase. The resin containing the polypeptide (0.05 mmol) was treated with dichloromethane and allowed to swell for 10 minutes. The solvent was then changed to DMF (3-5 ml) and Cu-TBTA ligand solution (125 μl of a 20 mM solution) was added after 10 min. The suspension was purged with argon and then ascorbic acid (5 μmol) was added. The solution was stirred for 2 h, and excess reagents were removed, the resin was washed with a solution of EDTA in DMF to remove excess copper. The polypeptide was digested and purified as described in Example 4.

Example 9 Polypeptides of the present invention

[00267] The polypeptides of the present invention have been synthesized. These include the compounds listed in Table 4.

Table 4. Compounds of the present invention

Connection number Subsequence SEQID NO. R3000 Ac-Nvl-C-Y-K-N-Y-H-azaTrp-E-Y-P-Tbg-Y-NH2 one R3001 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 2 R3002 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 3 R3003 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-P-NH2 four R3004 Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-Y-P-Phg-Tbg-NH2 5 R3005 Ac-Nvl-C-Y-azaTrp-(N-Me)G-Tbg-Nvl-azaTrp-E-Y-P-Phg-P-NH2 6 R3006 Ac-Y-E-N-Tbg-Y-azaTrp-E-Y-(N-Me)G-Nvl-(N-Me)S-NH2 7 R3007 [m-xylyl(2,7)]Ac-Nvl-C-K-E-Phg-Y-C-(N-Me)S-Tbg-K-azaTrp-E-Y-NH2 eight R3008 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 9 R3020 [m-xylyl(2,7)]M-C-S-E-R-Y-C-E-V-R-W-E-Y-NH2 ten R3021 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 eleven R3079 Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 12 R3055 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 13 R3120 Ac-Nvl-Nvl-Y-E-(N-Me)N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 fourteen R3057 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 fifteen R3056 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 16 R3054 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 17 R3029 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-NH2 eighteen R3048 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 19 R3072 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-NH2 twenty R3024 Ac-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 21 R3114 Ac-Nvl-Nvl-(N-Me)Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 22 R3050 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 23 R3025 Ac-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 24 R3061 Ac-Nvl-S-Y-E-A-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 25 R3041 Ac-Y-E-N-Tbg-Y-W-E-Y-P-Phg-Nvl-NH2 26 R3077 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-(PEG2000)NH2 27 R3030 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-NH2 28 R3062 Ac-Nvl-S-Y-E-N-A-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 29 R3066 Ac-Nvl-S-Y-E-N-Tbg-A-azaTrp-E-Y-P-Chg-Nvl-NH2 thirty R3011 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-NH2 31 R3070 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-A-Chg-Nvl-NH2 32 R3071 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-Y-P-A-Nvl-NH2 33 R3033 [m-xylyl(2,10)]Ac-Nvl-C-Phg-A-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 34 R3038 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 35 R3012 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 36 R3060 Ac-Nvl-S-Y-A-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 37 R3039 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-A-NH2 38 R3037 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)A-H-C-Nvl-NH2 39 R3076 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-K-(BODIPY-TMR-X)NH2 40 R3074 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Tyr(OMe)-(N-Me)S-H-C-Nvl-NH2 41 R3013 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-NH2 42 R3065 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-P-H-C-Nvl-NH2 43 R3073 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Phe(4-F)-(N-Me)S-H-C-Nvl-NH2 44 R3116 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-(N-Me)W-E-Y-P-Chg-Nvl-NH2 45 R3091 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-E-Y-(N-Me)S-A-C-Nvl-NH2 46 R3078 PEG2000-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 47 R3100 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-F-(N-Me)S-A-C-Nvl-NH2 48 R3121 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-Y-P-(N-Me)Phg-Nvl-NH2 49 R3043 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-NH2 fifty R3102 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-P-H-C-Nvl-NH2 51 R3026 Ac-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 52 R3031 [m-xylyl(2,10)]Ac-A-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 53 R3019 [m-xylyl(2,14)]Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-C-NH2 54 R3014 [m-xylyl(1,9)]Ac-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 55 R3104 [p-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 56 R3059 Ac-Nvl-S-A-E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 57 R3115 Ac-Nvl-Nvl-Y-(N-Me)E-N-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 58 R3110 Ac-Y-E-N-Tbg-Y-(1-Me)W-E-Y-P-Phg-Nvl-NH2 59 R3126 Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-C-P-Phg-Tbg-NH2 60 R3049 [o-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 61 R3069 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-E-A-P-Chg-Nvl-NH2 62 R3015 [m-xylyl(1,9)]Ac-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-NH2 63 R3068 Ac-Nvl-S-Y-E-N-Tbg-Y-azaTrp-A-Y-P-Chg-Nvl-NH2 64 R3105 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 65 R3106 [p-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 66 R3111 [m-xylyl(4,10)]Ac-Nvl-T-Phg-C-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 67 R3112 [m-xylyl(2,10)]Ac-Nle-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 68 R3113 [m-xylyl(3,11)]Ac-Y-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 69 R3134 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-(3-Cl-Phe)-(N-Me)S-A-C-Nvl-NH2 70 R3018 [m-xylyl(2,10)]Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-C-P-Phg-Nvl-NH2 71 R3027 Ac-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 72 R3028 Ac-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 73 R3032 [m-xylyl(2,10)]Ac-Nvl-C-A-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 74 R3058 [p-xylyl(2,10)]Ac-Nvl-C-Chg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 75 R3067 Ac-Nvl-S-Y-E-N-Tbg-Y-A-E-Y-P-Chg-Nvl-NH2 76 R3117 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-azaTrp-E-(N-Me)Y-P-Chg-Nvl-NH2 77 R3022 Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 78 R3016 [m-xylyl(1,9)]Ac-C-Tbg-Y-azaTrp-E-Y-(N-Me)S-H-C-NH2 79 R3089 [m-xylyl(2,10)]Ac-Chg-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 80 R3083 [m-xylyl(2,10)]Ac-V-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 81 R3087 [m-xylyl(2,10)]Ac-Nvl-C-(2-OMe)Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 82 R3103 [m-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 83 R3135 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-(D-Ala)-C-Nvl-NH2 84 R3034 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-A-E-Y-(N-Me)S-H-C-Nvl-NH2 85 R3035 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-A-Y-(N-Me)S-H-C-Nvl-NH2 86 R3036 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-A-(N-Me)S-H-C-Nvl-NH2 87 R3044 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-NH2 88 R3080 [m-xylyl(2,9)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-C-Nvl-NH2 89 R3085 [m-xylyl(2,10)]heptanoyl-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 90 R3086 [m-xylyl(5,13)]Ac-Nvl-S-Y-E-C-Tbg-Y-azaTrp-E-Y-P-Chg-C-Nvl-NH2 91 R3092 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-F-E-Y-(N-Me)S-A-C-Nvl-NH2 92 R3095 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-(homo)F-(N-Me)S-A-C-Nvl-NH2 93 R3096 [m-xylyl(2,10)]Ac-Nvl-C-Phg-Aib-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 94 R3122 [m-xylyl(2,10)]Ac-Nvl-C-Tiq-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 95 R3075 [m-xylyl(2,11)]Nvl-C-Y-(N-Me)S-Phg-(N-Me-4-F)Phe-(N-Me)S-H-(N-Me-4-F) Phe-G-C-NH2 96 R3107 [m-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 97 R3108 [p-xylyl(2,10)]Ac-Nvl-homoC-Phg-T-azaTrp-E-Y-(N-Me)S-H-homoC-Nvl-NH2 98 R3127 [m-xylyl(2,10)]Ac-Nvl-C-Y-N-N-Tbg-E-azaTrp-E-C-P-Phg-Tbg-NH2 99 R3133 [m-xylyl(2,10)]Ac-Nvl-C-Phg-(D-Ala)-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 100 R3009 [m-xylyl(2,10)]Ac-Nvl-C-Y-E-(N-Me)G-Tbg-Y-azaTrp-E-C-Nvl-P-Nvl-NH2 101 R3010 [m-xylyl(2,13)]Ac-Nvl-C-Y-E-(N-Me)G-Tbg-Y-azaTrp-E-Nvl-Nvl-P-C-NH2 102 R3017 [m-xylyl(2,8)]Ac-Nvl-C-Y-E-N-Tbg-Y-C-E-Y-P-Phg-Nvl-NH2 103 R3023 Ac-Y-P-Y-C-Phg-azaTrp-Tbg-E-Nvl-N-Y-Nvl-E-NH2 104 R3040 [cyclo(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl 105 R3042 [cyclo(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-NH2 106 R3045 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-NH2 107 R3046 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-NH2 108 R3047 [m-xylyl(2,7)]M-C-V-E-R-F-C-NH2 109 R3051 [m-xylyl(2,11)]Nvl-C-Y-(N-Me)S-Phg-(N-Me-4-F)Phe-(N-Me)S-H-(N-Me-4-F) Phe-(N-Me)G-C-NH2 110 R3052 [m-xylyl(2,9)]Nvl-C-Y-Tbg-Phg-N-(N-Me)G-L-C-Phg-(N-Me)A-NH2 111 R3053 [m-xylyl-bicyclo]Nvl-C-C-N-Tbg-Phg-C-Tbg-(N-Me)S-C-Tbg-NH2 112 R3063 Ac-Tbg-Y-azaTrp-E-Y-NH2 113 R3064 Ac-Y-azaTrp-E-Y-P-NH2 114 R3081 Ac-Y-E-N-Tbg-Y-azaTrp-(N-Me)E-Y-P-Phg-Nvl-NH2 115 R3082 [m-xylyl(1,9)]heptanoyl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 116 R3084 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-S-A-C-Nvl-NH2 117 R3088 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(5-F)W-E-Y-(N-Me)S-A-C-Nvl-NH2 118 R3090 [m-xylyl(2,10)]Ac-Nvl-C-F-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 119 R3093 [m-xylyl(2,10)]Ac-Nvl-C-(D-Chg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 120 R3094 Ac-Y-E-N-Tbg-Y-(5-MeO)W-E-Y-P-Phg-Nvl-NH2 121 R3097 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-D-Y-(N-Me)S-A-C-Nvl-NH2 122 R3098 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-Q-Y-(N-Me)S-A-C-Nvl-NH2 123 R3099 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-N-Y-(N-Me)S-A-C-Nvl-NH2 124 R3101 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-G-C-Nvl-NH2 125 R3109 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(1-Me-W)-E-Y-(N-Me)S-A-C-Nvl-NH2 126 R3118 Ac-Y-E-N-Tbg-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 127 R3119 Ac-Y-E-N-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 128 R3123 Ac-Y-E-N-Tbg-Y-azaTrp-(D-Glu)-Y-P-Phg-Nvl-NH2 129 R3124 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-V-Y-W-E-F-NH2 130 R3125 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-W-E-F-NH2 131 R3128 Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 132 R3129 [m-xylyl(2,8)]Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 133 R3130 Ac-Nvl-Nvl-Y-E-N-Tbg-(N-Me)Y-azaTrp-E-Y-P-Chg-Nvl-NH2 134 R3131 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-Asp(T)-Y-(N-Me)S-H-C-Nvl-NH2 135 R3132 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(D-Trp)-E-Y-(N-Me)S-H-C-Nvl-NH2 136 R3136 [m-xylyl(2,10)]heptanoyl-Nvl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 137 R3137 [m-xylyl(1,9)]heptanoyl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 138 R3138 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-W-E-F-NH2 139 R3139 [m-xylyl(1,6)]Ac-C-Tbg-E-R-F-C-D-Tbg-Y-W-E-F-NH2 140 R3140 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-Y-P-NH2 141 R3141 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-P-NH2 142 R3142 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-azaTrp-E-Y-P-NH2 143 R3143 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-W-E-Y-P-NH2 144 R3144 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 145 R3145 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 146 R3146 [m-xylyl(1,6)]Ac-C-Tbg-E-R-F-C-D-V-Y-W-E-F-NH2 147 R3147 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-propargyl-Gly-NH2 148 R3148 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-W-E-Y-P-Phg-Nvl-NH2 149 R3149 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-W-E-Y-P-(D-Phg)-Nvl-NH2 150 R3150 [m-xylyl(1,6)]Ac-C-V-A-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 151 R3151 [m-xylyl(1,6)]Ac-C-V-A-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 152 R3152 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 153 R3153 [m-xylyl(1,6)]Ac-C-V-E-A-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 154 R3154 [m-xylyl(1,6)]Ac-C-V-E-A-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 155 R3155 [m-xylyl(1,6)]Ac-C-V-E-R-A-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 156 R3156 [m-xylyl(1,6)]Ac-C-V-E-R-A-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 157 R3157 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-A-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 158 R3158 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-A-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 159 R3159 [m-xylyl(1,6)](desamino)C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 160 R3160 [m-xylyl(1,6)](desamino)C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-Nvl-NH2 161 R3161 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-K-NH2 162 R3162 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-(D-Phg)-K-NH2 163 R3163 [cyclo(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 164 R3164 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C12)-NH2 165 R3165 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C10)-NH2 166 R3166 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C8)-NH2 167 R3167 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(alpha-methyl)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 168 R3168 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-Asp(T)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 169 R3169 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 170 R3170 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-K 171 R3171 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C12) 172 R3172 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 173 R3173 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 174 R3174 [cyclo(1,6)]Ac-K-V-E-R-F-D-Asp(T)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 175 R3175 [cyclo(1,6)]Ac-K-V-E-R-F-D-D-Tbg-Y-azaTrp-E-Y-P-Chg-B20 176 R3176 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 177 R3177 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-W-P-Chg-Nvl 178 R3178 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(homo)Phe-P-Chg-Nvl 179 R3179 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(m-Cl-homo)Phe-P-Chg-Nvl 180 R3180 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-2Nal-P-Chg-Nvl 181 R3181 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-(3-aminomethyl)Phe-E-Y-P-Chg-Nvl 182 R3182 [cyclo-triazolyl(1,6)]Ac-X02-V-E-R-F-X31-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 183 R3183 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 184 R3184 [cyclo-thioalkyl(1,5)]V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 185 R3185 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-Cle-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 186 R3186 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-(Ac-pyran)-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 187 R3187 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-(3-aminomethyl)Phe-P-Chg-Nvl 188 R3188 [cyclo-olefinyl(1,6)]Ac-X30-V-E-R-F-X12-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 189 R3189 [m-xylyl(1,6)]Ac-C-A-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Phg-(Lys-C16) 190 R3190 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B20 191 R3191 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-K 192 R3192 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-K-NH2 193 R3193 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-B28 194 R3194 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16)-NH2 195 R3195 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-(Lys-C16) 196 R3196 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-K 197 R3197 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-W-E-Y-P-Chg-K14 198 R3198 [cyclo(1,6)](desamino)C-V-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 199 R3199 [cyclo(1,6)](desamino)C-(D-Ala)-E-R-F-C-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Chg-(Lys-C16) 200 R3200 [cyclo(1,6)]Ac-K-V-E-R-F-D-(N-Me)D-Tbg-Y-azaTrp-E-Y-P-Aib-(Lys-C16) 201

