US20210205415A1

US20210205415A1 - Highly active polypeptides and methods of making and using the same

Info

Publication number: US20210205415A1
Application number: US16/940,610
Authority: US
Inventors: Scott J. Shandler; Samuel H. Gellman
Original assignee: Longevity Biotech Inc
Current assignee: Longevity Biotech Inc
Priority date: 2010-04-22
Filing date: 2020-07-28
Publication date: 2021-07-08
Also published as: US20130096050A1; CA2797033C; US9782454B2; WO2011133948A3; US20180193422A1; CA2797033A1; WO2011133948A2; US10772934B2

Abstract

This invention relates to novel compositions comprising analogs of naturally occurring polypeptides, wherein the analog comprises an α-amino acid and at least one β-amino acid. Administration of the compositions may be used for effecting treatment or prevention of a plurality of disease states caused by dysfunctional biochemical or biological pathways. The compositions and methods of this invention are particularly useful to identify novel therapeutic modulators of in-vivo receptor activity with extended half-lives and relevant bioactivity as compared to the naturally translated polypeptides upon which the analogs are derived.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No. 15/691,811, filed Aug. 31, 2017, now issued as U.S. Pat. No. 10/772,934, which is a continuation of U.S. patent application Ser. No. 13/642,757, filed Jan. 2, 2013, now issued as U.S. Pat. No. 9,782,454, which is a National Stage entry of International Application No. PCT/US11/33684, filed on Apr. 22, 2011, which claims priority to U.S. Provisional Ser. No. 61/364,098, filed on Apr. 22, 2010; U.S. Provisional Ser. No. 61/364,359, filed on Jul. 14, 2010; U.S. Provisional Ser. No. 61/405,560, filed on Oct. 21, 2010; and U.S. Provisional Ser. No. 61/445,468, filed on Feb. 22, 2011, all of which are herein incorporated by reference in their entirety.

FIELD OF THE INVENTION

The invention relates generally to compositions comprising modified polypeptide sequences with greater resistance to degradation and equivalent and/or increased bioactivity as compared to naturally encoded, unmodified polypeptide sequences, and to methods of making the compositions and methods of using the compositions as pharmaceutically active agents to treat disease in animals, including humans.

BACKGROUND OF THE INVENTION

The secretin family is a family of well-conserved animal proteins with a variety of biological functions. Biologically active members of the secretin family are generally from about 26 to about 65 amino acids in length and are thought to have relatively simple alpha-helical secondary structures. Many members are originally produced in vivo as larger pro-peptides, which are eventually converted in the active forms. Members of the secretin family include the following proteins: GHRF, GIP, GLP-1, Glucagon, PACAP-27, PACAP-38, PHM, PrP, and secretin. The q25 region of chromosome 6 on the human genome encodes another secretin family member that is 170 amino acids long which becomes post-translationally cleaved to form vasoactive intestinal peptide (VIP). The active form of the VIP polypeptide is a 28 amino acid protein that functions, among other ways, to reduce arterial blood pressure, to increase vasodilation of blood vessel walls, to relax smooth muscle in the respiratory system and gastrointestinal tissues, reduce inflammatory responses through both promotion of Th2 differentiation as well as the reduction of Th1 responses, modulate both the innate and adaptive immune response, and to stimulate secretion of electrolytes in the gut. VIP has also been shown to be active in the central nervous system as a neurotransmitter and in communication with lymphocytes. Bioactivity of VIP is transmuted through three known receptor subtypes: VIP₁R, VIP₂R, and PAC₁R. These receptors are known to induce cAMP concentration as well as stimulate the production of intracellular calcium. Their affinities for secretins such as VIP vary depending upon the subtype and the amino acid sequence of the ligand.
Secretin family members have short half-lives. For instance, VIP has a half-life of about two minutes in the blood stream. It is desirable to identify polypeptides that mimic the function of secretins such as VIP, but have increased half-life and equivalent or more bioactivity than the naturally occurring VIP amino acid sequence. It is also desirable to identify another peptidomimetic of VIP to have association to one receptor subtype over another secretin receptor.
HDL cholesterol level is inversely related to the incidence of coronary heart disease and recently received increasing attention as a novel target in lipid management of treating atherosclerotic vascular disease. Direct vascular protective effects of HDL have been attributed to apolipoprotein (apo) A-I or apoA-I-associated molecules in HDL using direct intravenous injections of homologous HDL, 3 recombinant mutant apoA-Imilano or apoA-I gene therapy, or use of transgenic animals overexpressing apoA-I or apoAI-related molecules such as paraoxonase. A recent phase II randomized trial showed that 5 weekly intravenous injections of recombinant apoA-1milano induced rapid regression of coronary atherosclerotic lesions in humans. It is desirable to identify polypeptides that mimic the function of apoA-1 such as paraoxonase, but have increased half-life and equivalent or more bioactivity than the naturally occurring paraoxonase amino acid sequence. It is also desirable to identify another peptidomimetic of apoA-1 to have association to a natural ligand for apoA-1 as compared to wild-type sequences.
Cytokines mediate cellular activities in a number of ways. Cytokines support the proliferation, growth, and differentiation of pluripotential hematopoietic stem cells into vast numbers of progenitors comprising diverse cellular lineages making up a complex immune system. Proper and balanced interactions between the cellular components are necessary for a healthy immune response. The different cellular lineages often respond in a different manner when cytokines are administered in conjunction with other agents.
Cytokines mediate communication between cells of the immune system, e.g., antigen presenting cells (APCs) and T lymphocytes. Dendritic cells (DCs) are the most potent of antigen presenting cells. See, e.g., Paul (ed.) (1993) Fundamental Immunology 3d ed., Raven Press, NY. Antigen presentation refers to the cellular events in which a proteinaceous antigen is taken up, processed by antigen presenting cells (APC), and then recognized to initiate an immune response. The most active antigen presenting cells have been characterized as the macrophages (which are direct developmental products from monocytes), dendritic cells, and certain B cells. DCs are highly responsive to inflammatory stimuli such as bacterial lipopolysaccharides (LPS), and cytokines such as tumor necrosis factor alpha (TNFalpha). Cytokines or stimuli, such as LPS, can induce a series of phenotypic and functional changes in DC that are collectively referred to as maturation. See, e.g., Banchereau and Schmitt (eds.) (1995) Dendritic Cells in Fundamental and Clinical Immunoloy, Plenum Press, NY. It is desirable to identify polypeptides that mimic the function of cytokine families such as IL-10, IL-2, IL-4, IL-12, and IL-17, but have increased half-life and equivalent or more bioactivity than the naturally occurring IL-10, IL-2, IL-4, IL-12, and IL-17 representative amino acid sequences. It is also desirable to identify another peptidomimetic of a cytokine such as IL-17 to have association to a natural receptor for IL-17 as compared to wild-type sequences.
Chemists have long sought to extrapolate the power of biological catalysis and recognition to synthetic systems. These efforts have focused largely on low-molecular weight catalysts and receptors. Most biological systems, however, rely almost exclusively on large polymers such as proteins and RNA to perform complex biochemical and/or biological functions. There is a long-felt need to identify synthetic polymers of amino acids which display discrete and predictable folding propensities to mimic natural biological systems. Such polypeptides are designed to provide a molecular equivalent or improved functionality as compared to naturally occurring protein-protein interactions specifically because of their ability to mimic natural interactions in addition to their resistance to natural degradative enzymes in a subject. Whereas a naturally occurring probe, comprised entirely of α-amino acid residues, will be readily degraded by any number of proteases and peptidases, the secretin analogs of the present invention comprising a mixture of α- and β-amino acid residues are not degraded in the same manner
There is a need for secretin analogs that exhibit increased conformational constraints or increased conformational flexibility and greater half-lives. Increased conformational constraints may lock the active domain of the polypeptides into their active state. Increased conformational flexibility of the polypeptide may yield a high affinity selectivity for the naturally occurring polypeptide's natural biological target. There is a need for use of such analogs, compositions comprising such analogs, and methods of using the compositions as pharmaceutically active agents to treat disease in animals. New polypeptide analogs are disclosed that may provide one of more increased half-life, reduced degradation upon administration, reduced degradation upon solubilization, increased conformational constraints and that produce the same or greater biological effect as compared to naturally occurring secretin family members. The present invention addresses these and other needs associated with treatment and prevention of disease that implicate dysfunction of biological systems involving naturally occurring polypeptides.

SUMMARY OF THE INVENTION

In some embodiments, the invention relates to compositions comprising a helical polypeptide synthesized with a repeated pattern of β-amino acids at positions along the entire length of a polypeptide chain. For any of the peptides described herein, there may embodiments in which there are no β-amino acids within the peptide. The selected pattern of synthetic amino acids along the helical polypeptide decreases the rate at which the polypeptide may degrade when administered to a subject or when reconstituted or placed in solution. Selected side chains of the amino acids increase the conformational rigidity of the polypeptide in order to constrain the polypeptide in its active state. The selected pattern of synthetic amino acids along the helical polypeptide increases the half-life of the polypeptide as compared to naturally encoded polypeptides with the same α-amino acid sequence. In some embodiments, the polypeptide comprises β-amino acids that spatially aligned along a longitudinal axis of the analog in order to confer degradation resistance to the composition while preserving the native binding interface. In some embodiments, the composition comprises a secretin analog. In some embodiments, the composition comprises a vasoactive intestinal peptide (VIP) analog, wherein said analog comprises an α-amino acid and at least one β-amino acid.
In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 12 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 14 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 16 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 18 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 50 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 40 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 45 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 40 percent to about 45 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 40 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 35 percent to about 40 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 30 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 20 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 15 percent to about 20 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 25 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 25 percent to about 30 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a secretin analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 35 percent of the total number of amino acids of the analog.
In some embodiments, the invention relates to analogs of various protein targets. In some embodiments, the amino acid sequences upon which the analogs are based or derived include biologically active polypeptides chosen from the group of transcription factors, ligands for cellular receptors, hormones and extracellular binding peptides. In some embodiments, the invention comprises analogs of derived from amino acid sequences chosen from human and non-human enkephlin, LHRH, neuropeptides, glycoincretins, integrin, glucagons and glucagon-like peptides, antithrombotic peptides, cytokines and interleukins, transferrins, interferons, endothelins, natriuretic hormones, extracellular kinase ligands, angiotensin enzyme inhibitors, peptide antiviral compounds, thrombin, substance P, substance G, somatotropin, somatostatin, GnRH, bradykinin, vasopressin, insulin, and growth factors. The amino acid sequences of these proteins or peptides are known to the skilled artisan and can be obtained by numerous means. The amino acid sequences are incorporated herein by reference from databases such as, for example, GenBank.
As used herein, “glucagon-like peptide-1” or “GLP-1” shall include those polypeptides and proteins that have at least one biological activity of human GLP-1, including but not limited to those described in U.S. Patent Publication No. 20040127412, EP 0699686-A2 and EP0733,644, U.S. Pat. Nos. 5,545,618; 5,118,666; 5,512,549; WO 91/11457; WO 90/11296; WO 87/06941 which are incorporated by reference herein, as well as GLP-1 analogs, GLP-1 isoforms, GLP-1 mimetics, GLP-1 fragments, hybrid GLP-1 proteins, fusion proteins, oligomers and multimers, homologues, glycosylation pattern variants, and muteins, thereof, regardless of the biological activity of same, and further regardless of the method of synthesis or manufacture thereof including synthetic, transgenic, and gene activated methods. Numerous GLP-1 analogs and derivatives are known and are referred to herein as “GLP-1 compounds.” These GLP-1 analogs include the Exendins which are peptides found in the venom of the GILA-monster. Specific examples of GLP-1 include, but are not limited to, GLP-1(3-36), GLP-1(3-37), GLP-1(1-45), and Exendins 1 through 4. Further, it is possible to obtain GLP-1 through the use of recombinant DNA technology, as disclosed by Maniatis, T., et al., Molecular Biology: A Laboratory Manual, Cold Spring Harbor, N.Y. (1982), and produce GLP-1 in host cells by methods known to one of ordinary skill in the art.
The term “human GLP-1 (GLP-1)” or “GLP-1 polypeptide” refers to GLP-1 as described herein, as well as a polypeptide that retains at least one biological activity of a naturally-occurring GLP-1. GLP-1 polypeptides also include the pharmaceutically acceptable salts and prodrugs, and prodrugs of the salts, polymorphs, hydrates, solvates, biologically-active fragments, biologically active variants and stereoisomers of the naturally-occurring human GLP-1 as well as agonist, mimetic, and antagonist variants of the naturally-occurring human GLP-1, the family of exendins including exendins 1 through 4, and polypeptide fusions thereof. Examples of GLP-1 polypeptides include, but are not limited to, those described in U.S. Pat. No. 5,118,666; which is incorporated by reference herein. Fusions comprising additional amino acids at the amino terminus, carboxyl terminus, or both, are encompassed by the term “GLP-1 polypeptide.” Exemplary fusions include, but are not limited to, e.g., fusions for the purpose of purification (including, but not limited to, to poly-histidine or affinity epitopes), fusions with serum albumin binding peptides; fusions with serum proteins such as serum albumin; fusions with constant regions of immunoglobulin molecules such as Fc; and fusions with fatty acids. The naturally-occurring GLP-1 nucleic acid and amino acid sequences for various forms are known, as are variants such as single amino acid variants or splice variants.
The term “GLP-1 polypeptide” encompasses GLP-1 polypeptides comprising one or more amino acid substitutions, additions or deletions. Exemplary substitutions in a wide variety of amino acid positions in naturally-occurring GLP-1 have been described, including but not limited to, substitutions that modulate one or more of the biological activities of GLP-1, such as but not limited to, increase agonist activity, increase solubility of the polypeptide, convert the polypeptide into an antagonist, decrease peptidase or protease susceptibility, etc. and are encompassed by the term “GLP-1 polypeptide.”
Human GLP-1 antagonists include, but are not limited to, those with a substitutions at: 7, 8, 9, 22, 18, 29, 25, 32, 21, 28, 17, 24, 31, and 20 (other GLP-1 sequence of U.S. Patent Application Publication 2010-0048871). In some embodiments, the GLP-1 antagonist comprises a non-naturally encoded amino acid linked to a water soluble polymer that is present in a receptor binding region of the GLP-1 molecule. In some embodiments the water soluble polymer is coupled to the GLP-1 polypeptide at one or more of the amino acid positions: 7, 8, 9, 22, 18, 29, 25, 32, 21, 28, 17, 24, 31, and 20 (U.S. Patent Application Publication 2010-0048871).
For the GLP-1 amino acid sequence as well as the exendin-4 and exendin-3 amino acid sequence, {His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg} (GLP-1(7-36), SEQ ID NO: 1330); {His Ala Glu Gly Thr Phe Thr Ser Asp Val Ser Ser Tyr Leu Glu Gly Gln Ala Ala Lys Glu Phe Ile Ala Trp Leu Val Lys Gly Arg Gly} (GLP-1(7-37), SEQ ID NO:1331); {His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys GIn Met Glu Glu Glu Ala Val Arg Leu Phe lIe Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser} (exendin-4, SEQ ID NO:1332); and {His Ser Asp Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu Glu Ala Val Arg Leu Phe He Glu Trp Leu Lys Asn Gly Gly Pro Ser Ser Gly Ala Pro Pro Pro Ser} (exendin-3, SEQ ID NO:724). In some embodiments, GLP-1 polypeptides of the invention are substantially identical to the sequences above, or any other sequence of a GLP-1 polypeptide (see, U.S. Patent Application Publication 2010-0048871). Nucleic acid molecules encoding GLP-1 mutants and mutant GLP-1 polypeptides are well known. Examples of GLP-1 mutants include those disclosed in U.S. Patent Publication No. 20040127412A1; which is incorporated by reference herein.
A number of GLP-1 products are in preclinical and clinical development, including GLP-1 peptide analogs, conjugates, fusion proteins, and drug delivery or combination therapies. Some of the products in development are Exenatide (AC2993, Amylin/Eli Lilly), AVE-0010 (ZP10, Zealand Pharm/Aventis), BIM-51077 (Ipsen/Roche), Liraglutide (NN2211, Novo Nordisk), CJC-1131 (Conjuchem), Albugon (Human Genome Sciences/Glaxo Smith Kline), GLP-1 transferrin (Biorexis), AC2993 LAR (Amylin/Alkermes), GLP-1 nasal (Suntory) and GLP-1-INT (Transition Therapeutics).
The biological activities of GLP-1 have been disclosed and are known in the art, and can be found, for example, in U.S. Patent Publication No: 20040082507A1 and 20040232754A1 which are incorporated by reference herein.
Variants of GLP-1(7-37) and analogs thereof, also have been disclosed. These variants and analogs include, for example, Gln⁹-GLP-1(7-37), D-Gln⁹-GLP-1(7-37), acetyl-Lys⁹-GLP-1(7-37), Thr¹⁶-Lys¹⁸-GLP-1(7-37), Lys¹⁸-GLP-1(7-37) and the like, and derivatives thereof including, for example, acid addition salts, carboxylate salts, lower alkyl esters, and amides (see, e.g., WO 91/11457; EP0733,644 (1996); and U.S. Pat. No. 5,512,549 (1996), which are incorporated by reference). Generally, the various disclosed forms of GLP-1 are known to stimulate insulin secretion (insulinotropic action) and cAMP formation (see, e.g., Mojsov, S., Int. J. Peptide Protein Research, 40:333-343 (1992)).
As used herein, “T-20” or “DP-178” shall include those polypeptides and proteins that have at least one biological activity of human DP-178, as well as DP-178 analogs, DP-178 isoforms, DP-178 mimetics, DP-178 fragments, hybrid DP-178 proteins, fusion proteins, oligomers and multimers, homologues, glycosylation pattern variants, and muteins, thereof, regardless of the biological activity of same, and further regardless of the method of synthesis or manufacture thereof including, but not limited to, recombinant (whether produced from cDNA, genomic DNA, synthetic DNA or other form of nucleic acid), synthetic, transgenic, and gene activated methods. Hyphenated and non-hyphenated forms (T20, DP178) of the terms are equivalent.
The term “human DP-178” or “DP-178 polypeptide” refers to DP-178 or T-20 as described herein, as well as a polypeptide that retains at least one biological activity of a naturally-occurring DP-178. “DP-178” includes portions, analogs, and homologs of DP-178, all of which exhibit antiviral activity. Antiviral activity includes, but is not limited to, the inhibition of HIV transmission to uninfected CD-4+ cells. Further, the invention relates to the use of DP-178 and DP-178 fragments and/or analogs or homologs as inhibitors of retroviral transmission, in particular HIV, to uninfected cells, in both humans and non-humans. Non retroviral viruses whose transmission may be inhibited by the peptides of the invention include, but are not limited to enveloped viruses, human respiratory syncytial virus, canine distemper virus, Newcastle disease virus, human parainfluenza virus, and influenza viruses.
DP-178 polypeptides also include the pharmaceutically acceptable salts and prodrugs, and prodrugs of the salts, polymorphs, hydrates, solvates, biologically-active fragments, biologically active variants and stereoisomers of the naturally-occurring human DP-178 as well as agonist, mimetic, and antagonist variants of the naturally-occurring human DP-178, and polypeptide fusions thereof. Fusions comprising additional amino acids at the amino terminus, carboxyl terminus, or both, are encompassed by the term “DP-178 polypeptide.” Exemplary fusions include, but are not limited to, e.g., methionyl DP-178 in which a methionine is linked to the N-terminus of DP-178 resulting from the recombinant expression of DP-178, fusions for the purpose of purification (including, but not limited to, to poly-histidine or affinity epitopes), T-20 extended at the N-terminus, fusions with serum albumin binding peptides; fusions with serum proteins such as serum albumin; fusions with constant regions of immunoglobulin molecules such as Fc; and fusions with fatty acids. The naturally-occurring DP-178 nucleic acid and amino acid sequences are known, as are variants such as single amino acid variants or splice variants.
The term “DP-178 polypeptide” encompasses DP-178 polypeptides comprising one or more amino acid substitutions, additions or deletions. Exemplary substitutions in a wide variety of amino acid positions in naturally-occurring DP-178 have been described, including but not limited to, substitutions that modulate one or more of the biological activities of DP-178, such as but not limited to, increase agonist activity, increase solubility of the polypeptide, convert the polypeptide into an antagonist, decrease peptidase or protease susceptibility, etc. and are encompassed by the term “DP-178 polypeptide,” the DP-178 amino acid sequence, (Tyr Thr Ser Leu He His Ser Leu lIe Glu Glu Ser GIn Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe) (SEQ ID NO:1333). In some embodiments, DP-178 polypeptides of the invention are substantially identical to the following sequences or functional fragments thereof: (Tyr Thr Ser Leu He His Ser Leu Ile Glu Glu Ser GIn Asn Gln Gln Glu Lys Asn Glu Gln Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe); Glu Trp Asp Arg Glu Ile Asn Asn Tyr Thr Ser Leu Ile His Ser Leu Ile Glu Glu Ser Gln Asn GIn Gln Glu Lys Asn Glu GIn Glu Leu Leu Glu Leu Asp Lys Trp Ala Ser Leu Trp Asn Trp Phe (SEQ ID NO:1334); or any other sequence of a DP-178 polypeptide. Nucleic acid molecules encoding DP-178 mutants and mutant DP-178 polypeptides are well known.
A commercially available form of DP-178 is Fuzeon®. (enfuvirtide. Roche Laboratories Inc. and Trimeris, Inc.). Fuzeon® has an acetylated N terminus and a carboxamide as the C-terminus. It is used in combination with other antivirals in HIV-1 patients that show HIV-1 replication despite ongoing antiretroviral therapy.
As used herein, “PYY” and “peptide YY” shall include those polypeptides and proteins that have at least one biological activity of human PYY, as well as PYY analogs, PYY isoforms, PYY mimetics, PYY fragments, hybrid PYY proteins, fusion proteins, oligomers and multimers, homologues, glycosylation pattern variants, and muteins, thereof, regardless of the biological activity of same, and further regardless of the method of synthesis or manufacture thereof including, but not limited to, recombinant (whether produced from cDNA, genomic DNA, synthetic DNA or other form of nucleic acid), synthetic, transgenic, and gene activated methods.
The term “PYY” or “PYY polypeptide” refers to PYY as described herein, as well as a polypeptide that retains at least one biological activity of a naturally-occurring PYY. “PYY” includes portions, analogs, and homologs of PYY including, but not limited to, PYY(3-36), full-length PYY, PYY(22-36), and DPPIV resistant variants of PYY. The term “PYY” includes the human full length: Tyr Pro Ile Lys Pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr (SEQ ID NO: 561), which is disclosed in International Publication No. WO 02/47712 (which is the PCT counterpart to U.S. patent Publication No. 2002/0141985, which is hereby incorporated by reference) and the following amino acid sequences from Tatemoto, Proc Natl Acad Sci U.S.A. 79:2514-8, 1982, which are incorporated by reference herein:

1. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly (SEQ ID NO: 1375)
2. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Ser-Arg (SEQ ID NO: 1376)
3. Tyr-Tyr-Ala-Ser-Leu-Arg (SEQ ID NO: 1377)
4. His-Tyr-Leu-Asn-Leu-Val-Thr-Arg (SEQ ID NO: 1378)
5. Tyr-Pro-Ala-Lys-Pro-Glu-Ala-Pro-Gly-Glu-Asp-Ala-Ser-Pro-Glu-Glu-Leu-Ser-Arg-Tyr-Tyr-Ala-Ser-Leu-Arg-His-Tyr-Leu-Asn-Leu-Val-Thr-Arg-Gln-Arg-Tyr-NH₂(SEQ ID NO: 1379)

PYY agonists are also included in the term “PYY”. PYY agonists include any compound which elicits an effect of PYY to reduce nutrient availability, for example a compound (1) having activity in the food intake, gastric emptying, pancreatic secretion, or weight loss assays described in Examples 1, 2, 5, or 6 of WO 02/47712 and U.S. patent Publication No. 2002/0141985, and (2) which binds specifically in a Y receptor assay (Example 10 of WO 02/47712 and U.S. patent Publication No. 2002/0141985) or in a competitive binding assay with labeled PYY or PYY 13-361 from certain tissues having an abundance of Y receptors, including e.g., area postrema (Example 9 of WO 02/47712 and U.S. patent Publication No. 2002/0141985), wherein the PYY agonist is not pancreatic polypeptide. In some embodiments, PYY agonists would bind in such assays with an affinity of greater than about 1 μM, or with an affinity of greater than about 1 nM to about 5 nM.
Such agonists can comprise a polypeptide having a functional PYY domain, an active fragment of PYY, or a chemical or small molecule. PYY agonists may be peptide or peptide-nonpeptide hybrid molecules, and include “PYY agonist analogs,” which refer to any compound structurally similar to a PYY that have PYY activity typically by virtue of binding to or otherwise directly or indirectly interacting with a PYY receptor or other receptor or receptors with which PYY itself may interact to elicit a biological response. Such compounds include derivatives of PYY, fragments of PYY, extended PYY molecules having more than 36 amino acids, truncated PYY molecules having less than 36 amino acids, and substituted PYY molecules having one or more different amino acids as compared to the wild-type or consensus sequence, or any combination of the above. Such compounds may also be modified by processes such as pegylation, amidation, glycosylation, acylation, sulfation, phosphorylation, acetylation and cyclization.
One such PYY agonist analog is PYY (3-36), identified as Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Ile Lys pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr Val Thr Arg Gln Arg Tyr (SEQ ID NO:559); Eberlein, Eysselein et al., Peptides 10:797-803 (1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994). Additional PYY fragments and derivatives are described in U.S. Patent Publication 20050002927 whose sequences follow: All of the above referenced patent publications are incorporated by reference herein.
PYY polypeptides also include the pharmaceutically acceptable salts and prodrugs, and prodrugs of the salts, polymorphs, hydrates, solvates, biologically-active fragments, biologically active variants and stereoisomers of the naturally-occurring human PYY as well as agonist, mimetic, and antagonist variants of the naturally-occurring human PYY, and polypeptide fusions thereof. Fusions comprising additional amino acids at the amino terminus, carboxyl terminus, or both, are encompassed by the term “PYY polypeptide.” Exemplary fusions include, but are not limited to, e.g., fusions with serum albumin binding peptides; fusions with serum proteins such as serum albumin; fusions with constant regions of immunoglobulin molecules such as Fc; and fusions with fatty acids. The naturally-occurring PYY nucleic acid and amino acid sequences are known, as are variants such as single amino acid variants or splice variants.

The term “PYY polypeptide” encompasses PYY polypeptides comprising one or more amino acid substitutions, additions or deletions. Exemplary substitutions in a wide variety of amino acid positions in naturally-occurring PYY have been described, including but not limited to, substitutions that modulate one or more of the biological activities of PYY, such as but not limited to, increase agonist activity, increase solubility of the polypeptide, convert the polypeptide into an antagonist, decrease peptidase or protease susceptibility, etc. and are encompassed by the term “PYY polypeptide.”