[00268] The R3183 (SEQ ID NO: 184) and R3193 (SEQ ID NO: 194) polypeptides were synthesized according to the amino acid sequences of R3176 (SEQ ID NO: 177), except for the replacement of Nvl-NH2 with Lys. The side chain amino group of the Lys residue was modified with various lipophilic molecules resulting in lipidated polypeptides.

Example 10 Optimization and Testing of C5 Inhibitors

[00269] The polypeptides selected according to Example 3 and shown in Table 3 were tested for their ability to inhibit complement-mediated cell lysis. In addition, were synthesized, and tested, various optimized polypeptides in accordance with the methods of examples 4-8 (see table 4). Optimized polypeptide sequences include sequences obtained by various truncations, deletions, additions and/or substitutions in the compounds R3002 (SEQ ID NO: 3), R3008 (SEQ ID NO: 9) and R3021 (SEQ ID NO: 11) or by the formation of hybrid polypeptides containing combinations of regions selected from any of these three compounds.

Human hemolysis assay (erythrocyte lysis assay using complete human sera)

[00270] The polypeptides listed in Table 3, as well as their optimized derivatives (see Table 4), were evaluated for inhibitory activity using a red blood cell hemolysis assay. Antibody-sensitized sheep erythrocytes (Complement Technology, Tyler TX) were plated at 2.5 x 10 ⁷ cells/well with complete human serum (Complement Technology, Tyler TX) and polypeptides to determine the inhibitory effect of the polypeptides on erythrocyte lysis. Cells were centrifuged for 3 min at 2090g and resuspended in fresh GVB++ buffer (Complement Technology, Tyler TX). Human sera (Complement Technology, Tyler TX) were rapidly thawed at 37° C. and placed on ice and water until diluted in GVB++. Ten 6-fold serial dilutions of the polypeptides (from a 10 mM stock solution in DMSO) were made in DMSO and then added to buffer. 50 μl of each polypeptide dilution was combined with serum and 100 μl of cells in individual wells of a tissue culture treated 96-well microtiter plate (USA Scientific, Ocala, FL) and resuspended by pipetting. Samples were incubated at 37°C for one hour. After incubation, the plates were centrifuged at 2090 g for 2 minutes. 100 μl of the supernatant was transferred to a new plate and the optical density was read at 412 nm. The data were approximated using a logarithmic logistic model to build a dose-response curve and determine the IC ₅₀ . Used in the present description, the term "IC ₅₀ "refers to half the value of the maximum inhibitory concentration, used to indicate the amount of inhibitor needed to reduce a given response or process by half. Test compounds are shown in Table 5.

Table 5. Analyzed compounds

Connection number Avg. IC _fifty (nM) SEQID NO. R3000 >10000 one R3001 67.2 2 R3002 11.9 3 R3003 13.9 four R3004 53.5 5 R3005 66.7 6 R3006 267 7 R3007 314 eight R3008 97 9 R3009 >100000 101 R3010 >100000 102 R3011 112 31 R3012 148.5 36 R3013 344 42 R3014 1420 55 R3015 >3960 63 R3016 >13000 79 R3017 >100000 103 R3018 >5730 71 R3019 1320 54 R3020 24.6 ten R3021 27.5 eleven R3022 >10200 78 R3023 >100000 104 R3024 32.5 21 R3025 47.5 24 R3026 1020 52 R3027 >10000 72 R3028 >10000 73 R3029 18.5 eighteen R3030 83.6 28 R3031 1090 53 R3032 >10000 74 R3033 131 34 R3034 >50000 85 R3035 >50000 86 R3036 >50000 87 R3037 276 39 R3038 140 35 R3039 240 38 R3040 >100000 105 R3041 71.3 26 R3042 >100000 106 R3043 934 fifty R3044 >50000 88 R3045 >100000 107 R3046 >100000 108 R3047 >100000 109 R3048 19.3 19 R3049 >3100 61 R3050 42.9 23 R3051 >100000 110 R3052 >100000 111 R3053 >100000 112 R3054 14.1 17 R3055 10.4 13 R3056 13.8 16 R3057 12.4 fifteen R3058 >10000 75 R3059 2160 57 R3060 161 37 R3061 53.9 25 R3062 89.9 29 R3063 >100000 113 R3064 >100000 114 R3065 394 43 R3066 104 thirty R3067 >10000 76 R3068 >4500 64 R3069 >3670 62 R3070 123 32 R3071 128 33 R3072 26.9 twenty R3073 403 44 R3074 308 41 R3075 >75000 96 R3076 297 40 R3077 81.7 27 R3078 568 47 R3079 7.3 12 R3080 >50000 89 R3081 >100000 115 R3083 >25000 81 R3084 >100000 117 R3086 >50000 91 R3087 >25000 82 R3088 >100000 118 R3089 >15000 80 R3090 >100000 119 R3091 483 46 R3092 >50000 92 R3093 >100000 120 R3094 >100000 121 R3095 >50000 93 R3096 >50000 94 R3097 >100000 122 R3098 >100000 123 R3099 >100000 124 R3100 626 48 R3101 >100000 125 R3102 978 51 R3103 >25000 83 R3104 >2000 56 R3105 >5000 65 R3106 >5000 66 R3107 >75000 97 R3108 >75000 98 R3109 >100000 126 R3110 2940 59 R3111 >5000 67 R3112 >5000 68 R3113 >5000 69 R3114 36.6 22 R3115 2780 58 R3116 441 45 R3117 >10000 77 R3118 >100000 127 R3119 >100000 128 R3120 12.2 fourteen R3121 804 49 R3122 >50000 95 R3123 >100000 129 R3124 >100000 130 R3125 >100000 131 R3126 >3000 60 R3127 >75000 99 R3128 >100000 132 R3129 >100000 133 R3130 >100000 134 R3131 >100000 135 R3132 >100000 136 R3133 >75000 100 R3134 >5000 70 R3135 >25000 84 R3136 >50000 137 R3137 >100000 138 R3138 87.2 139 R3139 97.2 140 R3140 17.9 141 R3141 24.5 142 R3142 44.6 143 R3143 18.6 144 R3144 6.7 145 R3145 39 146 R3146 107 147 R3147 138 148 R3148 8.5 149 R3149 13.6 150 R3150 32 151 R3151 165 152 R3152 eleven 153 R3153 175 154 R3154 592 155 R3155 1530 156 R3156 >10000 157 R3157 84.5 158 R3158 327 159 R3159 7.6 160 R3160 37.1 161 R3161 7 162 R3162 16.5 163 R3163 17 164 R3164 36 165 R3165 18.5 166 R3166 17.5 167 R3167 eleven 168 R3168 7.5 169 R3169 5 170 R3170 4.5 171 R3172 12 173

Example 11 Alternative human hemolysis assay using C5-poor sera

[00271] The polypeptides shown in Table 6 were tested for functional activity in an erythrocyte hemolysis assay using C5-poor human sera and purified human C5, rather than complete human sera. To assess activity, antibody-sensitized sheep erythrocytes (Complement Technology, Tyler TX) were seeded at 2.5×10 ⁷ cells/well with 1.5% C5-poor human serum (Complement Technology, Tyler, TX) and 0.5 nM purified human C5 (Complement Technology, Tyler, TX). Antibody-sensitized sheep erythrocytes were centrifuged for 3 min at 2090g and resuspended in fresh GVB++ buffer (Complement Technology, Tyler, TX). C5-depleted human serum and purified human C5 were rapidly thawed at 37° C. and then stored in ice water, respectively. The stock polypeptide solution (10 mM in DMSO) was serially diluted in DMSO to give 10 6-fold dilutions and then GVB++ was added thereto. 50 µl of each polypeptide dilution was combined with 25 µl of C5-poor serum, 25 µl of purified human C5, and 100 µl of cells in individual wells of a 96-well microtiter plate treated for tissue culture (USA Scientific, Ocala, FL) and resuspended by pipetting. Samples were incubated at 37°C for one hour. After incubation, the plates were centrifuged at 2090 g for 2 minutes. 100 μl of the supernatant was transferred to a new plate and the optical density was read at 412 nm. The data were fitted using a logarithmic logistic model to build a dose-response curve and determine the IC ₅₀ .

Table 6. Analyzed compounds

Connection number Avg. IC _fifty (nM) SEQID NO. R3171 5.67 172 R3173 2.5 174 R3174 2.3 175 R3176 1.1 177 R3177 12 178 R3179 83 180 R3180 29 181 R3181 1496 182 R3182 13 183 R3183 13.25 184 R3184 four 185 R3185 12.5 189 R3186 eighteen 187 R3189 81.5 190 R3190 35.33 191 R3191 2.5 192 R3192 1.5 193 R3193 24 194 R3194 15.5 195 R3195 62.5 196 R3196 3 197 R3197 four 198 R3198 142 199 R3199 112 200 R3200 88.5 201

Example 12 Enzyme ImmunoAssay to Assess C5 Inhibition

[00272] C5 inhibitory activity was assessed by enzyme immunoassay (ELISA). Inhibition of C5a production and membrane attack complex (MAC) were measured using MicroVue ELISA kits (Quidel Corporation, San Diego, CA).

ELISA for C5a

[00273] The supernatant from the human erythrocyte hemolysis assay with compounds R3002 (SEQ ID NO: 3) and R3008 (SEQ ID NO: 9) was diluted 1:50 and analyzed by ELISA for C5a (FIG. 1). Both polypeptides inhibited the formation of C5a. R3002 (SEQ ID NO: 3) had an IC _{50 of} 5.4 nM, R3008 (SEQ ID NO: 9) had an IC _{50 of} 54.5 nM.

ELISA for membrane attack complex (MAC)

[00274] MAC-ELISA was performed on diluted supernatants (1:5) from the human erythrocyte hemolysis assay for R3008 (SEQ ID NO: 9) (FIG. 2). This polypeptide has been shown to inhibit MAC formation with an IC _{50 of} 33 nM.

Example 13 Characterization of Peptidomimetic Binding by Fluorescent Polarization

[00275] Fluorescence polarization (FP) measures binding events in a homogeneous solution (Banks, P. et al., Impact of a red-shifted dye label for high throughput fluorescence polarization assays of G protein-coupled receptors. J Biomol Screen. 2000 Oct;5(5):329-34 and Parker, GJ et al., Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays J Biomol Screen 2000 Apr;5(2 ):77-88). The key concept of FP is that the degree to which a fluorophore polarizes light is inversely proportional to its molecular rotation (Lea, WA et al., Fluorescence polarization assays in small molecule screening. Expert Opin Drug Discov. 2011 Jan;6(1):17 -32), and a fluorophore bound to a much larger target protein rotates more slowly than an unbound fluorophore, resulting in an increase in polarization that can be quantified. FP is increasingly being used in high throughput approaches as a way to measure ligand-target binding (Parker, GJ et al., Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase/phosphatase assays. J Biomol Screen. 2000 Apr;5(2):77-88), to determine the equilibrium dissociation constant (K _D ) (Prystay, L. et al., Determination of equilibrium dissociation constants in fluorescence polarization. J Biomol Screen. 2001 Jun;6(3) :141-50) and detection of potential drug compounds in competitive binding assays (Tian, W. et al., Development of novel fluorescence polarization-based assay for studying the β-catenin/Tcf4 interaction. J Biomol Screen. 2012 Apr;17( 4):530-4).

Materials and methods

[00276] FP was used to screen competitive polypeptide inhibitors of the C5 protein. Sample R3076 (SEQ ID NO: 40) was prepared by incubating the parent R3072 polypeptide (SEQ ID NO: 20) with BODIPY-TMR-X, SE (Life Technologies, Grand Island, NY) in DMF (Sigma, St. Louis, MO) in within 4 hours. The BODIPY-TMR dye was attached to the C-terminal lysine of the protein and the labeled sample was subsequently purified by high performance liquid chromatography.

[00277] The equilibrium dissociation constant (K _D ) for the binding of R3076 (SEQ ID NO: 40) to human C5 protein (Complement Technology, Tyler, TX) was determined by incubating a 25 nM solution of R3076 (SEQ ID NO: 40) while increasing protein concentration C5. Polarization was measured over time until binding reached equilibrium. K _D was determined using GraphPad Prism (using "Saturating Binding Curves, One Site - Specific Binding With Hill Slope" as a fitting curve for determining K _D ). Equilibrium was reached after 10 minutes, with values for K _D , curve slope and maximum binding remaining stable for 60 minutes. The final K _D value of 8.07 nM (standard deviation was 0.53) was determined by averaging the K _D values over the range of 10 to 60 minutes. Based on this information, 25 nM and 50 nM concentrations of R3076 (SEQ ID NO: 40) and C5 protein, respectively, were selected for use in the competitive assay. These concentrations represent the approximate level of protein required for 95% sample binding to C5 protein. R3023 (SEQ ID NO: 104) is a randomly shuffled polypeptide variant of R3002 (SEQ ID NO: 3) and is included in all assays as a negative control.

[00278] Human C5 protein was diluted to 200 nM in assay buffer consisting of TBS (EMD Millipore, Billerica, MA) + 0.005% Triton-X (Sigma, Saint Louis, MO). 10 µl of assay buffer was added to all wells of a black, non-binding, 384-well assay plate (Greiner, Monroe, NC), and 10 µl of diluted C5 protein stock solution was added to experimental and target control wells.

[00279] Sample R3076 (SEQ ID NO: 40) was diluted 1:10 in DMSO (Life Technologies, Grand Island, NY) and 30 μl of this mixture was diluted in 3 ml assay buffer to give a 100 nM working solution. 10 µl of this working solution was then added to each well in the assay plate. The assay plate was incubated at room temperature protected from light for 20 minutes to ensure binding equilibrium was reached.

[00280] The test items listed in Table 7 were serially diluted in DMSO and then assay buffer to give 10 2-fold dilutions and then quickly added to the assay plate in triplicate. The assay plate was incubated in a Paradigm plate reader (Molecular Devices, Sunnyvale, CA) for 60 minutes at 25°C.

[00281] After incubation for 60 minutes, the plate was read using the Paradigm FP protocol (Molecular Devices, Sunnyvale, CA) and the original polarization values were imported into a GraphPad Prism. K _i (using single site K _i curve fitting model, probe concentration = 25 nM, K _D = 8.07 nM, baseline limited to mean 0% binding control) and IC ₅₀ (logarithmic response to inhibitor, 4-Parameter Curve Fit) were defined in GraphPad.

results

[00282] All test subjects were able to compete with the labeled probe for binding to the human C5 protein (FIG. 3, Table 7). R3003 (SEQ ID NO: 4) was the most active polypeptide tested, with a K _i value of 9.54 nM. Binding of R3023 (SEQ ID NO: 104) was not detected even at the highest concentration of the tested polypeptide.

Table 7. Competitive fluorescence polarization data

Connection number SEQID NO K _i nM, exp. one K _i nM, exp. 2 IC _fifty nM, exp 1 IC _fifty nM, exp 2 Avg. K _i , nM Standard deviation K _i Avg. IC _fifty , nM Standard deviation IC _fifty R3003 four 10.39 8.69 72.65 64.06 9.54 1.20 68.36 6.07 R3011 31 73.17 86.91 294.8 261.3 80.04 9.72 278.1 23.69 R3014 55 1405 1585 6064 7579 1495 127.3 6822 1071 R3023 104 >1000 >1000 >1000 >1000 >1000 -- >1000 -- R3043 fifty 866.1 882.1 4332 4122 874.1 11.31 4227 148.5 R3050 23 71.08 57.6 266.9 292.7 64.34 9.53 279.8 18.24

[00283] The data presented in Table 7 was obtained from curve fitting performed using the GraphPad Prism software as described above. Triplicate values were averaged to obtain the points presented in each experiment. Of the polypeptides tested, R3003 (SEQ ID NO: 4) was initially identified by mRNA display selection. The affinity of R3003 (SEQ ID NO: 4) for C5 was confirmed by the results of FP analysis showing low K _i values as well as IC ₅₀ . The inhibitors R3011 (SEQ ID NO: 31) and R3050 (SEQ ID NO: 23) also showed relatively strong affinity for C5. The control polypeptide, R3023 (SEQ ID NO: 104), showed no affinity for C5, while the inhibitors R3014 (SEQ ID NO: 55) and R3043 (SEQ ID NO: 50) showed little affinity.