In some embodiments, PYY polypeptides of the invention are substantially identical to Ile Lys Pro Glu Ala Pro Gly Glu Asp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu Val Thr Arg Gln Arg Tyr (SEQ ID NO: 559) or any other sequence of a PYY polypeptide (see, U.S. Patent Application Publication 2010-0048871). Nucleic acid molecules encoding PYY mutants and mutant PYY polypeptides are well known.
Various references disclose modification of polypeptides by polymer conjugation or glycosylation. The term analog includes polypeptides conjugated to a polymer such as PEG and may be comprised of one or more additional derivitizations of cysteine, lysine, or other residues. In addition, analogs of the instant invention may comprise a linker or polymer, wherein the amino acid to which the linker or polymer is conjugated may be a non-natural amino acid, or may be conjugated to a naturally encoded amino acid utilizing techniques known in the art such as coupling to lysine or cysteine.
Polymer modification of polypeptides has been reported. U.S. Pat. No. 4,904,584 discloses PEGylated lysine depleted polypeptides, wherein at least one lysine residue has been deleted or replaced with any other amino acid residue. WO 99/67291 discloses a process for conjugating a protein with PEG, wherein at least one amino acid residue on the protein is deleted and the protein is contacted with PEG under conditions sufficient to achieve conjugation to the protein. WO 99/03887 discloses PEGylated variants of polypeptides belonging to the growth hormone superfamily, wherein a cysteine residue has been substituted with a non-essential amino acid residue located in a specified region of the polypeptide. WO 00/26354 discloses a method of producing a glycosylated polypeptide variant with reduced allergenicity, which as compared to a corresponding parent polypeptide comprises at least one additional glycosylation site. U.S. Pat. No. 5,218,092 discloses modification of granulocyte colony stimulating factor (G-CSF) and other polypeptides so as to introduce at least one additional carbohydrate chain as compared to the native polypeptide. Examples of PEGylated peptides include GW395058, a PEGylated peptide thrombopoietin receptor (TPOr) agonist (de Serres M., et al., Stem Cells. 1999; 17(4):203-9), and a PEGylated analogue of growth hormone releasing factor (PEG-GRP; D'Antonio M, et al. Growth Horm IGF Res. 2004 June; 14(3):226-34).
The term analog also includes glycosylated analogs, such as but not limited to, analogs glycosylated at any amino acid position, N-linked or O-linked glycosylated forms of the polypeptide. In addition, splice variants are also included. The term analog also includes heterodimers, homodimers, heteromultimers, or homomultimers of any one or more polypeptide, protein, carbohydrate, polymer, small molecule, linker, ligand, or other biologically active molecule of any type, linked by chemical means or expressed as a fusion protein, as well as polypeptide analogs containing, for example, specific deletions or other modifications yet maintain biological activity.
Various references disclose additional variants of GLP-1 and acylation of GLP-1, including, but not limited to, the GLP-1 parent analogs and acylation sites described in J. of Med. Chem. (2000) 43:1664-1669, which is incorporated herein by reference.
Those of skill in the art will appreciate that amino acid positions corresponding to positions in analogs can be readily identified in any other molecule such as analog fusions, variants, fragments, etc. For example, sequence alignment by visual means or computer programs such as BLAST can be used to align and identify a particular position in a protein that corresponds with a position in the analog of polypeptide sequences identified in this application or other GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin, ANP/BNP/CNP, Maxadilan/M65, Apolipoprotein mimetic polypeptides and any other analog sequences are intended to also refer to substitutions, deletions or additions in corresponding positions in GLP-1, VIP, PYY, IL-10, PACAP, Ghrelin, ANP/BNP/CNP, Maxadilan/M65, Apolipoprotein mimetic polypeptides fusions, variants, fragments, etc. described herein or known in the art and are expressly encompassed by the present invention.
The term analog encompasses polypeptides comprising one or more amino acid substitutions, additions or deletions. Analogs of the present invention may be comprised of modifications with one or more natural amino acids in conjunction with one or more non-natural amino acid modification. Exemplary substitutions in a wide variety of amino acid positions in naturally-occurring analogs have been described, including but not limited to substitutions that modulate one or more of the biological activities of the analogs, such as but not limited to, increase agonist activity, increase solubility of the polypeptide, convert the polypeptide into an antagonist, decrease peptidase or protease susceptibility, etc. and are encompassed by the term analog.
Human GLP-1 antagonists include, but are not limited to, those with a substitutions at: 19, 23, 26, 27, 28, 29, 30, and 33 of the consensus sequence identified in Table 4. In some embodiments, the GLP-1 antagonist comprises a non-naturally encoded amino acid linked to a water soluble polymer that is present in a receptor binding region of the GLP-1 molecule. In some embodiments, the water soluble polymer is coupled to the GLP-1 polypeptide at one or more of the amino acid positions: 19, 23, 26, 27, 30, and 33 of the consensus sequence identified in Table 4.
In some embodiments, the analogs further comprise an addition, substitution or deletion that modulates biological activity of the analogs. For example, the additions, substitution or deletions may modulate one or more properties or activities of the analog. For example, the additions, substitutions or deletions may modulate affinity for the analog receptor or binding partner, modulate (including but not limited to, increases or decreases) receptor dimerization, stabilize receptor dimers, modulate the conformation or one or more biological activities of a binding partner, modulate circulating half-life, modulate therapeutic half-life, modulate stability of the polypeptide, modulate cleavage by peptidases or proteases, modulate dose, modulate release or bio-availability, facilitate purification, or improve or alter a particular route of administration Similarly, analogs of the present invention may comprise protease cleavage sequences, reactive groups, antibody-binding domains (including but not limited to, FLAG or poly-His) or other affinity based sequences (including but not limited to, FLAG, poly-His, GST, etc.) or linked molecules (including but not limited to, biotin) that improve detection (including but not limited to, GFP), purification or other traits of the polypeptide.
A “non-naturally encoded amino acid” refers to an amino acid that is not one of the 20 common amino acids or pyrolysine or seienocysteine. Other terms that may be used synonymously with the term “non-naturally encoded amino acid” are “non-natural amino acid,” “unnatural amino acid,” “non-naturally-occurring amino acid,” and variously hyphenated and non-hyphenated versions thereof. The term “non-naturally encoded amino acid” also includes, but is not limited to, amino acids that occur by modification (e.g. post-translational modifications) of a naturally encoded amino acid (including but not limited to, the 20 common amino acids or pyrolysine and seienocysteine) but are not themselves naturally incorporated into a growing polypeptide chain by the translation complex. Examples of such non-naturally-occurring amino acids include, but are not limited to, N-acetylglucosaminyl-L-serine , N-acetylglucosaminyl-L-threonine, and O-phosphotyrosine.
An “amino terminus modification group” refers to any molecule that can be attached to the amino terminus of a polypeptide. Similarly, a “carboxy terminus modification group” refers to any molecule that can be attached to the carboxy terminus of a polypeptide. Terminus modification groups include, but are not limited to, various water soluble polymers, peptides or proteins such as serum albumin, immunoglobulin constant region portions such as Fc, or other moieties that increase serum half-life of peptides.
The terms “functional group”, “active moiety”, “activating group”, “leaving group”, “reactive site”, “chemically reactive group” and “chemically reactive moiety” are used in the art and herein to refer to distinct, definable portions or units of a molecule. The terms are somewhat synonymous in the chemical arts and are used herein to indicate the portions of molecules that perform some function or activity and are reactive with other molecules.
The term “linkage” or “linker” is used herein to refer to groups or bonds that normally are formed as the result of a chemical reaction and typically are covalent linkages. Hydrolytically stable linkages means that the linkages are substantially stable in water and do not react with water at useful pH values, including but not limited to, under physiological conditions for an extended period of time, perhaps even indefinitely. Hydrolytically unstable or degradable linkages mean that the linkages are degradable in water or in aqueous solutions, including for example, blood. Enzymatically unstable or degradable linkages mean that the linkage can be degraded by one or more enzymes. As understood in the art, PEG and related polymers may include degradable linkages in the polymer backbone or in the linker group between the polymer backbone and one or more of the terminal functional groups of the polymer molecule. For example, ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a biologically active agent generally hydrolyze under physiological conditions to release the agent. Other hydrolytically degradable linkages include, but are not limited to, carbonate linkages; imine linkages resulted from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; hydrazone linkages which are reaction product of a hydrazide and an aldehyde; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; peptide linkages formed by an amine group, including but not limited to, at an end of a polymer such as PEG, and a carboxyl group of a peptide; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5′ hydroxyl group of an oligonucleotide.
The term “biologically active molecule”, “biologically active moiety” or “biologically active agent” when used herein means any substance which can affect any physical or biochemical properties of a biological system, pathway, molecule, or interaction relating to an organism, including but not limited to, viruses, bacteria, bacteriophage, transposon, prion, insects, fungi, plants, animals, and humans In particular, as used herein, biologically active molecules include, but are not limited to, any substance intended for diagnosis, cure, mitigation, treatment, or prevention of disease in humans or other animals, or to otherwise enhance physical or mental well-being of humans or animals. Examples of biologically active molecules include, but are not limited to, peptides, proteins, enzymes, small molecule drugs, hard drugs, soft drugs, carbohydrates, inorganic atoms or molecules, dyes, lipids, nucleosides, radionuclides, oligonucleotides, toxins, cells, viruses, liposomes, microparticles and micelles. Classes of biologically active agents that are suitable for use with the invention include, but are not limited to, drugs, prodrugs, radionuclides, imaging agents, polymers, antibiotics, fungicides, anti-viral agents, anti-inflammatory agents, anti-tumor agents, cardiovascular agents, anti-anxiety agents, hormones, growth factors, steroidal agents, microbially derived toxins, and the like.
A “bifunctional polymer” refers to a polymer comprising two discrete functional groups that are capable of reacting specifically with other moieties (including but not limited to, amino acid side groups) to form covalent or non-covalent linkages. A bifunctional linker having one functional group reactive with a group on a particular biologically active component, and another group reactive with a group on a second biological component, may be used to form a conjugate that includes the first biologically active component, the bifunctional linker and the second biologically active component. Many procedures and linker molecules for attachment of various compounds to peptides are known. See, e.g., European Patent Application No 188,256; U.S. Pat. Nos. 4,671,958, 4,659,839, 4,414,148, 4,699,784; 4,680,338; 4,569,789; and 4,589,071 which are incorporated by reference herein. A “multi-functional polymer” refers to a polymer comprising two or more discrete functional groups that are capable of reacting specifically with other moieties (including but not limited to, amino acid side groups) to form covalent or non-covalent linkages. A bi-functional polymer or multi-functional polymer may be any desired molecular length or molecular weight, and may be selected to provide a particular desired spacing or conformation between one or more molecules linked to the analog and its binding partner or the analog.
Representative non-limiting classes of polypeptides useful in the present invention include those falling into the following therapeutic categories: adrenocorticotropic hormone peptides, adrenomedullin peptides, allatostatin peptides, amylin peptides, amyloid beta-protein fragment peptides, angiotensin peptides, antibiotic peptides, antigenic polypeptides, anti-microbial peptides, apoptosis related peptides, atrial natriuretic peptides, bag cell peptides, bombesin peptides, bone GLA peptides, bradykinin peptides, brain natriuretic peptides, C-peptides, C-type natriuretic peptides, calcitonin peptides, calcitonin gene related peptides, CART peptides, casomorphin peptides, chemotactic peptides, cholecystokinin peptides, colony-stimulating factor peptides, corticortropin releasing factor peptides, cortistatin peptides, cytokine peptides, dermorphin peptides, dynorphin peptides, endorphin peptides, endothelin peptides, ETa receptor antagonist peptides, ETh receptor antagonist peptides, enkephalin peptides, fibronectin peptides, galanin peptides, gastrin peptides, glucagon peptides, Gn-RH associated peptides, growth factor peptides, growth hormone peptides, GTP-binding protein fragment peptides, guanylin peptides, inhibin peptides, insulin peptides, interleukin peptides, laminin peptides, leptin peptides, leucokinin peptides, luteinizing hormone-releasing hormone peptides, mastoparan peptides, mast cell degranulating peptides, melanocyte stimulating hormone peptides, morphiceptin peptides, motilin peptides, neuro-peptides, neuropeptide Y peptides, neurotropic factor peptides, orexin peptides, opioid peptides, oxytocin peptides, PACAP peptides, pancreastatin peptides, pancreatic polypeptides, parathyroid hormone peptides, parathyroid hormone-related peptides, peptide T peptides, prolactin-releasing peptides, peptide YY peptides, renin substrate peptides, secretin peptides, somatostatin peptides, substance P peptides, tachykinin peptides, thyrotropin-releasing hormone peptides, toxin peptides, vasoactive intestinal peptides, vasopressin peptides, and virus related peptides. (see U.S. Pat. No. 6,858,580). Examples of polypeptides include, but are not limited to, pituitary hormones such as vasopressin, oxytocin, melanocyte stimulating hormones, adrenocorticotropic hormones, growth hormones; hypothalamic hormones such as growth hormone releasing factor, corticotropin releasing factor, prolactin releasing peptides, gonadotropin releasing hormone and its associated peptides, luteinizing hormone release hormones, thyrotropin releasing hormone, orexins, and somatostatin; thyroid hormones such as calcitonins, calcitonin precursors, and calcitonin gene related peptides; parathyroid hormones and their related proteins; pancreatic hormones such as insulin and insulin-like peptides, glucagon, somatostatin, pancreatic polypeptides, amylin, peptide YY, and neuropeptide Y; digestive hormones such as gastrin, gastrin releasing peptides, gastrin inhibitory peptides, cholecystokinin, secretin, motilin, and vasoactive intestinal peptide; natriuretic peptides such as atrial natriuretic peptides, brain natriuretic peptides, and C-type natriuretic peptides; neurokinins such as neurokinin A, neurokinin B, and substance P; renin related peptides such as renin substrates and inhibitors and angiotensins; endothelins, including big endothelin, endothelin A receptor antagonists, and sarafotoxin peptides; and other peptides such as adrenomedullin peptides, allatostatin peptides, amyloid beta protein fragments, antibiotic and antimicrobial peptides, apoptosis related peptides, bag cell peptides, bombesin, bone Gla protein peptides, CART peptides, chemotactic peptides, cortistatin peptides, fibronectin fragments and fibrin related peptides. FMRF and analog peptides, galanin and related peptides, growth factors and related peptides, G therapeutic peptide-binding protein fragments, guanylin and uroguanylin, inhibin peptides, interleukin and interleukin receptor proteins, laminin fragments, leptin fragment peptides, leucokinins, mast cell degranulating peptides, pituitary adenylate cyclase activating polypeptides, pancreastatin, peptide T, polypeptides, virus related peptides, signal transduction reagents, toxins, and miscellaneous peptides such as adjuvant peptide analogs, alpha mating factor, antiarrhythmic peptide, antifreeze polypeptide, anorexigenic peptide, bovine pineal antireproductive peptide, bursin, C3 peptide P16, tumor necrosis factor, cadherin peptide, chromogranin A fragment, contraceptive tetrapeptide, conantokin G, conantokin T, crustacean cardioactive peptide, C-telopeptide, cytochrome b588 peptide, decorsin, delicious peptide, delta-sleep-inducing peptide, diazempam-binding inhibitor fragment, nitric oxide synthase blocking peptide, OVA peptide, platelet calpain inhibitor (P1), plasminogen activator inhibitor 1, rigin, schizophrenia related peptide, serum thymic factor, sodium potassium A therapeutic peptidease inhibitor-1, speract, sperm activating peptide, systemin, thrombin receptor agonists, thymic humoral gamma2 factor, thymopentin, thymosin alpha 1, thymus factor, tuftsin, adipokinetic hormone, uremic pentapeptide, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-1), exendin-3, exendin-4, and other therapeutic peptides or fragments thereof. Additional examples of peptides include ghrelin, opioid peptides (casomorphin peptides, demorphins, endorphins, enkephalins, deltorphins, dynorphins, and analogs and derivatives of these), thymic peptides (thymopoietin, thymulin, thymopentin, thymosin, Thymic Humoral Factor (THF)), cell adhesion peptides, complement inhibitors, thrombin inhibitors, trypsin inhibitors, alpha-1 antitrypsin, Sea Urchin Sperm Activating Peptide, Asterosap, SHU-9119 MC3-R & MC4-R Antagonist, glaspimod (immunostimulant, useful against bacterial infections, fungal infections, immune deficiency immune disorder, leukopenia), HP-228 (melanocortin, useful against chemotherapy induced emesis, toxicity, pain, diabetes mellitus, inflammation, rheumatoid arthritis, obesity), alpha 2-plasmin inhibitor (plasmin inhibitor), APC tumor suppressor (tumor suppressor, useful against neoplasm), early pregnancy factor (immunosuppressor), endozepine diazepam binding inhibitor (receptor peptide), gamma interferon (useful against leukemia), glandular kallikrein-1 (immunostimulant), placental ribonuclease inhibitor, sarcolecin binding protein, surfactant protein D, Wilms' tumor suppressor, GABAB lb receptor peptide, prion related peptide (iPrP13), choline binding protein fragment (bacterial related peptide), telomerase inhibitor, cardiostatin peptide, endostatin derived peptide (angiogenesis inhibitor), prion inhibiting peptide, N-methyl D-aspartate receptor antagonist, C-peptide analog (useful against diabetic complications), RANTES, NTY receptors, NPY2-R (neuropeptide Y type 2-receptor) ligands, NC4R peptides, or fragments thereof. Other analogs and polypeptides upon which the analogs of the instant invention are derived are found in U.S. Pat. No. 6,849,714 which is incorporated by reference herein.
The hormones regulating insulin secretion belong to the so-called enteroinsular axis, designating a group of hormones released from the gastrointestinal mucosa in response to the presence and absorption of nutrients in the gut, which promote an early and potentiated release of insulin. The enhancing effect on insulin secretion, the so-called incretin effect, is probably essential for a normal glucose tolerance. Many of the gastrointestinal hormones, including gastrin and secretin (cholecystokinin is not insulinotropic in man), are insulinotropic, but the only physiologically important ones, those that are responsible for the incretin effect, are the glucose-dependent insulinotropic polypeptide, GIP, and glucagon-like peptide-1 (GLP-1).
GIP is composed of 42 amino acids, processed from a 153 amino acid precursor (Takeda et al., PNAS USA (1987) 84:7005-7008). GIP is secreted by K cells present in the duodenum and in the small intestinal mucosa in response to carbohydrate and lipid containing meals (Mortensen et al. Ann. NY Acad. Sci. (2000) 921:469-472). Expression of the GIP receptor has been shown in pancreatic islets, the adrenal cortex, gut, heart, adipose tissue, several regions of the brain, and the pituitary gland (Usdin et al. (1993) Endocrinology 133:2861-2870).
Because of its insulinotropic effect, GIP, isolated in 1973 (Pederson R A. Gastric Inhibitory Polypeptide. In Walsh J H, Dockray G J (eds.) Gut peptides: Biochemistry and Physiology. Raven Press, New York 1994, pp. 217-259) immediately attracted considerable interest among diabetologists. However, numerous investigations carried out during the following years clearly indicated that a defective secretion of GIP was not involved in the pathogenesis of insulin dependent diabetes mellitus (IDDM) or non insulin-dependent diabetes mellitus (NIDDM) (Krarup T., Endocr Rev 1988; 9: 122-134). Furthermore, as an insulinotropic hormone, GIP was found to be almost ineffective in NIDDM (Krarup T., Endocr Rev 1988; 9: 122-134). The other incretin hormone, GLP-1 is the most potent insulinotropic substance known (O'rskov C., Diabetologia 1992; 35:701-711). Unlike GIP, it is surprisingly effective in stimulating insulin secretion in NIDDM patients. In addition, and in contrast to the other insulinotropic hormones (perhaps with the exception of secretin), it also potently inhibits glucagon secretion. Because of these actions, it has pronounced blood glucose lowering effects particularly in patients with NIDDM.
GLP-1, a product of the proglucagon gene (Bell G I, et al., Nature 1983; 304: 368-371), is one of the members of the secretin-VIP family of peptides, and is established as an important gut hormone with regulatory function in glucose metabolism and gastrointestinal secretion and metabolism (Hoist J J., 1994; Gastroenterology. 1994 December; 107(6):1848-55). The glucagon gene is processed differently in the pancreas and in the intestine. In the pancreas (Hoist J J, et al., J Biol Chem, 1994; 269: 18827-18833), the processing leads to the formation and parallel secretion of 1) glucagon itself, occupying positions 33-61 of proglucagon (PG); 2) an N-terminal peptide of 30 amino acids (PG (1-30)) often called glicentin-related pancreatic peptide, GRPP (Moody A J, et al., Nature 1981; 289: 514-516; Thim L, et al., Biochim Biophys Acta 1982; 703:134-141); 3) a hexapeptide corresponding to PG (64-69); 4) and, finally, the so-called major proglucagon fragment (PG (72-158)), in which the two glucagon-like sequences are buried (Hoist J J, et al., J Biol Chem, 1994; 269: 18827-18833). Glucagon seems to be the only biologically active product. In contrast, in the intestinal mucosa, it is glucagon that is buried in a larger molecule, while the two glucagon-like peptides are formed separately (O'rskov C, et al., Endocrinology 1986; 119:1467-1475). The following products are formed and secreted in parallel: 1) glicentin, corresponding to PG (1-69), with the glucagon sequence occupying residues Nos. 33-61 (Thim L, et al., Regul Pept 1981; 2:139-151); 2) GLP-1(7-36)amide (PG (78-107))amide (O'rskov C, et al., J. Biol. Chem. 1989; 264:12826-12829), not as originally believed PG (72-107)amide or 108, which is inactive). Small amounts of C-terminally glycine-extended but equally bioactive GLP-1(7-37), (PG (78-108)) are also formed (Orskov C, et al., Diabetes 1991; 43: 535-539); 3) intervening peptide-2 (PG (111-122)amide) (Buhl T, et al., J. Biol. Chem. 1988; 263:8621-8624); and 4) GLP-2 (PG (126-158)) (Buhl T, et al., J. Biol. Chem. 1988; 263:8621-8624; O'rskov C, et al., FEBS letters, 1989; 247:193-106). A fraction of glicentin is cleaved further into GRPP (PG (1-30)) and oxyntomodulin (PG (33-69)) (Hoist J J. Biochem J. 1980; 187:337-343; Bataille D, et al., FEBS Lett 1982; 146:79-86).
Being secreted in parallel with glicentin/enteroglucagon, it follows that the many studies of enteroglucagon secretion (Hoist J J., Gastroenterology 1983; 84:1602-1613; Hoist J J, et al., Glucagon and other proglucagon-derived peptides. In Walsh J H, Dockray G J, eds. Gut peptides: Biochemistry and Physiology. Raven Press, New York, pp. 305-340, 1993) to some extent also apply to GLP-1 secretion, but GLP-1 is metabolized more quickly with a plasma half-life in humans of 2 minutes (O'rskov C, et al., Diabetes 1993; 42:658-661). Carbohydrate or fat-rich meals stimulate secretion (Elliott R M, et al., J Endocrinol 1993; 138: 159-166), presumably as a result of direct interaction of yet unabsorbed nutrients with the microvilli of the open-type L-cells of the gut mucosa.
The incretin function of GLP-1(29-31) has been clearly illustrated in experiments with the GLP-1 receptor antagonist, exendin 9-39, which dramatically reduces the incretin effect elicited by oral glucose in rats (Kolligs F, et al., Diabetes 1995 44: 16-19; Wang Z, et al., J. Clin. Invest. 1995 95: 417-421). The hormone interacts directly with the β-cells via the GLP-1 receptor (Thorens B., Proc Natl Acad Sci 1992; 89:8641-4645, U.S. Pat. Nos. 5,670,360 and 6,051,689, which are incorporated by reference herein) which belongs to the glucagon/VIP/calcitonin family of G-protein-coupled 7-transmembrane spanning receptors. The importance of the GLP-1 receptor in regulating insulin secretion was illustrated in recent experiments in which a targeted disruption of the GLP-1 receptor gene was carried out in mice. Animals homozygous for the disruption had greatly deteriorated glucose tolerance and fasting hyperglycaemia, and even heterozygous animals were glucose intolerant (Scrocchi L, et al., Diabetes 1996; 45: 21A). The signal transduction mechanism (Fehmann H C, et al., Endocrine Reviews, 1995; 16: 390-410) primarily involves activation of adenylate cyclase, but elevations of intracellular Ca²⁺ are also essential (Fehmann H C, et al., Endocrine Reviews, 1995; 16: 390-410; Gromada J, et al., Diabetes 1995; 44: 767-774). A model of GLP-1 receptor-ligand interaction is shown in Lopez de Maturana, R. et al. (2003) J. Biol. Chem. 278, 10195-10200. Lopez de Maturana et al. indicate that the N-terminal domain of the receptor binds to the conserved face of the central helix of exendin-4, GLP-1, and exendin (9-39). The N-terminal regions of exendin-4 and GLP-1 interact with the extracellular loops and/or the transmembrane regions of the GLP-1R. Also the N-terminal domain of the receptor interacts with the Trp-cage portion of the exendin-4 and exendin (9-39). Neidigh et al. Nature Structural Biology (2002) 9(6):425-430 describe the Trp-cage structure of Exendin-4 and mutants thereof.
The action of the hormone is best described as a potentiation of glucose stimulated insulin release (Fehmann H C, et al., Endocrine Reviews, 1995; 16: 390-410), but the mechanism that couples glucose and GLP-1 stimulation is not known. It may involve a calcium-induced calcium release (Gromada J, et al., Diabetes 1995; 44: 767-774; Holz G G. et al., J Biol Chem, 1996; 270: 17749-17759). As already mentioned, the insulinotropic action of GLP-1 is preserved in diabetic P-cells. The relation of the latter to its ability to convey “glucose competence” to isolated insulin-secreting cells (Gromada J, et al., Diabetes 1995, 44: 767-774; Holz G G, et al., Nature 1993, 361:362-365), which respond poorly to glucose or GLP-1 alone, but fully to a combination of the two, is also not known. Equally importantly, however, the hormone also potently inhibits glucagon secretion (O'rskov C, et al., Endocrinology 1988; 123:2009-2013). The mechanism is not known, but seems to be paracrine, via neighbouring insulin or somatostatin cells (Fehmann H C, et al., Endocrine Reviews, 1995; 16: 390-410). Also the glucagonostatic action is glucose-dependent, so that the inhibitory effect decreases as blood glucose decreases. Because of this dual effect, if the plasma GLP-1 concentrations increase either by increased secretion or by exogenous infusion, the molar ratio of insulin to glucagon in the blood that reaches the liver via the portal circulation is greatly increased, whereby hepatic glucose production decreases (Hvidberg A, et al., Metabolism 1994; 43:104-108). As a result blood glucose concentrations decrease. Because of the glucose dependency of the insulinotropic and glucagonostatic actions, the glucose lowering effect is self-limiting, and the hormone, therefore, does not cause hypoglycaemia regardless of dose (Qualmann C, et al., Acta Diabetologica, 1995; 32: 13-16). The effects are preserved in patients with diabetes mellitus (Nauck M A, et al., J Clin Invest 1993; 91:301-307), in whom infusions of slightly supraphysiological doses of GLP-1 may completely normalise blood glucose values in spite of poor metabolic control and secondary failure to sulphonylurea (Nauck M A, et al., Diabetologia 1993; 36:741-744). The importance of the glucagonostatic effect is illustrated by the finding that GLP-1 also lowers blood glucose in type-I diabetic patients without residual P-cell secretory capacity (Creutzfeldt W, et al., Diabetes Care 1996; 19: 580-586).
GLP-1 is involved in increasing beta-cell mass as well as regulating beta-cell differentiation, beta-cell proliferation and beta-cell survival (Stoffers D A, Horm Metab Res. 2004 November-December; 36(11-12):811-21), and has a role in increasing proinsulin gene transcription and biosynthesis.
In addition to its effects on the pancreatic islets, GLP-1 has powerful actions on the gastrointestinal tract. Infused in physiological amounts, GLP-1 potently inhibits pentagastrin-induced as well as meal-induced gastric acid secretion (Schjoldager B T G, et al., Dig. Dis. Sci. 1989; 35:703-708; Wettergren A, et al., Dig Dis Sci 1993; 38:665-673). It also inhibits gastric emptying rate and pancreatic enzyme secretion (Wettergren A., et al., Dig Dis Sci 1993; 38:665-673). Similar inhibitory effects on gastric and pancreatic secretion and motility may be elicited in humans upon perfusion of the ileum with carbohydrate- or lipid-containing solutions (Layer P, et al., Dig Dis Sci 1995; 40: 1074-1082; Layer P, et al., Digestion 1993; 54: 385-386). Concomitantly, GLP-1 secretion is greatly stimulated, and it has been speculated that GLP-1 may be at least partly responsible for this so-called “ileal-brake” effect (Layer P, et al., Digestion 1993; 54: 385-386). In fact, recent studies suggest that, physiologically, the ileal-brake effects of GLP-1 may be more important than its effects on the pancreatic islets. Thus, in dose response studies GLP-1 influences gastric emptying rate at infusion rates at least as low as those required to influence islet secretion (Nauck M, et al., Gut 1995; 37 (suppl. 2): A124).
GLP-1 seems to have an effect on food intake. Intraventricular administration of GLP-1 profoundly inhibits food intake in rats (Schick R R, vorm Walde T, Zimmermann J P, Schusdziarra V, Classen M. Glucagon-like peptide 1—a novel brain peptide involved in feeding regulation. in Ditschuneit H, Gries F A, Hauner H, Schusdziarra V, Wechsler J G (eds.) Obesity in Europe. John Libbey & Company Ltd., 1994; pp. 363-367; 42). This effect seems to be highly specific. Thus, N-terminally extended GLP-1 (PG 72-107) amide is inactive and appropriate doses of the GLP-1 antagonist, exendin 9-39, abolish the effects of GLP-1. Acute, peripheral administration of GLP-1 does not inhibit food intake acutely in rats (Turton M D, et al., Nature 1996; 379: 69-72). However, it remains possible that GLP-1 secreted from the intestinal L-cells may also act as a satiety signal.
Not only the insulinotropic effects but also the effects of GLP-1 on the gastrointestinal tract are preserved in diabetic patients (Willms B, et al., Diabetologia 1994; 37, supp1.1: A118), and may help curtailing meal-induced glucose excursions, but, more importantly, may also influence food intake. Administered intravenously, continuously for one week, GLP-1 at 4 ng/kg/min has been demonstrated to dramatically improve glycaemic control in NIDDM patients without significant side effects (Larsen J, et al., Diabetes 1996; 45, suppl. 2: 233A). The peptide is fully active after subcutaneous administration (Ritzel R, et al., Diabetologia 1995; 38: 720-725), but is rapidly degraded mainly due to degradation by dipeptidyl peptidase IV-like enzymes (Deacon C F, et al., J Clin Endocrinol Metab 1995; 80: 952-957; Deacon C F, et al., Diabetes 44: 1126-1131).
The amino acid sequence of GLP-1 is disclosed in Schmidt et al. (Diabetologia 28 704-707 (1985). Human GLP-1 is a 30-31 amino acid residue peptide originating from preproglucagon which is synthesized, i.a. in the L-cells in the distal ileum, in the pancreas and in the brain. Processing of preproglucagon to GLP-1(7-36)amide, GLP-1(7-37) and GLP-2 occurs mainly in the L-cells. Although the interesting pharmacological properties of GLP-1(7-37) and analogues thereof have attracted much attention in recent years only little is known about the structure of these molecules. The secondary structure of GLP-1 in micelles has been described by Thorton et al. (Biochemistry 33: 3532-3539 (1994)), but in normal solution, GLP-1 is considered a very flexible molecule. Derivatisation of this relatively small and very flexible molecule resulted in compounds whose plasma profile were highly protracted and still had retained activity.
GLP-1 and analogues of GLP-1 and fragments thereof are useful i.e. in the treatment of Type 1 and Type 2 diabetes and obesity.
WO 87/06941 discloses GLP-1 fragments, including GLP-1(7-37), and functional derivatives thereof and to their use as an insulinotropic agent. GLP-1(7-37), certain derivatives thereof and the use thereof to treat Diabetes mellitus in a mammal are disclosed in U.S. Pat. No. 5,120,712, which is incorporated by reference herein.
WO 90/11296 discloses GLP-1 fragments, including GLP-1(7-36), and functional derivatives thereof which have an insulinotropic activity which exceeds the insulinotropic activity of GLP-1(1-36) or GLP-1(1-37) and to their use as insulinotropic agents.
The amino acid sequence of GLP-1(7-36) and GLP-1(7-37) is: His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-X, wherein X is NH₂for GLP-1(7-36) (SEQ ID NO: 1330) and X is Gly for GLP-1(7-37) (SEQ ID NO: 1331).
WO 91/11457 discloses analogues of the active GLP-1 peptides 7-34, 7-35, 7-36, and 7-37 which can also be useful as GLP-1 moieties.
EP 0708179-A2 discloses GLP-1-like polypeptides and derivatives that include an N-terminal imidazole group and optionally an unbranched C₆-C₁₀acyl group in attached to the lysine residue in position 34.
EP 0699686-A2 discloses certain N-terminal truncated fragments of GLP-1 that are reported to be biologically active.
In some embodiments the compositions, pharmaceutical compositions comprise analogs, wherein the analog amino acid sequence is based upon the GLP-1 fragments, polypeptides, and functional derivatives disclosed above.
Another example of a peptide is T-20 (DP-178) which is a peptide corresponding to amino acids 638 to 673 of the HIV-1_LAItransmembrane protein (TM) gp41, the carboxyl-terminal helical segment of the extracellular portion of gp41. The extracellular portion of gp41 has another .alpha.-helical region which is the amino-terminal proposed zipper domain, DP-107, DP-107 exhibits potent antiviral activity by inhibiting viral fusion. It is a 38 amino acid peptide, corresponding to residues 558 to 595 of the HIV-1_LAItransmembrane gp41 protein. Studies with DP-107 have proven both are non-toxic in in vitro studies and in animals. U.S. Pat. No. 5,656,480, which is incorporated by reference herein, describes DP-107 and its antiviral activity. In some embodiments the compositions, pharmaceutical compositions comprise analogs, wherein the analog amino acid sequence is based upon the DP-107 fragments, polypeptides, and functional derivatives disclosed.
T-20 inhibits entry of HIV into cells by acting as a viral fusion inhibitor. The fusion process of HIV is well characterized. HIV binds to CD4 receptor via gp120, and upon binding to its receptor, gp120 goes through a series of conformational changes that allows it to bind to its coreceptors, CCR5 or CXCR4. After binding to both receptor and coreceptor, gp120 exposes gp41 to begin the fusion process. gp41 has two regions named heptad repeat 1 and 2 (HR1 and 2). The extracellular domain identified as HR1 is an β.-helical region which is the amino-terminal of a proposed zipper domain HR1 comes together with HR2 of gp41 to form a hairpin. The structure that it is formed is a α-helix bundle that places the HIV envelope in the proximity of the cellular membrane causing fusion between the two membranes. T-20 prevents the conformational changes necessary for viral fusion by binding the first heptad-repeat (HR1) of the gp41 transmembrane glycoprotein. Thus, the formation of the 6-helix bundle is blocked by T-20's binding to the HR1 region of gp41. The DP107 and DP178 domains (i.e., the HR1 and HR2 domains) of the HIV gp41 protein non-covalently complex with each other, and their interaction is required for the normal infectivity of the virus. Compounds that disrupt the interaction between DP107 and DP178, and/or between DP107-like and DP178-like peptides are antifusogenic, including antiviral.
DP-178 acts as a potent inhibitor of HIV-1 mediated CD-4⁺ cell-cell fusion (i.e., syncytial formation) and infection of CD-4⁺ cells by cell-free virus. Such anti-retroviral activity includes, but is not limited to, the inhibition of HIV transmission to uninfected CD-4⁺ cells. DP-178 act at low concentrations, and it has been proven that it is non-toxic in in vitro studies and in animals The amino acid conservation within the DP-178—corresponding regions of HIV-1 and HIV-2 has been described.
Potential uses for DP-178 peptides are described in U.S. Pat. Nos. 5,464,933 and 6,133,418, as well as U.S. Pat. Nos. 6,750,008 and 6,824,783, all of which are incorporated by reference herein, for use in inhibition of fusion events associated with HIV transmission.
Portions and homologs of DP178 and DP-107 as well as modulators of DP178/DP107, DP178-like/DP107-like or HR1/HR2 interactions have been investigated that show antiviral activity, and/or show anti-membrane fusion capability, or an ability to modulate intracellular processes involving coiled-coil peptide structures in retroviruses other than HIV-1 and nonretroviral viruses. Viruses in such studies include, simian immunodeficiency virus (U.S. Pat. No. 6,017,536), respiratory synctial virus (U.S. Pat. Nos. 6,228,983; 6,440,656; 6,479,055; 6,623,741), Epstein-Barr virus (U.S. Pat. Nos. 6,093,794; 6,518,013), parainfluenza virus (U.S. Pat. No. 6,333,395), influenza virus (U.S. Pat. Nos. 6,068,973; 6,060,065), and measles virus (U.S. Pat. No. 6,013,263). All of which are incorporated by reference herein.
A commercially available form of DP-178 is Fuzeon® (enfuvirtide, Roche Laboratories Inc. and Trimeris, Inc.). Fuzeon® has an acetylated N terminus and a carboxamide as the C-terminus, and is described by the following primary amino acid sequence: CH₃CO-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF--NH₂(SEQ ID NO: 784). It is used in combination with other antivirals in HIV-1 patients that show HIV-1 replication despite ongoing antiretroviral therapy.
U.S. Pat. Nos. 5,464,933 and 6,824,783, which are incorporated by reference herein, describes DP-178, DP-178 fragments and homologs, including, but not limited to, molecules with amino and carboxy terminal truncations, substitutions, insertions, deletions, additions, or macromolecular carrier groups as well as DP-178 molecules with chemical groups such as hydrophobic groups present at their amino and/or carboxy termini Additional variants, include but are not limited to, those described in U.S. Pat. No. 6,830,893 and the derivatives of DP-178 disclosed in U.S. Pat. No. 6,861,059. A set of T-20 hybrid polypeptides are described in U.S. Pat. Nos. 6,656,906, 6,562,787, 6,348,568 and 6,258,782, and a DP-178-toxin fusion is described in U.S. Pat. No. 6,627,197. In some embodiments the compositions, pharmaceutical compositions comprise analogs, wherein the analog amino acid sequence is based upon the T-20 and DP-178 fragments, polypeptides, and functional derivatives disclosed above.
HAART (Highly Active Anti-Retroviral Therapy) is the standard of therapy for HIV which combines drugs from a few classes of antiretroviral agents to reduce viral loads. U.S. Pat. No. 6,861,059, which is incorporated by reference herein, discloses methods of treating HIV-1 infection or inhibiting HIV-1 replication employing DP-178 or DP-107 or derivatives thereof, in combination with at least one other antiviral therapeutic agent such as a reverse transcriptase inhibitor (e.g. AZT, ddI, ddC, ddA, d4T, 3TC, or other dideoxynucleotides or dideoxyfluoronucleosides) or an inhibitor of HIV-1 protease (e.g. indinavir; ritonavir). Other antivirals include cytokines (e.g., rIFN.alpha., rIFN.beta., rIFN.gamma.), inhibitors of viral mRNA capping (e.g. ribavirin), inhibitors of HIV protease (e.g. ABT-538 and MK-639), amphotericin B as a lipid-binding molecule with anti-HIV activity, and castanospermine as an inhibitor of glycoprotein processing. In some embodiments, the pharmaceutical compositions comprises an analog of T20, wherein the analog amino acid sequence is based upon the T20 fragments, polypeptides, and functional derivatives disclosed above. In some embodiments, the pharmaceutical composition comprises an analog of T20, wherein the analog amino acid sequence is based upon the T20 fragments, polypeptides, and functional derivatives disclosed above and one other anti-viral agent. In some embodiments the pharmaceutical composition of the claimed invention comprises one another anti-viral agent chosen from the following: reverse transcriptase inhibitors, integrase inhibitors, protease inhibitors, cytokine antagonists, and chemokine receptor modulators described U.S. Pat. Nos. 6,855,724; 6,844,340; 6,841,558; 6,833,457; 6,825,210; 6,811,780; 6,809,109; 6,806,265; 6,768,007; 6,750,230; 6,706,706; 6,696,494; 6,673,821; 6,673,791; 6,667,314; 6,642,237; 6,599,911; 6,596,729; 6,593,346; 6,589,962; 6,586,430; 6,541,515; 6,538,002; 6,531,484; 6,511,994; 6,506,777; 6,500,844; 6,498,161; 6,472,410; 6,432,981; 6,410,726; 6,399,619; 6,395,743; 6,358,979; 6,265,434; 6,248,755; 6,245,806; and 6,172,110, which are incorporated by reference.
Potential delivery systems for DP-178 include, but are not limited to those described in U.S. Pat. Nos. 6,844,324 and 6,706,892. In addition, a process for producing T-20 in inclusion bodies was described in U.S. Pat. No. 6,858,410.
T20/DP178, T21/DP107, and fragments thereof have also been found to interact with N-formyl peptide receptor (FPR members). T-20 activates the N-formyl peptide receptor present in human phagocytes (Su et al. (1999) Blood 93(11):3885-3892) and is a chemoattractant and activator of monocytes and neutrophils (see U.S. Pat. No. 6,830,893). The FPR class receptors are G-protein-coupled, STM receptors that bind the chemoattractant fMLP (N-formyl-methionyl-leucyl-phenylalanine) and are involved in monocyte chemotaxis and the induction of a host immune response to a pathogen. The prototype FPR class receptor, FPR, binds fMLP with high affinity and is activated by low concentrations of fMLP. The binding of FPR by fMLP induces a cascade of G protein-mediated signaling events leading to phagocytic cell adhesion, chemotaxis, release of oxygen intermediates, enhanced phagocytosis and bacterial killing, as well as MAP kinase activation and gene transcription. (Krump et al., J Biol Chem 272:937 (1997); Prossnitz et al., Pharmacol Ther 74:73 (1997); Murphy, Annu. Rev. Immuno. 12: 593 (1994); and Murphy, The N-formyl peptide chemotactic receptors, Chemoattractant ligands and their receptors. CRC Press, Boca Raton, p. 269 (1996)). Another FPR class receptor is the highly homologous variant of FPR, named FPRL1 (also referred to as FPRH2 and LXA4R). FPRL1 was originally cloned as an orphan receptor (Murphy et al., J. Biol. Chem., 267:7637-7643 (1992); Ye et al., Biochem. Biophys. Res. Commun., 184:582-589 (1992); Bao et al., Genomics, 13:437-440 (1992); Gao, J. L. and P. M. Murphy, J. Biol. Chem., 268:25395-25401 (1993); and Nomura et al., Int. Immunol., 5:1239-1249 (1993)) but was subsequently found to mediate Ca²⁺ mobilization in response to high concentrations of fMLP. (Ye et al., Biochem. Biophys. Res. Commun., 184:582-589 (1992); and Gao, J. L. and P. M. Murphy, J. Biol. Chem. 268:25395-25401 (1993)). In some embodiments, the invention relates to a method of modulating an FPR member or CCR5 by:
a) contacting the FPR member or CCR5 molecule with a T20 analog, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the T20 analog to the FPR member or CCR5 in the presence and absence of an unknown compound; and
c) comparing the rate of association of the T20 analog to the FPR member or CCR5 in the presence of an unknown compound to the rate of association of the T20 analog to the FPR member or CCR5 in the absence of an unknown compound.
The chemokine receptor CCR5 is another G-protein-coupled, STM receptor and is a major fusion-cofactor exploited by most primary isolates of the human immunodeficiency virus type 1 (HIV-1). (Al Khatib et al., Science 1996, 272:1955; Doranz et al., Cell 1996, 85:1149; Deng et al., Nature 1996, 381:661; Dragic et al., Nature 1996; 381:667; Horuk, Immunol Today, 20:89 (1999); Dimitrov and Broder, “HIV and Membrane Receptors,” HIV and membrane fusion: Medical Intelligence Unit, Landes Bioscience, Austin, Tex., 1997:99; and Berger, AIDS 11, Suppl A:S3 (1997)). Individuals that fail to express CCR5 are largely resistant to HIV-1 infection. (Liu et al., Cell 1996, 86:367-77; Huang, Y, Nat Med 1996, 2:1240; Dean, et al., Science, 273:1856 (1996)). Due to its prominent role in HIV-1 fusion and entry, investigators have focused considerable research on developing molecules that interrupt the interaction between the HIV-1 envelope and CCR5. Chemokine ligands and antibodies specific for CCR5, for example, have been shown to inhibit HIV-1 entry and replication. (Cocchi et al., Science, 270:1811 (1995); Wu et al., J Exp Med, 186: 373 (1997); Proudfoot et al., J Biol Chem, 271:2599 (1996); Arenzana-Seisdedos et al., Nature, 383:400 (1996); Gong et al., J Biol Chem, 273:4289 (1998)). U.S. Pat. No. 6,808,877 discusses DP-178 and its role in phosphorylation and downregulation of CCR5 and/or the inhibition of HIV infection by acting as a ligand to the N-formyl peptide receptor.
Peptide YY (PYY) is a thirty six amino acid long peptide, first isolated from porcine intestinal tissue and mainly localized in intestinal endocrine cells. PYY is secreted postprandially by endocrine cells of the distal gastrointestinal tract and acts at the hypothalamus signaling satiety. See Batterham, R. L. et al., Nature 418:650-654 (2002), which is incorporated by reference herein. It has many biological activities, including a range of activities within the digestive system and potent inhibition of intestinal electrolyte and fluid secretion. Like its relatives, neuropeptide Y (NPY) and pancreatic polypeptide (PP), peptide YY (PYY) is bent into hairpin configuration that is important in bringing the free ends of the molecule together for binding to the receptors.
Recent studies have shown that fasting and postprandial PYY levels are low in obese subjects, which may account for their high appetite and food consumption. When administered intravenously, it suppresses appetite and food intake in both lean and obese subjects (Batterham, R. L. et al., N Engl J Med 349:941-948 (2003)). Other peptides from the pancreatic peptide (PP) family, like peptide YY fragments (e.g. PYY{3-36}), and PYY agonists (including those not in the PP family) also suppress appetite. Its oral activity, however, is negligible due to its low absorption and rapid degradation in the gastrointestinal tract. PYY {3-36} is identified as Ile Lys pro Glu Ala Pro Gly Glu ASp Ala Ser Pro Glu Glu Leu Asn Arg Tyr Tyr Ala Ser Leu Arg His Tyr Leu Asn Leu val Thr Arg Gln Arg Tyr; Eberlein, Eysselein et al., Peptides 10:797-803 (1989); and Grandy, Schimiczek et al., Regul Pept 51:151-9 (1994), which are incorporated by reference herein.
PYY {3-36} has a sequence identical to PYY over amino acids 3 to 36. PYY{3-36} contains approximately 40% of total peptide YY-like immunoreactivity in human and canine intestinal extracts and about 36% of total plasma peptide YY immunoreactivity in a fasting state to slightly over 50% following a meal. It is apparently a dipeptidyl peptidase-IV (DPP4) cleavage product of peptide YY. Peptide YY{3-36} is reportedly a selective ligand at the Y2 and Y5 receptors, which appear pharmacologically unique in preferring N-terminally truncated (i.e. C terminal fragments of) neuropeptide Y analogs. A PYY agonist may bind to a PYY receptor with higher or lower affinity, demonstrate a longer or shorter half-life in vivo or in vitro, or be more or less effective than native PYY. In some embodiments a functional fragment of PYY{3-36} is a fragment of the above sequence that shares the immunoreactivity in human and canine intestinal extracts.
Current antiobesity drugs have limited efficacy and numerous side effects. Crowley, V. E., Yeo, G. S. & O'Rahilly, S., Nat. Rev. Drug Discov 1, 276-86 (2002). With obesity reaching epidemic proportions worldwide, there is a pressing need for the development of adequate therapeutics in this area. In recent years, hormones and neuropeptides involved in the regulation of appetite, body energy expenditure, and fat mass accumulation such as PYY have emerged as potential antiobesity drugs. See McMinn, J E, Baskin, D. G. & Schwartz, M. W., Obes Rev 1:37-46 (2000), Drazen, D. L. & Woods, S. C., Curr Opin Clin Nutr Metab Care 6:621-629 (2003), which are incorporated by reference herein.
According to Batterham et al., Nature 418:650-654 (2002), which is hereby incorporated by reference, the peptide YY {3-36} system may provide a therapeutic target for the treatment of obesity. International Publication No. WO 02/47712 and U.S. Patent Application Publication No. 2002/0141985 disclose methods for treating obesity and diabetes with peptide YY and peptide YY agonists, such as peptide YY13-361. U.S. Patent Application Publication No. 20050002927 describes the use of at least one Y2 receptor-binding peptide, such as peptide YY, Neuropeptide Y (NPY) or Pancreatic Peptide (PP) for treating a variety of diseases and conditions in mammalian subjects such as obesity and epilepsy. In some embodiments the compositions, pharmaceutical compositions comprise analogs, wherein the analog amino acid sequence is based upon the PPY or the peptide YY {3-36} fragments, polypeptides, and functional derivatives disclosed above. In some embodiments, the invention relates to a pharmaceutical composition that comprise a PPY or peptide YY {3-36} analog, wherein the analog amino acid sequence is based upon the fragments, polypeptides, and functional derivatives disclosed above for treatment of obesity, diabetes, seizures associated with temporal lobe epilepsy, ulcers, irritable bowel disease and inflammatory bowel disease according to the dosing regimens disclosed below.
In some embodiments, the compositions of the claimed invention comprise analog of PYY(3-36), AC162352, Neuropeptide Y (NPY) (U.S. Pat. No US 2005/0136036 A1).
In addition, treatment with DPP-IV inhibitors prevents degradation of Peptide YY which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease and inflammatory bowel disease. Peptide YY and its analogs or agonists have been used to manipulate endocrine regulation of cell proliferation, nutrient transport, and intestinal water and electrolyte secretion. (U.S. Pat. No. 5,604,203; WO9820885A1; EP692971A1; U.S. Pat. No. 5,912,227, which are incorporated by reference herein). A role for peptide YY in the regulation of intestinal motility, secretion, and blood flow has also been suggested, as well as its use in a treatment of malabsorptive disorders. Analogs of PYY have been reported that emulate and enhance the duration, effect, biological activity and selectivity of the natural peptide in the treatment of pancreatic tumors (See U.S. Ser. No. 5,574,010, incorporated herein by reference).
Other suitable PYY agonists include those described in International Publication No. WO 98/20885, which is hereby incorporated by reference.
In one aspect, the invention provides a method of treating obesity in an obese or overweight animal by administering a therapeutically effective amount of PYY analog, a PYY agonist analog, or a mixture thereof with at least one delivery agent compound and to a subject in need thereof. While “obesity” is generally defined as a body mass index over 30, for purposes of this disclosure, any subject, including those with a body mass index of less than 30, who needs or wishes to reduce body weight is included in the scope of “obese.” Subjects who are insulin resistant, glucose intolerant, or have any form of diabetes mellitus (e.g., type 1, 2 or gestational diabetes) can benefit from this method.
In other aspects, the invention features methods of reducing food intake, treating diabetes mellitus, and improving lipid profile (including reducing LDL cholesterol and triglyceride levels and/or changing HDL cholesterol levels) comprising administering to a subject in need thereof a therapeutically effective amount of a PYY analog, a PYY agonist analog, or a mixture thereof with at least one delivery agent compound. In some embodiments, the methods of the invention are used to treat conditions or disorders which can be alleviated by reducing nutrient availability in a subject in need thereof, comprising administering to said subject in need thereof a therapeutically effective amount of a PYY analog, a PYY agonist analog, or a mixture thereof with at least one delivery agent compound. Such conditions and disorders include, but are not limited to, hypertension, dyslipidemia, cardiovascular disease, eating disorders, insulin-resistance, obesity, and diabetes mellitus of any kind.
Suitable PYY agonist analogs may be derived or based upon the amino acid sequence of PYY agonists that have a potency in one of the assays described in WO 02/47712 and U.S. patent Publication No. 2002/0141985 (which is herein incorporated by reference and discloses the activity of food intake, gastric emptying, pancreatic secretion, or weight reduction assays) which is greater than the potency of NPY in that same assay. A PYY analog and/or a PYY agonist analog with the delivery agent compound may be administered separately or together with one or more other compounds and compositions that exhibit a long term or short-term action to reduce nutrient availability, including, but not limited to other compounds and compositions that comprise an amylin or amylin agonist, a cholecystokinin (CCK) or CCK agonist, a leptin (OB protein) or leptin agonist, an exendin or exendin agonist, or a GLP-1 or GLP-1 agonist as described in U.S. Patent Publication 20050009748. Suitable amylin agonists include, for example, (25,28,29Pro-)-human amylin (also known as “pramlintide”, and described in U.S. Pat. Nos. 5,686,511 and 5,998,367), calcitonin (e.g., salmon calcitonin), including those described in U.S. Pat. No. 5,739,106, which is hereby incorporated by reference. The CCK used is preferably CCK octopeptide (CCK-8). Leptin is discussed in, for example, Pelleymounter, C. et al., Science 269: 540-543 (1995), Halaas, G. et al., Science 269: 543-6 (1995) and Campfield, S. et al., Science 269: 546-549 (1995). Suitable CCK agonist includes those described in U.S. Pat. No. 5,739,106, which is hereby incorporated by reference. Suitable exendins include exendin-3 and exendin-4, and exendin agonist compounds include, for example, those described in PCT Publications WO 99/07404, WO 99/25727, and WO 99/25728, all of which are hereby incorporated by reference. According to one embodiment, the composition of the present invention includes at least one delivery agent compound, PYY, a PYY agonist, or a mixture thereof, at least one amylin agonist, and a CCK agonist. Suitable combinations of amylin agonist and CCK agonist include, but are not limited to, those described in U.S. Pat. No. 5,739,106, which is hereby incorporated by reference.
In some embodiments, the pharmaceutical compositions comprises an analog of the polypeptides disclosed below, wherein the analog amino acid sequence is based upon fragments, polypeptides, and functional derivatives with 70%, 75%, 85%, 90%, 95%, 98%, or 99% sequence homology to the following polypeptides disclosed below:
Adrenocorticotropic hormone (ACTH) peptides including, but not limited to, ACTH, human; ACTH 1-10; ACTH 1-13, human; ACTH 1-16, human; ACTH 1-17; ACTH 1-24, human; ACTH 4-10; ACTH 4-11; ACTH 6-24; ACTH 7-38, human; ACTH 18-39, human; ACTH, rat; ACTH 12-39, rat; beta-cell tropin (ACTH 22-39); biotinyl-ACTH 1-24, human; biotinyl-ACTH 7-38, human; corticostatin, human; corticostatin, rabbit; {Met(02)⁴, DLys⁸, Phe⁹} ACTH 4-9, human; {Met(0)⁴, DLys⁸, Phe⁹} ACTH 4-9, human; N-acetyl, ACTH 1-17, human; and ebiratide.
Adrenomedullin peptides including, but not limited to, adrenomedullin, adrenomedullin 1-52, human; adrenomedullin 1-12, human; adrenomedullin 13-52, human; adrenomedullin 22-52, human; pro-adrenomedullin 45-92, human; pro-adrenomedullin 153-185, human; adrenomedullin 1-52, porcine; pro-adrenomedullin (N-20), porcine;
adrenomedullin 1-50, rat; adrenomedullin 11-50, rat; and proAM-N20 (proadrenomedullin N-terminal 20 peptide), rat.
Allatostatin peptides including, but not limited to, allatostatin I; allatostatin II; allatostatin III; and allatostatin IV.
Amylin peptides including, but not limited to, acetyl-amylin 8-37, human; acetylated amylin 8-37, rat; AC187 amylin antagonist; AC253 amylin antagonist; AC625 amylin antagonist; amylin 8-37, human; amylin (IAPP), cat; amylin (insulinoma or islet amyloid polypeptide(IAPP)); amylin amide, human; amylin 1-13 (diabetes-associated peptide 1-13), human; amylin 20-29 (IAPP 20-29), human; AC625 amylin antagonist; amylin 8-37, human; amylin (IAPP), cat; amylin, rat; amylin 8-37, rat; biotinyl-amylin, rat; and biotinyl-amylin amide, human
Amyloid beta-protein fragment peptides including, but not limited to, Alzheimer's disease beta-protein 12-28 (SP17); amyloid beta-protein 25-35; amyloid beta/A4-protein precursor 328-332; amyloid beta/A4 protein precursor (APP) 319-335; amyloid beta-protein 1-43; amyloid beta-protein 1-42; amyloid beta-protein 1-40; amyloid beta-protein 10-20; amyloid beta-protein 22-35; Alzheimer's disease beta-protein (SP28); beta-amyloid peptide 1-42, rat; beta-amyloid peptide 1-40, rat; beta-amyloid 1-11; beta-amyloid 31-35; beta-amyloid 32-35; beta-amyloid 35-25; beta-amyloid/A4 protein precursor 96-110; beta-amyloid precursor protein 657-676; beta-amyloid 1-38; (Gln¹¹)-Alzheimer's disease beta-protein; (Gln¹¹)-beta-amyloid 1-40; (Gln²²)-beta-amyloid 6-40; non-A beta component of Alzheimer's disease amyloid (NAC); P3, (A beta 17-40) Alzheimer's disease amyloid .beta.-peptide; and SAP (serum amyloid P component) 194-204.
Angiotensin peptides including, but not limited to, A-779; Ala-Pro-Gly-angiotensin II; (Ile³,Val⁵)-angiotensin II; angiotensin III antipeptide; angiogenin fragment 108-122; angiogenin fragment 108-123; angiotensin I converting enzyme inhibitor; angiotensin I, human; angiotensin I converting enzyme substrate; angiotensin I 1-7, human; angiopeptin; angiotensin II, human; angiotensin II antipeptide; angiotensin II 1-4, human; angiotensin II 3-8, human; angiotensin II 4-8, human; angiotensin II 5-8, human; angiotensin III ({Des-Asp¹}-angiotensin II), human; angiotensin III inhibitor ({Ile⁷}-angiotensin III); angiotensin-converting enzyme inhibitor (Neothunnus macropterus); {Asn¹, Val⁵}-angiotensin I, goosefish; {Asn¹, Val⁵, Asn⁹}-angiotensin I, salmon; {Asn¹, Val⁵, Gly⁹}-angiotensin I, eel; {Asn¹, Val⁵}-angiotensin I 1-7, eel, goosefish, salmon; {Asn¹,Val⁵}-angiotensin II; biotinyl-angiotensin I, human; biotinyl-angiotensin II, human; biotinyl-Ala-Ala-Ala-angiotensin II; {Des-Asp¹}-angiotensin I, human; {p-aminophenylalanine⁶}-angiotensin II; renin substrate (angiotensinogen 1-13), human; preangiotensinogen 1-14 (renin substrate tetradecapeptide), human; renin substrate tetradecapeptide (angiotensinogen 1-14), porcine; {Sar¹}-angiotensin II, {Sar¹}-angiotensin II 1-7 amide; {Sar¹, Ala⁸}-angiotensin II; {Sar¹, Ile⁸}-angiotensin II; {Sar¹, Thr⁸}-angiotensin II; {Sar¹, Tyr(Me)⁴}-angiotensin II (Sarmesin); {Sar¹, Val⁵, Ala⁸}-angiotensin II; {Sar¹, Ile⁷}-angiotensin III; synthetic tetradecapeptide renin substrate (No. 2); {Val⁴}-angiotensin III; {Val⁵}-angiotensin II; {Val⁵}-angiotensin I, human; {Val⁵}-angiotensin I; {Val⁵, Asn⁹}-angiotensin I, bullfrog; and {Val⁵, Ser⁹}-angiotensin I, fowl.
Antibiotic peptides including, but not limited to, Ac-SQNY; bactenecin, bovine; CAP 37 (20-44); carbormethoxycarbonyl-DPro-DPhe-OBz1; CD36 peptide P 139-155; CD36 peptide P 93-110; cecropin A-melittin hybrid peptide {CA(1-7)M(2-9)NH₂}; cecropin B, free acid; CYS(Bzl)84 CD fragment 81-92; defensin (human) HNP-2; dermaseptin; immunostimulating peptide, human; lactoferricin, bovine (BLFC); and magainin spacer.
Antigenic polypeptides, which can elicit an enhanced immune response, enhance an immune response and or cause an immunizingly effective response to diseases and/or disease causing agents including, but not limited to, adenoviruses; anthrax; Bordetella pertussus; botulism; bovine rhinotracheitis; Branhamella catarrhalis; canine hepatitis; canine distemper; Chlamydiae; cholera; coccidiomycosis; cowpox; cytomegalovirus; Dengue fever; dengue toxoplasmosis; diphtheria; encephalitis; enterotoxigenic E. coli; Epstein Barr virus; equine encephalitis; equine infectious anemia; equine influenza; equine pneumonia; equine rhinovirus; Escherichia coli; feline leukemia; flavivirus; globulin; Haemophilus influenza type b; Haemophilus influenzae; Haemophilus pertussis; Helicobacter pylori; Hemophilus; hepatitis; hepatitis A; hepatitis B; Hepatitis C; herpes viruses; HIV; HIV-1 viruses; HIV-2 viruses; HTLV; influenza; Japanese encephalitis; Klebsiellae species; Legionella pneumophila; Leishmania; leprosy; lyme disease; malaria immunogen; measles; meningitis; meningococcal; Meningococcal polysaccharide group A; Meningococcal polysaccharide group C; mumps; mumps virus; mycobacteria; Mycobacterium tuberculosis; Neisseria; Neisseria gonorrhea; Neisseria meningitidis; ovine blue tongue; ovine encephalitis; papilloma; parainfluenza; paramyxoviruses; Pertussis; plague; pneumococcus; Pneumocystis carinii; pneumonia; poliovirus; proteus species; Pseudomonas aeruginosa; rabies; respiratory syncytial virus; rotavirus; rubella; salmonellae; schistosomiasis; shigellae; simian immunodeficiency virus; smallpox; Staphylococcus aureus; Staphylococcus species; Streptococcus pneumoniae; Streptococcus pyogenes; Streptococcus species; swine influenza; tetanus; Treponema pallidum; typhoid; vaccinia; varicella-zoster virus; and Vibrio cholerae.
Anti-microbial peptides including, but not limited to, buforin I; buforin II; cecropin A; cecropin B; cecropin P1, porcine; gaegurin 2 (Rana rugosa); gaegurin 5 (Rana rugosa); indolicidin; protegrin-(PG)-I; magainin 1; and magainin 2; and T-22 {Tyr^5,12, Lys⁷}-poly-phemusin II peptide.
Apoptosis related peptides including, but not limited to, Alzheimer's disease beta-protein (SP28); calpain inhibitor peptide; caspase-1 inhibitor V; caspase-3, substrate IV; caspase-1 inhibitor I, cell-permeable; caspase-1 inhibitor VI; caspase-3 substrate III, fluorogenic; caspase-1 substrate V, fluorogenic; caspase-3 inhibitor I, cell-permeable; caspase-6 ICE inhibitor III; {Des-Ac, biotin}-ICE inhibitor III; IL-1B converting enzyme (ICE) inhibitor II; IL-1 B converting enzyme (ICE) substrate IV; MDL 28170; and MG-132.
Atrial natriuretic peptides including, but not limited to, alpha-ANP (alpha-chANP), chicken; anantin; ANP 1-11, rat; ANP 8-30, frog; ANP 11-30, frog; ANP-21 (fANP-21), frog; ANP-24 (fANP-24), frog; ANP-30, frog; ANP fragment 5-28, human, canine; ANP-7-23, human; ANP fragment 7-28, human, canine; alpha-atrial natriuretic polypeptide 1-28, human, canine; A71915, rat; atrial natriuretic factor 8-33, rat; atrial natriuretic polypeptide 3-28, human; atrial natriuretic polypeptide 4-28, human, canine; atrial natriuretic polypeptide 5-27; human; atrial natriuretic peptide (ANP), eel; atriopeptin I, rat, rabbit, mouse; atriopeptin II, rat, rabbit, mouse; atriopeptin III, rat, rabbit, mouse; atrial natriuretic factor (rANF), rat, auriculin A (rat ANF 126-149); auriculin B (rat ANF 126-150); beta-ANP (1-28, dimer, antiparallel); beta-rANF 17-48; biotinyl-alpha-ANP 1-28, human, canine; biotinyl-atrial natriuretic factor (biotinyl-rANF), rat; cardiodilatin 1-16, human; C-ANF 4-23, rat; Des-{Cys¹⁰⁵, Cys¹²¹}-atrial natriuretic factor 104-126, rat; {Met(O)¹²} ANP 1-28, human; {Mpr⁷,DAla⁹}ANP 7-28, amide, rat; prepro-ANF 104-116, human; prepro-ANF 26-55 (proANF 1-30), human; prepro-ANF 56-92 (proANF 31-67), human; prepro-ANF 104-123, human; {Tyr⁰}-atriopeptin I, rat, rabbit, mouse; {Tyr⁰}-atriopeptin II, rat, rabbit, mouse; {Tyr⁰-prepro ANF 104-123, human; urodilatin (CDD/ANP 95-126); ventricular natriuretic peptide (VNP), eel; and ventricular natriuretic peptide (VNP), rainbow trout.
Bag cell peptides including, but not limited to, alpha bag cell peptide; alpha-bag cell peptide 1-9; alpha-bag cell peptide 1-8; alpha-bag cell peptide 1-7; beta-bag cell factor, and gamma-bag cell factor.
Bombesin peptides including, but not limited to, alpha-s1 casein 101-123 (bovine milk); biotinyl-bombesin; bombesin 8-14; bombesin; {Leu¹³-psi (CH₂NH)Leu¹⁴}-bombesin; {D-Phe⁶, Des-Met¹⁴}-bombesin 6-14 ethylamide; {DPhe¹²} bombesin; {DPhe¹²,Leu¹⁴}-bombesin; {Tyr⁴}-bombesin; and {Tyr⁴,DPhe¹²}-bombesin.
Bone GLA peptides (BGP) including, but not limited to, bone GLA protein; bone GLA protein 45-49; {Glu¹⁷, Gla^21,24}-osteocalcin 1-49, human; myclopeptide-2 (MP-2); osteocalcin 1-49 human; osteocalcin 37-49, human; and {Tyr³⁸, Phe^42,46} bone GLA protein 38-49, human.
Bradykinin peptides including, but not limited to, {Ala^2,6, des-Pro³}-bradykinin; bradykinin; bradykinin (Bowfin. Gar); bradykinin potentiating peptide; bradykinin 1-3; bradykinin 1-5; bradykinin 1-6; bradykinin 1-7; bradykinin 2-7; bradykinin 2-9; {DPhe⁷} bradykinin; {Des-Arg⁹}-bradykinin; {Des-Arg¹⁰}-Lys-bradykinin ({Des-Arg¹⁰}-kallidin); {D-N-Me-Phe⁷}-bradykinin; {Des-Arg⁹, Leu⁸}-bradykinin; Lys-bradykinin (kallidin); Lys-(Des-Arg⁹, Leu⁸}-bradykinin ({Des-Arg¹⁰, Leu⁹}-kallidin); {Lys⁰-Hyp³}-bradykinin; ovokinin; {Lys⁰, Ala³}-bradykinin; Met-Lys-bradykinin; peptide K12 bradykinin potentiating peptide; {(pCl)Phe^5,8}-bradykinin; T-kinin (Ile-Ser-bradykinin); {Thi.^5,8, D-Phe⁷}-bradykinin; {Tyr⁰}-bradykinin; {Tyr⁵}-bradykinin; {Tyr⁸}-bradykinin; and kallikrein.
Brain natriuretic peptides (BNP) including, but not limited to, BNP 32, canine; BNP-like Peptide, eel; BNP-32, human; BNP-45, mouse; BNP-26, porcine; BNP-32, porcine; biotinyl-BNP-32, porcine; BNP-32, rat; biotinyl-BNP-32, rat; BNP45 (BNP 51-95, 5K cardiac natriuretic peptide), rat; and {Tyr⁰}-BNP 1-32, human.
C-peptides including, but not limited to, C-peptide; and {Tyr⁰}-C-peptide, human.