Example 14 Plasma Compound Stability Analysis

[00284] Compounds were analyzed for stability in human plasma under the following conditions. Human plasma was obtained from Bioreclamation (Westbury, NY) and collected with sodium heparin. The plasma pH was adjusted to pH 7.4. For test compounds, stock solutions were prepared in DMSO at a concentration of 10 mM. Aliquots of solutions in DMSO were injected into 1 ml of plasma, which was prewarmed to 37°C, to a final concentration of the test compound of 10 μm. The tubes were kept in a benchtop THERMOMIXER® (Eppendorf, Hauppauge, NY) throughout the duration of the experiment. Aliquots (100 µl) were taken at each time point and added to the wells of a 96-well plate that had been pre-filled with 300 µl of an acetonitrile solution containing a mixture of internal standards (metoprolol, propranolol and warfarin, each at a concentration of 500 ng/ml). Samples were stored at 4°C until the end of the experiment. After sampling at the end time point, the contents of the plate were mixed and then centrifuged at 3000 rpm for 10 minutes. Aliquots of the supernatant were removed and analyzed by LC-HRAMS. The liquid chromatography parameters are shown in Table 8 and the mass spectrometry parameters are shown in Table 9.

Table 8. Liquid Chromatography Parameters

Column: Luna C18 (Luna, Torrance, CA) 50 mm x 2.0 mm, 3 µm M.P. buffer: Water tank (A): 0.1% acetic acid in water Organic reservoir (B): 0.1% acetic acid in MeOH:MeCN=1:1 Gradient program: Time (min) Flow rate (ml/min) %A %B 0.0 0.3 100 0 5 0.3 0 100 7.5 0.3 0 100 7.6 0.45 100 0 10.5 0.3 100 0 Total run time: 10.5 minutes Autosampler: Agilent 1100 Bin (Agilent, Santa Clara, CA) Injection Loop Volume: 20 µl Injection volume: 10 µl 1st autosampler wash: Methanol/water 1:1; with 0.2% formic acid 2nd autosampler wash: Methanol/2-propanol 1:1; with 0.2% formic acid

Table 9. Mass Spectrometry Parameters

Tool: LTQ Orbitrap XL (Thermo Scientific, St. Louis, MO) positive mode:
Interface: Electrospray, positive mode (+5000V)
High resolution mass spectroscopy Mode: Capillary temperature: 275°C Ion source parameters: Capillary voltage: 47
Shielding gas: 45
Auxiliary gas: 15
Purge gas: 10 Orbitrap analyzer parameters: Scan range 200-2000, resolution = 30000 (full width at the end of the maximum)
Parameters for receiving MS/MS data
Selection Width: 2
Normalized collision energy: 35

[00285] The concentration of test compound R3050 (SEQ ID NO: 23) was determined by comparison with a previously determined calibration curve (Table 10).

Table 10 Stability Profile

Percentage of remaining connection in dynamics (h) 0 h 2 h 4 h 12 h 24 hours Half life (min) 100 108.9 100.4 88 98.1 >1440

[00286] Under these conditions, R3050 (SEQ ID NO: 23) has been shown to be very stable.

Example 15 Polypeptide Variants Containing Tryptophan Analogs

[00287] In some embodiments, the implementation of the polypeptides of the present invention include 7-azatryptophan. In order to determine the importance of this residue in C5 inhibition, amino acid substitution was carried out, where 7-azatryptophan was replaced with natural tryptophan, as well as various other tryptophan analogues, including 5-fluorotryptophan [(5-F)W], 1-methyl-tryptophan [ (1-Me)W], D-tryptophan and 5-methyl-O-tryptophan [(5-MeO)W]. Similar polypeptides with non-tryptophan substitutions were also analyzed.

[00288] Polypeptide variants R3002 (SEQ ID NO: 3) and R3008 (SEQ ID NO: 9) were synthesized and tested for their ability to inhibit erythrocyte lysis as described in Example 10 (Tables 11 and 12). Of the variants tested, all with 7-azatryptophan residue replacement showed a reduced ability to inhibit erythrocyte lysis as indicated by an increase in mean IC ₅₀ values (half maximum inhibitory concentration, a value used to indicate the amount of inhibitor needed to halve a given reaction or process).

Table 11 7-Azatryptophan R3002 Polypeptide Variants (SEQ ID NO: 3) Assayed by Human Hemolysis Assay

Connection number Subsequence Avg. IC _fifty (nM) SEQID NO R3002 Ac-Nvl-C-Y-E-N-Tbg-Y-azaTrp-E-Y-P-Phg-Nvl-NH2 11.9 3 R3041 Ac-Y-E-N-Tbg-Y-W-E-Y-P-Phg-Nvl-NH2 71.3 26 R3094 Ac-Y-E-N-Tbg-Y-(5-MeO)W-E-Y-P-Phg-Nvl-NH2 >100000 121 R3110 Ac-Y-E-N-Tbg-Y-(1-Me)W-E-Y-P-Phg-Nvl-NH2 2,940 59 R3118 Ac-Y-E-N-Tbg-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 >100000 127 R3119 Ac-Y-E-N-Y-(D-Trp)-E-Y-P-Phg-Nvl-NH2 >100000 128 R3128 Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 >100000 132 R3067 Ac-Nvl-S-Y-E-N-Tbg-Y-A-E-Y-P-Chg-Nvl-NH2 >10000 76 R3116 Ac-Nvl-Nvl-Y-E-N-Tbg-Y-(N-Me)W-E-Y-P-Chg-Nvl-NH2 441 45 R3017 [m-xylyl(2,8)]Ac-Nvl-C-Y-E-N-Tbg-Y-C-E-Y-P-Phg-Nvl-NH2 >100000 103 R3129 [m-xylyl(2,8)]Ac-Nvl-C-Y-N-N-Tbg-E-C-E-Y-P-Phg-Tbg-NH2 >100000 133

Table 12 7-Azatryptophan R3008 Polypeptide Variants (SEQ ID NO: 9) Assayed by Human Hemolysis Assay

Connection number Subsequence Avg. IC _fifty (nM) SEQID NO R3008 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-H-C-Nvl-P-Nvl-NH2 97 9 R3088 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(5-F)W-E-Y-(N-Me)S-A-C-Nvl-NH2 >100000 118 R3091 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-E-Y-(N-Me)S-A-C-Nvl-NH2 483 46 R3092 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-F-E-Y-(N-Me)S-A-C-Nvl-NH2 >50000 92 R3109 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(1-Me)W-E-Y-(N-Me)S-A-C-Nvl-NH2 >100000 126 R3131 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-W-Asp(T)-Y-(N-Me)S-H-C-Nvl-NH2 >100000 135 R3034 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-A-E-Y-(N-Me)S-H-C-Nvl-NH2 >50000 85 R3132 [m-xylyl(2,10)]Ac-Nvl-C-Phg-T-(D-Trp)-E-Y-(N-Me)S-H-C-Nvl-NH2 >100000 136

Example 16 Effect of Polypeptide Shortening and Amino Acid Removal Analyzed by Human Hemolysis Assay

[00289] C-terminally truncated variants of the R3021 polypeptide (SEQ ID NO 11) were synthesized and tested using the human hemolysis assay described in Example 10 for their ability to inhibit C5-dependent erythrocyte lysis. Average IC ₅₀ values (half maximum inhibitory concentration, a value used to indicate the amount of inhibitor needed to halve a given reaction or process) for each polypeptide tested are shown in Table 13 _. to inhibition of erythrocyte lysis with tryptophan-deprived variants having the highest IC ₅₀ values.

[00290] In addition, variants of the R3021 polypeptide (SEQ ID NO: 11) with internal amino acid deletions were synthesized and tested for their ability to inhibit C5-dependent erythrocyte lysis according to the method described in Example 10 (see Table 14). Additionally, the N-terminal methionine in these variants was replaced by an acetyl group. The average IC ₅₀ values for each polypeptide tested are shown in Table 14. Interestingly, replacement of the N-terminal methionine [R3048 (SEQ ID NO: 19)] alone with an acetyl group increased the ability of the polypeptide to inhibit erythrocyte lysis. Removal of internal residue D [R3124 (SEQ ID NO: 130)] or internal residues DVY [R3125 (SEQ ID NO: 131) corresponding to residues 8, 9 and 10 in R3021 (SEQ ID NO: 11)] resulted in a decrease in the ability polypeptide to inhibit erythrocyte lysis.

Table 13. C-terminally truncated R3021 polypeptide variants (SEQ ID NO: 11) assayed by human hemolysis assay

Connection number Subsequence Avg. IC _fifty (nM) SEQID NO R3021 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 27.5 eleven R3043 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-NH2 934 fifty R3044 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-NH2 >50000 88 R3045 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-NH2 >100000 107 R3046 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-NH2 >100000 108 R3047 [m-xylyl(2,7)]M-C-V-E-R-F-C-NH2 >100000 109

Table 14 Variants of the R3021 polypeptide (SEQ ID NO: 11) with internal deletion of amino acid residues analyzed by the human hemolysis assay

Connection number Subsequence Avg. IC _fifty (nM) SEQID NO R3021 [m-xylyl(2,7)]M-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 27.5 eleven R3048 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-V-Y-W-E-F-NH2 19.3 19 R3124 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-V-Y-W-E-F-NH2 >100000 130 R3125 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-W-E-F-NH2 >100000 131

Example 17 Incorporation of Albumin Binding Polypeptides

[00291] The polypeptides are conjugated to one or more polypeptides that modulate plasma protein binding. These polypeptides, referred to herein as "albumin-binding polypeptides", are shown in Table 15.

Table 15 Albumin binding polypeptides

Albumin-binding polypeptide sequences SEQID NO Ac-R-L-I-E-D-I-C-L-I-P-R-W-G-C-L-W-E-D-D-NH2 202 Q-R-L-M-E-D-I-C-L-P-R-W-G-C-L-W-E-D-D-F-NH2 203 Ac-Q-R-L-I-E-D-I-C-L-P-R-W-G-C-L-W-E-D-D-F-NH2 204

[00292] Albumin-binding polypeptides are cyclized by the formation of disulfide bonds between cysteine residues. In some embodiments, albumin-binding polypeptides are conjugated at their N- or C-terminus such that they have slightly different structures (eg, lack of an acetyl group).

Example 18 Incorporation of Cell Penetrating Polypeptides

[00293] The polypeptides are conjugated to a polypeptide that is able to enter cells. These polypeptides are listed in Table 16 and are described in Milletti, F., Cell-penetrating polypeptides: classes, origin, and current landscape. Drug Disc Today. 2012 Aug;17(15-16):850-60.