C-type natriuretic peptides (CNP) including, but not limited to, C-type natriuretic peptide, chicken; C-type natriuretic peptide-22 (CNP-22), porcine, rat, human; C-type natriuretic peptide-53 (CNP-53), human; C-type natriuretic peptide-53 (CNP-53), porcine, rat; C-type natriuretic peptide-53 (porcine, rat) 1-29 (CNP-531-29); prepro-CNP 1-27, rat; prepro-CNP 30-50, porcine, rat; vasonatrin peptide (VNP); and {Tyr⁰}-C-type natriuretic peptide-22 ({Tyr⁰}-CNP-22).
Calcitonin peptides including, but not limited to, biotinyl-calcitonin, human; biotinyl-calcitonin, rat; biotinyl-calcitonin, salmon; calcitonin, chicken; calcitonin, eel; calcitonin, human; calcitonin, porcine; calcitonin, rat; calcitonin, salmon; calcitonin 1-7, human; calcitonin 8-32, salmon; katacalcin (PDN-21) (C-procalcitonin); and N-proCT (amino-terminal procalcitonin cleavage peptide), human.
Calcitonin gene related peptides (CGRP) including, but not limited to, acetyl-alpha-CGRP 19-37, human; alpha-CGRP 19-37, human; alpha-CGRP 23-37, human; biotinyl-CGRP, human; biotinyl-CGRP II, human; biotinyl-CGRP, rat; beta-CGRP, rat; biotinyl-beta-CGRP, rat; CGRP, rat; CGRP, human; calcitonin C-terminal adjacent peptide; CGRP 1-19, human; CGRP 20-37, human; CGRP 8-37, human; CGRP II, human; CGRP, rat; CGRP 8-37, rat; CGRP 29-37, rat; CGRP 30-37, rat; CGRP 31-37, rat; CGRP 32-37, rat; CGRP 33-37, rat; CGRP 31-37, rat; ({Cys(Acm)^2,7}-CGRP; elcatonin; {Tyr⁰}-CGRP, human; {Tyr⁰}-CGRP II, human; {Tyr⁰}-CGRP 28-37, rat; {Tyr⁰}-CGRP, rat; and {Tyr²²}-CGRP 22-37, rat.
CART peptides including, but not limited to, CART, human; CART 55-102, human; CART, rat; and CART 55-102, rat.
Casomorphin peptides including, but not limited to, beta-casomorphin, human; beta-casomorphin 1-3; beta-casomorphin 1-3, amide; beta-casomorphin, bovine; beta-casomorphin 1-4, bovine; beta-casomorphin 1-5, bovine; beta-casomorphin 1-5, amide, bovine; beta-casomorphin 1-6, bovine; {DAla²}-beta-casomorphin 1-3, amide, bovine; {DAla²,Hyp⁴,Tyr⁵}-beta-casomorphin 1-5 amide; {DAla²,DPro⁴,Tyr⁵}-beta-casomorphin 1-5, amide; {DAla²,Tyr⁵}-beta-casomorphin 1-5, amide, bovine; {DAla^2,4,Tyr⁵}-beta-casomorphin 1-5, amide, bovine; {DAla², (pCl)Phe³}-beta-casomorphin, amide, bovine; {DAla²}-beta-casomorphin 1-4, amide, bovine; {DAla²}-beta-casomorphin 1-5, bovine; {DAla²}-beta-casomorphin 1-5, amide, bovine; {DAla²,Met⁵}-beta-casomorphin 1-5, bovine; {DPro²}-beta-casomorphin 1-5, amide, bovine; {DAla²}-beta-casomorphin 1-6, bovine; {DPro²}-beta-casomorphin 1-4, amide; {Des-Tyr¹}-beta-casomorphin, bovine; {DAla^2,4, Tyr⁵}-beta-casomorphin 1-5, amide, bovine; {DAla², (pCl)Phe³}-beta-casomorphin, amide, bovine; {DAla²}-beta-casomorphin 1-4, amide, bovine; {DAla²}-beta-casomorphin 1-5, bovine; {DAla²}-beta-casomorphin 1-5, amide, bovine; {DAla²,Met⁵}-beta-casomorphin 1-5, bovine; {DPro²}-beta-casomorphin 1-5, amide, bovine; {DAla²}-beta-casomorphin 1-6, bovine; {DPro²}-beta-casomorphin 14, amide; {Des-Tyr¹}-beta-casomorphin, bovine; and {Val³}-beta-casomorphin 1-4, amide, bovine.
Chemotactic peptides including, but not limited to, defensin 1 (human) HNP-1 (human neutrophil peptide-1); and N-formyl-Met-Leu-Phe.
Cholecystokinin (CCK) peptides including, but not limited to, caerulein; cholecystokinin; cholecystokinin-pancreozymin; CCK-33, human; cholecystokinin octapeptide 14 (non-sulfated) (CCK 26-29, unsulfated); cholecystokinin octapeptide (CCK 26-33); cholecystokinin octapeptide (non-sulfated) (CCK 26-33, unsulfated); cholecystokinin heptapeptide (CCK 27-33); cholecystokinin tetrapeptide (CCK 30-33); CCK-33, porcine; CR 1409, cholecystokinin antagonist; CCK flanking peptide (unsulfated); N-acetyl cholecystokinin, CCK 26-30, sulfated; N-acetyl cholecystokinin, CCK 26-31, sulfated; N-acetyl cholecystokinin, CCK 26-31, non-sulfated; prepro CCK fragment V-9-M; and proglumide.
Colony-stimulating factor peptides including, but not limited to, colony-stimulating factor (CSF); GMCSF; MCSF; and G-CSF.
Corticortropin releasing factor (CRF) peptides including, but not limited to, astressin; alpha-helical CRF 12-41; biotinyl-CRF, ovine; biotinyl-CRF, human, rat; CRF, bovine; CRF, human, rat; CRF, ovine; CRF, porcine; {Cys²¹}-CRF, human, rat; CRF antagonist (alpha-helical CRF 9-41); CRF 6-33, human, rat; {DPro⁵}-CRF, human, rat; {D-Phe¹², Nle^21,38}-CRF 12-41, human, rat; eosinophilotactic peptide; {Met(0)²¹}-CRF, ovine; {Nle²¹,Tyr³²}-CRF, ovine; prepro CRF 125-151, human; sauvagine, frog; {Tyr⁰}-CRF, human, rat; {Tyr⁰}-CRF, ovine; {Tyr⁰}-CRF 34-41, ovine; {Tyr⁰}-urocortin; urocortin amide, human; urocortin, rat; urotensin I (Catostomus commersoni); urotensin II; and urotensin II (Rana ridibunda).
Cortistatin peptides including, but not limited to, cortistatin 29; cortistatin 29 (1-13); {Tyr⁰}-cortistatin 29; pro-cortistatin 28-47; and pro-cortistatin 51-81.
Cytokine peptides including, but not limited to, tumor necrosis factor; and tumor necrosis factor-.beta. (TNF-.beta.).
Dermorphin peptides including, but not limited to, dermorphin and dermorphin analog 1-4.
Dynorphin peptides including, but not limited to, big dynorphin (prodynorphin 209-240), porcine; biotinyl-dynorphin A (biotinyl-prodynorphin 209-225); {DAla², DArg⁶}dynorphin A 1-13, porcine; {D-Ala²}-dynorphin A, porcine; {D-Ala²}-dynorphin A amide, porcine; {D-Ala²}-dynorphin A 1-13, amide, porcine; {D-Ala²}-dynorphin A 1-9, porcine; {DArg⁶}-dynorphin A 1-13, porcine; {DArg⁸}-dynorphin A 1-13, porcine; {Des-Tyr¹}-dynorphin A 1-8; {D-Pro¹⁰}-dynorphin A 1-11, porcine; dynorphin A amide, porcine; dynorphin A 1-6, porcine; dynorphin A 1-7, porcine; dynorphin A 1-8, porcine; dynorphin A 1-9, porcine; dynorphin A 1-10, porcine; dynorphin A 1-10 amide, porcine; dynorphin A 1-11, porcine; dynorphin A 1-12, porcine; dynorphin A 1-13, porcine; dynorphin A 1-13 amide, porcine; DAKLI (dynorphin A-analogue kappa ligand); DAKLI-biotin ({Arg^11,13}-dynorphin A (1-13)-Gly-NH(CH₂)₅NH-biotin); dynorphin A 2-17, porcine; dynorphin 2-17, amide, porcine; dynorphin A 2-12, porcine; dynorphin A 3-17, amide, porcine; dynorphin A 3-8, porcine; dynorphin A 3-13, porcine; dynorphin A 3-17, porcine; dynorphin A 7-17, porcine; dynorphin A 8-17, porcine; dynorphin A 6-17, porcine; dynorphin A 13-17, porcine; dynorphin A (prodynorphin 209-225), porcine; dynorphin B 1-9; {MeTyr¹, MeArg⁷, D-Leu⁸}-dynorphin 1-8 ethyl amide; {(nMe)Tyr¹} dynorphin A 1-13, amide, porcine; {Phe⁷}-dynorphin A 1-7, porcine; {Phe⁷}-dynorphin A 1-7, amide, porcine; and prodynorphin 228-256 (dynorphin B 29) (leumorphin), porcine.
Endorphin peptides including, but not limited to, alpha-neo-endorphin, porcine; beta-neoendorphin; Ac-beta-endorphin, camel, bovine, ovine; Ac-beta-endorphin 1-27, camel, bovine, ovine; Ac-beta-endorphin, human; Ac-beta-endorphin 1-26, human; Ac-beta-endorphin 1-27, human; Ac-gamma-endorphin (Ac-beta-lipotropin 61-77); acetyl-alpha-endorphin; alpha-endorphin (beta-lipotropin 61-76); alpha-neo-endorphin analog; alpha-neo-endorphin 1-7; {Arg⁸}-alpha-neoendorphin 1-8; beta-endorphin (beta-lipotropin 61-91), camel, bovine, ovine; beta-endorphin 1-27, camel, bovine, ovine; beta-endorphin, equine; beta-endorphin (beta-lipotropin 61-91), human; beta-endorphin (1-5)+(16-31), human; beta-endorphin 1-26, human; beta-endorphin 1-27, human; beta-endorphin 6-31, human; beta-endorphin 18-31, human; beta-endorphin, porcine; beta-endorphin, rat; beta-lipotropin 1-10, porcine; beta-lipotropin 60-65; beta-lipotropin 61-64; beta-lipotropin 61-69; beta-lipotropin 88-91; biotinyl-beta-endorphin (biotinyl-bets-lipotropin 61-91); biocytin-beta-endorphin, human; gamma-endorphin (beta-lipotropin 61-77); {DAla²}-alpha-neo-endorphin 1-2, amide; {DAla²}-beta-lipotropin 61-69; {DAla²}-gamma-endorphin; {Des-Tyr¹}-beta-endorphin, human; {Des-Tyr¹}-gamma-endorphin (beta-lipotropin 62-77); {Leu⁵}-beta-endorphin, camel, bovine, ovine; {Met⁵, Lys⁶}-alpha-neo-endorphin 1-6; {Met⁵, Lys^6,7}-alpha-neo-endorphin 1-7; and {Met⁵, Lys⁶, Arg⁷}-alpha-neo-endorphin 1-7.
Endothelin peptides including, but not limited to, endothelin-1 (ET-1); endothelin-1{Biotin-Lys⁹}; endothelin-1 (1-15), human; endothelin-1 (1-15), amide, human; Ac-endothelin-1 (16-21), human; Ac-{DTrp¹⁶}-endothelin-1 (16-21), human; {Ala^3,11}-endothelin-1; {Dpr1, Asp¹⁵}-endothelin-1; {Ala²}-endothelin-3, human; {Ala¹⁸}-endothelin-1, human; {Asn¹⁸}-endothelin-1, human; {Res-701-1}-endothelin B receptor antagonist; Suc-{Glu⁹, Ala^11,15}-endothelin-1 (8-21), IRL-1620; endothelin-C-terminal hexapeptide; {D-Val²²}-big endothelin-1 (16-38), human; endothelin-2 (ET-2), human, canine; endothelin-3 (ET-3), human, rat, porcine, rabbit; biotinyl-endothelin-3 (biotinyl-ET-3); prepro-endothelin-1 (94-109), porcine; BQ-518; BQ-610; BQ-788; endothelium-dependent relaxation antagonist; FR139317; IRL-1038; JKC-301; JKC-302; PD-145065; PD-142893; sarafotoxin S6a (Atractaspis engaddensis); sarafotoxin S6b (Atractaspis engaddensis); sarafotoxin S6c (Atractaspis engaddensis); {Lys⁴}-sarafotoxin S6c; sarafotoxin S6d; big endothelin-1, human; biotinyl-big endothelin-1, human; big endothelin-1 (1-39), porcine; big endothelin-3 (22-41), amide, human; big endothelin-1 (22-39), rat; big endothelin-1 (1-39), bovine; big endothelin-1 (22-39), bovine; big endothelin-1 (19-38), human; big endothelin-1 (22-38), human; big endothelin-2, human; big endothelin-2 (22-37), human; big endothelin-3, human; big endothelin-1, porcine; big endothelin-1 (22-39) (prepro-endothelin-1 (74-91)); big endothelin-1, rat; big endothelin-2 (1-38), human; big endothelin-2 (22-38), human; big endothelin-3, rat; biotinyl-big endothelin-1, human; and {Tyr¹²³}-prepro-endothelin (110-130), amide, human
ETa receptor antagonist peptides including, but not limited to, {BQ-123}; {BE18257B}; {BE-18257A}/{W-7338A}; {BQ-485}; FR139317; PD-151242; and TTA-386.
ETb receptor antagonist peptides including, but not limited to, 03Q-30201; {RES-701-3}; and {IRL-1720}
Enkephalin peptides including, but not limited to, adrenorphin, free acid; amidorphin (proenkephalin A (104-129)-NII2), bovine; BAM-12P (bovine adrenal medulla enkephalin; {D-Ala², D-Leu⁵}-enkephalin; {D-Ala², D-Met⁵}-enkephalin; {DAla²}-Leu-enkephalin, amide; {DAla², Leu⁵, Arg⁶}-enkephalin; {Des-Tyr¹,DPen^2,5}-enkephalin; {Des-Tyr¹,DPen²,Pen⁵}-enkephalin; {Des-Tyr¹}-Leu-enkephalin; {D-Pen^2,5}-enkephalin; {DPen², Pen⁵}-enkephalin; enkephalinase substrate; {D-Pen², pCI-Phe⁴, D-Pen⁵}-enkephalin; Leu-enkephalin; Leu-enkephalin, amide; biotinyl-Leu-enkephalin; {D-Ala²}-Leu-enkephalin; {D-Ser²}-Leu-enkephalin-Thr (delta-receptor peptide) (DSLET); {D-Thr²}-Leu-enkephalin-Thr (DTLET); {Lys⁶}-Leu-enkephalin; {Met⁵,Arg⁶}-enkephalin; {Met⁵,Arg⁶-enkephalin-Arg; {Met⁵,Arg⁶,Phe⁷}-enkephalin, amide; Met-enkephalin; biotinyl-Met-enkephalin; {D-Ala²}-Met-enkephalin; {D-Ala²}-Met-enkephalin, amide; Met-enkephalin-Arg-Phe; Met-enkephalin, amide; {Ala²}-Met-enkephalin, amide; {DMet²,Pro⁵}-enkephalin, amide; {DTrp²}-Met-enkephalin, amide, metorphinamide (adrenorphin); peptide B, bovine; 3200-Dalton adrenal peptide E, bovine; peptide F, bovine; preproenkephalin B 186-204, human; spinorphin, bovine; and thiorphan (D,L,3-mercapto-2-benzylpropanoyl-glycine).
Fibronectin peptides including, but not limited to platelet factor-4 (58-70), human; echistatin (Echis carinatus); E, P, L selectin conserved region; fibronectin analog; fibronectin-binding protein; fibrinopeptide A, human; {Tyr⁰}-fibrinopeptide A, human; fibrinopeptide B, human; {Glu³}-fibrinopeptide B, human; {Tyr¹⁵}-fibrinopeptide B, human; fibrinogen beta-chain fragment of 24-42; fibrinogen binding inhibitor peptide; fibronectin related peptide (collagen binding fragment); fibrinolysis inhibiting factor; FN--C/H-1 (fibronectin heparin-binding fragment); FN--C/H--V (fibronectin heparin-binding fragment); heparin-binding peptide; laminin penta peptide, amide; Leu-Asp-Val-NH₂(LDV-NH₂), human, bovine, rat, chicken; necrofibrin, human; necrofibrin, rat; and platelet membrane glycoprotein IIB peptide 296-306.
Galanin peptides including, but not limited to, galanin, human; galanin 1-19, human; preprogalanin 1-30, human; preprogalanin 65-88, human; preprogalanin 89-123, human; galanin, porcine; galanin 1-16, porcine, rat; galanin, rat; biotinyl-galanin, rat; preprogalanin 28-67, rat; galanin 1-13-bradykinin 2-9, amide; M40, galanin 1-13-Pro-Pro-(Ala-Leu) 2-Ala-amide; C7, galanin 1-13-spantide-amide; GMAP 1-41, amide; GMAP 16-41, amide; GMAP 25-41, amide; galantide; and entero-kassinin.
Gastrin peptides including, but not limited to, gastrin, chicken; gastric inhibitory peptide (GIP), human; gastrin I, human; biotinyl-gastrin I, human; big gastrin-1, human; gastrin releasing peptide, human; gastrin releasing peptide 1-16, human; gastric inhibitory polypeptide (GIP), porcine; gastrin releasing peptide, porcine; biotinyl-gastrin releasing peptide, porcine; gastrin releasing peptide 14-27, porcine, human; little gastrin, rat; pentagastrin; gastric inhibitory peptide 1-30, porcine; gastric inhibitory peptide 1-30, amide, porcine; {Tyr⁰-gastric inhibitory peptide 23-42, human; and gastric inhibitory peptide, rat.
Glucagon peptides including, but not limited to, {Des-His¹-Glu⁹}-glucagon, exendin-4, glucagon, human; biotinyl-glucagon, human; glucagon 19-29, human; glucagon 22-29, human; {Des-His¹-Glu⁹}-glucagon, amide; glucagon-like peptide 1, amide; glucagon-like peptide 1, human; glucagon-like peptide 1 (7-36); glucagon-like peptide 2, rat; biotinyl-glucagon-like peptide-1 (7-36) (biofinyl-preproglucagon 78-107, amide); glucagon-like peptide 2, human; intervening peptide-2; oxyntomodulin/glucagon 37; and valosin (peptide VQY), porcine.
Gn-RH associated peptides (GAP) including, but not limited to, Gn-RH associated peptide 25-53, human; Gn-RH associated peptide 1-24, human; Gn-RH associated peptide 1-13, human; Gn-RH associated peptide 1-13, rat; gonadotropin releasing peptide, follicular, human; {Tyr⁰}-GAP ({Tyr⁰}-Gn-RH Precursor Peptide 14-69), human; and proopiomelanocortin (POMC) precursor 27-52, porcine.
Growth factor peptides including, but not limited to, cell growth factors; epidermal growth factors; tumor growth factor; alpha-TGF; beta-TF; alpha-TGF 34-43, rat; EGF, human; acidic fibroblast growth factor; basic fibroblast growth factor; basic fibroblast growth factor 13-18; basic fibroblast growth factor 120-125; brain derived acidic fibroblast growth factor 1-11; brain derived basic fibroblast growth factor 1-24; brain derived acidic fibroblast growth factor 102-111; {Cys(Acm^20,31)}-epidermal growth factor 20-31; epidermal growth factor receptor peptide 985-996; insulin-like growth factor (IGF)-I, chicken; IGF-I, rat; IGF-I, human; Des (1-3) IGF-I, human; R3 IGF-I, human; R3 IGF-I, human; long R3 IGF-I, human; adjuvant peptide analog; anorexigenic peptide; Des (1-6) IGF-II, human; R6 IGF-II, human; IGF-I analogue; IGF 1 (24-41); IGF 1 (57-70); IGF I (30-41); IGF II; IGF II (33-40); {Tyr⁰}-IGF II (33-40); liver cell growth factor; midkine; midkine 60-121, human; N-acetyl, alpha-TGF 34-43, methyl ester, rat; nerve growth factor (NGF), mouse; platelet-derived growth factor; platelet-derived growth factor antagonist; transforming growth factor-alpha, human; and transforming growth factor-I, rat.
Growth hormone peptides including, but not limited to, growth hormone (hGH), human; growth hormone 1-43, human; growth hormone 6-13, human; growth hormone releasing factor, human; growth hormone releasing factor, bovine; growth hormone releasing factor, porcine; growth hormone releasing factor 1-29, amide, rat; growth hormone pro-releasing factor, human; biotinyl-growth hormone releasing factor, human; growth hormone releasing factor 1-29, amide, human; {D-Ala²}-growth hormone releasing factor 1-29, amide, human; {N-Ac-Tyr¹, D-Arg²}-GRF 1-29, amide; {His¹, Nle²⁷}-growth hormone releasing factor 1-32, amide; growth hormone releasing factor 1-37, human; growth hormone releasing factor 140, human; growth hormone releasing factor 1-40, amide, human; growth hormone releasing factor 30-44, amide, human; growth hormone releasing factor, mouse; growth hormone releasing factor, ovine; growth hormone releasing factor, rat; biotinyl-growth hormone releasing factor, rat; GHRP-6 ({His¹, Lys⁶}-GHRP); hexarelin (growth hormone releasing hexapeptide); and {D-Lys³}-GHRP-6.
GTP-binding protein fragment peptides including, but not limited to, {Arg⁸}-GTP-binding protein fragment, Gs alpha; GTP-binding protein fragment, G beta; GTP-binding protein fragment, GAlpha; GTP-binding protein fragment, Go Alpha; GTP-binding protein fragment, Gs Alpha; and GTP-binding protein fragment, G Alpha i2.
Guanylin peptides including, but not limited to, guanylin, human; guanylin, rat; and uroguanylin.
Inhibin peptides including, but not limited to, inhibin, bovine; inhibin, alpha-subunit 1-32, human; {Tyr⁰}-inhibin, alpha-subunit 1-32, human; seminal plasma inhibin-like peptide, human; {Tyr⁰}-seminal plasma inhibin-like peptide, human; inhibin, alpha-subunit 1-32, porcine; and {Tyr⁰}-inhibin, alpha-subunit 1-32, porcine.
Insulin peptides including, but not limited to, insulin, human; insulin, porcine; IGF-I, human; insulin-like growth factor II (69-84); pro-insulin-like growth factor 11 (68-102), human; pro-insulin-like growth factor II (105-128), human; {Asp^B28}-insulin, human; {Lys^B28}-insulin, human; {Leu^B28}-insulin, human; {Val^B28}-insulin, human; {Ala^B28}-insulin, human; {Asp^B28, Pro^B29}-insulin, human; {Lys^B28, Pro^B29}-insulin, human; {Leu^B28Pro^B29}-insulin, human; {Val^B28, Pro^B29}-insulin, human; {Ala^B28, Pro^B29}-insulin, human; {Gly^A21}-insulin, human; {Gly^A21Gln^B30}-insulin, human; {Ala^A21}-insulin, human; {Ala^A21Gln^B30} insulin, human; {Gln^B30}-insulin, human; {Gln^B30}-insulin, human; {Gly^A21Glu^B30}-insulin, human; {Gly^A21Gln^B3Glu^B30}-insulin, human; {Gln^B3Glu^B30}-insulin, human; B22-B30 insulin, human; B23-B30 insulin, human; B25-B30 insulin, human; B26-B30 insulin, human; B27-B30 insulin, human; B29-B30 insulin, human; the A chain of human insulin, and the B chain of human insulin.
Interleukin peptides including, but not limited to, interleukin-1 beta 165-181, rat; and interleukin-8 (IL-8, CINC/gro), rat.
Lamimin peptides including, but not limited to, laminin; alpha1 (I)-CB3 435-438, rat; and laminin binding inhibitor.
Leptin peptides including, but not limited to, leptin 93-105, human; leptin 22-56, rat; Tyr-leptin 26-39, human; and leptin 116-130, amide, mouse.
Leucokinin peptides including, but not limited to, leucomyosuppressin (LMS); leucopyrokinin (LPK); leucokinin I; leucokinin II; leucokinin III; leucokinin IV; leucokinin VI; leucokinin VII; and leucokinin VIII.
Luteinizing hormone-releasing hormone peptides including, but not limited to, antide; Gn-RH II, chicken; luteinizing hormone-releasing hormone (LH-RH) (GnRH); biotinyl-LH-RH; cetrorelix (D-20761); {D-Ala⁶}-LH-RH; {Gln⁸}-LH-RH (Chicken LH-RH); {DLeu⁶, Val⁷} LH-RH 1-9, ethyl amide; {D-Lys⁶}-LH-RH; {D-Phe², Pro³, D-Phe⁶}-LH-RH; {DPhe², DAla⁶} LH-RH; {Des-Gly¹⁰}-LH-RH, ethyl amide; {D-Ala⁶, Des-Gly¹⁰}-LH-RH, ethyl amide; {DTrp⁶}-LH-RH, ethyl amide; {D-Trp⁶, Des-Gly¹⁰}-LH-RH, ethyl amide (Deslorelin); {DSer(But)₆, Des-Gly¹⁰}-LH-RH, ethyl amide; ethyl amide; leuprolide; LH-RH 4-10; LH-RH 7-10; LH-RH, free acid; LH-RH, lanprey; LH-RH, salmon; {Lys⁸}-LH-RH; {Trp⁷,Leu⁸} LH-RH, free acid; and {(t-Bu)DSer⁶, (Aza)Gly¹⁰}-LH-RH.
Mastoparan peptides including, but not limited to, mastoparan; mas7; mas8; mas17; and mastoparan X.
Mast cell degranulating peptides including, but not limited to, mast cell degranulating peptide HR-1; and mast cell degranulating peptide HR-2.
Melanocyte stimulating hormone (MSH) peptides including, but not limited to, {Ac-Cys⁴,DPhe⁷, Cys¹⁰} alpha-MSH 4-13, amide; alpha-melanocyte stimulating hormone; alpha-MSH, free acid; beta-MSH, porcine; biotinyl-alpha-melanocyte stimulating hormone; biotinyl-{Nle⁴, D-Phe⁷} alpha-melanocyte stimulating hormone; {Des-Acetyl}-alpha-MSH; {DPhe⁷}-alpha-MSH, amide; gamma-1-MSH, amide; {Lys⁰}-gamma-1-MSH, amide; MSH release inhibiting factor, amide; {Nle⁴}-alpha-MSH, amide; {Nle⁴, D-Phe⁷}-alpha-MSH; N-Acetyl, {Nle⁴,DPhe⁷} alpha-MSH 4-10, amide; beta-MSH, human; and gamma-MSH.
Morphiceptin peptides including, but not limited to, morphiceptin (beta-casomorphin 14 amide); {D-Pro⁴}-morphiceptin; and {N-MePhe³,D-Pro⁴}-morphiceptin.
Motilin peptides including, but not limited to, motilin, canine; motilin, porcine; biotinyl-motilin, porcine; and {Leu¹³}-motilin, porcine.
Neuro-peptides including, but not limited to, Ac-Asp-Glu; Achatina cardio-excitatory peptide-1 (ACEP-1) (Achatina fulica); adipokinetic hormone (AKH) (Locust); adipokinetic hormone (Heliothis zea and Manduca sexta); alytesin; Tabanus atratus adipokinetic hormone (Taa-AKH); adipokinetic hormone II (Locusta migratoria); adipokinetic hormone II (Schistocera gregaria); adipokinetic hormone III (AKH-3); adipokinetic hormone G (AKH-G) (Gryllus bimaculatus); allatotropin (AT) (Manduca sexta); allatotropin 6-13 (Manduca sexta); APGW amide (Lymnaea stagnalis); buccalin; cerebellin; {Des-Ser¹}-cerebellin; corazonin (American Cockroach Periplaneta americana); crustacean cardioactive peptide (CCAP); crustacean erythrophore; DF2 (Procambarus clarkii); diazepam-binding inhibitor fragment, human; diazepam binding inhibitor fragment (ODN); eledoisin related peptide; FMRF amide (molluscan cardioexcitatory neuropeptide); Gly-Pro-Glu (GPE), human; granuliberin R; head activator neuropeptide; {His⁷}-corazonin; stick insect hypertrehalosaemic factor II; Tabanus atratus hypotrehalosemic hormone (Taa-HoTH); isoguvacine hydrochloride; bicuculline methiodide; piperidine-4-sulphonic acid; joining peptide of proopiomelanocortin (POMC), bovine; joining peptide, rat; KSAYMRF amide (P. redivivus); kassinin; kinetensin; levitide; litorin; LUQ 81-91 (Aplysia californica); LUQ 83-91 (Aplysia californica); myoactive peptide I (Periplanetin CC-1) (Neuro-hormone D); myoactive peptide II (Periplanetin CC-2); myomodulin; neuron specific peptide; neuron specific enolase 404-443, rat; neuropeptide FF; neuropeptide K, porcine; NEI (prepro-MCH 131-143) neuropeptide, rat; NGE (prepro-MCH110-128) neuropeptide, rat; NFI (Procambarus clarkii); PBAN-1 (Bombyx mori); Hez-PBAN (Heliothis zea); SCPB (cardioactive peptide from aplysia); secretoneurin, rat; uperolein; urechistachykinin I; urechistachykinin II; xenopsin-related peptide I; xenopsin-related peptide II; pedal peptide (Pep), aplysia; peptide F1, lobster, phyllomedusin; polistes mastoparan; proctolin; ranatensin; Ro I (Lubber Grasshopper, Romalea microptera); Ro II (Lubber Grasshopper, Romalea microptera); SALMF amide 1 (S1); SALMF amide 2 (S2); and SCPA.
Neuropeptide Y (NPY) peptides including, but not limited to, {Leu³¹, Pro³⁴} neuropeptide Y, human; neuropeptide F (Moniezia expansa); B1BP3226 NPY antagonist; Bis (31/31′) {{Cys³¹, Trp³², Nva³⁴} NPY 31-36}; neuropeptide Y, human, rat; neuropeptide Y 1-24 amide, human; biotinyl-neuropeptide Y; {D-Tyr27,36, D-Thr³²}-NPY 27-36; Des 10-17 (cyclo 7-21) {Cys^7,21, Pro³⁴}-NPY; C₂-NPY; {Leu³¹, Pro³⁴} neuropeptide Y, human neuropeptide Y, free acid, human; neuropeptide Y, free acid, porcine; prepro NPY 68-97, human; N-acetyl-{Leu²⁸, Leu³¹} NPY 24-36; neuropeptide Y, porcine; {D-Trp³²}-neuropeptide Y, porcine; {D-Trp³²} NPY 1-36, human; {Leu¹⁷,DTrp³²} neuropeptide Y, human; {Leu³¹, Pro³⁴}-NPY, porcine; NPY 2-36, porcine; NPY 3-36, human; NPY 3-36, porcine; NPY 13-36, human; NPY 13-36, porcine; NPY 16-36, porcine; NPY 18-36, porcine; NPY 20-36; NFY 22-36; NPY 26-36; {Pro³⁴}-NPY 1-36, human; {Pro³⁴}-neuropeptide Y, porcine; PYX-1; PYX-2; T4-{NPY(33-36)}4; and Tyr(OMe)²¹}-neuropeptide Y, human.
Neurotropic factor peptides including, but not limited to, glial derived neurotropic factor (GDNF); brain derived neurotropic factor (BDNF); and ciliary neurotropic factor (CNTF).
Orexin peptides including, but not limited to, orexin A; orexin B, human; orexin B, rat, mouse.
Opioid peptides including, but not limited to, alpha-casein fragment 90-95; BAM-18P; casomokinin L; casoxin D; crystalline; DALDA; dermenkephalin (deltorphin) (Phylomedusa sauvagei); {D-Ala²}-deltorphin I; {D-Ala²}-deltorphin II; endomorphin-1; endomorphin-2; kyotorphin; {DArg²}-kyotorphin; morphine tolerance peptide; morphine modulating peptide, C-terminal fragment; morphine modulating neuropeptide (A-18-F--NH2); nociceptin {orphanin FQ} (ORL1 agonist); TIPP; Tyr-MIF-1; Tyr-W-MIF-1; valorphin; LW-hemorphin-6, human; Leu-valorphin-Arg; and Z-Pro-D-Leu.
Oxytocin peptides including, but not limited to, {Asu⁶}-oxytocin; oxytocin; biotinyl-oxytocin; {Thr⁴, Gly⁷}-oxytocin; and tocinoic acid ({Ile³}-pressinoic acid).
PACAP (pituitary adenylating cyclase activating peptide) peptides including, but not limited to, PACAP 1-27, human, ovine, rat; PACAP (1-27)-Gly-Lys-Arg-NH₂, human; {Des-Gln¹⁶}-PACAP 6-27, human, ovine, rat; PACAP38, frog; PACAP27-NH₂, human, ovine, rat; biotinyl-PACAP27-NH2, human, ovine, rat; PACAP 6-27, human, ovine, rat; PACAP38, human, ovine, rat; biotinyl-PACAP38, human, ovine, rat; PACAP 6-38, human, ovine, rat; PACAP27-NH₂, human, ovine, rat; biotinyl-PACAP27-NH₂, human, ovine, rat; PACAP 6-27, human, ovine, rat; PACAP38, human, ovine, rat; biotinyl-PACAP38, human, ovine, rat; PACAP 6-38, human, ovine, rat; PACAP38 16-38, human, ovine, rat; PACAP38 31-38, human, ovine, rat; PACAP38 31-38, human, ovine, rat; PACAP-related peptide (PRP), human; and PACAP-related peptide (PRP), rat.
Pancreastatin peptides including, but not limited to, chromostatin, bovine; pancreastatin (hPST-52) (chromogranin A 250-301, amide); pancreastatin 24-52 (hPST-29), human; chromogranin A 286-301, amide, human; pancreastatin, porcine; biotinyl-pancreastatin, porcine; {Nle⁸}-pancreastatin, porcine; {Tyr⁰,Nle⁸}-pancreastatin, porcine; {Tyr⁰}-pancreastatin, porcine; parastatin 1-19 (chromogranin A 347-365), porcine; pancreastatin (chromogranin A 264-314-amide, rat; biotinyl-pancreastatin (biotinyl-chromogranin A 264-314-amide; {Tyr⁰}-pancreastatin, rat; pancreastatin 26-51, rat; and pancreastatin 33-49, porcine.
Pancreatic polypeptides including, but not limited to, pancreatic polypeptide, avian; pancreatic polypeptide, human; C-fragment pancreatic polypeptide acid, human; C-fragment pancreatic polypeptide amide, human; pancreatic polypeptide (Rana temporaria); pancreatic polypeptide, rat; and pancreatic polypeptide, salmon.
Parathyroid hormone peptides including, but not limited to, {Asp⁷⁶-parathyroid hormone 39-84, human; {Asp⁷⁶}-parathyroid hormone 53-84, human; {Asp⁷⁶}-parathyroid hormone 1-84, hormone; {Asn⁷⁶}-parathyroid hormone 64-84, human; {Asn⁸, Leu¹⁸}-parathyroid hormone 1-34, human; {Cys^5,28}-parathyroid hormone 1-34, human; hypercalcemia malignancy factor 1-40; {Leu¹⁸}-parathyroid hormone 1-34, human; {Lys(biotinyl)¹³, Nle^8,18, Tyr³⁴}-parathyroid hormone 1-34 amide; {Nle^8,18, Tyr³⁴}-parathyroid hormone 1-34 amide; {Nle^8,18, Tyr³⁴}-parathyroid hormone 3-34 amide, bovine; {Nle^8,18, Tyr³⁴}-parathyroid hormone 1-34, human; {Nle^8,18, Tyr³⁴}-parathyroid hormone 1-34 amide human; {Nle^8,18, Tyr³⁴}-parathyroid hormone 3-34 amide, human; {Nle^8,18, Tyr³⁴}-parathyroid hormone 7-34 amide, bovine; {Nle^8,21, Tyr³⁴}-parathyroid hormone 1-34 amide, rat; parathyroid hormone 44-68, human; parathyroid hormone 1-34, bovine; parathyroid hormone 3-34, bovine; parathyroid hormone 1-31 amide, human; parathyroid hormone 1-34, human; parathyroid hormone 13-34, human; parathyroid hormone 1-34, rat; parathyroid hormone 1-38, human; parathyroid hormone 1-44, human; parathyroid hormone 28-48, human; parathyroid hormone 39-68, human; parathyroid hormone 39-84, human; parathyroid hormone 53-84, human; parathyroid hormone 69-84, human; parathyroid hormone 70-84, human; {Pro³⁴}-peptide YY (PYY), human; {Tyr⁰}-hypercalcemia malignancy factor 1-40; {Tyr⁰}-parathyroid hormone 1-44, human; {Tyr⁰}-parathyroid hormone 1-34, human; {Tyr¹}-parathyroid hormone 1-34, human; {Tyr²⁷}-parathyroid hormone 27-48, human; {Tyr³⁴}-parathyroid hormone 7-34 amide, bovine; {Tyr⁴³}-parathyroid hormone 43-68, human; {Tyr⁵², Asn⁷⁶}-parathyroid hormone 52-84, human; and {Tyr⁶³}-parathyroid hormone 63-84, human.
Parathyroid hormone (PTH)-related peptides including, but not limited to, PTHrP ({Tyr³⁶}-PTHrP 1-36 amide), chicken; hHCF-(1-34)--NH2 (humoral hypercalcemic factor), human; PTH-related protein 1-34, human; biotinyl-PTH-related protein 1-34, human; {Tyr⁰}-PTH-related protein 1-34, human; {Tyr³⁴}-PTH-related protein 1-34 amide, human; PTH-related protein 1-37, human; PTH-related protein 7-34 amide, human; PTH-related protein 38-64 amide, human; PTH-related protein 67-86 amide, human; PTH-related protein 107-111, human, rat, mouse; PTH-related protein 107-111 free acid; PTH-related protein 107-138, human; and PTH-related protein 109-111, human.
Peptide T peptides including, but not limited to, peptide T; {D-Ala¹}-peptide T; and {D-Ala¹}-peptide T amide.
Prolactin-releasing peptides including, but not limited to, prolactin-releasing peptide 31, human; prolactin-releasing peptide 20, human; prolactin-releasing peptide 31, rat; prolactin-releasing peptide 20, rat; prolactin-releasing peptide 31, bovine; and prolactin-releasing peptide 20, bovine.
Peptide YY (PYY) peptides including, but not limited to, PYY, human; PYY 3-36, human; biotinyl-PYY, human; PYY, porcine, rat; and {Leu³¹, Pro³⁴}-PYY, human
Renin substrate peptides including, but not limited to, acetyl, angiotensinogen 1-14, human; angiotensinogen 1-14, porcine; renin substrate tetradecapeptide, rat; {Cys⁸}-renin substrate tetradecapeptide, rat; {Leu⁸}-renin substrate tetradecapeptide, rat; and {Val⁸}-renin substrate tetradecapeptide, rat.
Secretin peptides including, but not limited to, secretin, canine; secretin, chicken; secretin, human; biotinyl-secretin, human; secretin, porcine; and secretin, rat.
Somatostatin (GIF) peptides including, but not limited to, BIM-23027; biotinyl-somatostatin; biotinylated cortistatin 17, human; cortistatin 14, rat; cortistatin 17, human; {Tyr⁰}-cortistatin 17, human; cortistatin 29, rat; {D-Trp⁸}-somatostatin; {DTrp⁸,DCys¹⁴}-somatostatin; {DTrp⁸,Tyr¹¹}-somatostatin; {D-Trp¹¹}-somatostatin; NTB (Naltriben); {Nle⁸}-somatostatin 1-28; octreotide (SMS 201-995); prosomatostatin 1-32, porcine; {Tyr⁰}-somatostatin; {Tyr⁰}-somatostatin;{Tyr¹}-somatostatin 28 (1-14); {Tyr¹¹}-somatostatin; {Tyr⁰}, D-Trp⁸}-somatostatin; somatostatin; somatostatin antagonist; somatostatin-25; somatostatin-28; somatostatin 28 (1-12); biotinyl-somatostatin-28; {Tyr⁰}-somatostatin-28; {Leu8, D-Trp²², Tyr²⁵}-somatostatin 28; biotinyl-{Leu⁸, D-Trp²², Tyr²⁵}-somatostatin-28; somatostatin-28 (1-14); and somatostatin analog, RC-160.
Substance P peptides including, but not limited to, G protein antagonist-2; Ac-{Arg⁶, Sar⁹, Met(02)¹¹}-substance P 6-11; {Arg³}-substance P; Ac-Trp-3,5-bis(trifluoromethyl)benzyl ester; Ac-{Arg⁶, Sar⁹, Met(O2)¹¹}-substance P 6-11; {D-Ala⁴}-substance P 4-11; {Tyr⁶, D-Phe⁷, D-His⁹}-substance P 6-11 (sendide); biotinyl-substance P; biotinyl-NTE{Arg³}-substance P; (Tyr⁸}-substance P; {Sar⁹, Met(O2)¹¹}-substance P; {D-Pro², DTrp^7,9}-substance P; {D-Pro⁴, O-Trp^7,9}-substance P 4-11; substance P 4-11; {DTrp^2,7,9}-substance P; {(Dehydro)Pro^2,4, Pro⁹}-substance P; {Dehydro-Pro⁴}-substance P 4-11; {Glp⁵,(Me)Phe⁸,Sar⁹}-substance P 5-11; {Glp⁵,Sar⁹}-substance P 5-11; {Glp⁵}-substance P 5-11; hepta-substance P (substance P 5-11); hexa-substance P(substance P 6-11); {MePhe⁸,Sar⁹}-substance P; {Nle¹¹}-substance P; Octa-substance P(substance P 4-11); {pGlu¹}-hexa-substance P ({pGlu⁶}-substance P 6-11); {pGlu⁶, D-Pro⁹}-substance P 6-11; {(pNO₂)Phe⁷Nle¹¹}-substance P; penta-substance P (substance P 7-11); {Pro⁹}-substance P; GR73632, substance P 7-11; {Sar⁴}-substance P 4-11; {Sar⁹}-substance P; septide ({pGlu⁶, Pro⁹}-substance P 6-11); spantide I; spantide II; substance P; substance P, cod; substance P, trout; substance P antagonist; substance P-Gly-Lys-Arg; substance P 1-4; substance P 1-6; substance P 1-7; substance P 1-9; deca-substance P (substance P 2-11); nona-substance P (substance P 3-11); substance P tetrapeptide (substance P 8-11); substance P tripeptide (substance P 9-11); substance P, free acid; substance P methyl ester, and {Tyr⁸,Nle¹¹} substance P.
Tachykinin peptides including, but not limited to, {Ala⁵, beta-Ala⁸} neurokinin A 4-10; eledoisin; locustatachykinin I (Lom-TK-I) (Locusta migratoria); locustatachykinin II (Lom-TK-II) (Locusta migratoria); neurokinin A 4-10; neurokinin A (neuromedin L, substance K); neurokinin A, cod and trout; biotinyl-neurokinin A (biotinyl-neuromedin L, biotinyl-substance K); {Tyr⁰}-neurokinin A; {Tyr⁶}-substance K; FR64349; {Lys³, Gly⁸-(R)-gamma-lactam-Leu⁹}-neurokinin A 3-10; GR83074; GR87389; GR94800; {Beta-Ala⁸}-neurokinin A 4-10; {Nle¹⁰}-neurokinin A 4-10; {Trp⁷, beta-Ala⁸}-neurokinin A 4-10; neurokinin B (neuromedin K); biotinyl-neurokinin B (biotinyl-neuromedin K); {MePhe⁷}-neurokinin B; {Pro⁷}-neurokinin B; {Tyr⁰}-neurokinin B; neuromedin B, porcine; biotinyl-neuromedin B, porcine; neuromedin B-30, porcine; neuromedin B-32, porcine; neuromedin B receptor antagonist; neuromedin C, porcine; neuromedin N, porcine; neuromedin (U-8), porcine; neuromedin (U-25), porcine; neuromedin U, rat; neuropeptide-gamma (gamma-preprotachykinin 72-92); PG-KII; phyllolitorin; {Leu⁸}-phyllolitorin (Phyllomedusa sauvagei); physalaemin; physalaemin 1-11; scyliorhinin II, amide, dogfish; senktide, selective neurokinin B receptor peptide; {Ser²}-neuromedin C; beta-preprotachykinin 69-91, human; beta-preprotachykinin 111-129, human; tachyplesin I; xenopsin; and xenopsin 25 (xenin 25), human
Thyrotropin-releasing hormone (TRH) peptides including, but not limited to, biotinyl-thyrotropin-releasing hormone; {Glu¹}-TRH; His-Pro-diketopiperazine; {3-Me-His²}-TRH; pGlu-Gln-Pro-amide; pGlu-His; {Phe²}-TRH; prepro TRH 53-74; prepro TRH 83-106; prepro-TRH 160-169 (Ps4, TRH-potentiating peptide); prepro-TRH 178-199, thyrotropin-releasing hormone (TRH); TRH, free acid; TRH--SH Pro; and TRH precursor peptide.
Toxin peptides including, but not limited to, omega-agatoxin TK; agelenin, (spider, Agelena opulenta); apamin (honeybee, Apis mellifera); calcicudine (CaC) (green mamba, Dedroaspis angusticeps); calciseptine (black mamba, Dendroaspis polylepis polylepis); charybdotoxin (ChTX) (scorpion, Leiurus quinquestriatus var. hebraeus); chlorotoxin; conotoxin GI (marine snail, Conus geographus); conotoxin GS (marine snail, Conus geographus); conotoxin MI (Marine Conus magus); alpha-conotoxin EI, Conus ermineus; alpha-conotoxin SIA; alpha-conotoxin ImI; alpha-conotoxin SI (cone snail, Conus striatus); micro-conotoxin GIIIB (marine snail, Conus geographus); omega-conotoxin GVIA (marine snail, Conus geographus); omega-conotoxin MVIIA (Conus magus); omega-conotoxin MVIIC (Conus magus); omega-conotoxin SVIB, (cone snail, Conus striatus); endotoxin inhibitor; geographutoxin I (GTX-I) (.mu.-Conotoxin GIIIA); iberiotoxin (IbTX) (scorpion, Buthus tamulus); kaliotoxin 1-37; kaliotoxin (scorpion, Androctonus mauretanicus mauretanicus); mast cell-degranulating peptide (MCD-peptide, peptide 401); margatoxin (MgTX) (scorpion, Centruriodes margaritatus); neurotoxin NSTX-3 (Papua New Guinean spider, Nephilia maculata); PLTX-II (spider, Plectreurys tristes); scyllatoxin (leiurotoxin I); and stichodactyla toxin (ShK).
Vasoactive intestinal peptides (VIP/PHI) including, but not limited to, VIP, human, porcine, rat, ovine; VIP-Gly-Lys-Arg-NH₂; biotinyl-PHI (biotinyl-PHI-27), porcine; {Glp¹⁶} VIP 16-28, porcine; PHI (PHI-27), porcine; PHI (PHI-27), rat; PHM-27 (PHI), human; prepro VIP 81-122, human; prepro VIP/PHM 111-122; prepro VIP/PHM 156-170; biotinyl-PHM-27 (biotinyl-PHI), human; vasoactive intestinal contractor (endothelin-beta); vasoactive intestinal octacosa-peptide, chicken; vasoactive intestinal peptide, guinea pig; biotinyl-VIP, human, porcine, rat; vasoactive intestinal peptide 1-12, human, porcine, rat; vasoactive intestinal peptide 10-28, human, porcine, rat; vasoactive intestinal peptide 11-28, human, porcine, rat, ovine; vasoactive intestinal peptide (cod, Gadus morhua); vasoactive intestinal peptide 6-28; vasoactive intestinal peptide antagonist; vasoactive intestinal peptide antagonist ({Ac-Tyr¹, D-Phe²}-GHRF 1-29 amide); vasoactive intestinal peptide receptor antagonist (4-Cl-D-Phe⁶, Leu¹⁷}-VIP); and vasoactive intestinal peptide receptor binding inhibitor, L-8-K. Additional constructs include but are not limited to, Ala{^11,22,28} VIP, Ala{^{2,8,9,11,19,22,24,25,27,28}}VIP, {K^15,R¹⁶, L²⁷}-VIP(1-7)/GRF(8-27), Ro25-1553, Ro25-1392, BAY55-9837, R3P65, Maxadilan, PG97-269, PG99-465, Max.d.4., and M65 (Dickson & Finlayson, Pharmacology & Therapeutics, Volume 121, Issue 3, March 2009, Pages 294-316).
Vasopressin (ADH) peptides including, but not limited to, vasopressin; {Asu^1,6,Arg⁸}-vasopressin; vasotocin; {Asu^1,6,Arg⁸}-vasotocin; {Lys⁸}-vasopressin; pressinoic acid; {Arg⁸}-desamino vasopressin desglycinamide; {Arg⁸}-vasopressin (AVP); {Arg⁸}-vasopressin desglycinamide; biotinyl-{Arg⁸}-vasopressin (biotinyl-AVP); {D-Arg⁸}-vasopressin; desamino-{Arg⁸}-vasopressin; desamino-{D-Arg⁸}-vasopressin (DDAVP); {deamino-{D-3-(3′-pyridyl-Ala)}-{Arg⁸}-vasopressin; {1-(beta-Mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosinel-{Arg⁸}-vasopressin; vasopressin metabolite neuropeptide {pGlu⁴, Cys⁶}; vasopressin metabolite neuropeptide {pGlu⁴, Cys⁶}; {Lys⁸}-deamino vasopressin desglycinamide; {Lys⁸}-vasopressin; {Mpr¹,Val⁴,DArg⁸}-vasopressin; {Phe², Ile³, Orn⁸}-vasopressin ({Phe², Orn⁸}-vasotocin); {Arg⁸}-vasotocin; and {d(CH₂)₅, Tyr(Me)₂, Orn⁸}-vasotocin.
Virus related peptides including, but not limited to, viral membrane fusion proteins, fluorogenic human CMV protease substrate; HCV core protein 59-68; HCV NS4A protein 1840 (JT strain); HCV NS4A protein 21-34 (JT strain); hepatitis B virus receptor binding fragment; hepatitis B virus pre-S region 120-145; {Ala¹²⁷}-hepatitis B virus pre-S region 120-131; herpes virus inhibitor 2; HIV envelope protein fragment 254-274; HIV gag fragment 129-135; HIV substrate; P 18 peptide; peptide T; {3,5 diiodo-Tyr⁷} peptide T; RISK HIV-1 inhibitory peptide; T20; T21; V3 decapeptide P 18-110; and virus replication inhibiting peptide.
The human hormone glucagon is a 29-amino acid peptide hormone produced in the A-cells of the pancreas. The hormone belongs to a multi-gene family of structurally related peptides that include secretin, gastric inhibitory peptide, vasoactive intestinal peptide and glicentin. These peptides variously regulate carbohydrate metabolism, gastrointestinal mobility and secretory processing. The principal recognized actions of pancreatic glucagon, however, are to promote hepatic glycogenolysis and glyconeogenesis, resulting in an elevation of blood sugar levels. In this regard, the actions of glucagon are counter regulatory to those of insulin and may contribute to the hyperglycemia that accompanies Diabetes mellitus {(Lund, P. K., et al., Proc. Natl. Acad. Sci. U.S.A., 79:345-349 (1982)}.
Glucagon has been found to be capable of binding to specific receptors which lie on the surface of insulin producing cells. Glucagon, when bound to these receptors, stimulates the rapid synthesis of cAMP by these cells. cAMP, in turn, has been found to stimulate insulin expression {Korman, L. Y., et al., Diabetes, 34:717-722 (1985)}. Insulin acts to inhibit glucagon synthesis {Ganong, W. F., Review of Medical Physiology, Lange Publications, Los Altos, Calif., p. 273 (1979)}. Thus, the expression of glucagon is carefully regulated by insulin, and ultimately by the serum glucose level.
The glucagon gene is initially translated from a 360 base pair precursor to form the polypeptide, preproglucagon {Lund, et al., Proc. Natl. Acad. Sci. U.S.A. 79:345-349 (1982)}. This polypeptide is subsequently processed to form proglucagon. Patzelt, C., et al., Nature, 282:260-266 (1979) demonstrated that proglucagon was subsequently cleaved into glucagon and a second polypeptide. Subsequent work by Lund, P. K., et al. supra, Lopez L. C., et al., Proc. Natl. Acad. Sci. U.S.A., 80:5485-5489 (1983), and Bell, G. I., et al., Nature 302:716-718 (1983), demonstrated that the proglucagon molecule was cleaved immediately after lysine-arginine dipeptide residues. Studies of proglucagon produced by channel catfish (Ictalurus punctata) indicated that glucagon from this animal was also proteolytically cleaved after adjacent lysine-arginine dipeptide residues {Andrews P. C., et al., J. Biol. Chem., 260:3910-3914 (1985), Lopez, L. C., et al., Proc. Natl. Acad. Sci. U.S.A., 80:5485-5489 (1983)}. Bell, G. I., et al., supra, discovered that mammalian proglucagon was cleaved at lysine-arginine or arginine-arginine dipeptides, and demonstrated that the proglucagon molecule contained three discrete and highly homologous peptide molecules which were designated glucagon, glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2). Lopez, et al., concluded that glucagon-like peptide 1 was 37 amino acid residues long and that glucagon-like peptide 2 was 34 amino acid residues long. Analogous studies on the structure of rat preproglucagon revealed a similar pattern of proteolytic cleavage between adjacent lysine-arginine or arginine-arginine dipeptide residues, resulting in the formation of glucagon, GLP-1 and GLP-2 {Heinrich, G., et al., Endocrinol., 115:2176-2181 (1984)}.
Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide expressed in a tissue-specific manner from the pleiotropic glucagon gene. GLP-2 shows remarkable homology in terms of amino acid sequence to glucagon and Glucagon-like peptide-1 (GLP-1). Further, different mammalian forms of GLP-2 are highly conserved. The sequence of human GLP-2, is as follows: His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-A-la-Arg-Asp-Phe-Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp. Further, a large number of agonist GLP-2 peptides that are described in PCT Application PCT/CA97/00252, filed Apr. 11, 1997. Analogs are described in U.S. Pat. No. 6,051,557, and examples of GLP-2 variants are found in U.S. Pat. Nos. 5,990,077 and 6,184,201.
Recently it was demonstrated that GLP-2 is an intestinotrophic peptide hormone (Drucker et al., (1996) PNAS, 93:7911-7916). When given exogenously, GLP-2 can produce a marked increase in the proliferation of small intestinal epithelium of the test mice, apparently with no undesirable side effects. Subsequently it was shown that peptide analogs of native GLP-2 with certain modifications to the peptide sequence possess enhanced intestinotrophic activity (U.S. patent application Ser. No. 08/669,791). Moreover, GLP-2 has also been shown to increase D-Glucose maximal transport rate across the intestinal basolateral membrane (Cheeseman and Tseng (1996) American Journal of Physiology 271:G477-G482).
A number of peptide hormones (IGF-2, IGF-1, GH), structurally unrelated to GLP-2, have been demonstrated to have varying degrees of intestinotrophic activity. (U.S. Pat. No. 5,482,926, WO 91/12018, U.S. Pat. No. 5,288,703). However, none of the above peptide hormones possess the efficacy or specificity of GLP-2 in promoting proliferation of the intestine epithelium. GLP-2 acts synergistically with the peptide hormones IGF-1 and/or GH to promote the proliferation of cells in the large intestine. Furthermore, the intestinotrophic effects on the small and large intestines of this combination therapy are greater than that seen with any one of alone. Coadministration of GLP-2 with IGF-2 to promote growth of small and/or large intestine tissue is discussed in U.S. Pat. No. 5,952,301.
Nucleic acid encoding the GLP-2 receptor has been isolated and methods to identify GLP-2 receptor agonists are described (U.S. patent application Ser. No. 08/767,224 and U.S. Ser. No. 08/845,546). GLP-2's role in diseases involving the esophagus and the stomach, in assisting patients at risk of developing a malfunctioning of the upper gastrointestinal tract, and in increasing tissue growth in the upper gastrointestinal tract have been discussed (see U.S. Pat. No. 6,051,557). GLP-2 receptor agonists act to enhance functioning of the large intestine. (U.S. Pat. No. 6,297,214). GLP-2 and peptidic agonists of GLP-2 can cause proliferation of the tissue of large intestine. GLP-2 may also be useful to treat or prevent inflammatory conditions of the large intestine, including inflammatory bowel diseases (U.S. Pat. No. 6,586,399).
A very wide variety of non-naturally encoded amino acids are suitable for use in the present invention. Any number of non-naturally encoded amino acids can be introduced into an analog. In general, the introduced non-naturally encoded amino acids are substantially chemically inert toward the 20 common, genetically-encoded amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine). In some embodiments, the non-naturally encoded amino acids include side chain functional groups that react efficiently and selectively with functional groups not found in the 20 common amino acids (including but not limited to, azido, ketone, aldehyde and aminooxy groups) to form stable conjugates. For example, an analog that includes a non-naturally encoded amino acid containing an azido functional group can be reacted with a polymer (including but not limited to, poly(ethylene glycol) or, alternatively, a second polypeptide containing an alkyne moiety to form a stable conjugate resulting for the selective reaction of the azide and the alkyne functional groups to form a Huisgen {3+2} cycloaddition product.
In some embodiments, the composition or pharmaceutical compositions of the claimed invention comprises an analog of a polypeptide, wherein the analog amino acid sequence is based upon the fragments, polypeptides, and functional derivatives disclosed herein and wherein the analog comprises at least one or a plurality of non-natural amino acids and at least one or a plurality of β-amino acid residues. A non-natural amino acid typically possesses an R group that is any substituent other than one component of the twenty natural amino acids, and may be suitable for use in the present invention. Because the non-naturally encoded amino acids of the invention typically differ from the natural amino acids only in the structure of the side chain, the non-naturally encoded amino acids form amide bonds with other amino acids, including but not limited to, natural or non-naturally encoded, in the same manner in which they are formed in naturally occurring polypeptides. However, the non-natural amino acids have side chain groups that distinguish them from the natural amino acids. For example, R optionally comprises an alkyl-, aryl-, acyl-, keto-, azido-, hydroxyl-, hydrazine, cyano-, halo-, hydrazide, alkenyl, alkynyl, ether, thiol, seleno-, sulfonyl-, borate, boronate, phospho, phosphono, phosphine, heterocyclic, enone, imine, aldehyde, ester, thioacid, hydroxylamine, amino group, or the like or any combination thereof. Other non-naturally occurring amino acids of interest that may be suitable for use in the present invention include, but are not limited to, amino acids comprising a photoactivatable cross-linker, spin-labeled amino acids, fluorescent amino acids, metal binding amino acids, metal-containing amino acids, radioactive amino acids, amino acids with novel functional groups, amino acids that covalently or noncovalently interact with other molecules, photocaged and/or photoisomerizable amino acids, amino acids comprising biotin or a biotin analogue, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, amino acids comprising polyethylene glycol or polyether, heavy atom substituted amino acids, chemically cleavable and/or photocleavable amino acids, amino acids with an elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons, carbon-linked sugar-containing amino acids, redox-active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moiety.
Exemplary non-natural amino acids that may be suitable for use in the present invention and that are useful for reactions with water soluble polymers include, but are not limited to, those with carbonyl, aminooxy, hydrazine, hydrazide, semicarbazide, azide and alkyne reactive groups. In some embodiments, non-naturally encoded amino acids comprise a saccharide moiety. Examples of such amino acids include N-acetyl-L-glucosaminyl-L-serine, N-acetyl-L-galactosaminyl-L-serine, N-acetyl-L-glucosaminyl-L-threonine, N-acetyl-L-glucosaminyl-L-asparagine and O-mannosaminyl-L-serine. Examples of such amino acids also include examples where the naturally-occurring N- or O-linkage between the amino acid and the saccharide is replaced by a covalent linkage not commonly found in nature—including but not limited to, an alkene, an oxime, a thioether, an amide and the like. Examples of such amino acids also include saccharides that are not commonly found in naturally-occurring proteins such as 2-deoxy-glucose, 2-deoxygalactose and the like.
Many of the non-naturally encoded amino acids provided herein are commercially available, e.g., from Sigma-Aldrich (St. Louis, Mo., USA), Novabiochem (a division of EMD Biosciences, Darmstadt, Germany), or Peptech (Burlington, Mass., USA). Those that are not commercially available are optionally synthesized as provided herein or using standard methods known to those of skill in the art. In some embodiments, the invention relates to a method of manufacturing a polypeptide analog wherein the polypeptide analog is manufactured using a synthesis technique disclosed in the following references, which are incorporated herein by reference: For organic synthesis techniques, see, e.g., Organic Chemistry by Fessendon and Fessendon, (1982, Second Edition, Willard Grant Press, Boston Mass.); Advanced Organic Chemistry by March (Third Edition, 1985, Wiley and Sons, New York); and Advanced Organic Chemistry by Carey and Sundberg (Third Edition, Parts A and B, 1990, Plenum Press, New York). See, also, U.S. Patent Application Publications 2003/0082575 and 2003/0108885, which is incorporated by reference herein. In addition to unnatural (or non-natural) amino acids that contain novel side chains, unnatural amino acids that may be suitable for use in the present invention also optionally comprise modified backbone structures, including but not limited to, as illustrated by the structures of Formula II and III of U.S. Patent Application Publication 2010-0048871, wherein Z typically comprises OH, NH₂, SH, NH—R, or S—R; X and Y, which can be the same or different, typically comprise S or O, and R and R, which are optionally the same or different, are typically selected from the same list of constituents for the R group described above for the unnatural amino acids as well as hydrogen. For example, unnatural amino acids of the invention optionally comprise substitutions in the amino or carboxyl group as illustrated by Formulas II and III. Unnatural amino acids of this type include, but are not limited to, α-hydroxy acids, α-thioacids, α-aminothiocarboxylates, including but not limited to, with side chains corresponding to the common twenty natural amino acids or unnatural side chains. In addition, substitutions at the α-carbon optionally include, but are not limited to, L, D, or α-α-disubstituted amino acids such as D-glutamate, D-alanine, D-methyl-O-tyrosine, aminobutyric acid, and the like. Other structural alternatives include cyclic amino acids, such as proline analogues as well as 3, 4, 6, 7, 8, and 9 membered ring proline analogues, β amino acids such as substituted β-alanine.
In some embodiments, the composition or pharmaceutical compositions of the claimed invention comprises an analog of a polypeptide, wherein the analog amino acid sequence is based upon the fragments, polypeptides, and functional derivatives disclosed herein and wherein the analog comprises at least one or a plurality of unnatural amino acid or non-natural amino acid and at least one or a plurality of β-amino acid residues, wherein the unnatural amino acids based on natural amino acids, such as tyrosine, glutamine, phenylalanine, and the like, and are suitable for use in the present invention. Tyrosine analogs include, but are not limited to, para-substituted tyrosines, ortho-substituted tyrosines, and meta substituted tyrosines, where the substituted tyrosine comprises, including but not limited to, a keto group (including but not limited to, an acetyl group), a benzoyl group, an amino group, a hydrazine, an hydroxyamine, a thiol group, a carboxy group, an isopropyl group, a methyl group, a C₆-C₂₀straight chain or branched hydrocarbon, a saturated or unsaturated hydrocarbon, an O-methyl group, a polyether group, a nitro group, an alkynyl group or the like. In addition, multiply substituted aryl rings are also contemplated. Glutamine analogs that may be suitable for use in the present invention include, but are not limited to, α.-hydroxy derivatives, cyclic derivatives, and amide substituted glutamine derivatives. Example phenylalanine analogs that may be suitable for use in the present invention include, but are not limited to, para-substituted phenylalanines, ortho-substituted phenylalanines, and meta-substituted phenylalanines, where the substituent comprises, including but not limited to, a hydroxy group, a methoxy group, a methyl group, an allyl group, an aldehyde, an azido, an iodo, a bromo, a keto group (including but not limited to, an acetyl group), a benzoyl, an alkynyl group, or the like. Specific examples of unnatural amino acids that may be suitable for use in the present invention include, but are not limited to, a p-acetyl-L-phenylalanine, an O-methyl-L-tyrosine, an L-3-(2-naphthyl)alanine, a 3-methyl-phenylalanine, an 0-4-allyl-L-tyrosine, a 4-propyl-L-tyrosine, a tri-O-acetyl-GlcNAcβ-serine, an L-Dopa, a fluorinated phenylalanine, an isopropyl-L-phenylalanine, a p-azido-L-phenylalanine, a p-acyl-L-phenylalanine, a p-benzoyl-L-phenylalanine, an L-phosphoserine, a phosphonoserine, a phosphonotyrosine, a p-iodo-phenylalanine, a p-bromophenylalanine, a p-amino-L-phenylalanine, an isopropyl-L-phenylalanine, and a p-propargyloxy-phenylalanine, and the like. Examples of structures of a variety of unnatural amino acids that may be suitable for use in the present invention are provided in, for example, WO 2002/085923 entitled “In vivo incorporation of unnatural amino acids.” See also Kiick et al., (2002). Incorporation of azides into recombinant proteins for chemoselective modification by the Staudinger ligation, PNAS 99:19-24, for additional methionine analogs.
The chemical moieties via unnatural amino acids that can be incorporated into analogs offer a variety of advantages and manipulations of the protein. For example, the unique reactivity of a keto functional group allows selective modification of proteins with any of a number of hydrazine- or hydroxylamine-containing reagents in vitro and in vivo. A heavy atom unnatural amino acid, for example, can be useful for phasing X-ray structure data. The site-specific introduction of heavy atoms using unnatural amino acids also provides selectivity and flexibility in choosing positions for heavy atoms. In some embodiments, the composition or pharmaceutical compositions of the claimed invention comprises an analog of a polypeptide, wherein the analog amino acid sequence is based upon the fragments, polypeptides, and functional derivatives disclosed herein and wherein the analog comprises at least one or a plurality of unnatural amino acid or non-natural amino acid and at least one or a plurality of β-amino acid residues, wherein the unnatural amino is a photoreactive unnatural amino acid chosen from (including but not limited to, amino acids with benzophenone and arylazides (including but not limited to, phenylazide) side chains), for example, allow for efficient in vivo and in vitro photocrosslinking of protein. Examples of photoreactive unnatural amino acids include, but are not limited to, p-azido-phenylalanine and p-benzoyl-phenylalanine. The protein with the photoreactive unnatural amino acids can then be crosslinked at will by excitation of the photoreactive group-providing temporal control. In one example, the methyl group of an unnatural amino can be substituted with an isotopically labeled, including but not limited to, methyl group, as a probe of local structure and dynamics, including but not limited to, with the use of nuclear magnetic resonance and vibrational spectroscopy. Alkynyl or azido functional groups, for example, allow the selective modification of proteins with molecules through a {3+2} cycloaddition reaction.
A non-natural amino acid incorporated into a polypeptide at the amino terminus can be composed of an R group that is any substituent other than one used in the twenty natural amino acids and a second reactive group different from the NH₂group normally present in α-amino acids. A similar non-natural amino acid can be incorporated at the carboxyl terminus with a second reactive group different from the COOH group normally present in α-amino acids.
Many of the unnatural amino acids suitable for use in the present invention are commercially available, e.g., from Sigma (USA) or Aldrich (Milwaukee, Wis., USA). Those that are not commercially available are optionally synthesized as provided herein or as provided in various publications or using standard methods known to those of skill in the art. For organic synthesis techniques, see, e.g., Organic Chemistry by Fessendon and Fessendon, (1982, Second Edition, Willard Grant Press, Boston, Mass.); Advanced Organic Chemistry by March (Third Edition, 1985, Wiley and Sons, New York); and Advanced Organic Chemistry by Carey and Sundberg (Third Edition, Parts A and B, 1990, Plenum Press, New York). Additional publications describing the synthesis of unnatural amino acids include, e.g., WO 2002/085923 entitled “In vivo incorporation of Unnatural Amino Acids;” Matsoukas et al., (1995) J. Med. Chem., 38, 4660-4669; King, F. E. & Kidd, D. A. A. (1949) A New Synthesis of Glutamine and of γ-Dipeptides of Glutamic Acid from Phthylated Intermediates. J. Chem. Soc., 3315-3319; Friedman, O. M. & Chattenji, R. (1959) Synthesis of Derivatives of Glutamine as Model Substrates for Anti-Tumor Agents. J. Am. Chem. Soc. 81, 3750-3752; Craig, J. C. et al. (1988) Absolute Configuration of the Enantiomers of 7-Chloro-4 {{4-(diethylamino)-}-methylbutyl}amino}quinoline (Chloroquine). J. Org. Chem. 53, 1167-1170; Azoulay, M., Vilmont, M. & Frappier, F. (1991) Glutamine analogues as Potential Antimalarials, Eur. J. Med. Chem. 26, 201-5; Koskinen, A. M. P. & Rapoport, H. (1989) Synthesis of 4-Substituted Prolines as Conformationally Constrained Amino Acid Analogues. J. Org. Chem. 54, 1859-1866; Christie, B. D. & Rapoport, H. (1985) Synthesis of Optically Pure Pipecolates from L-Asparagine. Application to the Total Synthesis of (+)-Apovincamine through Amino Acid Decarbonylation and Iminium Ion Cyclization. J. Org. Chem. 50:1239-1246; Barton et al., (1987) Synthesis of Novel alpha-Amino-Acids and Derivatives Using Radical Chemistry: Synthesis of L- and D-alpha-Amino-Adipic Acids, L-alpha-aminopimelic Acid and Appropriate Unsaturated Derivatives. Tetrahedron 43:4297-4308; and, Subasinghe et al., (1992) Quisqualic acid analogues: synthesis of beta-heterocyclic 2-aminopropanoic acid derivatives and their activity at a novel quisqualate-sensitized site. J. Med. Chem. 35:4602-7. See also, patent applications entitled “Protein Arrays,” filed Dec. 22, 2003, Ser. No. 10/744,899 and Ser. No. 60/435,821 filed on Dec. 22, 2002.
In some embodiments, the composition comprises a transcription factor analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an enkephlin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an LHRH analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a neuropeptide analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an glycointegrin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an integrin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a glucagon or glucagon-like peptide analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an antithrombotic peptides analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a vassopressin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a cytokine or interleukin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an interferon analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an endothelin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an natriuretic hormone analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an extracellular kinase ligand analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an angiotensin enzyme inhibitor analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an antiviral peptide analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a thrombin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a substance P analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a substance G analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a somatotropin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a somatostatin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a GnRH analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a bradykinin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises an insulin analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a growth factor analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. Any of the compositions above may be used in the methods disclosed in this instant specification.
In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 60 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 12 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 14 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 16 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 18 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 40 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 45 percent to about 50 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 40 percent to about 45 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 40 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 35 percent to about 40 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 30 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 10 percent to about 20 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 15 percent to about 20 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 20 percent to about 25 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 25 percent to about 30 percent of the total number of amino acids of the analog. In some embodiments, the composition comprises a VIP analog wherein the total number of β-amino acids in the analog is from about 30 percent to about 35 percent of the total number of amino acids of the analog.
In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids in the analog is from 1 to 3 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids in the analog is from 2 to 4 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is from 3 to 5 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is from 4 to 6 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is from 5 to 7 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 1 β-amino acid for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 2 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 3 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 4 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 5 β-amino acids for every 7 amino acids of the analog. In some embodiments, the composition comprises a VIP analog, wherein the ratio of total β-amino acids to amino acids in the analog is 6 β-amino acids for every 7 amino acids of the analog.
In another embodiment of the invention, the composition comprises a VIP analog, wherein the analog comprises a repetitive pattern of β-amino acids from the amino-terminus to the carboxy-terminus selected from the following: ααααααβ, αααααβα, ααααβαα, αααβααα, ααβαααα, αβααααα, βαααααα, αααααββ, ααααββα, αααββαα, ααββααα, αββαααα, ββααααα, βαααααβ, βααααβα, βαααβαα, βααβααα, β βαααα, αβααααβ, αβαααβα, αβααβαα, αβαβααα, ααβαααβ, ααβααβα, ααβαβαα, αααβααβ, αααβαβα, and ααααβαβ.
Some embodiments of the claimed invention include pharmaceutical compositions. In some embodiments, the pharmaceutical composition comprises any of the aforementioned compositions in combination with a pharmaceutically acceptable carrier. In another embodiment of the invention, the pharmaceutical composition comprises a secretin analog and one other active agent, wherein the secretin analog comprises at least one α-amino acid and at least one β-amino acid.
In another embodiment of the invention, the pharmaceutical composition comprises a VIP analog and one other active agent, wherein the VIP analog comprises at least one α-amino acid and at least one β-amino acid.
The invention further relates to uses of a composition comprising a secretin analog in the preparation of a medicament for treating or preventing pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction. The invention further relates to use of a composition comprising a VIP analog in the preparation of a medicament for treating or preventing pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction.
In some embodiments, the invention relates to methods of manufacturing any one of the aforementioned compositions, pharmaceutical compositions, or a pharmaceutical salt derived therefrom comprising catalyzing a reaction between at least one α-amino acid with at least one β-amino acid.
The invention also relates to methods of treating or preventing pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction comprising administrating any one of the compositions or pharmaceutical compositions comprising a secretin family analog, or a pharmaceutical salt derived therefrom, to a subject in need thereof.
The present invention also relates to methods of inhibiting secretion of TNF-α in a subject comprising administering a composition comprising a vasoactive intestinal peptide (VIP) analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments, the method comprises administering the composition comprising any of the percentages of β-amino acids.
The present invention is also directed towards kits comprising any of the aforementioned compositions or pharmaceutical compositions comprising a secretin analog, wherein the secretin analog comprises an α-amino acid and at least one β-amino The present invention is directed toward kits comprising any of the aforementioned compositions or pharmaceutical compositions comprising a VIP analog, wherein the VIP analog comprises an α-amino acid and at least on β-amino acid. In some embodiments, the kit further comprises a vehicle for administration of the composition.
The present invention also relates to methods of identifying a modulator of human receptor activity comprising:
a) contacting a human receptor with a secretin analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the secretin analog to the human receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the secretin analog to the human receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human receptor in the absence of an unknown compound.
The present invention also relates to methods of identifying a modulator of animal receptor activity comprising:
a) contacting an animal receptor with a secretin analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the secretin analog to the animal receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the secretin analog to the animal receptor in the presence of an unknown compound to the rate of association of the secretin analog to the animal receptor in the absence of an unknown compound.
The present invention also relates to methods of identifying a modulator of human secretin receptor activity comprising:
a) contacting a human secretin receptor with a secretin analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the secretin analog to the human secretin receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the secretin analog to the human secretin receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human secretin receptor in the absence of an unknown compound.
The present invention also relates to methods of identifying a modulator of human VIP receptor activity comprising:
a) contacting a human VIP receptor with the VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the VIP analog to the human VIP receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows MALDI-TOF data of a purified VIP analogue which illustrates the expected mass (within a reasonable tolerance) of both singly charged and doubly charged species of the analogue after chemical synthesis, cleavage from resin, and subsequent purification of the analogue through a C18 HPLC column.