Table 16 Cell Penetrating Polypeptides

Cell-penetrating polypeptides SEQID NO R-K-K-R-R-R-E-S-R-K-K-R-R-R-E-S 205 R-K-K-R-R-Q-R-R-R 206 R-Q-I-K-I-W-F-Q-N-R-R-M-K-W-K-K 207 A-A-V-L-L-P-V-L-L-A-A-P 208 V-P-T-L-K 209 P-L-I-L-L-R-L-L-R-G-Q-F 210

Example 19 Analysis of Polypeptide Mixtures Containing Amino Acid Stereoisomers

[00294] The R3136 (SEQ ID NO: 137) and R3137 (SEQ ID NO: 138) polypeptides were synthesized according to the amino acid sequences R3085 (SEQ ID NO: 90) and R3082 (SEQ ID NO: 116), respectively, except replacing Phg in each of them with D-Phg (see Table 17). Compositions containing either R3136 (SEQ ID NO: 137) and R3085 (SEQ ID NO: 90) or R3137 (SEQ ID NO: 138) and R3082 (SEQ ID NO: 116) were analyzed for their ability to inhibit erythrocyte lysis in the assay hemolysis in humans described in Example 10. The composition containing R3136 (SEQ ID NO: 137) and R3085 (SEQ ID NO: 90) gave an average IC ₅₀ (nM) > 50,000, while the composition containing R3137 (SEQ ID NO: 90) : 138) and R3082 (SEQ ID NO: 116) gave an average IC ₅₀ (nM) > 100,000.

Table 17. Compounds used in mixtures of polypeptides with amino acid stereoisomers

Connection number Subsequence SEQID NO. R3136 [m-xylyl(2,10)]heptanoyl-Nvl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 137 R3137 [m-xylyl(1,9)]heptanoyl-C-(D-Phg)-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 138 R3085 [m-xylyl(2,10)]heptanoyl-Nvl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 90 R3082 [m-xylyl(1,9)]heptanoyl-C-Phg-T-azaTrp-E-Y-(N-Me)S-A-C-Nvl-NH2 116

Example 20 Primate Pharmacokinetic Studies

[00295] Pharmacokinetic studies were performed in primates (except humans) using the compounds listed in table 18. In the table "Comp." refers to the connection, and "Average" refers to the average.

Table 18. Compounds tested in studies in vivo

conn. no. Subsequence Avg.
IC _fifty SEQID NO. R3152 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl-NH2 16.4 153 R3201 [m-xylyl(1,6)]Ac-C-V-E-R-F-C-D-Tbg-Y-azaTrp-E-Y-P-Chg-Nvl 7.7 211

[00296] The plasma concentration of the R3152 polypeptide (SEQ ID NO: 153) was determined in cynomolgus monkeys after a single intravenous (IV) dose. Three males received 3 mg/kg of the polypeptide and the plasma concentration of the polypeptide was determined by LC-MS/MS after acetonitrile precipitation and extraction on a Sirocco Protein Precipitation plate (Waters Corporation, Milford, MA). Pharmacokinetic parameters (PK) were calculated from the time curve (see Figure 4) of pooled plasma concentrations of R3152 (SEQ ID NO: 153) determined immediately post-dose and up to 48 hours post-dose. Plasma drug levels fell rapidly during the initial distribution phase (<1 hour) and then remained constant and detectable for 48 hours. R3152 (SEQ ID NO: 153) had a mean terminal half-life of 10.9 ± 0.8 h. The mean clearance rate was 0.129 ± 0.0122 L/h/kg, which is approximately 5% of the blood flow in the liver of a typical monkey (2 .6 l/h/kg). The mean volume of distribution was 1.49±0.152 L/kg, approximately twice the total body water for a typical monkey (0.7 L/kg). The mean AUC∞ was 23319±2120 h*ng/ml.

[00297] R3152 (SEQ ID NO: 153) binds with high affinity to primate C5 protein and blocks complement pathways by preventing the formation of C5a and C5b products and the production of the multimeric membrane attack complex (MAC). Inhibition of Complement-mediated MAC formation in plasma samples from the above pharmacokinetic study using a conventional ex vivo assay (see human hemolysis assay described in Example 10) in which plasma was diluted 1:100 and incubated with activated sheep erythrocytes (Complement Technology, Tyler , TX). At each time point, hemolytic activity was determined as an indicator of active serum complement (see Figure 4). In plasma containing >200 ng/ml R3152 (SEQ ID NO: 153), there is a clear inhibition of complement-mediated hemolysis, indicating blockade of MAC formation. Exogenous R3152 (SEQ ID NO: 153) added to normal cynomolgus monkey plasma has an IC _{50 of} 2-20 ng/mL. Hemolytic activity returns to normal levels 48 hours post-dose, after which the plasma level of R3152 (SEQ ID NO: 153) falls below 100 ng/ml.

Example 21 Pharmacokinetic Studies in Rats

[00298] The dose of R3152 (SEQ ID NO: 153) was delivered via intravenous (IV) or subcutaneous (SC) administration to male rats at 2 and 30 mg/kg, respectively (FIG. 5). After IV administration, R3152 (SEQ ID NO: 153) was monitored by LC-MS/MS after precipitation with acetonitrile and extraction on a Sirocco Protein Precipitation plate (Waters Corporation, Milford, MA) as described above. Pharmacokinetic (PK) parameters were calculated from the combined plasma concentration time curve (FIG. 5) of R3152 (SEQ ID NO: 153) and its equally active C-terminally deamidated metabolite, R3201 (SEQ ID NO: 211).

[00299] R3152 (SEQ ID NO: 153)/R3201 (SEQ ID NO: 211) showed a rapid distribution phase followed by a slow elimination with t _1/2 =5.3 hours. A similar elimination rate was observed after SC administration of 30 mg/kg with approximately 65% dose bioavailability based on AUC. The T _max of 4 hours and the prolonged action of the drug observed with SC administration allowed for a wider coverage of therapeutic plasma concentration. Because R3152 (SEQ ID NO: 153) and R3201 (SEQ ID NO: 211) do not bind to rat C5, very little inhibitory activity was observed in the ex vivo hemolysis assay.

[00300] Lipidized and non-lipidated compounds R3183 (SEQ ID NO: 184) and R3176 (SEQ ID NO: 177), respectively, were evaluated for pharmacokinetic properties in male Sprague-Dawley rats following intravenous or subcutaneous administration. Figure 6 shows the results. The left panel of Figure 6 shows the results for male Sprague-Dawley rats (n=3) administered the polypeptides intravenously at a single dose of 2 mg/kg. Blood samples were collected at the indicated time points, plasma was isolated and analyzed for the content of the specified compound using LC-MS. Black circles: R3176 (SEQ ID NO: 177) (non-lipidated compound); open circles: R3183 (SEQ ID NO: 184) (C16 lipidated compound). The right panel of Figure 6 shows the results for male Sprague-Dawley rats (n=3) administered the polypeptides subcutaneously at a single dose of 15 mg/kg. Blood samples were collected at the indicated time points, plasma was isolated and analyzed for the content of the specified compound using LC-MS. Black circles: R3176 (SEQ ID NO: 177) (non-lipidated compound); open circles: R3183 (SEQ ID NO: 184) (C16 lipidated compound). Lipidation resulted in an increase in compound exposure, which was assessed by determining the area under the curve (AUC), which increased 2.1-fold with intravenous and 2.7-fold with subcutaneous administration.

Example 22 Inhibition of Hemolysis in the Thrombin-Induced Complement Pathway

[00301] Thrombin can induce complement activity by cleaving C5 to C5 _T , which will then be cleaved to C5a and C5b _T . C5b _T , like C5b, will bind to C6 and the rest of the terminal components of the complement pathway, C7, C8, and C9, leading to the formation of a membrane attack complex (MAC) causing erythrocyte lysis (Krisinger, et al., (2014). Blood. 120 (8):1717-1725). Therefore, R3183 and an anti-C5 monoclonal antibody similar to ECULIZUMAB® were tested for their ability to inhibit hemolysis via the thrombin-induced complement pathway.

[00302] To assess inhibitor activity, C5 (Complement Technology, Tyler, TX) was added to reach a concentration of 400 nM, and the sample was incubated with C6 at a final concentration of 600 nM (Complement Technology, Tyler, TX) and thrombin at a concentration of 50 nM (Enzyme Research Laborites, South Bend, IN) at 37° C. for 30 minutes, in the presence of R3183 or an anti-C5 monoclonal antibody similar to ECULIZUMAB®, or in the absence of an inhibitor. The reaction was stopped with the addition of hirudin to 150 nM (Cell Sciences, Canton, MA) in GVB+EDTA buffer (Complement Technology, Tyler, TX) and incubated for 5 minutes at room temperature. These diluted samples were mixed with antibody-sensitized sheep erythrocytes (Complement Technology, Tyler, TX) in a 96-well microtiter plate (USA Scientific, Ocala, FL) and incubated at 37° C. for 5 minutes. C7 (Complement Technology, Tyler, TX) was then added to the wells to reach a concentration of 15 nM and the plate was returned to 37° C. for 15 minutes. Then complex C8 (10 nM; Complement Technology, Tyler, TX) and C9 (25 nM; Complement Technology, Tyler, TX) were added to the assay mixture and the samples were incubated for 30 minutes at 37°C. After incubation, the plate was centrifuged at 1000g, 100 μl of the supernatant was transferred to a new microtiter plate, and the absorbance was read at 412 nm. The data obtained are presented in Fig.7. R3183 was found to inhibit hemolysis via the thrombin-induced complement pathway at concentrations above 6 ng/mL, whereas anti-C5 monoclonal antibodies did not.

--->

SEQUENCE LIST

<110> RA PHARMACEUTICALS, INC.