FIG. 2 presents circular dichroism data of a VIP analogue diluted in a 10 mM sodium phosphate buffer at pH of 7.5. The signal exhibited for the structure of the VIP analogue is similar to previously characterized α-amino acid/β amino acid peptides of similar backbone length and concentration, which indicates a substantial helical content (Home et. al., J. Am. Chem. Soc., 2007, 129 (14), pp 4178-4180; Home et. al. PNAS, Sep. 1, 2009, vol. 106, no. 35, 14751-14756).

FIG. 3 illustrates in vitro functional EC₅₀data of a VIP analogue tested in the presence of VIPR1 (VPAC₁) or VIPR2 (VPAC₂) receptors as compared to the binding of wild-type VIP protein to the same receptors. The data show that the analogue achieves full activation of VIPR1 (˜100%, relative to maximum activation), but has an EC₅₀at a concentration higher than the EC₅₀of wild-type VIP protein.

FIG. 4 illustrates data from an in vitro antagonist inhibition assay in which competition for VIPR1 (VPAC₁) or VIPR2 (VPAC₂) was measured by the amount of VIP analogue capable of inhibiting the association of wild-type VIP to its receptors.

FIG. 5 illustrates helical wheel diagrams of repeating patterns of α- or β-amino acids residues in alignment along one longitudinal axis of a folded molecular structure from N-terminus to C-terminus when the unnatural polypeptides adopt a helical conformation, where the position of β-amino acids are represented by solid dots.