<120> MODULATION OF COMPLEMENT ACTIVITY

<130> 2011.1005PCT

<140> PCT/US2015/035473

<141> 2015-06-12

<150> 62/108.772

<151> 2015-01-28

<150> 62/077.460

<151> 2014-11-10

<150> 62/011.368

<151> 2014-06-12

<160> 212

<170>PatentIn version 3.5

<210> 1

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 1

Val Cys Tyr Lys Asn Tyr His Trp Glu Tyr Pro Gly Tyr

1 5 10

<210> 2

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<221> Modified remainder

<222> (13)..(13)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 2

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Gly Val Ser

1 5 10

<210> 3

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 3

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 4

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<223> C-terminal NH2

<400> 4

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Pro

1 5 10

<210> 5

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 5

Val Cys Tyr Asn Asn Gly Glu Trp Glu Tyr Pro Gly Gly

1 5 10

<210> 6

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (5)..(5)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Nvl

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<223> C-terminal NH2

<400> 6

Val Cys Tyr Trp Gly Gly Val Trp Glu Tyr Pro Gly Pro

1 5 10

<210> 7

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(9)..(9)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<221> Modified remainder

<222> (11)..(11)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 7

Tyr Glu Asn Gly Tyr Trp Glu Tyr Gly Val Ser

1 5 10

<210> 8

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Tbg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> 7-Azatryptophan

<220>

<223> C-terminal NH2

<400> 8

Val Cys Lys Glu Gly Tyr Cys Ser Gly Lys Trp Glu Tyr

1 5 10

<210> 9

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 9

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val Pro Val

1 5 10

<210> 10

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 10

Met Cys Ser Glu Arg Tyr Cys Glu Val Arg Trp Glu Tyr

1 5 10

<210> 11

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 11

Met Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Phe

1 5 10

<210> 12

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 12

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 13

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 13

Val Ser Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 14

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222> (5)..(5)

<223> (N-Me)Asn

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 14

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 15

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Tbg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Phg

<220>

<221> Modified remainder

<222> (16)..(16)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 15

Met Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 16

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 16

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 17

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 17

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 18

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<223> C-terminal NH2

<400> 18

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly

1 5 10

<210> 19

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 19

Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Phe

1 5 10

<210> 20

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 20

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val Lys

1 5 10

<210> 21

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Tbg

<220>

<221> Modified remainder

<222>(7)..(7)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Phg

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 21

Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 22

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222> (3)..(3)

<223> (N-Me)Tyr

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 22

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 23

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 23

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 24

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 24

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 25

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 25

Val Ser Tyr Glu Ala Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 26

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 26

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 27

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal (PEG2000)NH2

<400> 27

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val Lys

1 5 10

<210> 28

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<223> C-terminal NH2

<400> 28

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro

1 5 10

<210> 29

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 29

Val Ser Tyr Glu Asn Ala Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 30

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 30

Val Ser Tyr Glu Asn Gly Ala Trp Glu Tyr Pro Gly Val

1 5 10

<210> 31

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 31

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val Pro

1 5 10

<210> 32

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 32

Val Ser Tyr Glu Asn Gly Tyr Trp Glu Tyr Ala Gly Val

1 5 10

<210> 33

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 33

Val Ser Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Ala Val

1 5 10

<210> 34

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 34

Val Cys Gly Ala Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 35

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 35

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 36

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 36

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 37

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 37

Val Ser Tyr Ala Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 38

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 38

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Ala

1 5 10

<210> 39

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ala

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 39

Val Cys Gly Thr Trp Glu Tyr Ala His Cys Val

1 5 10

<210> 40

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal (BODIPY-TMR-X)NH2

<400> 40

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val Lys

1 5 10

<210> 41

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Tyr(OMe)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 41

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 42

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 42

Val Cys Gly Thr Trp Glu Tyr Ser His Cys

1 5 10

<210> 43

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 43

Val Cys Gly Thr Trp Glu Tyr Pro His Cys Val

1 5 10

<210> 44

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Phe(4-F)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 44

Val Cys Gly Thr Trp Glu Phe Ser His Cys Val

1 5 10

<210> 45

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Trp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 45

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 46

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 46

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 47

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal PEG2000

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 47

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 48

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 48

Val Cys Gly Thr Trp Glu Phe Ser Ala Cys Val

1 5 10

<210> 49

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> (N-Me)Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 49

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 50

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 50

Met Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu

1 5 10

<210> 51

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 51

Val Cys Gly Thr Trp Glu Tyr Pro His Cys Val

1 5 10

<210> 52

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Tbg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Phg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 52

Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 53

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 53

Ala Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 54

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(14)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 54

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val Cys

1 5 10

<210> 55

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 55

Cys Gly Thr Trp Glu Tyr Ser His Cys Val Pro Val

1 5 10

<210> 56

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> HomoCys

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 56

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 57

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 57

Val Ser Ala Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 58

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222> (4)..(4)

<223> (N-Me)Glu

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 58

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 59

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> (1-Me)Trp

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 59

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 60

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 60

Val Cys Tyr Asn Asn Gly Glu Trp Glu Cys Pro Gly Gly

1 5 10

<210> 61

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 61

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 62

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 62

Val Ser Tyr Glu Asn Gly Tyr Trp Glu Ala Pro Gly Val

1 5 10

<210> 63

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 63

Cys Gly Thr Trp Glu Tyr Ser His Cys

fifteen

<210> 64

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 64

Val Ser Tyr Glu Asn Gly Tyr Trp Ala Tyr Pro Gly Val

1 5 10

<210> 65

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> HomoCys

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 65

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 66

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> HomoCys

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 66

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 67

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> other signs

<222> (4)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 67

Val Thr Gly Cys Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 68

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223>Nle

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 68

Leu Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 69

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Nvl

<220>

<221> other signs

<222> (3)..(11)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Phg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(9)..(9)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 69

Tyr Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 70

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (3-Cl-Phe)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 70

Val Cys Gly Thr Trp Glu Phe Ser Ala Cys Val

1 5 10

<210> 71

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 71

Val Cys Tyr Glu Asn Gly Tyr Trp Glu Cys Pro Gly Val

1 5 10

<210> 72

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Tbg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Phg

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 72

Asn Gly Tyr Trp Glu Tyr Pro Gly Val

fifteen

<210> 73

<211> 8

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Tbg

<220>

<221> Modified remainder

<222> (3)..(3)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 73

Gly Tyr Trp Glu Tyr Pro Gly Val

fifteen

<210> 74

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 74

Val Cys Ala Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 75

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Chg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 75

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 76

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 76

Val Ser Tyr Glu Asn Gly Tyr Ala Glu Tyr Pro Gly Val

1 5 10

<210> 77

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (10)..(10)

<223> (N-Me)Tyr

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 77

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 78

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 78

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val Pro Val

1 5 10

<210> 79

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Tbg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<223> C-terminal NH2

<400> 79

Cys Gly Tyr Trp Glu Tyr Ser His Cys

fifteen

<210> 80

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Chg

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 80

Gly Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 81

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 81

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 82

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> (2-OMe)Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 82

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 83

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (2)..(2)

<223> HomoCys

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 83

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 84

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222>(9)..(9)

<223> D-ala

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 84

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 85

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 85

Val Cys Gly Thr Ala Glu Tyr Ser His Cys Val

1 5 10

<210> 86

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 86

Val Cys Gly Thr Trp Ala Tyr Ser His Cys Val

1 5 10

<210> 87

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 87

Val Cys Gly Thr Trp Glu Ala Ser His Cys Val

1 5 10

<210> 88

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 88

Met Cys Val Glu Arg Phe Cys Asp Val Tyr Trp

1 5 10

<210> 89

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 89

Val Cys Gly Thr Trp Glu Tyr Ser Cys Val

1 5 10

<210> 90

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal heptanoyl

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 90

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 91

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (5)..(13)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 91

Val Ser Tyr Glu Cys Gly Tyr Trp Glu Tyr Pro Gly Cys Val

1 5 10

<210> 92

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 92

Val Cys Gly Thr Phe Glu Tyr Ser Ala Cys Val

1 5 10

<210> 93

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (homo)Phe

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 93

Val Cys Gly Thr Trp Glu Phe Ser Ala Cys Val

1 5 10

<210> 94

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Aib

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 94

Val Cys Gly Xaa Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 95

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Tiq

<220>

<221> Modified remainder

<222>(5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 95

Val Cys Xaa Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 96

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(11)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (4)..(4)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Phg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 4-F-(N-Me)Phe

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222>(9)..(9)

<223> 4-F-(N-Me)Phe

<220>

<223> C-terminal NH2

<400> 96

Val Cys Tyr Ser Gly Phe Ser His Phe Gly Cys

1 5 10

<210> 97

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (2)..(2)

<223> HomoCys

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> HomoCys

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 97

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 98

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (2)..(2)

<223> HomoCys

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> HomoCys

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 98

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 99

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 99

Val Cys Tyr Asn Asn Gly Glu Trp Glu Cys Pro Gly Gly

1 5 10

<210> 100

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> D-ala

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 100

Val Cys Gly Ala Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 101

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 101

Val Cys Tyr Glu Gly Gly Tyr Trp Glu Cys Val Pro Val

1 5 10

<210> 102

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(13)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (10)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 102

Val Cys Tyr Glu Gly Gly Tyr Trp Glu Val Val Pro Cys

1 5 10

<210> 103

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(8)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 103

Val Cys Tyr Glu Asn Gly Tyr Cys Glu Tyr Pro Gly Val

1 5 10

<210> 104

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Phg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Tbg

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Nvl

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 104

Tyr Pro Tyr Cys Gly Trp Gly Glu Val Asn Tyr Val Glu

1 5 10

<210> 105

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<400> 105

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val Pro Val

1 5 10

<210> 106

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 106

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 107

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 107

Met Cys Val Glu Arg Phe Cys Asp Val Tyr

1 5 10

<210> 108

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 108

Met Cys Val Glu Arg Phe Cys Asp Val

fifteen

<210> 109

<211> 7

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (2)..(7)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 109

Met Cys Val Glu Arg Phe Cys

fifteen

<210> 110

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(11)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (4)..(4)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222>(5)..(5)

<223> Phg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 4-F-(N-Me)Phe

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222>(9)..(9)

<223> 4-F-(N-Me)Phe

<220>

<221> Modified remainder

<222> (10)..(10)

<223> (N-Me)Gly

<220>

<223> C-terminal NH2

<400> 110

Val Cys Tyr Ser Gly Phe Ser His Phe Gly Cys

1 5 10

<210> 111

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Phg

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Gly

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> (N-Me)Ala

<220>

<223> C-terminal NH2

<400> 111

Val Cys Tyr Gly Gly Asn Gly Leu Cys Gly Ala

1 5 10

<210> 112

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(11)

<223> Bicyclic

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Phg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222>(9)..(9)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 112

Val Cys Cys Asn Gly Gly Cys Gly Ser Cys Gly

1 5 10

<210> 113

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Tbg

<220>

<221> Modified remainder

<222> (3)..(3)

<223> 7-Azatryptophan

<220>

<223> C-terminal NH2

<400> 113

Gly Tyr Trp Glu Tyr

fifteen

<210> 114

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (2)..(2)