FIG. 6 illustrates a helical wheel diagram of the predicted α-helical portion of VIP polypeptide, positions 10-28.

FIG. 7 illustrates multiple VIP analog sequences and their corresponding helical wheel diagrams, where the position of β-amino acids are represented by solid dots.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

Various terms relating to the methods and other aspects of the present invention are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definition provided herein.
As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.
The term “about” as used herein when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of ±20%, ±10%, ±5%, ±1%, or ±0.1% from the specified value, as such variations are appropriate to perform the disclosed methods.
The term “active state” refers to the conformation or set of conformations of a polypeptide that allows functional domain or domains of the polypeptide to associate or disassociate with another compound, macromolecule, or ligand. In some embodiments, the association or disassociation of the polypeptide with another compound, macromolecule, or ligand may propagate or inhibit a biologic signal.
The terms “amino acid” refer to a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the α-carbon. Suitable amino acids include, without limitation, both the D- and L-isomers of the naturally-occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. in some embodiments, a single “amino acid” might have multiple sidechain moieties, as available per an extended aliphatic or aromatic backbone scaffold. Unless the context specifically indicates otherwise, the term amino acid, as used herein, is intended to include amino acid analogs.
The term “analog” refers to any polypeptide comprising at least one α-amino acid and at least one β-amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based. In some embodiments, an analog is any polypeptide comprising at least one β-amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based and wherein the addition of one or more β-amino acid residues constrains an alpha helical structure in the polypeptide. In some embodiments, an analog is any polypeptide comprising at least one β-amino acid residue, wherein the polypeptide is structurally similar to a naturally occurring full-length protein and shares the biochemical or biological activity of the naturally occurring full-length protein upon which the analog is based. In some embodiments, the non-natural amino acid residue is a monomer of an aliphatic polypeptide. In some embodiments the aliphatic analogs are chosen from oligoureas, azapeptides, pyrrolinones, α-aminoxy-peptides, and sugar-based peptides. In some embodiments, the composition comprises a non-natural β-amino acid. In some embodiments, the analog is a fragment of the full-length protein upon which the analog is based. In some embodiments, fragments are from about 5 to about 75 amino acids in length as compared to the naturally occurring, fully translated and fully processed protein sequences. In some embodiments, the analogs comprise a fragment of a naturally translated full-length protein that induces the biochemical or biological activity of a biological pathway of a subject at a level equivalent to or increased as compared to the activity induced by a naturally occurring full-length protein upon which the analog is derived. In some embodiments, the analog is a truncated polypeptide as compared to the full-length, naturally translated or naturally occurring polypeptide upon which the truncated polypeptide is derived. In some embodiments, the analog is a synthetic polypeptide, wherein at least one of the amino acid residues of the polypeptide comprises at least one non-natural side chain. In some embodiments, the analogs of the invention comprise at least one non-natural amino acid chosen from one of the following structures aminoisobutyric acid, 3-Aminobutyric acid, and 2-hydroxy-4-(4-nitrophenyl)butyric acid. In some embodiments, the analog has a polypeptide backbone of identical length and similar homology to the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments, the analog is about 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% homologous to at least one of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments, the analog is an agonist or antagonist of one or more of the following receptors: VPAC1, VPAC2, or PAC1. In some embodiments, the analog is a fragment of one of the polypeptides disclosed in Tables 1, 2, 3, and 4 and shares the same or improved biological or biochemical activity as compared to the biological or biochemical activity of the polypeptides disclosed in Tables 1, 2, 3, and/or 4 upon which the analog amino acid sequence is derived. In some embodiments, the analog is an agonist or antagonist of the receptor of the the full-length, naturally translated or naturally occurring polypeptide upon which the amino acid sequence of the agonist or antagonist is derived. In some embodiments, the analog is an agonist or antagonist of the receptor of the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In such embodiments, the amino acid sequence of the agonists or antagonists are derived from the amino acid sequence of the the polypeptides disclosed in Tables 1, 2, 3, and/or 4. In some embodiments the analog of the present invention is modified by a bioactive lipid moiety on at least one amino acid residue of the analog. In such embodiments, the lipid moieties may be chosen from the following lipid molecules: LPA, progesterone, prostanoids, S1P, LPA, cannabinoids, 2-arachidonylglycerol. In some embodiments, the side chain or terminal end of the amino acid residues of the polypeptides disclosed in Tables 1, 2, 3, and/or 4 may be modified with the bioreactive lipid moieties. In some embodiments, the analogs of the present invention are derived from one of the following sequences:

	(SEQ ID NO: 6)
	HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK-NH₂;

	(SEQ ID NO: 5)
	HSDGIFTDSYSRYRKQMAVKKYLAAVL-NH₂;

	(SEQ ID NO: 9)
	HSDGTFTSELSRLRDSARLQRLLQGLV-NH₂;

	(SEQ ID NO: 1335)
	HSDGTFTSDYSKYLDSRRAQDFVQWLMNT-NH₂;

	(SEQ ID NO: 7)
	HADGVFTSDFSKLLGQLSAKKYLESLM-NH₂

The term “α-amino acid” refers to any and all natural and unnatural α-amino acids and their respective residues (i.e., the form of the amino acid when incorporated into a polypeptide molecule), without limitation. In some embodiments, “α-amino acid” explicitly encompasses the conventional and well-known naturally occurring amino acids, as well as all synthetic variations, derivatives, and analogs thereof. In some embodiments, “α-amino acid” means alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and/or valine. In some embodiments, α-amino acids also include analogs such as N-methylated α-amino acids, hydroxylated α-amino acids, and aminoxy acids. In some embodiments, α-amino refers to include N-alkyl α-amino acids (such as N-methyl glycine), hydroxylysine, 3-hydroxyproline, 4-hydroxyproline, nor-valine, nor-leucine, and ornithine.
The terms “β-amino acid” and “β-amino acid residue” refer to any and all β-amino acids and their respective residues (i.e., the form of the amino acid when incorporated into a polypeptide molecule), without limitation. In some embodiments, the terms “β-amino acid” refers to those β-amino acids described in U.S. Pat. No. 6,060,585, issued May 9, 2000, incorporated herein by reference, and those described in allowed U.S. Pat. No. 6,683,154, issued Jan. 27, 2004; U.S. Pat. No. 6,710,186, issued Mar. 23, 2004; and U.S. Pat. No. 6,727,368, issued Apr. 27, 2004, all of which are incorporated herein by reference. Further still, cyclic imino carboxylic acids and gem-di-substituted cyclic imino carboxylic acids (both of which are a type of cyclically-constrained β-amino acid) may also be used in the invention. In some embodiments, the term “β-amino acid” refers to residues disclosed in U.S. Pat. No. 6,958,384, issued Oct. 25, 2005, incorporated herein by reference. Further still, these β-residues may also take the form of the gem-di-substituted cyclic amino acids disclosed in U.S. Pat. No. 6,710,186, incorporated herein by reference. In some embodiments, the terms “β-amino acid” refers to β-homo amino acids. In some embodiments the β-amino acids refers to the selection of an amino acid chosen from the following:
R¹is selected from the group consisting hydrogen and an amino protecting group; R²is selected from the group consisting of hydrogen and a carboxy protecting group; and when R³is bonded to a carbon atom, R³is selected from the group consisting of hydrogen, hydroxy, linear or branched C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl, —(CH₂)_n+1, —OR⁴, —(CH₂)_n+1—SR⁴, —(CH₂)_n+1—S(═O)—CH₂—R⁴, —(CH₂)_n+1—S(═O)₂—CH₂—R⁴, —(CH₂)_n+1—NR⁴R⁴, —(CH₂)_n+1—NHC(═O)R⁴, —(CH₂)_n+1—NHS(═O)₂—CH₂—R⁴, —(CH₂)_n+1—O—(CH₂)_m—R⁵, —(CH₂)_n+1—S—(CH₂)_mR⁵, —(CH₂)_n+1—S(═O)—(CH₂)_m—R⁵, —(CH₂)_n+1—S(═O)₂—(CH₂)_m—R⁵, —(CH₂)_n+1—NH-(CH₂)_m—R⁵, —(CH₂)_n+1—N—{(CH₂)_m—R⁵}₂, —(CH₂)_n+1—NHC(═O)—(CH₂)_n+1—R⁵, and —(CH₂)_n+1—NHS(═O)₂—(CH₂)_m—R⁵; wherein each R⁴is independently selected from the group consisting of hydrogen, C₁-C₆alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to S heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆alkyl, mono- or bicyclic heteroaryl-C₁-C₆alkyl; and wherein R⁵is selected from the group consisting of hydroxy, C₁-C₆alkyloxy, aryloxy, heteroaryloxy, thio, C₁-C₆alkylthio, C₁-C₆alkylsulfinyl, C₁-C₆alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C₁-C₆alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C₁-C₆alkylamino, carboxylic acid, carboxamide, mono- or di-C₁-C₆alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C₁-C₆alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substituent(s) is selected from the group consisting of C₁-C₆alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; and when R³is bonded to a nitrogen atom, R³is independently selected from the group consisting of those listed above for when R³is attached to a carbon atom, and further selected from the group consisting of —S(═O)₂—CH₂—R⁴, —C(═O)—R⁴—S(═O)₂—(CH₂)_mR⁵, and —C(═O)—(CH₂)_n+1—R⁵; wherein R⁴and R⁵are as defined hereinabove, and m is an integer of from 2-6 and n is an integer of from 0-6; provided that when the β-amino acid is of formula R³is not hydrogen; racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof; and salts thereof. In some embodiments the β-amino acids refers to the selection of an amino acid chosen from the following:
In some embodiments the β-amino acids refers to the following formula:
In some embodiments the β-amino acids refers to the following formula:
wherein the NH₂and/or COOH groups are replaced with functional peptide bonds.
In some embodiments the term “β-amino acid” refers to:

- wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C₄-C₈cycloalkyl, cycloalkenyl or heterocyclic ring having one or more nitrogen atoms as the sole heteroatom;
- the substituents on carbon atoms of the rings being independently selected from the group consisting of linear or branched C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl, —(CH₂)_n+1—OR⁴, —(CH₂)_n+1—SR⁴, —(CH₂)_n+1—S(═O)—CH₂—R⁴, —(CH₂)_n+1—S(═O)₂—CH₂—R⁴, —(CH₂)_n+1—NR⁴R⁴, —(CH₂)_n+1—NHC(═O)R⁴, —(CH₂)_n+1—NHS(═O)₂—CH₂—R⁴, —(CH₂)_n+1—O—(CH₂)_m—R⁵, —(CH₂)_n+1—S—(CH₂)_m—R⁵, —(CH₂)_n+1—S(═O)—(CH₂)_m—R⁵, —(CH₂)_n+1—S(═O)₂—(CH₂)_m—R⁵, —(CH₂)_n+1—NH—(CH₂)_m—R⁵, —(CH₂)_n+1—N—{(CH₂)_m—R⁵}₂, —(CH₂)_n+1—NHC(═O)—(CH₂)_n+1—R⁵, and (CH₂)_n+1—NHS(═O)₂—(CH₂)_m—R⁵;
- wherein R⁴is independently selected from the group consisting of hydrogen, C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl; and
- wherein R⁵is selected from the group consisting of hydroxy, C₁-C₆-alkyloxy, aryloxy, heteroaryloxy, thio, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C₁-C₆-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C₁-C₆-alkylamino, carboxylic acid, carboxamide, mono- or di-C₁-C₆-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C₁-C₆-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroaryl-sulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substituent(s) is selected from the group consisting of C₁-C₆-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and
- m is an integer of from 2-6 and n is an integer of from 0-6;
- the substituents on heteroatoms of the ring being independently selected from the group consisting of —S(═O)²—CH₂—R⁴—C(═O)—R⁴—S(═O)₂—(CH₂)_m—R⁵, and —C(═O)—(CH₂)_n+1—R⁵; wherein R⁴and R⁵are as defined hereinabove, and m is an integer of from 2-6 and n is an integer of from 0-6;
- provided that when X & Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted;
- R¹is selected from the group consisting hydrogen and an amino protecting group;
- R²is selected. from the group consisting of hydrogen and a carboxy protecting group;
- racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof;
- and salts thereof.

In some embodiments the term “β-amino acid” refers to selection of an amino acid chosen from the following: β³or β². In some embodiments the term “β-amino acid” refers to selection of an amino acid chosen from the following:
wherein R, R′, R″, and R′″ are any substituent.
In some embodiments the term “β-amino acid” refers to selection of an amino acid chosen from the following:
wherein R, R′, R″, and R′″ is an amine, hydroxy, hydroxyl, carbonyl, H, ═O, —OH, —COOH, —N, —CH₃, —CH₂—X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene, alkyl, alkylhalo, arylamido, alkylheterocycle, alkylamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocyclyl; wherein X is any substituent.
In some embodiments the term “β-amino acid” refers to selection of an amino acid chosen from the following:
wherein R, R′, R″, and R′″ are any substituent, provided that: (i) R is not O, N, or halo when the R is in a β³-residue, (ii) R and R′ are not O, N, or halo when the R and R′ are in a β^3,3-residue; (iii) R is not O, N, or halo when the R is in a β^{, 3}-residue; (iv) R and R′ are not O, N, or halo when the R and R′ are in a β^2,3,3-residue; (v) R″ is not O, N, or halo when the R″ is in a β^2,2,3-residue; (vi) R and R′ are not O, N, or halo when the R and R′ are in a β^2,2,3,3-residue.
In some embodiments the term “β-amino acid” refers to selection of an amino acid chosen from the following:
wherein R, R′, R″, and R′″ is an amine, hydroxy, hydroxyl, carbonyl, H, ═O, —OH, —COOH, —N, —CH₃, —CH₂—X, halo, aryl, arylalkoxy, arylalkyl, alkynyl, alkenyl, alkylene, alkyl, alkylhalo, arylamido, alkylheterocycle, alkylamino, alkylguanidino, alkanol, alkylcarboxy, cycloalkyl, heteroaryl, heteroarylalkyl, heteroarylalkoxy, or heterocyclyl;
wherein X is any substituent; , provided that: (i) R is not O, N, or halo when the R is in a β³-residue, (ii) R and R′ are not O, N, or halo when the R and R′ are in a β^3,3-residue; (iii) R is not O, N, or halo when the R is in a β^2,3-residue; (iv) R and R′ are not O, N, or halo when the R and R′ are in a β^2,3,3-residue; (v) R″ is not O, N, or halo when the R″ is in a β^2,2,3-residue; (vi) R and R′ are not O, N, or halo when the R and R′ are in a β^2,2,3,3-residue.
A “cyclic” beta-amino acid is acid is an amino acid of the following formula I:
wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C₄-C₈cycloalkyl or cycloalkenyl group; wherein substituents on carbon atoms of the rings being independently selected from the group consisting of linear or branched C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl, —(CH2)_n+1-OR₄, —(CH2)_n+1-SR₄, —(CH₂)_n+1—S(═O)—CH₂—R₄, —(CH₂)_n+1—S(═O)₂—CH₂—R₄, —(CH₂)_n+1—NR₄R₄, —(CH₂)_n+1—NHC(═O)R₄, —(CH₂)_n+1—NHS(═O)₂—CH₂—R₄, —(CH₂)_n+1—O—(CH₂)_m—R₅, —(CH₂)_n+1—S—(CH₂)_m—R₅, —(CH₂)_n+1—S(═O)—(CH₂)_m—R₅, —(CH₂)_n+1—S(═O)₂—(CH₂)_m—R₅, —(CH₂)_n+1—NH—(CH₂)_m—R₅, —(CH₂)_n+1—N—{(CH₂)_m—R₅}₂, —(CH₂)_n+1—NHC(═O)—(CH₂)_n+1—R₅, and —(CH₂)_n+1—NHS(═O)₂—(CH₂)_m—R₅; wherein R₄is independently selected from the group consisting of hydrogen, C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl; and wherein R₅is selected from the group consisting of hydroxy, C₁-C₆-alkyloxy, aryloxy, heteroaryloxy, thio, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C₁-C₆-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C₁-C₆-alkylamino, carboxylic acid, carboxamide, mono- or di-C₁-C₆-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C₁-C₆-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substituent(s) is selected from the group consisting of C₁-C₆-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; the substituents on heteroatoms of the ring being independently selected from the group consisting of —S(═O)₂—CH₂—R₄—C(═O)—R₄—S(═O)₂—(CH₂)_m—R₅, and —C(═O)—(CH₂)_n+1—R₅; wherein R₄and R₅are as defined hereinabove, and m is an integer of from 2-6 and n is an integer between 0 and 6; provided that when X and Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted; R₁is selected from the group consisting hydrogen and an amino protecting group; R₂is selected from the group consisting of hydrogen and a carboxy protecting group; racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof; and salts thereof.
A “heterocyclic” beta-amino acid is an amino acid of formula I, wherein X and Y combined, together with the carbon atoms to which they are bonded, define a substituted or unsubstituted C₄-C₈cyclically or cycloalkenyl group having one or more nitrogen, oxygen or sulfur atoms as a heteroatom(s) within the cycloalkyl or cycloalkenyl group; wherein substituents on carbon atoms of the cycloalkyl or cycloalkenyl rings being independently selected from the group consisting of linear or branched C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl, —(CH₂)_n+1—OR₄, —(CH2)_n+1-SR₄, —(CH₂)_n+1—S(═O)—CH₂—R₄, —(CH₂)_n+1—S(═O)₂CH₂—R₄, —(CH₂)_n+1—NR₄R₄, —(CH₂)_n+1—NHC(═O)R₄, —(CH₂)_n+1—NHS(═O)₂—CH₂—R₄, —(CH₂)_n+1—O—(CH₂)_m—R₅, —(CH₂)_n+1—S—(CH₂)_m—R₅, —(CH₂)_n+1—S(═O)(CH₂)_m—R₅, —(CH₂)_n+1—S(═O)₂—(CH₂)_m—R₅, —(CH₂)_n+1—NH—(CH₂)_m—R₅, —(CH₂)_n+1—N—{(CH₂)_m—R₅}₂, —(CH₂)_n+1—NHC(═O)—(CH₂)_n+1—R₅, and —(CH₂)_n+1—NHS(═O)₂—(CH₂)_m—R₅; wherein R₄is independently selected from the group consisting of hydrogen, C₁-C₆-alkyl, alkenyl, or alkynyl; mono- or bicyclic aryl, mono- or bicyclic heteroaryl having up to 5 heteroatoms selected from N, O, and S; mono- or bicyclic aryl-C₁-C₆-alkyl, mono- or bicyclic heteroaryl-C₁-C₆-alkyl; and wherein R₅is selected from the group consisting of hydroxy, C₁-C₆-alkyloxy, aryloxy, heteroaryloxy, thio, C₁-C₆-alkylthio, C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, arylthio, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, amino, mono- or di-C₁-C₆-alkylamino, mono- or diarylamino, mono- or diheteroarylamino, N-alkyl-N-arylamino, N-alkyl-N-heteroarylamino, N-aryl-N-heteroarylamino, aryl-C₁-C₆-alkylamino, carboxylic acid, carboxamide, mono- or di-C₁-C₆-alkylcarboxamide, mono- or diarylcarboxamide, mono- or diheteroarylcarboxamide, N-alkyl-N-arylcarboxamide, N-alkyl-N-heteroarylcarboxamide, N-aryl-N-heteroarylcarboxamide, sulfonic acid, sulfonamide, mono- or di-C₁-C₆-alkylsulfonamide, mono- or diarylsulfonamide, mono- or diheteroarylsulfonamide, N-alkyl-N-arylsulfonamide, N-alkyl-N-heteroarylsulfonamide, N-aryl-N-heteroarylsulfonamide, urea; mono- di- or tri-substituted urea, wherein the substituent(s) is selected from the group consisting of C₁-C₆-alkyl, aryl, heteroaryl; O-alkylurethane, O-arylurethane, and O-heteroarylurethane; and m is an integer of from 2-6 and n is an integer of from 0-6; the substituents on heteroatoms of the ring being independently selected from the group consisting of —S(═O)₂—CH₂—R₄—C(═O)—R₄—S(═O)₂—(CH₂)_m—R₅, and —C(═O)—(CH₂)_n+1—R₅; wherein R₄and R₅are as defined hereinabove, and m is an integer of from 2-6 and n is an integer between 0 and 6; provided that when X and Y together with the carbons to which they are bonded define a five- or six-membered cycloalkyl or a five-membered heterocyclic ring having one nitrogen as the sole heteroatom, and the nitrogen is bonded to a carbon atom adjacent to the carboxy carbon of Formula I, the cycloalkyl or heterocyclic ring is substituted; R₁is selected from the group consisting hydrogen and an amino protecting group; R2 is selected from the group consisting of hydrogen and a carboxy protecting group; racemic mixtures thereof, isolated or enriched enantiomers thereof; isolated or enriched diastereomers thereof; and salts thereof.
In some embodiments, at least one of the β-amino acid residues in the analog is replaced with at least one β-amino acid residue that is cyclically constrained via a ring encompassing its β²and β³carbon atoms. In another embodiment of the invention, most or all of the inserted β-amino acid residues are cyclically constrained. In another version of the invention, at least one of the β-amino acid residues is unsubstituted at its β²and β³carbon atoms. Alternatively, all of the β-amino acid residues may be substituted at their β²and β³carbon atoms (with linear, branched or cyclic substituents). In some embodiments, the cyclic substituents of the claimed invention comprise side chains that are covalently bonded to the side chains of other contiguous amino acids. In some embodiments, the cyclic substituents of the claimed invention comprise side chains that are covalently bonded to the side chains of other non-contiguous amino acids. In some embodiments the cyclic substituents of the claimed invention do not include side chains that are covalently bonded to the side chains of other contiguous or non-contiguous amino acids. In some embodiments the terms beta-3 or beta-2 amino acid refers to β3-homo β2-homo amino acids.
A “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., K, R, H), acidic side chains (e.g., D, E), uncharged polar side chains (e.g., G, N, Q, S, T, Y, C, H), nonpolar side chains (e.g., G, A, V, L, I, P, F, M, W), beta-branched side chains (e.g., T, V, I) and aromatic side chains (e.g., Y, F, W, H). Thus, a predicted nonessential amino acid residue in a VIP analog, for example, replaced with another amino acid residue from the same side chain family. Other examples of acceptable substitutions are substitutions based on isosteric considerations (e.g. norleucine for methionine) or other properties (e.g. 2-thienylalanine for phenylalanine).
As used herein, the term “derived from” in the context of the relationship between a chemical structure or amino acid sequence and a related chemical structure or related amino acid sequence describes a chemical structure or amino acid sequence that may be homologous to or structurally similar to the related chemical structure or related amino acid sequence.
As used herein, the term “inflammatory disease” refers to any disease, condition, or ailment that results from an immune response or a pathogen infection, which in some instances may be characterized by one or more of pain, swelling, and redness of a tissue types. In some embodiments, inflammatory disease refers to rheumatoid arthritis, Crohn's disease, sepsis, ulcerative colitis, irritable bowel disease, chronic irritable bowel syndrome, and allergies such as allergic rhinitis.
A “non-essential” amino acid residue is a residue that can be altered from the wild-type sequence of a polypeptide (e.g., a short domain of VIP) without abolishing or substantially altering its essential biological or biochemical activity (e.g., receptor binding or activation). An “essential” amino acid residue is a residue that, when altered from the wild-type sequence of the polypeptide, results in abolishing or substantially abolishing the polypeptide's essential biological or biochemical activity.
A “non-natural side chain” is a modified or synthetic chain of atoms joined by covalent bond to the α-carbon atom, β-carbon atom, or γ-carbon atom which does not make up the backbone of the polypeptide chain of amino acids. The natural side chain, or R group, of of alanine is a methyl group. In some embodiments, the non-natural side chain of the composition is a methyl group in which on e or more of the hydrogen atoms is replaced by a deuterium atom.
The term “polypeptide” encompasses two or more naturally or non-naturally-occurring amino acids joined by a covalent bond (e.g., an amide bond). Polypeptides as described herein include full-length proteins (e.g., fully processed pro-proteins or full-length synthetic polypeptides) as well as shorter amino acid sequences (e.g., fragments of naturally-occurring proteins or synthetic polypeptide fragments).
The term “salt” refers to acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. Examples of these acids and bases are well known to those of ordinary skill in the art. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable acids may be of utility in the preparation and purification of the compound in question. Salts include those formed from hydrochloric, hydrobromic, sulphuric, phosphoric, citric, tartaric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic and benzenesulphonic acids.
In some embodiments, salts of the compositions comprising either a secretin or VIP analog may be formed by reacting the free base, or a salt, enantiomer or racemate thereof, with one or more equivalents of the appropriate acid. In some embodiments, pharmaceutical acceptable salts of the present invention refer to analogs having at least one basic group or at least one basic radical. In some embodiments, pharmaceutical acceptable salts of the present invention comprise a free amino group, a free guanidino group, a pyrazinyl radical, or a pyridyl radical that forms acid addition salts. In some embodiments, the pharmaceutical acceptable salts of the present invention refer to analogs that are acid addition salts of the subject compounds with (for example) inorganic acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example aliphatic mono- or di-carboxylic acids, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or amino acids such as arginine or lysine, aromatic carboxylic acids, such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, aromatic-aliphatic carboxylic acids, such as mandelic acid or cinnamic acid, heteroaromatic carboxylic acids, such as nicotinic acid or isonicotinic acid, aliphatic sulfonic acids, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, or aromatic sulfonic acids, for example benzene-, p-toluene- or naphthalene-2-sulfonic acid. When several basic groups are present mono- or poly-acid addition salts may be formed. The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, for example, water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents, which may be removed in vacuo or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. In some embodiments, the salts may be those that are physiologically tolerated by a patient. Salts according to the present invention may be found in their anhydrous form or as in hydrated crystalline form (i.e., complexed or crystallized with one or more molecules of water).
The term “subject” is used throughout the specification to describe an animal to whom treatment with the compositions according to the present invention is provided or administered. For treatment of those conditions which are specific for a specific subject, such as a human being, the term “patient” may be interchangeably used. In some instances in the description of the present invention, the term “patient” will refer to human patients. In some embodiments, the subject may be a mammal to whom the present invention is provided or administered. In some embodiments, the subject may be a non-human animal to whom the present invention is provided or administered.
The term “soluble” or “water soluble” refers to solubility that is higher than 1/100,000 (mg/ml). The solubility of a substance, or solute, is the maximum mass of that substance that can be dissolved completely in a specified mass of the solvent, such as water. “Practically insoluble” or “insoluble,” on the other hand, refers to an aqueous solubility that is 1/10,000 (mg/ml) or less. Water soluble or soluble substances include, for example, polyethylene glycol. In some embodiments, the polypeptide of the claimed invention may be bound by polyethylene glycol to better solubilize the composition comprising the peptide.
The terms “treating” and “to treat”, mean to alleviate symptoms, eliminate the causation either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms. The term “treatment” includes alleviation, elimination of causation (temporary or permanent) of, or prevention of symptoms and disorders associated with any condition. The treatment may be a pre-treatment as well as a treatment at the onset of symptoms.
“Effective amount” refers to an amount of a compound, material, or composition, as described herein effective to achieve a particular biological result such as, but not limited to, biological results disclosed, described, or exemplified herein. Such results may include, but are not limited to, the effective reduction of symptoms associated with any of the disease states mentioned herein, as determined by any means suitable in the art. The effective amount of the composition may be dependent on any number of variables, including without limitation, the species, breed, size, height, weight, age, overall health of the subject, the type of formulation, the mode or manner or administration, the type and/or severity of the particular condition being treated, or the need to modulate the activity of the molecular pathway induced by association of the analog to its receptor. The appropriate effective amount can be routinely determined by those of skill in the art using routine optimization techniques and the skilled and informed judgment of the practitioner and other factors evident to those skilled in the art. A therapeutically effective dose of the analogs described herein may provide partial or complete biological activity as compared to the biological activity induced by the wild-type or naturally occurring polypeptides upon which the analogs are derived. A therapeutically effective dose of the analogs described herein may provide a sustained biochemical or biological affect and/or an increased resistance to degradation when placed in solution as compared with the normal affect observed when the naturally occurring and fully processed translated protein is administered to the same subject.
The term “fragment” refers to any analog of a naturally occurring polypeptide disclosed herein that comprises at least 4 amino acids identical to the naturally occurring polypeptide upon which the analog is based. The term “functional fragment” refers to any fragment of any analog of a naturally occurring polypeptide disclosed herein that comprises at least 4 amino acids identical to the naturally occurring polypeptide upon which the analog is based and shares the function of the naturally occurring polypeptide upon which the analog is based. In some embodiments, the compositions or pharmaceutical composition comprises an analog comprising at least one β-amino acid. wherein the analog is a fragment of VIP, a secretin family member, an interleukin, or any of the polypeptides disclosed in the instant application. In some embodiments, the compositions or pharmaceutical composition comprises an analog comprising at least one β-amino acid, wherein the analog is a fragment of VIP, a secretin family member, an interleukin, or any of the polypeptides disclosed in the instant application and wherein the fragment shares at least 4 contiguous amino acid residues with the naturally occurring polypeptide upon which the analog is based and wherein the fragment retains the biological activity of the naturally occurring polypeptide upon which the analog is based. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 27 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 26 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 25 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 24 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 23 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 22 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 21 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 20 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 19 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 18 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 19 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 17 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 16 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 15 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 14 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about β amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 12 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 11 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 10 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 9 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment of VIP that comprises between about 1 to about 8 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 7 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 6 amino acids of the naturally occurring VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 5 amino acids of the naturally occurring
VIP sequence. In some embodiments, the VIP analog is a fragment that comprises between about 1 to about 4 amino acids of the naturally occurring VIP sequence. In some embodiments, the analog is modified with at least one PEG molecule on at least one of the non-natural amino acids.
The term “halo” or “halogen” refers to fluorine, chlorine, bromine or iodine or a radical thereof.
The term “alkyl” refers to a hydrocarbon chain that is a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C₁-C₁₀indicates that the group has from 1 to 10 (inclusive) carbon atoms in it. In the absence of any numerical designation, “alkyl” is a chain (straight or branched) having 1 to 20 (inclusive) carbon atoms in it. In some embodiments the alkyl group is chosen from: C₁-C₁₀, C₂-C₁₀, C₃-C₁₀, C₄-C₁₀, C₅-C₁₀, C₆-C₁₀, C₈-C₁₀, C₉-C₁₀, C₁-C₁₀, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅, C₁-C₆, C₁-C₈, or C₁-C₉,
The term “alkylene” refers to a divalent alkyl (i.e., —R—).
The term “alkenyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C₂-C₁₀indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkenyl” refers to a C₂-C₆alkenyl chain. In the absence of any numerical designation, “alkenyl” is a chain (straight or branched) having 2 to 20 (inclusive) carbon atoms in it.
The term “alkynyl” refers to a hydrocarbon chain that is a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C₂-C₁₀indicates that the group has from 2 to 10 (inclusive) carbon atoms in it. The term “lower alkynyl” refers to a C₂-C₆alkynyl chain. In the absence of any numerical designation, “alkynyl” is a chain (straight or branched) having about 2 to about 20 (inclusive) carbon atoms in it.
The term “aryl” refers to an aromatic ring system. In some embodiments, the aryl group of the analog include substituents, wherein 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 atoms of each ring are substituted by a substituent. In some embodiments, the aryl group refers to a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of aryl groups include phenyl, naphthyl and the like. The term “arylalkyl” or the term “aralkyl” refers to alkyl substituted with an aryl. The term “arylalkoxy” refers to an alkoxy substituted with aryl. “Arylalkyl” refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with an alkyl group, as defined above. Representative examples of an arylalkyl group include, but are not limited to, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-propylphenyl, 3-propylphenyl, 4-propylphenyl, 2-butylphenyl, 3-butylphenyl, 4-butylphenyl, 2-pentylphenyl, 3-pentylphenyl, 4-pentylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isobutylphenyl, 3-isobutylphenyl, 4-isobutylphenyl, 2-sec-butylphenyl, 3-sec-butylphenyl, 4-sec-butylphenyl, 2-t-butylphenyl, 3-t-butylphenyl and 4-t-butylphenyl.
“Arylamido” refers to an aryl group, as defined above, wherein one of the aryl group's hydrogen atoms has been replaced with one or more —C(O)NH₂groups. Representative examples of an arylamido group include 2-C(O)NH₂-phenyl, 3-C(O)NH₂-phenyl, 4-C(O)NH₂-phenyl, 2-C(O)NH₂-pyridyl, 3-C(O)NH₂-pyridyl, and 4-C(O)NH₂-pyridyl.
“Alkylheterocycle” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a heterocycle. Representative examples of an alkylheterocyclo group include, but are not limited to, —CH₂CH₂-morpholine, —CH₂CH₂piperidine, —CH₂CH₂CH₂-morpholine, and —CH₂CH₂CH₂-imidazole.
“Alkylamido” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a —C(O)NH₂group. Representative examples of an alkylamido group include, but are not limited to, —CH₂C(O)NH₂, —CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂CH₂C(O)NH₂, —CH₂CH₂CH₂CH₂CH₂C(O)NH₂, —CH₂CH(C(O)NH₂)CH₃, —CH₂CH(C(O)NH₂)CH₂CH₃, —CH(C(O)NH₂)CH₂CH₃, —C(CH₃)₂CH₂C(O)NH₂, —CH₂CH₂NHC(O)CH₃, —CH₂CH₂NHC(O)CH₂CH₃, and —CH₂CH₂NHC(O)CH═CH₂.
“Alkylamino” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a —NH₂group. Representative examples of an alkylamido group include, but are not limited to —CH₂NH₂, CH₂CH₂NH₂, CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂NH₂, —CH₂CH₂CH₂CH₂CH₂NH₂.
“Alkylguanidino” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a —NH₂(C═NH)NH₂group. Representative examples of an alkylamido group include, but are not limited to —CH₂NH₂(C═NH)NH₂, CH₂CH₂NH₂(C═NH)NH₂, CH₂CH₂CH₂NH₂(C═NH)NH₂, —CH₂CH₂CH₂CH₂NH₂(C═NH)NH₂, —CH₂CH₂CH₂CH₂CH₂NH₂(C═NH)NH₂. In some embodiments alkyl units can be found on the N atom(s) of the alkylamino or alkylguanidino groups (for example, —CH₂NH(CH₃), CH₂N(CH₃)₂).
“Alkanol” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a hydroxyl group. Representative examples of an alkanol group include, but are not limited to, —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂OH, —CH₂CH₂CH₂CH₂CH₂OH, —CH₂CH(OH)CH₃, —CH₂CH(OH)CH₂CH₃, —CH(OH)CH₃and —C(CH₃)₂CH₂OH.
“Alkylcarboxy” refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a —COOH group. Representative examples of an alkylcarboxy group include, but are not limited to, —CH₂COOH, —CH₂CH₂COOH, —CH₂CH₂CH₂COOH, —CH₂CH₂CH₂CH₂COOH, —CH₂CH(COOH)CH₃, —CH₂CH₂CH₂CH₂CH₂COOH, —CH₂CH(COOH)CH₂CH₃, —CH(COOH)CH₂CH₃and —C(CH₃)₂CH₂COOH.
The term “cycloalkyl” as employed herein includes saturated and partially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons, 3 to 8 carbons, or 3 to 6 carbons, wherein the cycloalkyl group additionally is optionally substituted. Some cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
The term “heteroaryl” refers to an aromatic 5-10 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3, or 4 atoms of each ring are substituted by a substituent. Examples of heteroaryl groups include, but are not limited to, pyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl, thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.
The term “heteroarylalkyl” or the term “heteroaralkyl” refers to an alkyl substituted with a heteroaryl. The term “heteroarylalkoxy” refers to an alkoxy substituted with heteroaryl.
The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of O, N, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring are substituted by a substituent. Examples of heterocyclyl groups include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.
The term “substituent” refers to a group replacing a second atom or group such as a hydrogen atom on any molecule, compound or moiety. Suitable substituents include, without limitation, halo, hydroxy, mercapto, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, thioalkoxy, aryloxy, amino, alkoxycarbonyl, amido, carboxy, alkanesulfonyl, alkylcarbonyl, and cyano groups.
In some embodiments, the composition comprises an analog comprises one or more asymmetric centers and thus occur as racemates and racemic mixtures, single enantiomers, individual diastereomers and diastereomeric mixtures. Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof. These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization. Such methods are disclosed generally in Chiral Separation Techniques: A Practical Approach (2nd Ed.), G. Subramanian (ed.), Wiley-VCH, 2000; T. E. Beesley and R. P. W. Scott, Chiral Chromatography, John Wiley & Sons, 1999; and Satinder Ahuja, Chiral Separations by Chromatography, Am. Chem. Soc., 2000. Furthermore, there are equally well-known methods for the quantitation of enantiomeric excess or purity, for example, GC, HPLC, CE, or NMR, and assignment of absolute configuration and conformation, for example, CD ORD, X-ray crystallography, or NMR.
All tautomeric forms and isomeric forms and mixtures, whether individual geometric isomers or stereoisomers or racemic or non-racemic mixtures, of a chemical structure or entire analog is intended, unless the specific stereochemistry or isomeric form is specifically indicated in the analog name, chemical name or structure. All such isomeric forms of these compositions are included in the present invention unless expressly provided otherwise. In some embodiments, the analogs of this invention are also represented in multiple tautomeric forms, in such instances, the invention includes all tautomeric forms of the analogs described herein (e.g., if alkylation of a ring system results in alkylation at multiple sites, the invention includes all such reaction products). All such isomeric forms of such analogs are included in the present invention unless expressly provided otherwise. All crystal forms of the analogs described herein are included in the present invention unless expressly provided otherwise. All deuterated form of the analogs described herein are included in the present invention. In some embodiments as least one hydrogen atom of the analog is replace with a deuterium atom. In some embodiments at least one hydrogen atom that is involved with a hydrogen-bond is replaced with a deuterium atom. In some embodiments at least one solvent exchangeable hydrogen atom is replaced with a deuterium atom. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 1% to about 100% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 90% to about 100% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 80% to about 90% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 70% to about 80% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 60% to about 70% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 50% to about 60% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 40% to about 50% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 30% to about 40% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 20% to about 30% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 10% to about 20% of their hydrogen replaced with deuterium atoms. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 5% to about 10% of their hydrogen replaced with deuterium atoms. If the analog of the claimed invention includes a methyl group, a deuterated analog may have one, two, or three of the hydrogens replaced by deuterium atoms. In some embodiments, the analog may contain one or more radioisotopes. In some embodiments, as least one hydrogen atom of the analog is replace with a tritium atom. In some embodiments, the compositions, pharmaceutical compositions, and analogs contained therein comprise from about 1% to about 5% of their hydrogens are replaced with tritium atoms.
As used herein, the terms “increase” and “decrease” mean, respectively, to cause a statistically significantly (i.e., p<0.15) increase or decrease of at least 1%, 2%, or 5%.
As used herein, the recitation of a numerical range for a variable is intended to convey that the invention may be practiced with the variable equal to any of the values within that range. Thus, for a variable which is inherently discrete, the variable is equal to any integer value within the numerical range, including the end-points of the range. Similarly, for a variable which is inherently continuous, the variable is equal to any real value within the numerical range, including the end-points of the range. As an example, and without limitation, a variable which is described as having values between 0 and 2 takes the values 0, 1 or 2 if the variable is inherently discrete, and takes the values 0.0, 0.1, 0.01, 0.001, 10⁻¹², 10⁻¹¹, 10⁻¹⁰, 10⁻⁹, 10−⁸, 10⁻⁷, 10⁻⁶, 10⁻⁵, 10⁻⁴or any other real values ≥0 and ≤2 if the variable is inherently continuous.
As used herein, unless specifically indicated otherwise, the word “or” is used in the inclusive sense of “and/or” and not the exclusive sense of “either/or.”
The term “biological activity” encompasses structural and functional properties of a macrocycle of the invention. Biological activity is, for example, structural stability, alpha-helicity, affinity for a target, resistance to proteolytic degradation, cell penetrability, intracellular stability, in vivo stability, or any combination thereof.
The terms “prodrug” or “prodrug derivative” mean a covalently-bonded derivative or carrier of the analog of the claimed invention or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). In general, such prodrugs have metabolically cleavable groups and are rapidly transformed in vivo to yield the analog of the claimed invention, for example, by hydrolysis in blood, and generally include esters and amide analogs of the analogs. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the analogs using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: “Design and Applications of Prodrugs”; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K. B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder et al. (eds.), Vol. 42, Academic Press, 1985, particularly pp. 309-396; Burger's Medicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; and Bioreversible Carriers in Drug Design, E. B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties. In some embodiments, the analog may be a prodrug that, when administered to the subject becomes biologically active.
In some embodiments, the invention relates to a composition or pharmaceutical composition comprising a pharmaceutically acceptable prodrug that, when administered to the subject becomes biologically active. The term “pharmaceutically acceptable prodrug” as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
In some embodiments, the analog of the claimed invention is a pharmaceutically-acceptable acid addition salt. The term “pharmaceutically-acceptable acid addition salt” means those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, trichloroacetic acid, trifluoroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 2-acetoxybenzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphoric acid, hemisulfic acid, heptanoic acid, hexanoic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, maleic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, picric acid, pivalic acid, propionic acid, pyruvic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, undecanoic acid, and the like. In some embodiments, the analog of the claimed invention is a pharmaceutically-acceptable base addition salt. The term “pharmaceutically-acceptable base addition salt” means those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Suitable salts include the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically-acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamine, polyamine resins, and the like. In some embodiments, the composition of the claimed invention comprises at least one organic nontoxic bases chosen from isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
The term “solvate” means a physical association of a compound with one or more solvent molecules or a complex of variable stoichiometry formed by a solute (the analog of the claimed invention) and a solvent, for example, water, ethanol, or acetic acid. This physical association may involve varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. In general, the solvents selected do not interfere with the biological activity of the solute. Solvates encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
The invention relates to compositions comprising an analog of a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 80% to 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 80% to 85% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 85% to 90% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 90% to 95% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is from about 95% to 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the invention relates to a composition comprising an analog of a naturally occurring polypeptide sequence wherein the analog is about 95%, 96%, 97%, 98%, or 99% homologous to a naturally occurring polypeptide sequence. In some embodiments the analog is derived from the naturally occurring polypeptide of the secretin family In some embodiments, the analog is derived from the naturally occurring polypeptide of the secretin family and has at least one β-amino acid residue and/or at least one modified amino acid residue comprising APC or ACPC. Table 1 below illustrates the known wild-type sequences of each naturally occurring human secretin family members:

TABLE 1

Amino Acid Sequences for Peptides of the
Secretin Family

GHRF	YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQER
	GARARL (SEQ ID NO: 1)

GIP	YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKH
	NITQ (SEQ ID NO: 2)

GLP-1	HDEFERHAEGTFTSDVSSYLEGQAAQGFIAWLVKGRG
	(SEQ ID NO: 3)

Glucagon	HSQGTFTSDYSKYLDSRRAQDFVQWLMNT
	(SEQ ID NO: 4)

PACAP-27	HSDGIFTDSYSRYRKQMAVKKYLAAVL
	(SEQ ID NO: 5)

PACAP-38	HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK
	(SEQ ID NO: 6)

PHM	HADGVFTSDFSKLLGQLSAKKYLESLM
	(SEQ ID NO: 7)

PrP	DVAHGILNEAYRKVLGQLSAGKHLQSLVA
	(SEQ ID NO: 8)

Secretin	HSDGTFTSELSRLREGARLQRLLQGLV
	(SEQ ID NO: 9)

VIP	HSDAVFTDNYTRLRKQMAVKKYLNSILN
	(SEQ ID NO: 10)

TABLE 2

Amino Acid Sequences for Interleukins

IL-10

>gi|10835141|ref|NP_000563.1|interleukin-10

precursor {Homo sapiens}

MHSSALLCCLVLLTGVRASPGQGTQSENSCTHFPGNLPNMLRDLRDAFSR

VKTFFQMKDQLDNLLLKESLLEDFKGYLGCQALSEMIQFYLEEVMPQAEN

QDPDIKAHVNSLGENLKTLRLRLRRCHRFLPCENKSKAVEQVKNAFNKLQ

EKGIYKAMSEFDIFINYIEAYMTMKIRN (SEQ ID NO: 11)

IL-4

>gi|4504669|ref|NP_000580.1|interleukin-4 isoform

1 precursor {Homo sapiens}

MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKTLCTE

LTVTDIFAASKNTTEKETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRH

KQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLENFLERLKTIMREKYSK

CSS (SEQ ID NO: 12)

>gi|27477092|ref|NP_758858.1|interleukin-4 isoform

2 precursor {Homo sapiens}

MGLTSQLLPPLFFLLACAGNFVHGHKCDITLQEIIKTLNSLTEQKNTTEK

ETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWG

LAGLNSCPVKEANQSTLENFLERLKMREKYSKCSS

(SEQ ID NO: 13)

IL-5

>gi|4504671|ref|NP_000870.1|interleukin 5

precursor {Homo sapiens}

MRMLLHLSLLALGAAYVYAIPTEIPTSALVKETLALLSTHRTLLIANETL

RIPVPVHKNHQLCTEEIFQGIGTLESQTVQGGTVERLFKNLSLIKKYIDG

QKKKCGEERRRVNQFLDYLQEFLGVMNTEWIIES(SEQ ID NO: 14)

IL-8

>gi|10834978|ref|NP_000575.1|interleukin-8

precursor {Homo sapiens}

MTSKLAVALLAAFLISAALCEGAVLPRSAKELRCQCIKTYSKPFHPKFIK

ELRVIESGPHCANTEIIVKLSDGRELCLDPKENWVQRVVEKFLKRAENS

(SEQ ID NO: 15)

IL-12A

>gi|24430219|ref|NP_000873.2|interleukin-12

subunit alpha precursor {Homo sapiens}

MWPPGSASQPPPSPAAATGLHPAARPVSLQCRLSMCPARSLLLVATLVLL

DHLSLARNLPVATPDPGMFPCLHHSQNLLRAVSNMLQKARQTLEFYPCTS

EEIDHEDITKDKTSTVEACLPLELTKNESCLNSRETSFITNGSCLASRKT

SFMMALCLSSIYEDLKMYQVEFKTMNAKLLMDPKRQIFLDQNMLAVIDEL

MQALNFNSETVPQKSSLEEPDFYKTKIKLCILLHAFRIRAVTIDRVMSYL

NAS (SEQ ID NO: 16)

IL-12B

>gi|24497438|ref|NP_002178. 2|interleukin-12

subunit beta precursor {Homo sapiens}

MCHQQLVISWFSLVFLASPLVAIWELKKDVYVVELDWYPDAPGEMVVLTC

DTPEEDGITWTLDQSSEVLGSGKTLTIQVKEFGDAGQYTCHKGGEVLSHS

LLLLHKKEDGIWSTDILKDQKEPKNKTFLRCEAKNYSGRFTCWWLTTIST

DLTFSVKSSRGSSDPQGVTCGAATLSAERVRGDNKEYEYSVECQEDSACP

AAEESLPIEVMVDAVHKLKYENYTSSFFIRDIIKPDPPKNLQLKPLKNSR

QVEVSWEYPDTWSTPHSYFSLTFCVQVQGKSKREKKDRVFTDKTSATVIC

RKNASISVRAQDRYYSSSWSEWASVPCS (SEQ ID NO: 17)

IL-2

>gi|28178861|ref|NP_000577.2|interleukin 2

precursor {Homo sapiens}

MYRMQLLSCIALSLALVTNSAPTSSSTKKTQLQLEHLLLDLQMILNGINN

YKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHL

RPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIIS

TLT (SEQ ID NO: 18)

IL-15

gi|26787984|ref|NP_751914.1|interleukin 15

preproprotein {Homo sapiens}

MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANW

VNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISL

ESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS

FVHIVQMFINTS (SEQ ID NO: 19)

gi|10835153|ref|NP_000576.1|interleukin 15

preproprotein {Homo sapiens}

MRISKPHLRSISIQCYLCLLLNSHFLTEAGIHVFILGCFSAGLPKTEANW

VNVISDLKKIEDLIQSMHIDATLYTESDVHPSCKVTAMKCFLLELQVISL

ESGDASIHDTVENLIILANNSLSSNGNVTESGCKECEELEEKNIKEFLQS

FVHIVQMFINTS (SEQ ID NO: 20)

IL-17

>gi|4504651|ref|NP_002181.1|interleukin 17A

precursor {Homo sapiens}

MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLN

IHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCI

NADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPI

VHHVA (SEQ ID NO: 21)

IL-18

>gi|4504653|ref|NP_001553.1|interleukin-18

proprotein {Homo sapiens}

MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRN

LNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTI

SVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQ

FESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNED

(SEQ ID NO: 22)

interleukin-18-binding protein isoform a

precursor {Homo sapiens}

>gi|89111125|ref|NP_001034748.1|interleukin-18-

binding protein isoform a precursor {Homo sapiens}

MTMRHNWTPDLSPLWVLLLCAHVVTLLVRATPVSQTTTAATASVRSTKDP

CPSQPPVFPAAKQCPALEVTWPEVEVPLNGTLSLSCVACSRFPNFSILYW

LGNGSFIEHLPGRLWEGSTSRERGSTGTQLCKALVLEQLTPALHSTNFSC

VLVDPEQVVQRHVVLAQLWAGLRATLPPTQEALPSSHSSPQQQ

(SEQ ID NO: 23)

IL-21

>gi|11141875|ref|NP_068575.1|interleukin-21

{Homo sapiens}

MRSSPGNMERIVICLMVIFLGTLVHKSSSQGQDRHMIRMRQLIDIVDQLK

NYVNDLVPEFLPAPEDVETNCEWSAFSCFQKAQLKSANTGNNERIINVSI

KKLKRKPPSTNAGRRQKHRLTCPSCDSYEKKPPKEFLERFKSLLQKMIHQ

HLSSRTHGSEDS(SEQ ID NO: 24)

IL-22

>gi|10092625|ref|NP_065386.1|interleukin-22

precursor {Homo sapiens}

MAALQKSVSSFLMGTLATSCLLLLALLVQGGAAAPISSHCRLDKSNFQQP

YITNRTFMLAKEASLADNNTDVRLIGEKLFHGVSMSERCYLMKQVLNFTL

EEVLFPQSDRFQPYMQEVVPFLARLSNRLSTCHIEGDDLHIQRNVQKLKD

TVKKLGESGEIKAIGELDLLFMSLRNACI (SEQ ID NO: 25)

IL-24

>gi|5803086|ref|NP_006841.1|interleukin 24 isoform

1 precursor {Homo sapiens}

MNFQQRLQSLWTLARPFCPPLLATASQMQMVVLPCLGFTLLLWSQVSGAQ

GQEFHFGPCQVKGVVPQKLWEAFWAVKDTMQAQDNITSARLLQQEVLQNV

SDAESCYLVHTLLEFYLKTVFKNYHNRTVEVRTLKSFSTLANNFVLIVSQ

LQPSQENEMFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWM

QKFYKL (SEQ ID NO: 26)

>gi|31317246|ref|NP_851936.1|interleukin-24

isoform 2 {Homo sapiens}

MFSIRDSAHRRFLLFRRAFKQLDVEAALTKALGEVDILLTWMQKFYKL

(SEQ ID NO: 27)

IL-26

>gi|8923756|ref|NP_060872.1|interleukin-26

precursor {Homo sapiens}

MLVNFILRCGLLLVTLSLAIAKHKQSSFTKSCYPRGTLSQAVDALYIKAA

WLKATIPEDRIKNIRLLKKKTKKQFMKNCQFQEQLLSFFMEDVFGQLQLQ

GCKKIRFVEDFHSLRQKLSHCISCASSAREMKSITRMKRIFYRIGNKGIY

KAISELDILLSWIKKLLESSQ (SEQ ID NO: 28)

TABLE 3

Amino Acid Sequences for
Anti-inflammatory Neuropeptides

pro-opiomelanocortin preproprotein {Homo sapiens}

>gi|4505949|ref|NP_000930.1|pro-opiomelanocortin

preproprotein {Homo sapiens}

MPRSCCSRSGALLLALLLQASMEVRGWCLESSQCQDLTTESNLLECIRAC

KPDLSAETPMFPGNGDEQPLTENPRKYVMGHFRWDRFGRRNSSSSGSSGA

GQKREDVSAGEDCGPLPEGGPEPRSDGAKPGPREGKRSYSMEHFRWGKPV

GKKRRPVKVYPNGAEDESAEAFPLEFKRELTGQRLREGDGPDGPADDGAG

AQADLEHSLLVAAEKKDEGPYRMEHFRWGSPPKDKRYGGFMTSEKSQTPL

VTLFKNAIIKNAYKKGE (SEQ ID NO: 29)

Active form:

oc-MSH SYSMEHFRWGKPV-NH2 (SEQ ID NO: 581)

>gi|490074|emb|CAA00890.1|ACTH {Homo sapiens}

GPSYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF

urocortin preproprotein {Homo sapiens}

>gi|4507803|ref|NP_003344.1|urocortin

preproprotein {Homo sapiens}

MRQAGRAALLAALLLLVQLCPGSSQRSPEAAGVQDPSLRWSPGARNQGGG

ARALLLLLAERFPRRAGPGRLGLGTAGERPRRDNPSLSIDLTFHLLRTLL

ELARTQSQRERA(SEQ ID NO: 30) EQNRIIFDSVGK

Active form:

Urocortin DNPSLSIDLTFHLLRTLLELADTQSQRERAQNRIIFDSV-

NH2 (SEQ ID NO: 1336)

urocortin-2 preproprotein {Homo sapiens}

>gi|15082240|ref|NP_149976.1|urocortin-2

preproprotein {Homo sapiens}

MTRCALLLLMVLMLGRVLVVPVTPIPTFQLRPQNSPQTTPRPAASESPSA

APTWPWAAQSHCSPTRHPGSRIVLSLDVPIGLLQILLEQARARAAREQAT

TNARILARVGHC (SEQ ID NO: 31)

nrocortin-3 preproprotein {Homo sapiens}

>gi|45238845|ref|NP_444277.2|urocortin-3

preproprotein {Homo sapiens}

MLMPVHFLLLLLLLLGGPRTGLPHKFYKAKPIFSCLNTALSEAEKGQWED

ASLLSKRSFHYLRSRDASSGEEEEGKEKKTFPISGARGGARGTRYRYVSQ

AQPRGKPRQDTAKSPHRTKFTLSLDVPTNIMNLLFNIAKAKNLRAQAAAN

AHLMAQIGRKK (SEQ ID NO: 32)

adrenomedullin precursor {Homo sapiens}

>gi|4501945|ref|NP_001115.1|adrenomedullin

precursor {Homo sapiens}

MKLVSVALMYLGSLAFLGADTARLDVASEFRKKWNKWALSRGKRELRMSS

SYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARIRVKRYRQSMN

NFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGYGRRR

RRSLPEAGPGRTLVSSKPQAHGAPAPPSGSAPHFL

(SEQ ID NO: 33)

gi|41152110|ref|NP_079142.2|adrenomedullin 2

precursor {Homo sapiens}

MARIPTAALGCISLLCLQLPGSLSRSLGGDPRPVKPREPPARSPSSSLQP

RHPAPRPVVWKLHRALQAQRGAGLAPVMGQPLRDGGRQHSGPRRHSGPRR

TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSYG

(SEQ ID NO: 1337)

Active portion:

Adrenomeclullin

YRQSMNNFQGLRFG{CRFGTC}TVQKLAHQIYQFTDKDKDNVAPRNKISP

QGY-NH2 (SEQ ID NO: 1338)

eortistatin preproprotein {Homo sapiens}

>gi|41327683|ref|NP_001293.2|cortistatin

preproprotein {Homo sapiens}

MYRHKNSWRLGLKYPPSSKEETQVPKTLISGLPGRKSSSRVGEKLQSAHK

MPLSPGLLLLLLSGATATAALPLEGGPTGRDSEHMQEAAGIRKSSLLTFL

AWWFEWTSQASAGPLIGEEAREVARRQEGAPPQQSARRDRMPCRNFFWKT

FSSCK (SEQ ID NO: 34)

Active form:

Cortistatin DRMP{CKNFFWKTFSSC}K-NH2

(SEQ ID NO: 1339)

somatostatin preproprotein {Homo sapiens}

>gi|4507243|ref|NP_001039.1|somatostatin

preproprotein {Homo sapiens}

MLSCRLQCALAALSIVLALGCVTGAPSDPRLRQFLQKSLAAAAGKQELAK

YFLAELLSEPNQTENDALEPEDLSQAAEQDEMRLELQRSANSNPAMAPRE

RKAGCKNFFWKTFTSC (SEQ ID NO: 35)

appetite-regulating hormone isoforml preproprotein

{Homo sapiens}

>gi|7706519|ref|NP_057446.1|appetite-regulating

hormone isoform 1 preproprotein {Homo sapiens}

MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQQRKESKKPPAKLQP

RALAGWLRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGK

FLQDILWEEAKEAPADK (SEQ ID NO: 36)

appetite-regulating hormone isoform 2

preproprotein {Homo sapiens}

>gi|201860279|ref|NP_001128413.1|appetite-

regulating hormone isoform 2 preproprotein

{Homo sapiens}

MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQRKESKKPPAKLQPR

ALAGWLRPEDGGQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKF

LQDILWEEAKEAPADK (SEQ ID NO: 37)

appetite-regulating hormone isoform 3

preproprotein {Homo sapiens}

>gi|201860281|ref|NP_001128416.1|appetite-

regulating hormone isoform 3 preproprotein

{Homo sapiens}

MFTCWWSYLRSTLAAVPGEASRVQQRKESKKPPAKLQPRALAGWLRPEDG

GQAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKE

APADK (SEQ ID NO: 38)

appetite-regulating hormone isoform 4

preproprotein {Homo sapiens}

>gi|201860283|ref|NP_001128417.1|appetite-

regulating hormone isoform 4 preproprotein

{Homo sapiens}

MFTCWWSYLRSTLAAVPGEASRVQRKESKKPPAKLQPRALAGWLRPEDGG

QAEGAEDELEVRFNAPFDVGIKLSGVQYQQHSQALGKFLQDILWEEAKEA

PADK (SEQ ID NO: 39)

appetite-regulating hormone isoform 5

preproprotein {Homo sapiens}

>gi|201860285|ref|NP_001128418.1|appetite-

regulating hormone isoform 5 preproprotein

{Homo sapiens}

MFTCWWSYLRSTLAAVPGEASRVQFNAPFDVGIKLSGVQYQQHSQALGKF

LQDILWEEAKEAPADK (SEQ ID NO: 40)

ghrelin {Homo sapiens}

>gi|53794041|gb|AAU93610.1|ghrelin {Homo sapiens}

MPSPGTVCSLLLLGMLWLDLAMAGSSFLSPEHQRVQ

(SEQ ID NO: 41)

Active form: Ghrelin GSSFLSPEHQRVQQRKESKKPPAKLPQ

R-NH2 (SEQ ID NO: 567)

(Expert Opin. Biol. Tiler. (2007) 7(4): 461-478)

In some embodiments, the composition comprises a VIP analog. In some embodiments, the composition comprises a Secretin analog. In some embodiments, the composition comprises a PrP analog. In some embodiments, the composition comprises a PrP analog. In some embodiments, the composition comprises a PHM analog. In some embodiments, the composition comprises a PACAP-27 analog. In some embodiments, the composition comprises a PACAP-38 analog. In some embodiments, the composition comprises a Glucagon analog. In some embodiments, the composition comprises a GLP-1 analog. In some embodiments, the composition comprises a GIP analog. In some embodiments, the composition comprises a GHRF analog. In some embodiments, the composition comprises a secretin family analog that is derived from mammalian amino acid sequences of secretin family polypeptides other than humans In some embodiments, the secretin family analog may be selective for one particular receptor versus another. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds to, VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VPAC1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VPAC2. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, PAC1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VIPR1. In some embodiments, the composition comprises a secretin analog wherein the secretin analog is selective for, or preferentially binds, VIPR2. In some embodiments, the secretin analog is an agonist of at least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. In some embodiments, the the secretin analog is an antagonist of at least one of the following: VPAC1, VPAC2, PAC1, VIPR1, or VIPR2.
In some embodiments, the composition comprises a apolipoprotein A-1 analog. In some embodiments the apoA-1 analog is from about 80% to about 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 80% to about 85% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 85% to about 90% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 90% to about 95% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 95% to about 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is about 95%, 96%, 97%, 98%, or 99% homologous to the human sequence of apolipoprotein A-1. In some embodiments the apoA-1 analog is from about 80% to about 85% homologous to the following of apolipoprotein A-1 analog: DWFKAFYDKVAEKFKEAF (SEQ ID NO:533).
In some embodiments, the composition comprises a cytokine or interleukin analog. In some embodiments the cytokine or interleukin analog is from about 80% to about 99% homologous to the human sequence of cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 80% to about 85% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 85% to about 90% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 90% to about 95% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 95% to about 99% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is about 95%, 96%, 97%, 98%, or 99% homologous to the human sequence of a cytokine or interleukin. In some embodiments the cytokine or interleukin analog is from about 80% to about 99% homologous to a cytokine or interleukin chosen from IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-15, IL-17, IL-18, IL-21,IL-22, IL-23, IL-24, IL-26, IFN-γ, TNF-α, and TNF-β. In some embodiments, the cytokine or interleukin analog comprises at least one non-natural amino acid within the structure that corresponds to helix F in the naturally occurring polypeptide sequence upon which the analog is based or derived. In some embodiments, the cytokine or interleukin analog comprises at least one non-natural amino acid within the structure that corresponds to AB loop in the naturally occurring polypeptide sequence upon which the analog is based or derived.
The invention relates to the manufacturing of a synthetic polypeptide which is an amino acid sequence that corresponds to the sequence of a biologically active polypeptide or fragment thereof. In the synthetic polypeptide, from about 14% to about 50% of the α-amino acid residues found in the biologically active polypeptide or fragment are replaced with β-amino acid residues. In another embodiment of the invention, the α-amino acid residues and the β-amino acid residues are distributed in a repeating pattern. Human cells are then contacted with the synthetic polypeptide to induce the biochemical pathway or biological activity ordinarily induced by the naturally occurring polypeptide upon which the analog is based.
The compositions of the invention may be prepared by the synthetic chemical procedures described herein, as well as other procedures similar to those which may be used for making β-amino acid peptides. Such procedures include both solution and solid phase procedures, e.g., using either Boc and Fmoc methodologies. The compounds of the invention may be synthesized using solid phase synthesis techniques. Fmoc-N-Protected β-amino acids can be used to synthesize poly-α/β-peptides by conventional manual solid-phase synthesis procedures under standard conditions on any number of solid supports, including ortho-chloro-trityl chloride resin. Esterification of Fmoc-β-amino acids with the ortho-chloro-trityl resin can be performed according to the method of Barbs et. al., Tetrahedron Lett., 1989, 30, 3943. The resin (150 mg, 1.05 mmol Cl) is swelled in 2 ml CH₂Cl₂for 10 min A solution of the Fmoc-protected β-amino acid in CH₂Cl₂and iPr₂EtN are then added successively and the suspension is mixed under argon for 4 h. Subsequently, the resin is filtered and washed with CH₂Cl₂/MeOH/iPr₂EtN (17:2:1, 3×3 min), CH₂Cl₂(3×3 min), DMF (2×3 min), CH₂Cl₂(3×3 min), and MeOH (2×3 min). The substitution of the resin is determined on a 3 mg sample by measuring the absorbance of the dibenzofulvene adduct at 300 nm. The Fmoc group is removed using 20% piperidine in DMF (4 ml, 2×20 min) under Ar bubbling. The resin is then filtered and washed with DMF (6×3 min). For each coupling step, a solution of the β-amino acid (3 equiv.), BOP (3 equiv.) and HOBT (3 equiv.) in DMF (2 ml) and iPr₂EtN (9 eq) are added successively to the resin and the suspension is mixed for 1 h under Ar. Monitoring of the coupling reaction is performed with 2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Battersby, Anal. Biochem. (1976), 71, 260). In the case of a positive TNBS test (indicating incomplete coupling), the suspension is allowed to react for a further 1 h. The resin is then filtered and washed with DMF (3×3 min) prior to the following Fmoc deprotection step. After the removal of the last Fmoc protecting group, the resin is washed with DMF (6×3 min), CH₂Cl₂(3×3 min), Et₂O (3×3 min) and dried under vacuum for 3 h. Finally the peptides are cleaved from the resin using 2% TFA in CH₂Cl₂(2 ml, 5×15 min) under Ar. The solvent is removed and the oily residues are triturated in ether to give the crude α-/β-polypeptides. The compounds are further purified by HPLC.
The compositions of the invention may be prepared by the synthetic chemical procedures described herein, as well as other procedures similar to those which may be used for making β-amino acid peptides. Such procedures include both solution and solid phase procedures, e.g., using either Boc or Fmoc methodologies. The compounds of the invention may be synthesized using solid phase synthesis techniques. Fmoc-N-Protected β-amino acids can be used to synthesize poly-α/β-peptides by conventional manual solid-phase synthesis procedures under standard conditions on any number of solid supports, including ortho-chloro-trityl chloride resin, Wang resin (NovaBiochem 0.75 mmol substitution) and Rink amid resin (NovaBiochem 0.55 mmol substitution). Resin is typically swelled in 100% DMF for 30 minutes then deprotected using 20% piperidine in DMF for 2 minutes at 80° (3×). Fmoc protected amino acids (natural or non-natural) can then be coupled to the resin using a cocktail of AA:HATU:DIEA:Resin (3:2.5:4:1, LiCL 0.8M final concentration) in DMF for 2 minutes at 70° (3×). The resin is then washed (3×) with DMF, DCM (dichloromethane) (3×) and again with DMF (3×) between deprotection and coupling steps. Monitoring of the coupling reaction is performed with 2,4,6-trinitrobenzene-sulfonic acid (TNBS) (W. S. Hancock and J. E. Battersby, Anal. Biochem. (1976), 71, 260). In the case of a positive TNBS test (indicating incomplete coupling), the suspension is allowed to react for another three times. This process is repeated until the desired product has been achieved. After the removal of the last Fmoc protecting group, the resin is washed with DMF (3×), CH₂Cl₂(3×) and DMF again (3×). The remaining free-amine group is then acetylated using a cocktail of DIEA:Ac₂O (1:1) for 5 minutes at room temperature. Full-length peptides were then cleaved from solid support using TFA:TIS:H₂O (95:2.5:2.5) for 150 minutes, precipitated in cold ethyl ether and lyophilized The polymer was reconstituted in a 1:1 solution of A:B (A: H₂0, 0.1% TFA) (B: 90:10:0.1 acetonitrile/H₂O/TFA).
The compositions described herein may be prepared by successive amide bond-forming procedures in which amide bonds are formed between the β-amino group of a first β-amino acid residue or a precursor thereof and the α-carboxyl group of a second β-amino acid residue or α-amino acid residue or a precursor thereof. The amide bond-forming step may be repeated as many times, and with specific α-amino acid residues and/or β-amino acid residues and/or precursors thereof, as required to give the desired α/β-polypeptide. Also analogs comprising two, three, or more amino acid residues (α- or β-) may be joined together to yield larger analogs comprising any combination of α-, or β-amino acids. Cyclic compounds may be prepared by forming peptide bonds between the N-terminal and C-terminal ends of a previously synthesized linear polypeptide or through the disulfide crosslinking of sidechains of non-adjacent residues. β³-amino acids may be produced enantioselectively from corresponding β-amino acids. For instance, by Arndt-Eisert homologation of N-protected α-amino acids. Homologation may be followed by coupling of the reactive diazoketone intermediate of the Wolff rearrangement with a β-amino acid residue.
In some embodiments, the analog of the invention comprises a repeating pattern of the β-amino acid residues in alignment on a longitudinal axis of the analog in order to constrain the conformation of the analog in an active state or to avoid disruption of the active site. That is, in the folded structure adopted by the analogs of the present invention, the repeating pattern of α- or β-amino acids residues disposes the synthetic non-natural amino acid residues in alignment along one longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the unnatural polypeptides adopt a helical conformation. In some embodiments, the analog of the invention comprises the alignment of β-amino acids or ACPC or APC along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the residue positions in a solid dot represent non-natural amino acid residues. In some embodiments, the analog of the invention comprises the alignment along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the positions with solid dots represent β³-amino acid residues. In some embodiments, the analog of the invention comprises the alignment along a longitudinal axis of the folded molecular structure from N-terminus to C-terminus when the polypeptide adopts a helical conformation chosen from any of the conformations shown in FIG. 5, wherein the positions with solid dots represent β-amino acid residues.
The repeating pattern of β-amino acid residues and α-amino acid residues may be a pattern of from about two to about seven residues in length, such as (βαααααα), (βαααβαα), (ααααααβ), (ααααβ), (αααβ), (ααβ), (ααβαααβ), (ααβαβαβ), and (αβ). All unique patterns of α- or β-amino acids residues from about two to about fourteen residues in length are explicitly within the scope of the invention. All unique patterns of α- or β-amino acids residues from about two to about seven residues in length are explicitly within the scope of the invention. In some embodiments, the composition comprises an analog, wherein the analog wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus, and wherein the analog is an agonist or antagonist of the receptor to which it selectively binds or associates. For instance, in some embodiments, the analog is a VIP analog or a functional fragment thereof that selectivity binds to VPAC1, VPAC2, or PAC1 and wherein the VIP analog of functional fragment thereof is an agonist or antagonist of at least one receptor chosen from: VPAC1, VPAC2, and PAC1. In some embodiments, the methods of treatment or prevention include administration of VIP analogs, wherein the VIP analog is an an agonist or antagonist of at least one receptor chosen from: VPAC1, VPAC2, and PAC1. In some embodiments, the composition comprises an analog, wherein the analog wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: ααααααβ, αααααβα, ααααβαα, αααβααα, ααβαααα, αβααααα, βαααααα, αααααββ, ααααββα, αααββαα, ααββααα, αββαααα, ββααααα, βαααααβ, βααααβα, βαααβαα, βααβααα, β βαααα, αβααααβ, αβαααβα, αβααβαα, αβαβααα, ααβαααβ, ααβααβα, ααβαβαα, αααβααβ, αααβαβα, and ααααβαβ. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: βααβαααβααβαααβααα, βααβαααβααβαααββαα, βααβαααβααβαααβββα, and βααβαααβααβαααββββ. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: ββαβαααβααβαααβααβ; βαββαααβααβαααβααβ; βααββααβααβαααβααβ; βααβαβαβααβαααβααβ; βααβααββααβαααβααβ; βααβαααββαβαααβααβ; βααβαααβαββαααβααβ; βααβαααβααββααβααβ; βααβαααβααβαβαβααβ; βααβαααβααβααββααβ; βααβαααβααβαααββαβ; and βααβαααβααβαααβαββ. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: ββααβααβαααβααβααα; βαβαβααβαααβααβααα; βααββααβαααβααβααα; βαααββαβαααβααβααα; βαααβαββαααβααβααα; βαααβααββααβααβααα; βαααβααβαβαβααβααα; βαααβααβααββααβααα; βαααβααβαααββαβααα; βαααβααβαααβαββααα; βαααβααβαααβααββαα; βαααβααβαααβααβαβα; and βαααβααβαααβααβααβ.
In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: βααβαααβααβαααβααα, βααβαααβααβαααββαα, βααβαααβααβαααβββα, andβααβαααβααβαααββββ, wherein any α-amino acid residue may be a non-natural amino acid. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: βααβαααβααβαααβααα, βααβαααβααβαααββαα, βααβαααβααβαααβββα, and βααβαααβααβαααββββ, wherein at least one α-amino acid residue may be a non-natural amino acid. In some embodiments, the composition comprises an analog, wherein the analog comprises a repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus chosen from the following: βααβαααβααβαααβααα, βααβαααβααβαααββαα, βααβαααβααβαααβββα, andβααβαααβααβαααββββ, wherein from about 1 to about 10 α-amino acid residues may be a non-natural amino acid. In any of the above-mentioned patterns one or more of the β-amino acid residues may be replaced or modified with cyclic β-amino acid (cyclically-constrained beta amino acid), such as APC or ACPC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus: βααβαααβααβαααβααβ. In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-3 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-3 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-3 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-2 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-2 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-2 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-2 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-2 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-2 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any cyclic or heterocyclic beta-amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=cyclic or heterocyclic beta-amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=cyclic or heterocyclic beta-amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=cyclic or heterocyclic beta-amino acid
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-3 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-3 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-3 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta-3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-3 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanineα₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta-3 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta-3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta-3 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta 3-threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta 3-threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₂=any beta amino acid; α₃=an alpha lysine; α₄=an alpha glutamine; α₅=an alpha-leucine; β₃=any beta amino acid; α₆=an alpha valine; α₇=an alpha lysine; β₄=any beta amino acid; α₈=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-3 alanine; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=any beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta-3 amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₂=any beta-3 amino acid; α₃=an alpha lysine; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=any beta-3 amino acid; α₆=an alpha valine; α₇=an alpha lysine; β₄=any beta-3 amino acid; α₈=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=any beta-3 amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=any beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta-2 threonine; α₁=an alpha arginine; α₂=an alpha leucine; β₂=a beta-2 arginine; α₃=an alpha lysine; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=a beta-2 alanine; α₆=an alpha valine; α₇=an alpha lysine; β₄=a beta-2 lysine, α₈=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-2 alanine; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=a beta-2 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta-3 threonine or ACPC; α₁=an alpha arginine; α₂=an alpha leucine; β₂=a beta-3 arginine or APC; α₃=an alpha lysine; α₄=an alpha glutamine; α₅=an alpha-leucine; β₃=a beta-3 alanine or ACPC; α₆=an alpha valine; α₇=an alpha lysine; β₄=a beta-3 lysine or APC; α₈=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-3 alanine or ACPC; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=a beta-3 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α8=any alpha amino acid; β₄=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta-3 amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3 amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta-3 amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-3 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta-2 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta-2 amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta-2 amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta-2 amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-2 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid, β₂=any cyclic or heterocyclic beta-amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any cyclic or heterocyclic beta-amino acid; α6=any alpha amino acid, α7=any alpha amino acid; α8=any alpha amino acid, β₄=any cyclic or heterocyclic beta-amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid, α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=a beta-3 threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=a beta-3 lysine; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=a beta-3 tyrosine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃; wherein β₁=any beta amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₃=an alpha arginine; β₂=any beta amino acid; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=any beta amino acid; α₆=an alpha valine acid; α₇=an alpha lysine, α₈=an alpha lysine, β₄=any beta amino acid; α₉=an alpha leucine; α₁₀=an alpha asparagine, β₅=any beta amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃; wherein β₁=any beta-3 amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₃=an alpha arginine; β₂=any beta-3 amino acid; α₄=an alpha glutamine; α₅=an alpha leucine; =any beta-3 amino acid; α₆=an alpha valine acid; α₇=an alpha lysine, α₈=an alpha lysine, β₄=any beta-3 amino acid; α₉=an alpha leucine; α₁₀=an alpha asparagine, β₅=any beta-3 amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃; wherein β₁=any beta-2 amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₃=an alpha arginine; β₂=any beta-2 amino acid; α₇=an alpha glutamine; α₈=an alpha leucine; β₃=any beta-2 amino acid; α₆=an alpha valine acid; α₇=an alpha lysine, α₈=an alpha lysine, β₄=any beta-2 amino acid; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=any beta-2 amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃; wherein β₁=any cyclic and heterocyclic beta amino acid; α₁=an alpha arginine; α₂=an alpha leucine; α₃=an alpha arginine; β₂=any cyclic and heterocyclic beta amino acid; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=any cyclic and heterocyclic beta amino acid; α₆=an alpha valine acid; α₇=an alpha lysine; α₈=an alpha lysine; β₄=any cyclic and heterocyclic beta amino acid; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=any cyclic and heterocyclic beta amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=a beta-3 threonine or an ACPC; α₁=an alpha arginine; α₂=an alpha leucine; α₃=an alpha arginine; β₂=a beta-3 lysine or APC; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=a beta-3 alanine or ACPC; α₆=an alpha valine acid; α₇=an alpha lysine; α₈=an alpha lysine; β₄=a beta-3 tyrosine or; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-3 alanine or ACPC; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; β₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta-3, beta-2, cyclic or heterocyclic beta-amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta-3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta-3 amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta-3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta-3 amino acid; α₉=any alpha amino acid, α₁₀=any alpha amino acid; β₅=any beta-3 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta-2 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta-2 amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta-2 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta-2 amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta-2 amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta-2 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any cyclic or heterocyclic beta-amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any cyclic or heterocyclic beta-amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any cyclic or heterocyclic beta-amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any cyclic or heterocyclic beta-amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any cyclic or heterocyclic beta-amino acid; α₁₁=any alpha amino acid, α₁₂=any alpha amino acid, α₁₃=any alpha amino acid; and β₆=any cyclic or heterocyclic beta-amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-2 tyrosine; α₁=any alpha amino acid, α₂=any alpha amino acid, α₃=an alpha amino acid; β₂=a beta-2 arginine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-2 leucine; α₆=any alpha amino acid, α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-2 lysine; α₉=any alpha amino acid, α₁₀=any alpha amino acid; β₅=a beta-2 asparagine; α₁₁=any alpha amino acid, α₁₂=any alpha amino acid, α₁₃=any alpha amino acid; and β₆=a beta-2 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 tyrosine; α₁=any alpha amino acid, α₂=any alpha amino acid, α₃=an alpha amino acid, β₂=a beta-3 arginine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 leucine; α₆=any alpha amino acid, α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 lysine; α₉=any alpha amino acid, α₁₀=any alpha amino acid; β₅=a beta-3 asparagine; α₁₁=any alpha amino acid, α₁₂=any alpha amino acid, α₁₃=any alpha amino acid; and β₆=a beta-3 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=any beta amino acid; α₄=an alpha lysine, α₅=an alpha glutamine, β₃=any beta amino acid; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine, β₄=any beta amino acid; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=any beta amino acid; α₁₁=an alpha alanine, α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=any beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta-3 amino acid; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=any beta-3 amino acid; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=any beta-3 amino acid; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=any beta-3 amino acid; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=any beta-3 amino acid; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=any beta-3 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta-2 amino acid; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=any beta-2 amino acid; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=any beta-2 amino acid; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=any beta-2 amino acid; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=any beta-2 amino acid; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=any beta-2 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any cyclic or heterocyclic beta amino acid; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=any cyclic or heterocyclic beta amino acid; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=any cyclic or heterocyclic beta amino acid; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=any cyclic or heterocyclic beta amino acid; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=any cyclic or heterocyclic beta amino acid; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=any cyclic or heterocyclic beta amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=a beta-2 arginine or APC; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=any beta-2 amino acid; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=any beta-2 amino acid; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=any beta-2 amino acid; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=any beta-2 amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 tyrosine; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=a beta-3 arginine or APC; α₄=an alpha lysine, α₅=an alpha glutamine; β₃=a beta-3 leucine or ACPC; α₆=an alpha alanine; α₇=an alpha valine; α₅=an alpha lysine, β₄=a beta-3 lysine or APC; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=a beta-3 asparagine or ACPC; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=a beta-3 asparagine.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid; and
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and
wherein the C-terminus is optionally amidated; and
wherein the N-terminus is optionally acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid, α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid; and
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and
wherein the C-terminus is optionally amidated; and
wherein the N-terminus is optionally acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine or an ACPC; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid; and
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and
wherein the C-terminus is optionally amidated; and
wherein the N-terminus is optionally acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₈=an alpha leucine; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇βα₈ ₄α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; or a fragment thereof; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a non-natural amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine or an ACPC; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂αβ₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; or a fragment thereof; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a non-natural amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: APC, ACPC, a beta-2 homolog of a wild-type amino acid, or a beta-3 homolog of a wild-type amino acid.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid, β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₆=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein at least one or more of the amino acids HSDAVFTDNY (SEQ ID NO: 1340) or HSDAVFTDN (SEQ ID NO: 1341) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; β₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein the T at position 7 of p HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α6=any alpha amino acid; α7=any alpha amino acid; α8=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid, β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the T at position 7 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence, ACPC, or APC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus selected from the following:
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid, β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid;
β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and
β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid;
wherein the repetitive pattern is, optionally, preceded by:
HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃or β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆; or HSDAVFTDN (SEQ ID NO: 1341) if the composition comprises β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; and wherein the T at position 7 of
HSDAVFTDNY (SEQ ID NO: 1340) and, optionally, the D at position 8 of HSDAVFTDNY (SEQ ID NO: 1340) is substituted with a beta amino acid selected from the group chosen from: a beta-3 homolog of the wild-type amino acid sequence, a beta-2 homolog of the wild-type amino acid sequence ACPC, or APC.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus to the carboxy-terminus: βααβαααβααβαααβααβ. In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta 3-threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₅=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 asparagine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta 3-threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₅=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta 3-threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₅=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=an alpha arginine; α₅=an alpha leucine; β₂=any beta amino acid; α₃=an alpha lysine, α₄=an alpha glutamine; α₅=an alpha leucine; β₃=any beta amino acid; α₆=an alpha valine; α₇=an alpha lysine; β₄=any beta amino acid; α₈=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=any beta amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises, and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta-3 threonine or ACPC; α₁=an alpha arginine; α₂=an alpha leucine; β₂=a beta-3 arginine or APC; α₃=an alpha lysine; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=a beta-3 alanine or ACPC; α₆=an alpha valine; α₇=an alpha lysine; β₄=a beta-3 lysine or APC; α_s=an alpha tyrosine; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-3 alanine or ACPC; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=any beta amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=a beta-3 threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=any alpha amino acid; β₂=a beta-3 lysine; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 tyrosine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 alanine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃; wherein β₁=any beta amino acid; α₁=an alpha arginine; α₂=an alpha leucine; β₃=an alpha arginine; β₂=any beta amino acid; α₄=an alpha glutamine; α₅=an alpha leucine; β₃=any beta amino acid; α₆=an alpha valine acid; α₇=an alpha lysine; α₈=an alpha lysine, β₄=any beta amino acid; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=any beta amino acid; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃, wherein β₁=a beta-3 threonine or an ACPC; α₁=an alpha arginine, α₂=an alpha leucine; α₃=an alpha arginine; β₂=a beta-3 lysine or APC; α₁=an alpha glutamine; α₅=an alpha leucine; β₃=a beta-3 alanine or ACPC; α₆=an alpha valine acid, α₇=an alpha lysine; α₈=an alpha lysine; β₄=a beta-3 tyrosine or; α₉=an alpha leucine; α₁₀=an alpha asparagine; β₅=a beta-3 alanine or ACPC; α₁₁=an alpha isoleucine; α₁₂=an alpha leucine; α₁₃=an alpha asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY (SEQ ID NO: 1340) if the composition comprises; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341), and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 tyrosine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=a beta-3 arginine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 leucine; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 lysine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 asparagine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341), and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 tyrosine; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=a beta-3 arginine or APC; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=a beta-3 leucine or ACPC; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=a beta-3 lysine or APC; α₉=an alpha tyrosine; α₁₀=an alpha leucine; β₅=a beta-3 asparagine or ACPC; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine; α₁₃=an alpha leucine; and β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341), and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 tyrosine; α₁=an alpha threonine; α₂=an alpha arginine; α₃=an alpha leucine; β₂=a beta-3 arginine or APC; α₄=an alpha lysine; α₅=an alpha glutamine; β₃=a beta-3 leucine or ACPC; α₆=an alpha alanine; α₇=an alpha valine; α₈=an alpha lysine; β₄=a beta-3 lysine or APC; α₉=an alpha tyrosine; α₁₀=an alpha leucine, β₅=a beta-3 asparagine or ACPC; α₁₁=an alpha alanine; α₁₂=an alpha isoleucine, α₁₃=an alpha leucine; and β₆=a beta-3 asparagine; wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDN (SEQ ID NO: 1341); and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof
In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least one of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are non-natural or beta amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein at least one of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) is a beta-3, beta-2, cyclic, or heterocyclic beta amino acids. In some embodiments, the C-terminus is not amidated. In some embodiments, the N-terminus is not acylated. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein the the amino acids from HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are alpha amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein the the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are not alpha amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are beta-3 amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN or HSDAVFTDNY (SEQ ID NO: 1340) are beta-2 amino acids. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are ACPC or APC. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are cyclic. In some embodiments, the composition comprises HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340), wherein none of the amino acids from HSDAVFTDN (SEQ ID NO: 1341) or HSDAVFTDNY (SEQ ID NO: 1340) are heterocyclic.
“Selective” or “Selectivity” means that the analog of the present invention has a binding preference for one protein as compared to another protein. In some embodiments, the binding preference may be measured as an affinity for a protein in terms of half maximal inhibitory concentration (IC50). In some embodiments, the binding preference may be measured as an affinity for a protein in terms of half maximal effective concentration (EC50). For example, an analog selective to VPAC2 receptor with a selectivity to VPAC2 means that the analog may bind to VPAC1 receptor but has a higher binding affinity for a domain of the VPAC2 receptor if the analog is exposed to both VPAC1 and VPAC2 at similar or equivalent concentrations. As used herein, an analog that selectively binds to VPAC2 refers to an analog with increased selectivity for the VPAC2 receptor compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for VPAC2 may be an agonist of the VPAC2 receptor peptide. In some embodiments, the analog selective for VPAC2 may be an antagonist of VPAC2 receptor. In some embodiments, an analog selective to VPAC2 receptor means that the analog may bind to VPAC1 receptor but has a higher binding affinity for a domain of the VPAC2 receptor if the analog is exposed to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. In some embodiments, an analog selective to VPAC1 receptor means that the analog may bind to a domain of VPAC2 or PAC1 receptor but has a higher binding affinity for a domain of the VPAC1 receptor if the analog is exposed to to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. As used herein, an analog that selectively binds to VPAC1 refers to an analog with increased selectivity for the VPAC1 receptor compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for VPAC1 may be an agonist of the VPAC1 receptor peptide. In some embodiments, the analog selective for VPAC1 may be an antagonist of VPAC1 receptor. In some embodiments, an analog selective to VPAC1 receptor means that the analog may bind to VPAC2 receptor but has a higher binding affinity for a domain of the VPAC1 receptor if the analog is exposed to both VPAC1 receptor and VPAC2 receptor at similar or equivalent concentrations. As used herein, an analog that selectively binds to PAC1 refers to an analog with increased selectivity for the PAC1 receptor as compared to other known receptors or proteins to which the peptide may bind. In some embodiments, the analog selective for PAC1 may be an agonist of the PAC1 receptor peptide. In some embodiments, the analog selective for PAC1 may be an antagonist of PAC1 receptor. In some embodiments, an analog selective to PAC1 receptor means that the analog may bind to VPAC2 or VPAC1 receptors but has a higher binding affinity for a domain of the PAC1 receptor if the analog is exposed to to PAC1, VPAC1 receptor and VPAC2 receptors at similar or equivalent concentrations. The degree of selectivity may be determined by a ratio of VPAC2 receptor binding affinity to VPAC1 receptor binding affinity or by a ratio of VPAC2 receptor binding affinity to PAC1 receptor binding affinity. Binding affinity is determined as described below in Example 1.
In any of the embodiments described below wherein the polypeptide comprises a residue designated f, the residue designated f is D-Phe or L-Phe or S. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL; where residue designated f (position 2) is D-Phe, and wherein the analog interferes with the VPAC1 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe, and wherein the analog is an antagonist of the VPAC1 receptor. In some embodiments, the composition comprises a VIP analog is from about 80% to about 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 80% to about 85% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 85% to about 90% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 90% to about 95% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is from about 95% to about 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments the VIP analog is about 95%, 96%, 97%, 98%, or 99% homologous to HfDAVFTNSYRKVLKRLSARKLLQDIL, where residue designated f (position 2) is D-Phe. In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY; and
wherein residue designated f (position 2) is D-Phe
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅, wherein β₁=any beta 3 amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta 3 amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta 3 amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta 3 amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta 3 amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY, and
wherein residue designated f (position 2) is D-Phe
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition or pharmaceutical compositions comprise a VIP analog, wherein the analog is either: (a) an antagonist of VPAC1 receptor; or (b) interferes with VPAC1 receptor signaling pathway and comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅, wherein β₁=a beta-3 arginine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 leucine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 serine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 aspartic acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY; and
wherein residue designated f (position 2) is D-Phe
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof.
In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein at least one of the amino acids from HfDAVFTDN or HfDAVFTDNY are non-natural or beta amino acids, wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein at least one of the amino acids from HfDAVFTDN or HfDAVFTDNY is a beta-3, beta-2, cyclic, or heterocyclic beta amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the C-terminus is not amidated. In some embodiments, the N-terminus is not acylated. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein the the amino acids from HfDAVFTDN or HfDAVFTDNY are alpha amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein the the amino acids from HfDAVFTDN or HfDAVFTDNY are not alpha amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are beta-3 amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are beta-2 amino acids, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are ACPC or APC, and wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are cyclic, wherein residue designated f (position 2) is D-Phe. In some embodiments, the composition comprises HfDAVFTDN or HfDAVFTDNY, wherein none of the amino acids from HfDAVFTDN or HfDAVFTDNY are heterocyclic, and wherein residue designated f (position 2) is D-Phe.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof; and wherein residue designated f (position 2) is D-Phe.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅; wherein β₁=a beta-3 arginine or beta-3 tyrosine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=a beta-3 lysine or beta-3 leucine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 serine or a beta-3 leucine; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 leucine or beta-3 lysine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 aspartic acid or beta-3 glutamine; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof, and wherein residue designated f (position 2) is D-Phe.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅; wherein β₁=a beta-3 arginine, beta-3 tyrosine, or APC; α₁=any alpha amino acid, α₂=any alpha amino acid, α₃=an alpha amino acid; β₂=ACPC or APC; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=ACPC or a beta-3 leucine; α₆=any alpha amino acid, α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 leucine, beta-3 lysine, or APC; α₉=any alpha amino acid, α₁₀=any alpha amino acid; β₅=a beta-3 aspartic acid or ACPC; wherein the repetitive pattern is, optionally, preceded by: HfDAV FTNSY or HfDAV FTNS; and
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is, optionally, acylated;
or functional fragments thereof, and wherein residue designated f (position 2) is D-Phe.
In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

	HfDAV FTNSY ZKVXK RLXAR KLLQD IL

	HfDAV FTNSY RKVXK RLXAR ZLLQD IL

	HfDAV FTNSY RKVXK RLXAR KLLQX IL

	HfDAV FTNSY ZKVXK RLXAR ZLLQX IL

	HfDAV FTNSY RKVLZ RLXAR KLLQX IL

	HfDAV FTNSY ZKVLZ RLXAR KLLQX IL

	HfDAV FTNSY RKVXK RLSAR ZLLXD IL

	HfDAV FTNSY RKVXK RXSAR KLLXD IL

	HfDAV FTNSY RKVXK RXSAR ZLLXD IL

wherein residue designated f (position 2) is D-Phe, wherein each underlined residue is a beta amino acid, wherein X is a ACPC, wherein Z is APC, and wherein the analog interferes with the VPAC1 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

	HfDAV FTNSY Z KV X K RL X AR K LLQ D IL

	HfDAV FTNSY R KV X K RL X AR Z LLQ D IL

	HfDAV FTNSY R KV X K RL X AR K LLQ X IL

	HfDAV FTNSY Z KV X K RL X AR Z LLQ X IL

	HfDAV FTNSY R KVL Z RL X AR K L LQ X IL

	HfDAV FTNSY Z KVL Z RL X AR K L LQ X IL

	HfDAV FTNS Y RKV X K R L SAR Z LL X D IL

	HfDAV FTNS Y RKV X K R X SAR K LL X D IL

	HfDAV FTNS Y RKV X K R X SAR Z LL X D IL

wherein residue designated f (position 2) is D-Phe, wherein each underlined residue is a beta amino acid, wherein X is a ACPC, wherein Z is APC, and wherein the analog is an antagonist of the VPAC1 receptor; or functional fragments thereof.