<223> 7-Azatryptophan

<220>

<223> C-terminal NH2

<400> 114

Tyr Trp Glu Tyr Pro

fifteen

<210> 115

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Glu

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 115

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 116

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal heptanoyl

<220>

<221> other signs

<222> (1)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 116

Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 117

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 117

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 118

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> (5-F)Trp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 118

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 119

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 119

Val Cys Phe Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 120

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> D-Chg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 120

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 121

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> (5-MeO)Trp

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 121

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 122

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 122

Val Cys Gly Thr Trp Asp Tyr Ser Ala Cys Val

1 5 10

<210> 123

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 123

Val Cys Gly Thr Trp Gln Tyr Ser Ala Cys Val

1 5 10

<210> 124

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 124

Val Cys Gly Thr Trp Asn Tyr Ser Ala Cys Val

1 5 10

<210> 125

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 125

Val Cys Gly Thr Trp Glu Tyr Ser His Gly Cys Val

1 5 10

<210> 126

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> 1-Me-Trp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 126

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 127

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> D-Trp

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 127

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 128

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (5)..(5)

<223> D-Trp

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Phg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 128

Tyr Glu Asn Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 129

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Tbg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222>(7)..(7)

<223> D-Glu

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Phg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 129

Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 130

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 130

Cys Val Glu Arg Phe Cys Val Tyr Trp Glu Phe

1 5 10

<210> 131

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 131

Cys Val Glu Arg Phe Cys Trp Glu Phe

fifteen

<210> 132

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 132

Val Cys Tyr Asn Asn Gly Glu Cys Glu Tyr Pro Gly Gly

1 5 10

<210> 133

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(8)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Phg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 133

Val Cys Tyr Asn Asn Gly Glu Cys Glu Tyr Pro Gly Gly

1 5 10

<210> 134

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(2)

<223> Nvl

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tbg

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Tyr

<220>

<221> Modified remainder

<222>(8)..(8)

<223> 7-Azatryptophan

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Chg

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 134

Val Val Tyr Glu Asn Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 135

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Asp(T)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 135

Val Cys Gly Thr Trp Xaa Tyr Ser His Cys Val

1 5 10

<210> 136

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> D-Trp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 136

Val Cys Gly Thr Trp Glu Tyr Ser His Cys Val

1 5 10

<210> 137

<211> 11

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal heptanoyl

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Nvl

<220>

<221> other signs

<222> (2)..(10)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (3)..(3)

<223> D-Phg

<220>

<221> Modified remainder

<222> (5)..(5)

<223> azaTrp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (11)..(11)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 137

Val Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 138

<211> 10

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal heptanoyl

<220>

<221> other signs

<222> (1)..(9)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> D-Phg

<220>

<221> Modified remainder

<222> (4)..(4)

<223> azaTrp

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Ser

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 138

Cys Gly Thr Trp Glu Tyr Ser Ala Cys Val

1 5 10

<210> 139

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 139

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Phe

1 5 10

<210> 140

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Tbg

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 140

Cys Gly Glu Arg Phe Cys Asp Gly Tyr Trp Glu Phe

1 5 10

<210> 141

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 141

Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Tyr Pro

1 5 10

<210> 142

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<223> C-terminal NH2

<400> 142

Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Phe Pro

1 5 10

<210> 143

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<223> C-terminal NH2

<400> 143

Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Tyr Pro

1 5 10

<210> 144

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 144

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro

1 5 10

<210> 145

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 145

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 146

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 146

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 147

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (2)..(2)

<223> Tbg

<220>

<223> C-terminal NH2

<400> 147

Cys Gly Glu Arg Phe Cys Asp Val Tyr Trp Glu Phe

1 5 10

<210> 148

<211> 13

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Propargyl-Gly

<220>

<223> C-terminal NH2

<400> 148

Cys Val Glu Arg Phe Cys Asp Val Tyr Trp Glu Phe Gly

1 5 10

<210> 149

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 149

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 150

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 150

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 151

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 151

Cys Val Ala Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 152

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 152

Cys Val Ala Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 153

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 153

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 154

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 154

Cys Val Glu Ala Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 155

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 155

Cys Val Glu Ala Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 156

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 156

Cys Val Glu Arg Ala Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 157

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 157

Cys Val Glu Arg Ala Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 158

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 158

Cys Val Glu Arg Phe Cys Ala Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 159

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 159

Cys Val Glu Arg Phe Cys Ala Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 160

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (deamino)Cys

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 160

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 161

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (deamino)Cys

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 161

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 162

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<223> C-terminal NH2

<400> 162

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 163

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> D-Phg

<220>

<223> C-terminal NH2

<400> 163

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 164

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 164

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 165

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C12

<220>

<223> C-terminal NH2

<400> 165

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 166

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C10

<220>

<223> C-terminal NH2

<400> 166

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 167

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C8

<220>

<223> C-terminal NH2

<400> 167

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 168

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (alpha-methyl)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 168

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 169

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Asp(T)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 169

Cys Val Glu Arg Phe Cys Xaa Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 170

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 170

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 171

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<400> 171

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 172

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C12

<400> 172

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 173

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<220>

<223> C-terminal NH2

<400> 173

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 174

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 174

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 175

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Asp(T)

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 175

Lys Val Glu Arg Phe Asp Xaa Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 176

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> N-epsilon-(PEG2-gamma-glutamic acid-N-alpha-octadecanedioic acid) lysine

<400> 176

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 177

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 177

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 178

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 178

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Trp Pro Gly Val

1 5 10 15

<210> 179

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> (homo)Phe

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 179

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Phe Pro Gly Val

1 5 10 15

<210> 180

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> (m-Cl-homo)Phe

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 180

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Phe Pro Gly Val

1 5 10 15

<210> 181

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> 2Nal

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 181

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Ala Pro Gly Val

1 5 10 15

<210> 182

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> (3-aminomethyl)Phe

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 182

Cys Val Glu Arg Phe Cys Asp Gly Tyr Phe Glu Tyr Pro Gly Val

1 5 10 15

<210> 183

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclo-triazolyl bond between residues

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (S)-2-amino-5-azidopentanoic acid

<220>

<221> Modified remainder

<222>(6)..(6)

<223> (S)-2-aminopent-4-ic acid

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 183

Xaa Val Glu Arg Phe Xaa Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 184

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 184

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 185

<211> 14

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(5)

<223> Cyclo-thioalkyl bond between residues

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Chloroacetic acid-Val

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Tbg

<220>

<221> Modified remainder

<222>(9)..(9)

<223> azaTrp

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Chg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Nvl

<400> 185

Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10

<210> 186

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(7)..(7)

<223>Cle

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 186

Cys Val Glu Arg Phe Cys Leu Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 187

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Ac-pyran

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 187

Cys Val Glu Arg Phe Cys Xaa Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 188

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> (3-aminomethyl)Phe

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 188

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Phe Pro Gly Val

1 5 10 15

<210> 189

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclo-olefinyl bond between residues

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (S)-2-Aminohept-6-enoic acid

<220>

<221> Modified remainder

<222>(6)..(6)

<223> (S)-2-aminopent-4-enoic acid

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 189

Xaa Val Glu Arg Phe Xaa Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 190

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Phg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 190

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 191

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> N-epsilon-(PEG2-gamma-glutamic acid-N-octadecandionic acid) lysine

<400> 191

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 192

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<400> 192

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 193

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<223> C-terminal NH2

<400> 193

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 194

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> N-epsilon-(PEG24-gamma-glutamic acid-N-alpha-hexadecanoyl)-lysine

<400> 194

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 195

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<220>

<223> C-terminal NH2

<400> 195

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 196

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 196

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 197

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<400> 197

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 198

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> N-epsilon-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-

3-methylbutyl-L-lysine

<400> 198

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 199

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (deamino)Cys

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 199

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 200

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222> (1)..(1)

<223> (deamino)Cys

<220>

<221> Modified remainder

<222> (2)..(2)

<223> D-ala

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 200

Cys Ala Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Lys

1 5 10 15

<210> 201

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Cyclic

<220>

<221> Modified remainder

<222>(7)..(7)

<223> (N-Me)Asp

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Aib

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Lys-C16

<400> 201

Lys Val Glu Arg Phe Asp Asp Gly Tyr Trp Glu Tyr Pro Xaa Lys

1 5 10 15

<210> 202

<211> 19

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<223> C-terminal NH2

<400> 202

Arg Leu Ile Glu Asp Ile Cys Leu Ile Pro Arg Trp Gly Cys Leu Trp

1 5 10 15

Glu Asp Asp

<210> 203

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> C-terminal NH2

<400> 203

Gln Arg Leu Met Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp

1 5 10 15

Glu Asp Asp Phe

twenty

<210> 204

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<223> C-terminal NH2

<400> 204

Gln Arg Leu Ile Glu Asp Ile Cys Leu Pro Arg Trp Gly Cys Leu Trp

1 5 10 15

Glu Asp Asp Phe

twenty

<210> 205

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 205

Arg Lys Lys Arg Arg Arg Glu Ser Arg Lys Lys Arg Arg Arg Glu Ser

1 5 10 15

<210> 206

<211> 9

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 206

Arg Lys Lys Arg Arg Gln Arg Arg Arg

fifteen

<210> 207

<211> 16

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 207

Arg Gln Ile Lys Ile Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys

1 5 10 15

<210> 208

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 208

Ala Ala Val Leu Leu Pro Val Leu Leu Ala Ala Pro

1 5 10

<210> 209

<211> 5

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 209

Val Pro Thr Leu Lys

fifteen

<210> 210

<211> 12

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<400> 210

Pro Leu Ile Leu Leu Arg Leu Leu Arg Gly Gln Phe

1 5 10

<210> 211

<211> 15

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> N-terminal Ac

<220>

<221> other signs

<222> (1)..(6)

<223> Bridge element between residues

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Tbg

<220>

<221> Modified remainder

<222> (10)..(10)

<223> azaTrp

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Chg

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Nvl

<400> 211

Cys Val Glu Arg Phe Cys Asp Gly Tyr Trp Glu Tyr Pro Gly Val

1 5 10 15

<210> 212

<211> 20

<212> Protein

<213> Artificial sequence

<220>

<223> Artificial sequence description: synthetic peptide

<220>

<223> The N-terminus may be H, an acetyl group, an acyl group containing

straight or branched, saturated or unsaturated hydrocarbon chain

length from 1 to 20 carbon atoms, heptanoyl group, amide,

carbamate, urea, PEG or hydroxyalkyl starch

<220>

<221> Modified remainder

<222> (1)..(1)

<223> Met, Nvl or not present

<220>

<221> Modified remainder

<222> (2)..(2)

<223> (S)-2-amino-5-azidopentanoic acid, (S)-2-aminohept-6-enoic acid,

4-aminobutyric acid, 5-aminovaleric acid, 5-aminocaproic

acid, ornithine, Lys, homolysin, Glu, Asp, 3-thiopropionic acid,

Cys or not present

<220>

<221> Modified remainder

<222> (3)..(3)

<223> Ala, D-Ala, tertbutyl-Gly, Lys, Ser, Cys, Val or not present

<220>

<221> Modified remainder

<222> (4)..(4)

<223> Ala, Nvl, Val, Glu or not present

<220>

<221> Modified remainder

<222> (5)..(5)

<223> Ala, Cys, Arg, Ser, Glu, Phg, Nvl or not present

<220>

<221> Modified remainder

<222>(6)..(6)

<223> Tyr, Arg, Cys, Phe, N-methyltyrosine, Ala or not present

<220>

<221> Modified remainder

<222>(7)..(7)

<223> Glu, N-methylglutamic acid, Chg, Lys, Tyr, Pro,

N-methylserine, tert-butylglycine, Val, norleucine, Nvl,

7-Azatryptophan, Asn, Asp, (S)-2-aminopent-4-ic acid,

(S)-2-aminopent-4-enoic acid, Cys, Ala or not present

<220>

<221> Modified remainder

<222>(8)..(8)

<223> Asn, N-methyl-Asn, N-methyl-Gly, N-methyl-Ser, homo-Cys, Thr,

Tyr, Phg, Tbg, alpha-methyl L-Asp, (S)-2-amino-3-(1H-tetrazole-

5-yl)propionic acid, N-methyl-Asp, Cle, 4-amino-tetrahydro-

pyran-4-carboxylic acid, Arg, Glu, Asp, Cys, Ala or not present

<220>

<221> Modified remainder

<222>(9)..(9)

<223> Tbg, Phg, D-Phg, Chg, D-Chg, 1,2,3,4-tetrahydroisoquinoline-

1-carboxylic acid, Tyr, Tbg, Asn, Cys, N-methyl-4-fluoro-

phenylalanine, 2-O-methyl-Phg, Phe, Val, Ala or not present

<220>

<221> Modified remainder

<222> (10)..(10)

<223> Tyr, N-methyltyrosine, Thr, Glu, Nvl, Lys, Ala, D-Ala, His,

Cys, Phg, N-methylserine, N-methylglycine, aminoisobutyric

acid or Arg

<220>

<221> Modified remainder

<222> (11)..(11)

<223> 3-aminomethyl-L-phenylalanine, 7-azatryptophan, N-methyltryptophan,

1-methyltryptophan, 5-fluorotryptophan, Phe,

D-Trp, 5-methyl-O-tryptophan, Ala, His, Leu, Tbg, Cys or Trp

<220>

<221> Modified remainder

<222> (12)..(12)

<223> Glu, D-Glu, N-methyl-glutamic acid, Asn, Asp, Gln, Tbg,

Cys, N-methyl-4-fluorophenylalanine, N-methylserine,

(S)-2-amino-3-(1H-tetrazol-5-yl)propionic acid or Ala

<220>

<221> Modified remainder

<222> (13)..(13)

<223> Trp, homo-Phe, meta-chloro-homo-Phe, 2-naphthylalanine,

3-aminomethyl-L-Phe, Tyr, N-methyl-Tyr, Cys, Phe, Ala, Glu,

Gly, N-methyl-Gly, Phg, 4-fluoro-Phe, O-methyl-Tyr,

homo-Phe, 3-chloro-Phe, Nvl or not present

<220>

<221> Modified remainder

<222> (14)..(14)

<223> Propargylglycine, Pro, Ala, N-methylglycine, Ser,

N-methylserine, N-methylalanine, Nvl, Cys, Tbg

or not present

<220>

<221> Modified remainder

<222> (15)..(15)

<223> Aminoisobutyric acid, Tbg, Cys, Pro, Asn, phenylglycine,

D-phenylglycine, N-methyl-Phg, Nvl, His, Ala,

D-Ala, Chg or not present

<220>

<221> Modified remainder

<222> (16)..(16)

<223> Norvaline, Lys, Lysine N-epsilon caprylate, Lysine N-epsilon caprylate

N-epsilon-lauryl-lysine, N-epsilon-palmitoyl-lysine,

Pro, Cys, Tyr, Gly, propargyl-glycine, homoCys, N-methyl-

serine, tert-butylglycine or not present

<220>

<221> Modified remainder

<222> (17)..(17)

<223> Nvl, Cys, Lys, Ala or not present

<220>

<221> Modified remainder

<222> (18)..(18)

<223> Pro, Glu, Nvl or not present

<220>

<221> Modified remainder

<222> (19)..(19)

<223> Nvl and may not be present

<220>

<221> Modified remainder

<222> (20)..(20)

<223> N-epsilon-(PEG2-gamma-glutamic acid-N-alpha-octadecanedioic

acid) lysine, N-epsilon-(PEG24-gamma-glutamic acid-N-alpha-

hexadecanoyl) lysine, N-epsilon-1-(4,4-dimethyl-2,6-

dioxocylogex-1-ylidene)-3-methylbuty-L-lylysis or not present

<220>

<223> C-terminus can be modified with NH2 or N(CH3)2

<220>

<223> See attached description for details of substitutions

and preferred embodiments

<400> 212

Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa

1 5 10 15

Xaa Xaa Val Lys

twenty

<---

Claims (34)

1. A polypeptide with the formula R ₁ -Xaa0-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-R ₂ , in which: R ₁ is selected from the group consisting of acetyl group, H, acyl group, heptanoyl group, amide, carbamate, urea, polyethylene glycol (PEG), hydroxyalkyl starch and chloroacetic acid, or absent; Xaa0 is absent or stands for Met; Xaa1 is selected from the group consisting of Cys, Lys, (S)-2-amino-5-azidovaleric acid and 3-thiopropionic acid, or absent; Xaa2 is selected from the group consisting of Val, Ala and D-Ala, or absent; Xaa3 is selected from the group consisting of Glu, norvaline and Ala, or absent; Xaa4 is selected from the group consisting of Arg, Cys, Ala, Ser and norvaline, or absent; Xaa5 is selected from the group consisting of Phe, Tyr, N-methyltyrosine and Ala, or absent; Xaa6 is selected from the group consisting of Cys, Glu, N-methylglutamic acid, Asp, (S)-2-aminopept-4-ic acid and Ala; Xaa7 is selected from the group consisting of Asp, Asn, N-methylasparagine, alpha-methyl-L-aspartic acid, ( S )-2-amino-3-( 1H -tetrazol-5-yl)propionic acid, N-methyl -aspartic acid, cycloleucine, 4-amino-tetrahydropyran-4-carboxylic acid and Ala; Xaa8 is selected from the group consisting of tert-butylglycine, Val and Ala; Xaa9 stands for Tyr; Xaa10 is selected from the group consisting of 7-azatryptophan, Trp, 3-aminomethyl-L-phenylalanine, N-methyltryptophan and 1-methyltryptophan; Xaa11 is Glu; Xaa12 stands for Tyr; Xaa13 stands for Pro; Xaa14 is selected from the group consisting of cyclohexylglycine, phenylglycine, D-phenylglycine, N-methylphenylglycine, aminoisobutyric acid and Ala, or absent; Xaa15 is selected from the group consisting of norvaline, Lys and Pro, or absent; Xaa16 is absent or selected from the group consisting of N-ε-palmitoyllisin, N-ε-lauryllisin, N-ε-capryllisin, N-ε-lysine caprylate, B20, B28, K14, Cys and Lys; wherein B20 is N-ε-(PEG2-γ-glutamic acid-N-α-octodecanedioic acid)lysine; B28 is N-ε-(PEG24-gammaglutamic acid-N-α-hexadecanoyl)lysine; and K14 is N-ε-1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-3-methylbutyl-L-lysine; and R ₂ is -NH ₂ or absent; moreover, the polypeptide, if necessary, additionally contains a bridge element between two amino acids; and moreover, the polypeptide, if necessary, conjugated with PEG. 2. A polypeptide according to claim 1, further comprising a bridge element between two amino acids. 3. The polypeptide according to claim 2, where the specified bridge element contains a structure selected from the group consisting of structures I-XIX:

where each X is independently N or CH such that no ring contains more than 2 nitrogen atoms; each Z is independently a bond, NR, O, S, CH ₂ , C(O)NR, NRC(O), S(O) _v NR, NRS(O) _v ; each m is independently selected from 0, 1, 2, and 3; each v is independently selected from 1 and 2; each R is independently selected from H and C ₁ -C ₆ ; and each bridging element is connected to the polypeptide by independently selected C ₀ -C ₆ spacers. 4. The polypeptide of claim 2, wherein the bridging element comprises a feature selected from the group consisting of a disulfide bond, an amide bond (lactam), a thioether bond, an aromatic ring, an unsaturated aliphatic hydrocarbon chain, a saturated aliphatic hydrocarbon chain, and a triazole ring. 5. The polypeptide according to claim 1, comprising a cyclic loop, where the cyclic loop has a length selected from the group consisting of 1 amino acid, 2 amino acids, 3 amino acids, 4 amino acids, 5 amino acids, 6 amino acids, 7 amino acids, 8 amino acids, 9 amino acids , 10 amino acids, 11 amino acids, 12 amino acids, 13 amino acids, 14 amino acids, 15 amino acids and 16 amino acids. 6. A polypeptide according to claim 2, wherein the Xaa1 residue is a cysteine, and wherein the bridging element connects the Xaa1 residue and Xaa6. 7. The polypeptide of claim 4, wherein said feature includes an aromatic ring, and wherein said bridging element is formed by reaction with poly(bromomethyl)benzene. 8. The polypeptide of claim 7 wherein the poly(bromomethyl)benzene is selected from the group consisting of 1,2-bis(bromomethyl)benzene, 1,3-bis(bromomethyl)benzene and 1,4-bis(bromomethyl)benzene. 9. The polypeptide of claim 8, wherein the reagent is 1,3-bis(bromomethyl)benzene. 10. The polypeptide of claim 4, wherein said feature includes a disulfide bond between two cysteine residues. 11. A polypeptide according to claim 4, wherein said feature includes an aromatic ring, and wherein said bridging element is obtained by reaction with a compound selected from the group consisting of 2,6-bis(bromomethyl)pyridine, ( E )-1,4- dibromobut-2-ene and 1,2-bis(bromomethyl)-4-alkylbenzene.

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