In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

	(SEQ ID NO: 1342)
	HSDAV FTDNY TRLRK Q l AVK KYLN a ILN

	(SEQ ID NO: 1342)
	HSDAV FTDNY t RL r K QL a VK k YLN a I ln

	(SEQ ID NO: 1342)
	HSDAV FTDNY t RLR k QL a VK K y LN a ILN

	(SEQ ID NO: 1342)
	HSDAV FTDN y TRL r K Q l AVK k YL n A I ln

	(SEQ ID NO: 1343)
	HSDAV FTDNY t RL z K QL x VK k YLN x IL n

	(SEQ ID NO: 1344)
	HSDAV FTDNY t RL z K QL x VK z YLN x I ln

	(SEQ ID NO: 1345)
	HSDAV FTDNY x RL z K QL x VK k YLN x I ln

	(SEQ ID NO: 1346)
	HSDAV FTDNY x RL z K QL x VK z YLN x I ln

	(SEQ ID NO: 1347)
	HSDAV FTDNY t RLR z QL x VK K y LN x ILN

	(SEQ ID NO: 1348)
	HSDAV FTDNY x RLR z QL x VK K y LN x ILN

	(SEQ ID NO: 1349)
	HSDAV FTDN y TRL z K Q l AVK z YL x A I ln

	(SEQ ID NO: 1350)
	HSDAV FTDN y TRL z K Q x AVK k YL x A I ln

	(SEQ ID NO: 1351)
	HSDAV FTDN y TRL z K O x AVK z YL x A I ln

wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof.

In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433), and wherein the analog stimulates the VPAC2 receptor signaling pathway. In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433), wherein the analog is an agonist of the VPAC2 receptor. In some embodiments, the composition comprises a VIP analog is from about 80% to about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 80% to about 85% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 85% to about 90% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 90% to about 95% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is from about 95% to about 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is about 95%, 96%, 97%, 98%, or 99% homologous to HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433). In some embodiments the VIP analog is HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY (SEQ ID NO:433).
In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof.
In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta-3 threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=an alpha leucine; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 serine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof,
wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.
In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=any beta amino acid; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₄=any beta amino acid; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid, β₆=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof; and wherein the analog or functional fragment thereof is a VPAC2 agonist.
In some embodiments, the composition or pharmaceutical composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂β₂α₃α₄α₅β₃α₆α₇β₄α₈α₉α₁₀β₅α₁₁α₁₂β₆, wherein β₁=a beta-3 threonine; α₁=any alpha amino acid; α₂=any alpha amino acid; β₂=a beta-3 arginine; α₃=any alpha amino acid; α₄=any alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine; α₆=any alpha amino acid; α₇=any alpha amino acid; β₄=a beta-3 lysine; α₈=any alpha amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 serine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; β₆=a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAVFTDNY CSEQ ID NO: 1340); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=any beta amino acid; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=any beta amino acid; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=any beta amino acid; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=any beta amino acid; α₉=any alpha amino acid; α₁₀=any alpha amino acid, β₅=any beta amino acid; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=any beta amino acid; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 threonine or a beta-3 tyrosine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=a beta-3 lysine or a beta-3 arginine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine or a beta-3 valine; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid; β₄=a beta-3 tyrosine or a beta-3 lysine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 serine or a beta-3 glutamine; α₁₁=any alpha amino acid; α₁₂=any alpha amino acid; α₁₃=any alpha amino acid; and β₆=a beta-3 lysine or a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof.
In some embodiments, the composition comprises a VIP analog, wherein the analog comprises the following repetitive pattern of sequential β-amino acids from the amino-terminus: β₁α₁α₂α₃β₂α₄α₅β₃α₆α₇α₈β₄α₉α₁₀β₅α₁₁α₁₂α₁₃β₆; wherein β₁=a beta-3 threonine or a beta-3 tyrosine; α₁=any alpha amino acid; α₂=any alpha amino acid; α₃=an alpha amino acid; β₂=a beta-3 lysine or a beta-3 arginine; α₄=an alpha alpha amino acid; α₅=any alpha amino acid; β₃=a beta-3 alanine or a beta-3 valine; α₆=any alpha amino acid; α₇=any alpha amino acid; α₈=any alpha amino acid, α₄=a beta-3 tyrosine or a beta-3 lysine; α₉=any alpha amino acid; α₁₀=any alpha amino acid; β₅=a beta-3 serine or a beta-3 glutamine; α₁₁=any alpha amino acid, α₁₂=any alpha amino acid, α₁₃=any alpha amino acid; and β₆=a beta-3 lysine or a beta-3 asparagine; and wherein the repetitive pattern is, optionally, preceded by: HSDAV FTDNY (SEQ ID NO: 1340) or HSDAV FTDN (SEQ ID NO: 1341); and wherein the repetitive pattern is, optionally, succeeded by: K, KR, or KRY.
wherein the C-terminus is, optionally, amidated; and
wherein the N-terminus is unmodified or modified; or functional fragments thereof;
and wherein the analog or functional fragment thereof is a VPAC2 agonist.
In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog is between 75% and 100% homologous to one or more of the following sequences:

	(SEQ ID NO: 1353)
	HSDAVFTDNY X RL Z KQV X AK K YLQ S IK N KRY

	(SEQ ID NO: 1354)
	HSDAVFTDNY T RL Z KQV X AK Z YLQ S IK N KRY

	(SEQ ID NO: 1355)
	HSDAVFTDNY T RL Z KQV X AK K YLQ X IK N KRY

	(SEQ ID NO: 1356)
	HSDAVFTDNY X RL Z KQV X AK Z YLQ X IK X KRY

	(SEQ ID NO: 1357)
	HSDAVFTDNY T RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1358)
	HSDAVFTDNY X RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1359)
	HSDAVFTDN Y TRL Z KQ V SAK Z YL X SIK N KRY

	(SEQ ID NO: 1360)
	HSDAVFTDN Y TRL Z KQ X SAK K YL X SIK N KRY

	(SEQ ID NO: 1361)
	HSDAVFTDN Y TRL Z KQ X SAK Z YL X SIK N KRY

wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; and wherein the N-terminus is unmodified.

	(SEQ ID NO: 1353)
	HSDAVFTDNY X RL Z KQV X AK K YLQ S IK N KRY

	(SEQ ID NO: 1354)
	HSDAVFTDNY T RL Z KQV X AK Z YLQ S IK N KRY

	(SEQ ID NO: 1355)
	HSDAVFTDNY T RL Z KQV X AK K YLQ X IK N KRY

	(SEQ ID NO: 1356)
	HSDAVFTDNY X RL Z KQV X AK Z YLQ X IK X KRY

	(SEQ ID NO: 1357)
	HSDAVFTDNY T RLR Z QV X AKK Y LQ X IK N KRY

	(SEQ ID NO: 1358)
	HSDAVFTDNY X RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1359)
	HSDAVFTDN Y TRL Z KQ V SAK Z YL X SIK N KRY

	(SEQ ID NO: 1360)
	HSDAVFTDN Y TRL Z KQ X SAK K YL X SIK N KRY

	(SEQ ID NO: 1361)
	HSDAVFTDN Y TRL Z KQ X SAK Z YL X SIK N KRY

wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; and wherein the N-terminus is, optionally, modified.

	(SEQ ID NO: 1353)
	HSDAVFTDNY X RL Z KQV X AK K YLQ S IK N KRY

	(SEQ ID NO: 1354)
	HSDAVFTDNY T RL Z KQV X AK Z YLQ S IK N KRY

	(SEQ ID NO: 1355)
	HSDAVFTDNY T RL Z KQV X AK K YLQ X IK N KRY

	(SEQ ID NO: 1356)
	HSDAVFTDNY X RL Z KQV X XAK Z YLQ X IK X KRY

	(SEQ ID NO: 1357)
	HSDAVFTDNY T RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1358)
	HSDAVFTDNY X RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1359)
	HSDAVFTDN Y TRL Z KQ V SAK Z YL X SIK N KRY

	(SEQ ID NO: 1360)
	HSDAVFTDN Y TRL Z KQ X SAK K YL X SIK N KRY

	(SEQ ID NO: 1361)
	HSDAVFTDN Y TRL Z KQ X SAK Z YL X SIK N KRY

wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.

	(SEQ ID NO: 433)
	HSDAVFTDNY T RL R KQV A AK K YLQ S IK N KR Y

	(SEQ ID NO: 433)
	HSDAVFTDNY T RLR K QV A AKK Y LQ S IKN K R Y

	(SEQ ID NO: 433)
	HSDAVFTDN Y TRL R KQ V AAK K YL Q SIK N KR Y

	(SEQ ID NO: 1353)
	HSDAVFTDNY X RL Z KQV X AK K YLQ S IK N KRY

	(SEQ ID NO: 1354)
	HSDAVFTDNY T RL Z KQV X AK Z YLQ S IK N KRY

	(SEQ ID NO: 1355)
	HSDAVFTDNY T RL Z KQV X AK K YLQ X IK N KRY

	(SEQ ID NO: 1356)
	HSDAVFTDNY X RL Z KQV X AK Z YLQ X IK X KRY

	(SEQ ID NO: 1357)
	HSDAVFTDNY T RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1358)
	HSDAVFTDNY X RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1359)
	HSDAVFTDN Y TRL Z KQ V SAK Z YL X SIK N KRY

	(SEQ ID NO: 1360)
	HSDAVFTDN Y TRL Z KQ X SAK K YL X SIK N KRY

	(SEQ ID NO: 1361)
	HSDAVFTDN Y TRL Z KQ X SAK Z YL X SIK N KRY

wherein each underlined residue is an unnatural amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

wherein each underlined residue is a beta amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

	(SEQ ID NO: 433)
	HSDAVFTDNY T RL R KQV A AK K YLQ S IK N KR Y

	(SEQ ID NO: 433)
	HSDAVFTDNY T RLR K QV A AKK Y LQ S IKN K R Y

	(SEQ ID NO: 433)
	HSDAVFTDN Y TRL R KQ V AAK K YL Q SIK N KR Y

	(SEQ ID NO: 1353)
	HSDAVFTDNY X RL Z KQV X AK K YLQ S IK N KRY

	(SEQ ID NO: 1354)
	HSDAVFTDNY T RL Z KQV X AK Z YLQ S IK N KRY

	(SEQ ID NO: 1355)
	HSDAVFTDNY T RL Z KQV X AK K YLQ X IK N KRY

	(SEQ ID NO: 1356)
	HSDAVFTDNY X RL Z KQVXAK Z YLQ X IK X KRY

	(SEQ ID NO: 1357)
	HSDAVFTDNY T RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1358)
	HSDAVFTDNY X RLR Z QV X AKK Y LQ X IKN K RY

	(SEQ ID NO: 1359)
	HSDAVFTDN Y TRL Z KQ V SAK Z YL X SIK N KRY

	(SEQ ID NO: 1360)
	HSDAVFTDN Y TRL Z KQ X SAK K YL X SIK N KRY

	(SEQ ID NO: 1361)
	HSDAVFTDN Y TRL Z KQ X SAK Z YL X SIK N KRY

wherein each underlined residue is a beta-3 homo amino acid corresponding to the single code amino acid upon which it is based, wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 agonist.

In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to one or more of the following sequences:

wherein each underlined residue is any unnatural amino acid; any beta-2 amino acid; any beta-3 amino acid; or a beta-3 homo amino acid corresponding to the single code amino acid upon which it is based; wherein X is a ACPC, and wherein Z is APC; or functional fragments thereof; wherein the C-terminus is, optionally, amidated; wherein the N-terminus is, optionally, modified; and wherein the VIP analog or functional fragment thereof is a VPAC1 or VPAC2 agonist.

In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to:
(SEQ ID NO: 433)

HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY

or functional fragments thereof; and wherein the VIP analog or functional fragment thereof is a VPAC2 agonist.
In some embodiments, the invention relates to compositions or pharmaceutical compositions comprising a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid, and wherein the analog comprises an amino acid sequence that is between 75% and 100% homologous to any of the amino acid sequence provided in this application.
The invention relates to methods of manufacturing a composition comprising an analog, wherein the analog comprises an α-amino acid and at least one β-amino acid. In some embodiments, the invention relates to methods of manufacturing a composition comprising an analog, wherein the analog comprises an α-amino acid, at least one β-amino acid, and at least one modified amino acid residue comprising ACPC or APC. The invention relates to methods of manufacturing a composition comprising a secretin family analog, wherein the secretin family analog comprises an α-amino acid and at least one β-amino acid. The invention relates to methods of manufacturing a composition comprising a VIP analog, wherein the VIP analog comprises an α-amino acid and at least one β-amino acid. The method used to fabricate polypeptide compounds may be any means of polypeptide synthesis. Using methods of peptide synthesis, polypeptides fabricated according to the present method are generally less than about 100 residues long. In some embodiments, the invention relates to a method of manufacturing an analog (or fragments herein) comprising non-natural amino acids from from about 5 total residues to about 50 total residues, from about 10 total residues to about 20 total residues, from about 20 total residues to about 30 total residues, from about 30 total residues to about 40 total residues, from about 40 total residues to about 50 total residues, from about 50 to about 60 total residues, from about 60 to about 70 total residues from about 70 to about 80 total residues, from about 80 to about 90 total residues, and from about 90 to about 100 total residues. Ranges above and below these stated ranges are within the scope of the invention. Many commercial services, such as Abgent (San Diego, Calif., USA) offer peptide synthesis services up to about 100 residues. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 100 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 90 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 80 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 70 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 60 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 50 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 40 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 30 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 20 non-natural amino acids. In some embodiments, the invention relates to a method of manufacturing an analog comprising no more than 10 non-natural amino acids. In some embodiments, the method of manufacturing the analog comprises synthesizing the analog using at least one, and, in some embodiments, a plurality of the following non-naturally occurring amino acid residues: (2S,3R)-3-(amino)-2-hydroxy-4-(4-nitrophenyl)butyric acid, (2R,3R)-3-(amino)-2-hydroxy-4-phenylbutyric acid, (R)-3-(amino)-5-phenylpentanoic acid, (R)-3-(amino)-4-(2-naphthyl)butyric acid, (R)-2-methyl-β-Phe-OH, (R)-3,4-dimethoxy-β-Phe-OH, (R)-(3-pyridyl)-β-Ala-OH, (R)-3-(trifluoromethyl)-β-Phe-OH, (R)-3-cyano-β-Phe-OH, (R)-3-methoxy-β-Phe-OH, (R)-3-methyl-β-Phe-OH, (R)-4-(4-pyridyl)-β-HomoAla-OH, (R)-4-(trifluoromethyl)-β-HomoPhe-OH, (R)-4-(trifluoromethyl)-β-Phe-OH, (R)-4-bromo-β-Phe-OH, (R)-4-chloro-β-HomoPhe-OH, (R)-4-chloro-β-Phe-OH, (R)-4-cyano-β-HomoPhe-OH, (R)-4-cyano-β-Phe-OH, (R)-4-fluoro-β-Phe-OH, (R)-4-methoxy-β-Phe-OH, (R)-4-methyl-β-Phe-OH, (R)-β-Tyr-OH, (R)-4-(3-pyridyl)-β-HomoAla-OH, (R)-4-fluoro-β-HomoPhe-OH, (S)-5-phenylpentanoic acid, (S)-5-hexenoic acid, (S)-5-phenyl-pentanoic acid, (S)-6-phenyl-5-hexenoic acid, (S)-2-(trifluoromethyl)-β-HomoPhe-OH, (S)-2-(trifluoromethyl)-β-Phe-OH, (S)-2-cyano-β-HomoPhe-OH, (S)-2-methyl-β-Phe-OH, (S)-3,4-dimethoxy-β-Phe-OH, (S)-3-(trifluoromethyl)-β-HomoPhe-OH, (S)-3-(trifluoromethyl)-β-Phe-OH, (S)-3-cyano-β-Phe-OH, (S)-3-methoxy-β-Phe-OH, (S)-3-methyl-β-Phe-OH, (S)-4-(4-pyridyl)-β-HomoAla-OH, (S)-4-(trifluoromethyl)-β-Phe-OH, (S)-4-bromo-β-Phe-OH, (S)-4-chloro-β-HomoPhe-OH, (S)-4-chloro-β-Phe-OH, (S)-4-cyano-β-HomoPhe-OH, (S)-4-cyano-β-Phe-OH, (S)-4-fluoro-β-Phe-OH, (S)-4-iodo-β-HomoPhe-OH, (S)-4-methyl-β-HomoPhe-OH, (S)-4-methyl-β-Phe-OH, (S)-(3-Tyr-OH, (S)-γ,γ-diphenyl-β-HomoAla-OH, (S)-2-methyl-β-Homophe-OH, (S)-3,4-difluoro-β-HomoPhe-OH, (S)-3-(trifluoromethyl)-β-HomoPhe-OH, (S)-3-cyano-β-HomoPhe-OH, (S)-3-methyl-β-HomoPhe-OH, (S)-γ,γ-diphenyl-β-HomoAla-OH, 3-Amino-3-(3-bromophenyl)propionic acid, and 3-Amino-4,4,4-trifluorobutyric acid.
In some embodiments, the fragment comprises 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 amino acids of the wild type protein sequence. In some embodiments, the fragment comprises any of the above-mentioned numbers of amino acids located anywhere within the peptide. Thus, one skilled in the art understands that a fragment of any of these lengths can be walked along the length of the peptide, thus providing any fragment of the peptide with the same or similar function as the native or wild-type amino acid sequence.
One of ordinary skill in the art would readily appreciate that the protecting groups would be removed from the final chemical structure of the analog which becomes administered to a subject. One of ordinary skill would be able to predict the final chemical structure of the analog by using the protecting groups selectively to create a polypeptide with a desirable chirality or secondary structure. For instance, if the analog of the composition is manufactured using (S)-Fmoc-3-methyl-β-HomoPhe-OH, the final yielded product should comprise at least one β-amino acid residue of a 3-methyl-β-homophenylalanine.
In some embodiments, the method of manufacturing the analog comprises synthesizing the analog using at least one, and in some embodiments, a plurality of cyclic amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises the cyclic amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises at least one disulfide bridge that forms a cyclic chain of atoms along a side chain of two amino acid residues.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 10)

HSDAVFTDNYTRLRKQMAVKKYLNSILN;

wherein at least one of the amino acid residues is a β-amino acid residue, and at least one of the amino acid residues is an α-amino acid residue. In some embodiments, the at least one α-amino acid residue is a non-natural amino acid residue. In some embodiments, the amino acid residues at positions 1, 3, 6, 7, 10, and 23 of the VIP analog are not alanine, glycine, or any β amino acid residue with a methyl side chain.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVF
NYTRLR
A
YLN

wherein any of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀may be a beta-amino acid. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVFX₁X₂ NYTRLRX₃ QX₄ AX₅X₆X₇ YLNX₈ IX₉X₁₀

wherein any of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀are a β³-amino acid residue. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVFX₁X₂ NYTRLRX₃ QX₄ AX₅X₆X₇ YLNX₈ IX₉X₁₀

wherein any one or more of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀is a beta-amino acid, and wherein X₁=T; X₂=D; X₃=R or K; X₄=M or L; X₅=A or V; X₆=R or K; X₇=R or K; X₈=S or A; X₉=L or K; and X₁₀=N or K. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVFX₁X₂ NYTRLRX₃ QX ₄AX₅X₆X₇ YLNX₈ IX₉X₁₀

wherein any one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀is a β³-amino acid residue. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVFX₁X₂ NYTRLRX₃ QX₄ AX₅X₆X₇ YLNX₈ IX₉X₁₀

wherein any one or more of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀is a beta-amino acid, and wherein X₁=T; X₂=D; X₃=R or K; X₄=M or L; X₅=A or V; X₆=R or K; X₇=R or K; X₈=S or A; X₉=L or K; and X₁₀=N or K. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1362)

HSDAVFX₁X₂ NYTRLRX₃ QX₄ AX₅X₆X₇ YLNX₈ IX₉X₁₀

wherein any one or more of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, or X₁₀is a β³-amino acid residue. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1363)

HSDAVFX₁X₂ NYX₃RLX₄ X₅ QX₆ X₇ X₈X₉ X₁₀YLNX₁₁IX₁₂X₁₃

wherein X₃, X₄, X₇, X₁₀, and X₁₁are beta-amino acid residues derived from the naturally occurring α-amino acid residue at that position, and wherein X₁=T; X₂=D; X₅=R or K; X₆=M or L; X₈=A or V; X₉=R or K; X₁₀=R or K; X₁=S or A; X₁₂=L or K; and X₁₃=N or K. HSDAVFX₁X₂ NYX₃RLX₄ X₅ QX₆ X₇ X₈X₉ X₁₀YLNX₁₁IX₁₂X₁₃ (SEQ ID NO: 1363) wherein X₃, X₄, X₇, X₁₀, and X₁₁are β³-amino acid residues derived from the naturally occurring α-amino acid residue at that position. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1363)

HSDAVFX₁X₂ NYX₃RLX₄ X₅ QX₆ X₇ X₈X₉ X₁₀YLNX₁₁IX₁₂X₁₃

wherein at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, or X₁₃is a beta-amino acid, and wherein X₁=T; X₂=D; X₅=R or K; X₆=M or L; X₈=A or V; X₉=R or K; X₁₀=R or K; X₁₁=S or A; X₁₂=L or K; and X₁₃=N or K. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1363)

HSDAVFX₁X₂ NYX₃RLX₄ X₅ QX₆ X₇ X₈X₉ X₁₀YLNX₁₁IX₁₂X₁₃

wherein at least one of X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₁₁, X₁₂, or X₁₃is a β³-amino acid residue, and wherein X₁=T; X₂=D; X₅=R or K; X₆=M or L; X₈=A or V; X₉=R or K; X₁₀=R or K; X₁₁=S or A; X₁₂=L or K; and X₁₃=N or K. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1364)

X₁ TX₂LRX₃QLX₄ AX₅ X₆ YLQSIX₇X₈;

wherein X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈are non-natural amino acids and wherein the underlined residues are β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1364)

X₁ TX₂LRX₃QLX₄ AX₅ X₆ YLQSIX₇X₈;

wherein X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈are non-natural amino acids and wherein the underlined residues are β³-amino acid residues. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1365)

Y(OMe)TOrnLRAibQLUAAibOrnYLQSIOrnOrn,

wherein Orn=ornithine, Y(OMe)=O-methylated Tyrosine, Aib=α-aminoisobutyric acid, U=amino butyric acid (i.e., side chain=ethyl), and wherein each underlined position is a β-amino acid residue. In some embodiments at least one of the β-amino acid residue are β³-amino acid residues. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises at least 17% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 15% to about 30% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 15% to about 30% β-amino acid residues wherein the first ten amino acids of the amino acid sequence are alpha amino acids. In some embodiments, the VIP analog of the claimed invention comprises from about 16% to about 29% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 17% to about 29% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 18% to about 29% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 19% to about 29% β-amino acid residues. In some embodiments, the VIP analog of the claimed invention comprises from about 20% to about 29% β-amino acid residues.
In some embodiments, the VIP analog of the claimed invention comprises β-amino acid residues at residue positions 11, 14, 18, 21, and 25 of HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10). In some embodiments, the VIP analog of the claimed invention comprises β-amino acid residues at positions 11, 14, 18, 21, and 25 of HSDAVFTDNYTRLRKQMAVKKYLNSILN (SEQ ID NO: 10), wherein the position 11 is β³-homothreonine, position 14 is β³-homoarginine, position 18 is β³-homoalanine, position 21 is β³-homolysine, and position 25 is β³-homoserine. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), (S,R)-trans-2-aminocyclopentanecarboxylic acid ((S,R)-ACPC), (R,S)-trans-2-aminocyclopentanecarboxylic acid ((R,S)-ACPC), or (R,R)-trans-2-aminocyclopentanecarboxylic acid ((R,R)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC, (RS)-ACPC, (S,R)-ACPC, (RR)-ACPC), which is designated APC, if the amino acid is basic. In some embodiments, at least one of the β³-amino acid residues is substituted with a residue chosen from the following: (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC) if the amino acid is non-polar; or pyrrolidine analogue of (S,S)-ACPC if the residue is basic.
In some embodiments, the VIP analog of the claimed invention comprises the following sequence:
(SEQ ID NO: 1352)

HSDAVFTDNYX₁ RLX₂ KQLX₃ VKX₄ YLNX₅ ILN

wherein X₁, X₂, X₃, X₄, and X₅are β-amino acid residues and wherein all other α-amino residues are naturally-occurring or non-naturally occurring amino acid residues. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via a lactam ring. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via an amide bond. In some embodiments, the VIP analog of the claimed invention comprises one of the following sequences:

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRK QMAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRK QMAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRK QMAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRK QMAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRKQ MAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRKQ MAVK KALNS ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY ARLRKQ MAVK KALNS ILA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRK QMAAK KALAA IAA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRK QMAAK KALAA IAA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRK QMAAK KALAA IAA)

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRK QMAAK KALAA IAA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRKQ MAAK KALAA IAA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRKQ MAAK KALAA IAA

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRKQ MAAK KALAA IAA

wherein each underlined residue is: a β³-homoamino acid residue; or, if a non-polar (e.g., A, V), the underlined residues is/are (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC); or, if the underlined position is basic, (such as Lys or Arg), the underlined residue is a pyrrolidine analogue of (S,S)-ACPC, which is designated APC. (Note: Ac=acetyl; N^le=norleucine; K*---D* indicates that the side chains of these two residues are linked via an amide bond.) In some embodiments, the sidechains of K and D are not linked via any bond.

a/b-Peptide analogues will be synthesized:

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^le AVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^le AVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^le AVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^le AVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^leAVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^leAVK KYLND LKKGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TKLRK QN^leAVK KYLND LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^le AAK N^le YLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^le AAK N^leYLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^le AAK N^le YLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^le AAK N^le YLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^leAAK N^leYLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^leAAK N^le YLNN LKKGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TKLRK RN^leAAK N^leYLNN LKKGG T

wherein each underlined residue is: a β³-homoamino acid residue; or, if a non-polar (e.g., A, V), the underlined positions will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC); or if the underlined residue is basic, (such as Lys or Arg), the underlined residue is/are the pyrrolidine analogue of (S,S)-ACPC, which is designated APC; and wherein Ac=acetyl; N^le=norleucine; K*---D* indicates that the side chains of these two residues are linked via an amide bond. In some embodiments, the sidechains of K and D are not linked via any bond. In some embodiments, the VIP analog comprises a cyclic amino acid residue covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via the following synthetic linking structures:

In some embodiments, the analog does not comprise a cyclic substituent in its side chain. In some embodiments, the cyclic amino acid residues are not covalently bonded to one or more contiguous or non-contiguous amino acid sidechain residues via the following synthetic linking structures:
In some embodiments, the analogs of the present invention comprise at least one or a plurality of the following cyclic amino acid residues, some of which being described with a protecting group that becomes eliminated from the analog either during synthesis or when the analog is purified after synthesis:
L-β-HomohydroxyProline hydrochloride
(1R,2R)-Boc-2-aminocyclohexane carboxylic acid {(1R,2R)-ACHC}
(1R,2R)-Fmoc-2-aminocyclohexane carboxylic acid {(1R,2R)-ACHC}
(1R,2S)-Boc-2-aminocyclohexane carboxylic acid {(1R,2S)-ACHC}
(1R,2S)-Fmoc-2-aminocyclohexane carboxylic acid {(1R,2S)-ACHC}
(1S,2R)-Boc-2-aminocyclohexane carboxylic acid {(1S,2R)-ACHC}
(1S,2R)-Fmoc-2-aminocyclohexane carboxylic acid (1S,2R)-ACHC}
(1S,2S)-Boc-2-aminocyclohexane carboxylic acid {(1S,2S)-ACHC}
(1S,2S)-Fmoc-2-aminocyclohexane carboxylic acid {(1S,2S)-ACHC}
(1R,2R)-Boc-2-aminocyclopentane carboxylic acid {(1R,2R)-ACPC}
(1R,2R)-Fmoc-2-aminocyclopentane carboxylic acid {(1R,2R)-ACPC}
(1S,2S)-Boc-2-aminocyclopentane carboxylic acid {(1S,2S)-ACPC}
(1S,2S)-Fmoc-2-aminocyclopentane carboxylic acid {(1S,2S)-ACPC}
Boc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc
Fmoc-cis-2-aminocyclopentane carboxylic acid, cis-Acpc
(R)-Boc-(2-carboxymethyl)-piperidine, (R)-(1-piperidin-2-yl)-acetic acid
(R)-Fmoc-(2-carboxymethyl)-piperidine, (R)-(1-Fmoc-piperidin-2-yl)-acetic acid
(S)-Boc-(2-carboxymethyl)-piperidine (S)-(1-Boc-piperidin-2-yl)-acetic acid
(S)-Fmoc-(2-carboxymethyl)-piperidine (S)-(1-Fmoc-piperidin-2-yl)-acetic acid
(R,S)-Boc-2-carboxymorpholine Boc-Cop
(R,S)-Boc-2-carboxymorpholine Fmoc-Cop
(R,S)-Boc-nipecotic acid Boc-Nip
(R,S)-Boc-nipecotic acid Fmoc-Nip
(R)-Fmoc-nipecotic acid (R)-Fmoc-Nip
(R)-Fmoc-nipecotic acid (R)-Boc-Nip
(3S)-Boc-1-pyrrolidine-3-carboxylic acid (3S)-Boc-beta-Pro-OH
(3S)-Fmoc-1-pyrrolidine-3-carboxylic acid (3S)-Fmoc-beta-Pro-OH
In some embodiments, the analogs of the present invention comprise at least one or a plurality of non-natural amino acid residues that can modified by PEGylation. In some embodiments the analogs or fragments of the polypeptides related to this invention comprise PEG molecules which are covalently bound to the side chain of the α, or β amino acids in the polypeptide. In some embodiments, the polypeptides of this invention comprise the PEGylated cyclic amino acid residues or cyclic amino acid side chains. PEG molecule(s) may be covalently attached to any Lys, Cys, K(W) or K(CO(CH₂)₂SH) residue at any position in the analog or fragment of analog. In some embodiments, the analog or a fragment thereof comprises a C-terminal extension may comprise one or more Cys residues which may be PEGylated. In some embodiment of the invention the polypeptides or fragments thereof may comprise one or more PEGylated residues in either or both sequences.
In some embodiments, the analog or fragment thereof comprises a PEG molecule covalently attached to one or all of the β-residue within the analog. In some embodiments, the analog is at least one PEG molecule covalently attached to a residue in the C-terminal extension of the analog or fragment thereof. In some embodiments, the analog comprises more than one PEG molecule, there may be a combination of Lys, Cys, K(CO(CH₂)₂SH), K(W) and carboxy-terminal amino acid PEGylation. For example, if there are two PEG molecules, one may be attached to a Lys residue and one may be attached to a Cys residue. In some embodiments, the polypeptide comprises one or more covalently bound PEG molecules, wherein at least one of the PEG molecules is branched. In some embodiments, one or more of the PEG molecules are linear. In some embodiments, the composition comprises one or more PEG molecule, wherein the PEG molecule is between about 200 daltons and about 100,000 daltons in molecular weight. In some embodiments, the PEG molecule is chosen from 10,000, 20,000, 30,000, 40,000, 50,000 and 60,000 daltons. In some embodiments, it is chosen from 20,000, 30,000, 40,000, or 60,000 daltons. Where there are two PEG molecules covalently attached to the analog or fragment thereof, each is 1,000 to 40,000 daltons and, they have molecular weights of 20,000 and 20,000 daltons, 10,000 and 30,000 daltons, 30,000 and 30,000 daltons, or 20,000 and 40,000 daltons. In some embodiments mini-PEGs™ are covalently bound to at least one residue or side chain of an a, or β-amino acid. In some embodiments, the mini-PEG™ is chosen from the following list of products: 8-Amino-3,6-Dioxaoctanoic Acid, 11-Amino-3,6,9-Trioxaundecanoic Acid, 8-Amino-3,6-Dioxaoctanoic Acid DCHA, 11-Amino-3,6,9-Trioxaundecanoic Acid DCHA.
In some embodiments the method of treatment or prevention of a human disorder depends upon the analog being synthesized. For instance: Peptides for triggering B and T cell activity can be used to treat autoimmune disease, including uveitis, collagen-induced, adjuvant and rheumatoid arthritis, thyroiditis, myasthenia gravis, multiple sclerosis and diabetes. Examples of these peptides are interleukins (referenced in Aulitzky, W E; Schuler, M; Peschel, C.; Huber, C.; Interleukins. Clinical pharmacology and therapeutic use. Drugs. 48(5):667-77, November 1994) and cytokines (referenced in Peters, M.; Actions of cytokines on the immune response and viral interactions: an overview. Hepatology. 23(4):909-16, April 1996).
Enkephlin analogs, agonist analogs and antagonist analogs can be used to treat AIDS, ARC, and cancer, pain modulation, Huntington's, Parkinson's diseases.
LHRH and analogs, agonists and antagonists can be used to treat prostatic tumors and reproductive physiopathology, including breast cancer, and infertility.
Peptides and peptidomimetics that target crucial enzymes, oncogenes or oncogene products, tumor-suppressor genes and their products, growth factors and their corresponding receptors can be used to treat cancer. Examples of these peptides are described in Unger, C. Current concepts of treatment in medical oncology: new anticancer drugs. Journal of Cancer Research & Clinical Oncology. 122(4):189-98, 1996.
Neuropeptide Y and other pancreatic polypeptides, and analogs, agonists and antagonists can be used to treat stress, anxiety, neurodegenerative diseases, depression and associated vasoconstrictive activities.
Gluco-incretins, including gastric inhibitory polypeptide, glucose-dependent insulinotropic polypeptide, PACAP/Glucagon and glucagon-like polypeptide-1 and 2 and analogs, agonists and antagonists can be used to treat Type II diabetic hyperglycaemia. Atrial natriuretic factor and analogs, agonists and antagonists can be used to treat congestive heart failure.
Integrin and analogs, agonists and antagonists can be used to treat osteoporosis, scar formation, bone synthesis, inhibition of vascular occlusion, and inhibition of tumor invasion and metastasis.
Glucagon, glucagon-like peptide 1, PACAP/Glucagon, and analogs, agonists and antagonists can be used to treat diabetes cardiovascular emergencies.
Antithrombotic peptides and analogs, agonists and antagonists can be used to treat cardiovascular and cerebrovascular diseases. Examples of these peptides RGD, D-Phe-Pro-Arg and others named are described in Ojima I.; Chakravarty S.; Dong Q. Antithrombotic agents: from RGD to peptide mimetics. Bioorganic & Medicinal Chemistry. 3(4):337-60, 1995.
Cytokines/interleukins and analogs, agonists and antagonists can be used to treat inflammatory disease, immune response dysfunction, hematopoiesis, mycosis fungoides, aplastic anemia, thrombocytopenia, and malignant melanoma. Examples of these peptides are Interleukins, referenced in Aulitzky et al. and Peters et al., which is herein incorporated by reference.
Endothelin and analogs, agonists and antagonists can be used to treat arterial hypertension, myocardial infarction, congestive heart failure, atherosclerosis, shock conditions, renal failure, asthma and vasospasm Natriuretic hormones and analogs, agonists and antagonists can be used to treat cardiovasicular disease and acute renal failure. Examples of these peptides are named and described in Espiner, E. A.; Richards, A. M.; Yandle, T. G.; Nicholls, M. G.; Natriuretic hormones. Endocrinology & Metabolism Clinics of North America. 24(3):481-509, 1995.
Peptides that activate or inhibit tyrosine kinase, or bind to TK-activating or inhibiting peptides and analogs, agonists and antagonists can be used to treat chronic myelogenous and acute lymphocytic leukemias, breast and ovarian cancers and other tyrosine kinase associated diseases. Examples of these peptides are described in Smithgall, T E.; SH2 and SH3 domains: potential targets for anti-cancer drug design. Journal of Pharmacological & Toxicological Methods. 34(3):125-32, 1995.
Renin inhibitors analogs, agonists and antagonists can be used to treat cardiovascular disease, including hypertension and congestive heart failure. Examples of these peptides are described in Rosenberg, S. H.; Renin inhibition. Cardiovascular Drugs & Therapy. 9(5):645-55, 1995.
Angiotensin-converting enzyme inhibitors, analogs, agonists and antagonists can be used to treat cardiovascular disease, including hypertension and congestive heart failure. Peptides that activate or inhibit tyrosine phosphorylases can be used to treat cardiovascular diseases. Examples of these peptides are described in Srivastava, A. K.; Protein tyrosine phosphorylation in cardiovascular system. Molecular & Cellular Biochemistry. 149-150:87-94, 1995.
Peptide based antivirals can be used to treat viral diseases. Examples of these peptides are described in Toes, R. E.; Feltkamp, M. C.; Ressing, M. E.; Vierboom, M. P.; Blom, R. J.; Brandt, R. M; Hartman, M.; Offringa, R.; Melief, C. J.; Kast, W. M.; Cellular immunity against DNA tumour viruses: possibilities for peptide-based vaccines and immune escape. Biochemical Society Transactions. 23(3):692-6, 1995.
Corticotropin releasing factor and peptide analogs, agonist analogs and antagonist analogs can be used to treat disease associated with high CRF, i.e Alzheimer's disease, anorexia nervosa, depressive disorders, arthritis, and multiple sclerosis.
Peptide agonist analogs and antagonist analogs of platelet-derived wound-healing formula (PDWHF) can be used as a therapy for donor tissue limitations and wound-healing constraints in surgery. Examples of these peptides are described in Rudkin, G. H.; Miller, T. A.; Growth factors in surgery. Plastic & Reconstructive Surgery. 97(2):469-76, 1996. Fibronectin, fibrinopeptide inhibitors and analogs, agonists and antagonists can be used to treat metastasis (i.e. enzyme inhibition, tumor cell migration, invasion, and metastasis).
Chemokine (types of cytokine, including interleukin-8, RANTES, and monocyte chemotactic peptide) analogs, agonist analogs and antagonist analogs can be used to treat arthritis, hypersensitivity, angiogenesis, renal disease, glomerulonephritis, inflammation, and hematopoiesis.
Neutral endopeptidase inhibitors analogs, agonist analogs and antagonist analogs can be used to treat hypertension and inflammation. Examples of these peptides are described in Gregoire, J. R; Sheps, S. G; Newer antihypertensive drugs. Current Opinion in Cardiology. 10(5):445-9, 1995.
Substance P analogs, agonist analogs and antagonist analogs can be used to treat immune system dysfunction, pain transmission/perception and in autonomic reflexes and behaviors. Alpha-melanocyte-stimulating hormone analogs, agonist analogs and antagonist analogs can be used to treat AIDS, rheumatoid arthritis, and myocardial infarction.
Bradykinin (BK) analogs, agonist analogs and antagonist analogs can be used to treat inflammatory diseases (edema, etc), asthma, allergic reactions (rhinitis, etc), anesthetic uses, and septic shock.
Secretin analogs can be used to treat cardiovascular emergencies.
GnRH analogs, agonist analogs and antagonist analogs can be used to treat hormone-dependent breast and prostate tumors.
Somatostatin analogs, agonist analogs and antagonist analogs can be used to treat gut neuroendocrine tumors.
Gastrin, Gastrin Releasing Peptide analogs, agonist analogs and antagonist analogs can be used as an adjuvant to chemotherapy or surgery in small cell lung cancer and other malignancies, or to treat allergic respiratory diseases, asthma and allergic rhinitis.
Laminin analogs, agonist analogs and antagonist analogs, the Laminin derivative antimetastatic drug YIGSR analogs, Laminin-derived synthetic peptides analogs, agonist analogs and antagonist analogs can be used to treat tumor cell growth, angiogenesis, regeneration studies, vascularization of the eye with diabetes, and ischemia. The peptides of this category can inhibit the tumor growth and metastasis of leukemic cells and may be useful as a potential therapeutic reagent for leukemic infiltrations. Peptides containing this sequence also inhibit experimental metastasis. Exemplary references include McGowan K A. Marinkovich M P Laminins and human disease. Microscopy Research & Technique. 51(3):262-79, Nov. 1, 2000; Yoshida N. Ishii E. Nomizu M. Yamada Y. Mohri S. Kinukawa N. Matsuzaki A. Oshima K. Hara T. Miyazaki S. The laminin-derived peptide YIGSR (Tyr-Ile-Gly-Ser-Arg) inhibits human pre-B leukemic cell growth and dissemination to organs in SCID mice. British Journal of Cancer. 80(12): 1898-904, 1999. Examples of these peptides are also described in Kleinman, H. K.; Weeks, B. S.; Schnaper, H. W.; Kibbey, M. C.; Yamamura, K.; Grant, D. S; The laminins: a family of basement membrane glycoproteins important in cell differentiation and tumor metastases. Vitamins & Hormones. 47:161-86, 1993.
Defensins, corticostatins, dermaseptins, mangainins, and other antibiotic (antibacterial and antimicrobial) peptides analogs, agonist analogs and antagonist analogs can be used to treat infections, tissue inflammation and endocrine regulation.
Vasopressin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, stress and Diabetes insipidus.
Oxytocin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders and to induce labor.
ACTH-related peptides and analogs, agonist analogs and antagonist analogs can be used as neurotrophic, neuroprotective, and peripheral demyelinating neuropathy agents. Amyloid-beta peptide analogs, agonist analogs and antagonist analogs can be used to treat Alzheimer's disease.
Epidermal growth factor, receptor analogs, agonist analogs and antagonist analogs can be used to treat necrotizing enterocolitis, Zollinger-Ellison syndrome, gastrointestinal ulceration, colitis, and congenital microvillus atrophycarcinomas.
Leukocyte adhesion molecule analogs, agonist analogs and antagonist analogs can be used to treat atherosclerosis, inflammation. Examples of these peptides are described in Barker, J. N.; Adhesion molecules in cutaneous inflammation. Ciba Foundation Symposium. 189:91-101.
Major histocompatibility complex (MHC) analogs, agonist analogs and antagonist analogs can be used to treat autoimmune, immunodysfunctional, immuno modulatory diseases and as well as used for their corresponding therapies. Examples of these peptides are described in Appella, E.; Padlan, E. A.; Hunt, D. F; Analysis of the structure of naturally processed peptides bound by class I and class II major histocompatibility complex molecules. EXS. 73:105-19, 1995.
Corticotropin releasing factor analogs can be used to treat neurological disorders.
Neurotrophins (including brain-derived neurotrophic factor (BDNF), nerve growth factor, and neurotrophin 3) analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders.
Cytotoxic T-cell activating peptide analogs, agonist analogs and antagonist analogs can be used to treat infectious diseases and cancer. Examples of these peptides are described in: Chesnut R. W.; Sette, A.; Celis, E.; Wentworth, P.; Kubo, R. T.; Alexander, J.; Ishioka, G.; Vitiello, A.; Grey, H. M; Design and testing of peptide-based cytotoxic T-cell-mediated immunotherapeutics to treat infectious diseases and cancer. Pharmaceutical Biotechnology. 6:847-74, 1995.
Peptide immunogens for prevention of HIV-1 and HTLV-I retroviral infections can be used to treat AIDS. Examples of these peptides are described in Hart, M. K.; Palker, T. J.; Haynes, B F; Design of experimental synthetic peptide immunogens for prevention of HIV-1 and HTLV-I retroviral infections. Pharmaceutical Biotechnology. 6:821-45, 1995.
Galanin analogs, agonist analogs and antagonist analogs can be used to treat Alzheimer's disease, depression, eating disorders, chronic pain, prevention of ischemic damage, and growth hormone modulation.
Tachykinins (neurokinin A and neurokinin B) analogs, agonist analogs and antagonist analogs can be used to treat pain transmission/perception and in autonomic reflexes and behaviors.
RGD containing peptide analogs can be used to treat various diseases involved with cell adhesion, antithrombotics, and acute renal failure.
Osteogenic growth peptide analogs, agonist analogs and antagonist analogs can be used as treatment of systemic bone loss. Examples of these peptides are described in Bab IA. Regulatory role of osteogenic growth peptide in proliferation, osteogenesis, and hemopoiesis. Clinical Orthopaedics & Related Research. (313):64-8, 1995.
Parathyroid hormone, parathyroid hormone related-peptide analogs, agonist analogs and antagonist analogs can be used to treat diseases affecting calcium homeostasis (hypercalcemia), bone metabolism, vascular disease, and atherosclerosis.
Kallidin analogs, agonist analogs and antagonist analogs can be used to treat tissue injury or inflammation and pain signaling pathological conditions of the CNS.
T cell receptor peptide analogs, agonist analogs and antagonist analogs can be used in immunotherapy. Examples of these peptides are described in Brostoff, S W; T cell receptor peptide vaccines as immunotherapy. Agents & Actions—Supplements. 47:53-8, 1995.
Platelet-derived growth factor (PDGF) analogs, agonist analogs and antagonist analogs can be used to treat non-neoplastic hyperproliferative disorders, therapy for donor tissue limitations and wound-healing constraints in surgery.
Amylin, calcitonin gene related peptides (CGRP) analogs, agonist analogs and antagonist analogs can be used to treat insulin-dependent diabetes.
VIP analogs, agonist analogs and antagonist analogs can be used to treat allergic respiratory diseases, asthma and allergic rhinitis, and nervous control of reproductive functions.
Growth hormone-releasing hormone (GHRH) analogs, agonist analogs and antagonist analogs can be used to treat growth hormone deficiency and immunomodulation.
HIV protease inhibiting peptide analogs, agonist analogs and antagonist analogs can be used to treat AIDS. Examples of these peptides are described in Bugelski, P. J.; Kirsh, R.; Hart, T. K; HIV protease inhibitors: effects on viral maturation and physiologic function in macrophages. Journal of Leukocyte Biology. 56(3):374-80, 1994.
Thymopoietin active fragment peptides analogs, agonist analogs and antagonist analogs can be used to treat rheumatoid arthritis and virus infections.
Cecropins analogs, agonist analogs and antagonist analogs can be used as antibacterials.
Thyroid releasing hormone (TRH) analogs, agonist analogs and antagonist analogs can be used to treat spinal cord injury and shock.
Erythropoietin (EPO) analogs, agonist analogs and antagonist analogs can be used to treat anemia.
Fibroblast growth factor (FGF), receptor analogs, agonist analogs and antagonist analogs can be as stimulation of bone formation, as well as used as a treatment for Kaposi's sarcoma, neuron regeneration, prostate growth, tumor growth inhibition, and angiogenesis.
Stem cell factor analogs, agonist analogs and antagonist analogs can be used to treat anemias. GP120, GP160, CD4 fragment peptides analogs, agonist analogs and antagonist analogs can be used to treat HIV and AIDS.
Insulin-like growth factor (IGF) analogs, agonist analogs and antagonist analogs, and IGF receptor analogs, agonist analogs and antagonist analogs can be used to treat breast and other cancers, noninsulin-dependent diabetest mellitus, cell proliferation, apoptosis, hematopoiesis, HIV, AIDS, growth disorders, osteoporosis, and insulin resistance.
Colony stimulating factors (granulocyte-macrophage colony-stimulating factor (GMCSF), granulocyte colony-stimulating factor (GCSF), and macrophage colony-stimulating factor (MCSF) analogs, agonist analogs and antagonist analogs can be used to treat anemias.
Kentsin analogs, agonist analogs and antagonist analogs can be used for immunomodulation.
Lymphocyte activating peptide (LAP) analogs, agonist analogs and antagonist analogs can be used for immunomodulation. Examples of these peptides are described in Loleit, M.; Deres, K.; Wiesmuller, K. H.; Jung, G.; Eckert, M.; Bessler, W. G; Biological activity of the Escherichia coli lipoprotein: detection of novel lymphocyte activating peptide segments of the molecule and their conformational characterization. Biological Chemistry Hoppe-Seyler. 375(6):407-12, June 1994.
Tuftsin analogs, agonist analogs and antagonist analogs can be used for immunomodulation.
Prolactin analogs, agonist analogs and antagonist analogs can be used to treat rheumatic diseases, systemic lupus erythematosus, and hyperprolactemia.
Angiotensin II analogs, agonist analogs and antagonist analogs and Angiotensin II receptor(s) analogs, agonist analogs and antagonist analogs can be used to treat hypertension, hemodynamic regulation, neurological disorders, diabetic nephropathies, aortoarterities induced RVH, hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus and thyroid dysfunction.
Dynorphin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, pain management, algesia, spinal cord injury and epilepsy.
Calcitonin analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, immune system dysfunction, calcium homeostasis, and osteoporosis.
Pituitary adenylate cyclase activating polypeptide analogs, agonist analogs and antagonist analogs may modulate growth, signal transduction vasoactivity roles.
Cholecystokinin analogs, agonist analogs and antagonist analogs can be used to treat feeding disorders, panic disorders, and anti-opioid properties.
Pepstatin analogs, agonist analogs and antagonist analogs can be used as pepsin and HIV protease inhibitors (AIDS).
Bestatin analogs, agonist analogs and antagonist analogs can be used to treat muscular dystrophy, anticancer, antileukemia, immune response modulator, and acute non-lymphocytic leukemia.
Leupeptin analogs, agonist analogs and antagonist analogs can be used as a protease inhibitor, exact role in diseases not determined yet.
Luteinizing hormone and releasing hormone analogs, agonist analogs and antagonist analogs can be used as a infertility male contraceptive.
Neurotensin analogs, agonist analogs and antagonist analogs can be used, e.g., as antipsychotic, analgesic, anti-cancer, and/or neuroprotective agents, e.g., for treating stroke victims, e.g., by inducing hypothermia so as to provide neuroprotection.
Motilin analogs, agonist analogs and antagonist analogs can be used for the control of gastric emptying.
Insulin analogs, agonist analogs and antagonist analogs can be used to treat diabetes.
Transforming growth factor (TGF) analogs, agonist analogs and antagonist analogs can be used for cell proliferation and differentiation, cancer treatment, immunoregulation, therapy for donor tissue limitations, and wound-healing constraints in surgery.
Bone morphogenetic proteins (BMPs) analogs, agonist analogs and antagonist analogs can be used as therapy for donor tissue limitations, osteogenesis, and wound-healing constraints in surgery.
Bombesin and Enterostatin analogs, agonist analogs and antagonist analogs can be used to prevent the proliferation of tumor cells, modulation of feeding, and neuroendocrine functions. These peptides fall within a supercategory of the neuromedins described above. These peptides are described in such exemplary references as Yamada K. Wada E. Wada K. Bombesin-like peptides: studies on food intake and social behaviour with receptor knock-out mice. Annals of Medicine. 32(8):519-29, November 2000; Ohki-Hamazaki H. Neuromedin B. Progress in Neurobiology. 62(3):297-312, October 2000; Still CD. Future trends in weight management. Journal of the American Osteopathic Association. 99(10 Su Pt 2):518-9, 1999; Martinez V. Tache Y. Bombesin and the brain-gut axis. Peptides. 21(11):1617-25, 2000; Afferent signals regulating food intake. Proceedings of the Nutrition Society. 59(3):373-84, 2000; Takenaka Y. Nakamura F. Jinsmaa Y. Lipkowski A W. Yoshikawa M. Enterostatin (VPDPR) has anti-analgesic and anti-amnesic activities. Bioscience Biotechnology & Biochemistry. 65(1):236-8, 2001 J.
Glucagon, glucagon-like peptide 1 analogs, agonist analogs and antagonist analogs can be used to treat diabetes cardiovascular emergencies.
Pancreastatin, chromogranins A, B and C analogs, agonist analogs and antagonist analogs—conditions associated with inhibition of insulin secretion, exocrine pancreatic secretion and gastric acid secretion, and stimulation of secretion.
Endorphins analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, alleviating pain, treatment of opioid abuse, obesity, and diabetes. Examples of these peptides are named and described in Dalayeun, J. F.; Nores, J. M.; Bergal, S.; Physiology of beta-endorphins. A close-up view and a review of the literature. Biomedicine & Pharmacotherapy. 47(8):311-20, 1993.
Miscellaneous opioid peptides analogs, agonist analogs and antagonist analogs, including (but not limited to) adrenal peptide E analogs, alpha casein fragment analogs, beta casomorphin analogs, dermorphin analogs, kyotorphin analogs, metophamide neuropeptide FF (NPFF) analogs, melanocyte inhibiting factor analogs, agonist analogs and antagonist analogs can be used to treat neurological disorders, alleviating pain, as well as for the treatment of opioid abuse.
Vasotocin analogs, agonist analogs and antagonist analogs can be used for sleep disorders including but not limited to insomnia.
Protein kinase C and inhibitors analogs, agonist analogs and antagonist analogs can be used to treat cancer, apoptosis, smooth muscle function, and Alzheimer's disease. Examples of these peptides are named and described in Philip, P. A.; Harris, A. L; Potential for protein kinase C inhibitors in cancer therapy. Cancer Treatment & Research. 78:3-27, 1995.
Amyloid, amyloid fibrin, analogs, agonist analogs and antagonist analogs can be used to treat neurodegenerative diseases and diabetes.
Calpain and other calmodulin-inhibitory protein analogs, agonist analogs and antagonist analogs can be used to treat neurodegenerative disorders, cerebral ischaemia, cataracts, myocardial ischaemia, muscular dystrophy and platelet aggregation.
Charybdotoxin and Apamin analogs, agonist analogs and antagonist analogs can be used for treatment of neurodegenerative diseases and pain and cerebral ischemia.
Phospholipase A2 analogs, agonist analogs and antagonist analogs and Phospholipase A2 receptor inhibiting/activating peptides analogs, agonist analogs and antagonist analogs can be used to treat acute pancreatitis, pancreatic cancer, abdominal trauma, and inflammation, e.g., sepsis, infections, acute pancreatitis, various forms of arthritis, cancer, complications of pregnancy, and postoperative states.
Potassium channel activating and inhibiting analogs, agonist analogs and antagonist analogs can be used to treat various diseases. Examples of these peptides are described in Edwards, G.; Weston, A. H; Pharmacology of the potassium channel openers. Cardiovascular Drugs & Therapy. 9 Suppl 2:185-93, March 1995.
IgG activators, inhibitors analogs, agonist analogs and antagonist analogs can be used to treat autoimmune diseases and immune dysfunctions. Examples of these peptides are described in Mouthon, L.; Kaveri, S. V.; Spalter, S. H.; Lacroix-Desmazes, S.; Lefranc, C.; Desai, R.; Kazatchkine, M. D; Mechanisms of action of intravenous immune globulin in immune-mediated diseases. Clinical & Experimental Immunology. 104 Suppl 1:3-9, 1996.
Endotoxin and inhibitor analogs, agonist analogs and antagonist analogs can be used for decreasing cardiac output, systemic hypotension, decreased blood flow and O₂delivery to tissues, intense pulmonary vasoconstriction and hypertension, bronchoconstriction, increased permeability, pulmonary oedema, ventilation-to-perfusion inequalities, hypoxaemia, and haemoconcentration. Examples of these peptides are named and described in Burrell, R; Human responses to bacterial endotoxin. Circulatory Shock. 43(3):137-53, July 1994.
Orphan receptor ligand analogs, agonist analogs and antagonist analogs (including but not limited to ADNF, Adrenomedullin, Apelin, Ghrelin, Mastoparan (MCD peptides), Melanin concentrating hormone, Nociceptin/Nocistatin, Orexin, Receptor activity modulating protein, Urotensin) can be used to treat obesity, weight problems, neuropathy, sleep deprivation, sleep disorder including insomnia, and lung cell repair. These orphan receptor ligands are described in such references as In DS. Orphan G protein-coupled receptor s and beyond. Japanese Journal of Pharmacology. 90(2): 101-6, 2002; Maguire J J. Discovering orphan receptor function using human in vitro pharmacology. Current Opinion in Pharmacology. 3(2):135-9, 2003; Szekeres P G. Functional assays for identifying ligands at orphan G protein-coupled receptors. Receptor s & Channels. 8(5-6):297-308, 2002; Shiau A K. Coward P. Schwarz M. Lehmann J M. Orphan nuclear receptor s: from new ligand discovery technologies to novel signaling pathways. Current Opinion in Drug Discovery & Development. 4(5):575-90, 2001; Civelli O. Nothacker H P. Saito Y. Wang Z. Lin S H. Reinscheid R K. Novel neurotransmitters as natural ligands of orphan G-protein-coupled receptor s. Trends in Neurosciences. 24(4):230-7, 2001; Darland T. Heinricher M M. Grandy D K. Orphan in F Q/nociceptin: a role in pain and analgesia, but so much more. Trends in Neurosciences. 21(5):215-21, 1998, the disclosures of which are incorporated herein by reference.
Another embodiment of the invention includes analogs of Glycoprotein IIb/IIIa inhibitors. The central role of platelet-rich thrombus in the pathogenesis of acute coronary syndromes (ACSs) is well-known. Glycoprotein IIb/IIIa (Gp IIb/IIIa) receptor analogs, agonist analogs and antagonist analogs can be used as potent modulators of platelet function that may be expected to affect favorably the natural history of ACSs. Exemplary references for this category include Bhatt D L. Topol E J. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. JAMA. 284(12):1549-58, 2000; Kereiakes D J. Oral blockade of the platelet glycoprotein IIb/IIIa receptor: fact or fancy?. American Heart Journal. 138(1 Pt 2):S39-46, 1999; Bassand J P. Low-molecular-weight heparin and other antithrombotic agents in the setting of a fast-track revascularization in unstable coronary artery disease. Haemostasis. 30 Suppl 2:114-21; discussion 106-7, 2000.
Apo-lipoprotein A-I analogs, agonist analogs and antagonist analogs may increase the HDL levels of subjects upon administration. Analogs of the present invention that are homologous to Apo-lipoprotein A-I may be useful to treat or prevent liver disease and inflammatory diseases including but not limited to artherosclerosis. Analogs of the present invention that are homologous to Apo-lipoprotein A-I may be useful to increase the amount of formation of pre-β1 HDL in human plasma.
The cytokine analogs of the present invention may treat or prevent autoimmune disease, inflammatory disease, and dysfunctional growth or differentiation of cells such as cellular proliferative disorders, the development of neoplasia, tumors, and cancer.
The present invention provides for the use of an antibody or binding composition which specifically binds to a specified analog. in some embodiments the antibody specifically binds the analog derived from a mammalian polypeptide, e.g., a polypeptide derived from a primate, human, cat, dog, rat, or mouse. Antibodies can be raised to various analogs, including individual, polymorphic, allelic, strain, or species variants, and fragments thereof, both in their naturally occurring (full-length) forms or in their synthetic forms. Additionally, antibodies can be raised to the analogs in their inactive state or active state. Anti-idiotypic antibodies may also be used.
A number of immunogens may be selected to produce antibodies specifically reactive with ligand or receptor proteins. Synthetic analogs may serve as an immunogen for the production of monoclonal or polyclonal antibodies. Such antibodies may be used as antagonists or agonists for their targets modulating the disease state associated with the naturally occurring proteins and analogs listed above. Synthetic polypeptides of the claimed invention may also be used either in pure or impure form. Synthetic peptides, made using the appropriate protein sequences, may also be used as an immunogen for the production of antibodies. Naturally folded or denatured material can be used, as appropriate, for producing antibodies. Either monoclonal or polyclonal antibodies may be generated, e.g., for subsequent use in immunoassays to measure the protein, or for immunopurification methods. Methods of producing polyclonal antibodies are well known to those of skill in the art.
Typically, an immunogen, such as a purified analog of the invention, is mixed with an adjuvant and animals are immunized with the mixture. The animal's immune response to the immunogen preparation is monitored by taking test bleeds and determining the titer of reactivity to the protein of interest. For example, when appropriately high titers of antibody to the immunogen are obtained, usually after repeated immunizations, blood is collected from the animal and antisera are prepared. Further fractionation of the antisera to enrich for antibodies reactive to the protein can be performed if desired. See, e.g., Harlow and Lane; or Coligan. Immunization can also be performed through other methods, e.g., DNA vector immunization. See, e.g., Wang, et al. (1997) Virology 228:278-284.
Monoclonal antibodies may be obtained by various techniques familiar to researchers skilled in the art. Typically, spleen cells from an animal immunized with a desired analog are immortalized, commonly by fusion with a myeloma cell. See, Kohler and Milstein (1976) Eur. J. Immunol. 6:511-519. Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. See, e.g., Doyle, et al. (eds. 1994 and periodic supplements) Cell and Tissue Culture: Laboratory Procedures, John Wiley and Sons, New York, N.Y. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. Alternatively, one may isolate DNA sequences which encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells according, e.g., to the general protocol outlined by Huse, et al. (1989) Science 246:1275-1281.
Antibodies or binding compositions, including binding fragments, single chain antibodies, F_v, F_ab, single domain V_H, disulfide-bridged F_v, single-chain F_vor F(_ab′)₂fragments of antibodies, diabodies, and triabodies against predetermined fragments of the analogs can be raised by immunization of animals with analogs or conjugates of analogs or receptor proteins with carrier proteins. Monoclonal antibodies are prepared from cells secreting the desired antibody. These antibodies can be screened for binding to analogs described herein. These monoclonal antibodies will usually bind with at least a K_Dof about 1 mM, usually at least about 300 μM, typically at least about 10 μM, at least about 30 μM, at least about 10 μM, and at least about 3 μM or more. These antibodies can be screened for binding to the naturally occurring polypeptides upon which the analogs are derived.
In some instances, it is desirable to prepare monoclonal antibodies (mAbs) from various mammalian hosts, such as mice, rodents, primates, humans, etc. Description of techniques for preparing such monoclonal antibodies may be found in, e.g., Stites, et al. (eds.) Basic and Clinical Immunology, 4th ed., Lange Medical Publications, Los Altos, Calif., and references cited therein; Harlow and Lane (1988) Antibodies: A Laboratory Manual CSH Press; Goding (1986) Monoclonal Antibodies: Principles and Practice, 2nd ed., Academic Press, New York, N.Y.; and particularly in Kohler and Milstein (1975) Nature 256:495-497, which discusses one method of generating monoclonal antibodies. Summarized briefly, this method involves injecting an animal with an analog described herein. The animal is then sacrificed and cells taken from its spleen, which are then fused with myeloma cells. The result is a hybrid cell or “hybridoma” that is capable of reproducing in vitro. The population of hybridomas is then screened to isolate individual clones, each of which secrete a single antibody species to the analog. In this manner, the individual antibody species obtained are the products of immortalized and cloned single B cells from the immune animal generated in response to a specific site recognized on the immunogenic substance.
Other suitable techniques involve selection of libraries of antibodies in phage or similar vectors. See, e.g., Huse, et al. (1989) Science 246:1275-1281; and Ward, et al. (1989) Nature 341:544-546. The polypeptides and antibodies of the present invention may be used with or without modification, including chimeric or humanized antibodies. Frequently, the polypeptides and antibodies will be labeled by joining, either covalently or non-covalently, a substance which provides for a detectable signal. A wide variety of labels and conjugation techniques are known and are reported extensively in both the scientific and patent literature. Suitable labels include radionuclides, enzymes, substrates, cofactors, inhibitors, fluorescent moieties, chemiluminescent moieties, magnetic particles, and the like. Patents teaching the use of such labels include U.S. Pat. Nos. 3,817,837; 3,850,752; 3,939,350; 3,996,345; 4,277,437; 4,275,149; and 4,366,241. Also, recombinant immunoglobulins may be produced, see, Cabilly, U.S. Pat. No. 4,816,567; and Queen, et al. (1989) Proc. Nat'l Acad. Sci. USA 86:10029-10033; or made in transgenic mice, see Mendez, et al. (1997) Nature Genetics 15:146-156; also see Abgenix and Medarex technologies.
The instant invention is related to pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom that comprise analogs that comprise isotopes. In some embodiments, the compositions of the claimed invention may contain any isotope described in Cyr and Pearson (Stabilization of radiopharmaceutical compositions using hydrophilic thioethers and hydrophilic 6-hydroxy chromans Cyr, John E.; Pearson, Daniel A. (Diatide, Inc., USA). PCT Int. Appl. (2002), WO 200260491 A2 20020808), which is herein incorporated by reference. In some embodiments the compositions of the invention comprise analog that comprise one or more of the following isotopes: ¹²⁵I, ¹³¹I, ²¹¹At, ⁴⁷Sc, ⁶⁷Cu, ⁷²Ga, ⁹⁰Y, ¹⁵³Sm, ¹⁵⁹Gd, ¹⁶⁵Dy, ¹⁶⁶Ho, ¹⁷⁵Yb, ¹⁷⁷Lu, ²¹²Bi, ²¹³Bi, ⁶⁸Ga, ⁹⁹Tc, ¹¹¹In, ¹²³I, and ³H.
The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a liquid or solid dosage form. Such compositions may include any type of dosage form such as tablets, capsules, powders, liquid formulations, delayed or sustained release, patches, snuffs, nasal sprays and the like. The formulations may additionally include other ingredients such as dyes, preservatives, buffers and anti-oxidants, for example The physical form and content of the pharmaceutical formulations contemplated are conventional preparations that can be formulated by those skilled in the pharmaceutical formulation field and are based on well established principles and compositions described in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition, 1995; British Pharmacopoeia 2000, each of which is incorporated herein by reference. The compositions of the present invention may also include other active agents useful in the treatment of cardiovascular conditions. Solid forms can be prepared according to any means suitable in the art. For example, capsules are prepared by mixing the analog composition with a suitable diluent and filling the proper amount of the mixture in capsules. Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants and disintegrators as well as the compound. Diluents, but are not limited to, include various types of starch, cellulose, crystalline cellulose, microcrystalline cellulose, lactose, fructose, sucrose, mannitol or other sugar alcohols, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Non-limiting examples of tablet binders include, but are not limited to, starches, gelatin and sugars such as lactose, fructose, glucose and the like. Natural and synthetic gums are also convenient, including, but are not limited to, acacia, alginates, methylcellulose, polyvinylpyrrolidone and the like. Polyethylene glycol, ethylcellulose and waxes can also serve as binders.
A lubricant can be used in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant include, but are not limited to, such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.
Tablets can be coated with sugar as a flavor and sealant, or with film-forming protecting agents to modify the dissolution properties of the tablet. The compounds may also be formulated as chewable tablets, by using large amounts of pleasant-tasting substances such as mannitol in the formulation, as is now well-established in the art.
Also contemplated are liquid formulations and solid form preparations which are intended to be converted, shortly before use, to liquid form preparations. Such liquid forms include, but are not limited to, solutions, suspensions, syrups, slurries, and emulsions. Liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats or oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). These preparations may contain, in addition to the active agent, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. The compositions may be in powder form for constitution with a suitable vehicle such as sterile water, saline solution, or alcohol, before use. Preparations may also contain mucosal enhancers.
In some embodiments, the oral transmucosal solid dosage further comprises a permeation enhancer. In some embodiments, the permeation enhancer is chosen from: a bile salt, sodium dodecyl sulfate, dimethyl sulfoxide, sodium lauryl sulfate, a derivative of a saturated or a unsaturated fatty acid, a surfactant, a bile salt analog, and a derivative of a bile salt. In some embodiments the oral transmucosal dosage form is chosen from: a chewing gum, a patch, a lozenge, a lozenge-on-a-handle, a tablet, a troche, a pastille, a sachet, a sublingual tablet, and a rapid disintegrating tablet. In some embodiments, the oral transmucosal solid dosage form of wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, lubricating agent, diluent, base, or buffering agent. In some embodiments, the oral transmucosal solid dosage form further comprises a sustained release agent. The invention is directed to an oral transmucosal solid dosage form comprising from wherein the concentration of analog is from about 0.01% to about 90% of the dry matter weight of the composition.
Solid dosage forms such as lozenges and tablets may also be used for oral transmucosal delivery of pharmaceuticals. For example, nitroglycerin sublingual tablets have been on the market for many years. The sublingual tablets are designed to deliver small amounts of the potent nitroglycerin, which is almost immediately dissolved and absorbed. On the other hand, most lozenges or tablets are typically designed to dissolve in the mouth over a period of at least several minutes which allows extended dissolution of the lozenge and absorption of the drug.
Administration of lozenges or sublingual tablets generally utilize an “open” delivery system, in which the drug delivery conditions are influenced by the conditions of the surrounding environment, such as rate of saliva secretion, pH of the saliva, or other conditions beyond the control of the formulation.
A lozenge-on-a-handle (similar to a lollipop) is another dosage form suitable for transmucosal drug delivery. In addition to being non-invasive and providing a particularly easy method of delivery, the lozenge-on-a-handle (or lozenge with an integrated oral transmucosal applicator) dosage form allows a patient or caregiver to move the dosage form in and out of the mouth to titrate the dose. This practice is called dose-to-effect, in which a patient or caregiver controls the administration of the dose until the expected therapeutic effect is achieved. This is particularly important for certain symptoms, such as pain, nausea, motion sickness, and premedication prior to anesthesia because each patient needs a different amount of medication to treat these symptoms. For these types of treatments, the patient is the only one who knows how much medication is enough. Once the appropriate amount of drug is delivered, the patient or caregiver can remove the lozenge-on-a-handle, thus, stopping delivery of the drug. This feature is especially important for particularly potent drugs, which may present a significant advantage of terminating drug administration once the desired effect is achieved.
As used herein, the term “oral transmucosal delivery” (OTD) refers to the delivery of a pharmaceutical agent across a mucous membrane in the oral cavity, pharyngeal cavity, or esophagus, and may be contrasted, for example, with traditional oral delivery, in which absorption of the drug occurs in the intestines. Accordingly, routes of administration in which the pharmaceutical agent is absorbed through the buccal, sublingual, gingival, pharyngeal, and/or esophageal mucosa are all encompassed within “oral transmucosal delivery,” as that term is used herein. Oral transmucosal delivery involves the administration of an oral transmucosal solid dosage form to the oral cavity of a patient, which is held in the oral cavity and dissolved, thereby releasing the pharmaceutical agent for oral transmucosal delivery. Of course, as the solid dosage form dissolves in the oral cavity, some of the saliva containing the pharmaceutical agent may be swallowed, and a portion of the drug may ultimately be absorbed from the intestines.
The compositions of the invention can be administered in a sustained release composition, such as those described in, for example, U.S. Pat. Nos. 5,672,659 and 5,595,760, and herein incorporate by reference. The use of immediate or sustained release compositions depends on the type of condition being treated.
The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for inducing or increasing the naturally occurring biological activity of the wild-type polypeptide upon which the analog is derived. The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for inducing or increasing the naturally occurring biological activity of the wild-type secretin polypeptide upon which the analog is derived. The pharmaceutical compositions of the instant invention or the pharmaceutical acceptable salts derived therefrom may be in a dosage amount in an effective amount for increasing the half-life of the composition when administered to a human being or other subject. In some embodiments the secretin analog is VIP.
The present invention also encompasses methods of using the compositions comprising a VIP analog. Any of these methods may involve the administration of a pharmaceutical composition comprising a VIP analog wherein the VIP analog is in a therapeutically effective dose. Any of these methods may involve the administration of a pharmaceutical composition comprising a VIP analog wherein the VIP analog is selective for VPAC1, VPAC2, PAC1, VIPR1, or VIPR2. The composition comprising an analog of the invention produces a broad range of activities, depending on the dosage administered. The present invention encompasses methods of treating or preventing pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction comprising administering to at least one patient in need thereof, mammal in need thereof or human in need thereof a composition or pharmaceutical composition comprising a secretin family analog in a therapeutically effective amount. The compositions of the invention may also be used at lower doses in order to prevent pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. The compositions of the invention may also be used to prevent pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject susceptible to those indications. In some embodiments, the method of prevention comprising administering the composition or pharmaceutical compositions of the invention after the subject is tested for susceptibility or genetic propensity for developing the disease, indication or disorder.
The pharmaceutical composition comprising a pharmaceutically acceptable carrier/diluent and an analog comprising an α-amino acid and at least one β-amino acid may be formulated by one having ordinary skill in the art with compositions selected depending upon the chosen mode of administration. Suitable pharmaceutical carriers are described in the most recent edition of Remington's Pharmaceutical Sciences, A. Osol, a standard reference text in this field, which is incorporated herein in its entirety.
For parenteral administration, analog can be, for example, formulated as a solution, suspension, emulsion or lyophilized powder in association with a pharmaceutically acceptable parenteral vehicle. Examples of such vehicles are water, saline, Ringer's solution, dextrose solution, and 5% human serum albumin Liposomes and nonaqueous vehicles such as fixed oils may also be used. The vehicle or lyophilized powder may contain additives that maintain isotonicity (e.g., sodium chloride, mannitol) and chemical stability (e.g., buffers and preservatives). The formulation is sterilized by commonly used techniques. For example, a parenteral composition suitable for administration by injection is prepared by dissolving 1.5% by weight of analog in 0.9% sodium chloride solution.
The present invention relates to routes of administration include intramuscular, sublingual, intravenous, intraperitoneal, intrathecal, intravaginal, intraurethral, intradermal, intrabuccal, via inhalation, via nebulizer and via subcutaneous injection. Alternatively, the pharmaceutical composition may be introduced by various means into cells that are removed from the individual. Such means include, for example, microprojectile bombardment and liposome or other nanoparticle device.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In solid dosage forms, the analogs are generally admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, starch, or other generally regarded as safe (GRAS) additives. Such dosage forms can also comprise, as is normal practice, an additional substance other than an inert diluent, e.g., lubricating agent such as magnesium state. With capsules, tablets, and pills, the dosage forms may also comprise a buffering agent. Tablets and pills can additionally be prepared with enteric coatings, or in a controlled release form, using techniques know in the art.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions and syrups, with the elixirs containing an inert diluent commonly used in the art, such as water. These compositions can also include one or more adjuvants, such as wetting agent, an emulsifying agent, a suspending agent, a sweetening agent, a flavoring agent or a perfuming agent.
In another embodiment of the invention the composition of the invention is used to treat a patient suffering from, or susceptible to, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject. In some embodiments, the invention relates to compositions comprising a secretin family analog for treatment or prevention of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small lung cell cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments, the secretin family analog of the invention comprises an analog of VIP.
One of skill in the art will recognize that the appropriate dosage of the compositions and pharmaceutical compositions may vary depending on the individual being treated and the purpose. For example, the age, body weight, and medical history of the individual patient may affect the therapeutic efficacy of the therapy. Further, a lower dosage of the composition may be needed to produce a transient cessation of symptoms, while a larger dose may be needed to produce a complete cessation of symptoms associated with the disease, disorder, or indication. A competent physician can consider these factors and adjust the dosing regimen to ensure the dose is achieving the desired therapeutic outcome without undue experimentation. It is also noted that the clinician and/or treating physician will know how and when to interrupt, adjust, and/or terminate therapy in conjunction with individual patient response. Dosages may also depend on the strength of the particular analog chosen for the pharmaceutical composition.
The dose of the composition or pharmaceutical compositions may vary. The dose of the composition may be once per day. In some embodiments, multiple doses may be administered to the subject per day. In some embodiments, the total dosage is administered in at least two application periods. In some embodiments, the period can be an hour, a day, a month, a year, a week, or a two-week period. In an additional embodiment of the invention, the total dosage is administered in two or more separate application periods, or separate doses.
In some embodiments, subjects can be administered the composition in which the composition is provided in a daily dose range of about 0.0001 mg/kg to about 5000 mg/kg of the weight of the subject. The dose administered to the subject can also be measured in terms of total amount of analog administered per day. In some embodiments, a subject is administered from about 0.001 to about 3000 milligrams of analog per day. In some embodiments, a subject is administered up to about 2000 milligrams of analog per day. In some embodiments, a subject is administered up to about 1800 milligrams of analog per day. In some embodiments, a subject is administered up to about 1600 milligrams of analog per day. In some embodiments, a subject is administered up to about 1400 milligrams of analog per day. In some embodiments, a subject is administered up to about 1200 milligrams of analog per day. In some embodiments, a subject is administered up to about 1000 milligrams of analog per day. In some embodiments, a subject is administered up to about 800 milligrams of analog per day. In some embodiments, a subject is administered from about 0.001 milligrams to about 700 milligrams of analog per dose. In some embodiments, a subject is administered up to about 700 milligrams of analog per dose. In some embodiments, a subject is administered up to about 600 milligrams of analog per dose. In some embodiments, a subject is administered up to about 500 milligrams of analog per dose. In some embodiments, a subject is administered up to about 400 milligrams of analog per dose. In some embodiments, a subject is administered up to about 300 milligrams of secretin analog per dose. In some embodiments, a subject is administered up to about 200 milligrams of analog per dose. In some embodiments, a subject is administered up to about 100 milligrams of analog per dose. In some embodiments, a subject is administered up to about 50 milligrams of analog per dose.
In some embodiments, subjects can be administered the composition in which the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dose range of about 0.0001 mg/kg to about 5000 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 450 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 400 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 350 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 300 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 250 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 200 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 150 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 100 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 50 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 25 mg/kg of the weight of the subject.
In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 10 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 5 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 1 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.1 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.01 mg/kg of the weight of the subject. In some embodiments, the composition comprising a VIP analog or pharmaceutically acceptable salt thereof is administered in a daily dosage of up about 0.001 mg/kg of the weight of the subject. The dose administered to the subject can also be measured in terms of total amount of VIP analog administered per day.
In some embodiments, a subject in need thereof is administered from about 1 ng to about 500 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 1 ng to about 10 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 10 ng to about 20 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 10 ng to about 100 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 100 ng to about 200 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 200 ng to about 300 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 300 ng to about 400 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 400 ng to about 500 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 500 ng to about 600 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 600 ng to about 700 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 800 ng to about 900 ng of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 900 ng to about 1 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 1 μg to about 100 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 100 μg to about 200 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 200 μg to about 300 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 300 μg to about 400 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 400 μg to about 500 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 500 μg to about 600 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 600 μg to about 700 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 800 μg to about 900 μg of analog or pharmaceutically salt thereof per day. In some embodiments, a subject in need thereof is administered from about 900 μg to about 1 mg of analog or pharmaceutically salt thereof per day.
In some embodiments, a subject in need thereof is administered from about 0.0001 to about 3000 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 2000 milligrams of VIP analog or pharmaceutically salt thereof day. In some embodiments, a subject is administered up to about 1800 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1600 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1400 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1200 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 1000 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered up to about 800 milligrams of VIP analog or pharmaceutically salt thereof per day. In some embodiments, a subject is administered from about 0.0001 milligrams to about 700 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 700 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 600 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 500 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 400 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 300 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 200 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 100 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 50 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 25 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 15 milligrams of VIP analog or pharmaceutically salt thereof per dose.
In some embodiments, a subject is administered up to about 10 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 5 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 1 milligram of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 0.1 milligrams of VIP analog or pharmaceutically salt thereof per dose. In some embodiments, a subject is administered up to about 0.001 milligrams of VIP analog or pharmaceutically salt thereof per dose.
The dose administered to the subject can also be measured in terms of total amount of VIP analog or pharmaceutically salt thereof administered per ounce of liquid prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.25 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.25 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 2.0 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.9 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.8 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.7 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.6 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.4 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.3 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.2 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.1 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 1.0 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.9 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.8 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.7 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.6 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.5 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.4 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.3 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.2 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.1 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.01 grams per ounce of solution. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.0001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.00001 grams per ounce of solution prepared. In some embodiments, the VIP analog or pharmaceutically salt thereof is at a concentration of about 0.000001 grams per ounce of solution prepared.
Dosage may be measured in terms of mass amount of analog per liter of liquid formulation prepared. One skilled in the art can increase or decrease the concentration of the analog in the dose depending upon the strength of biological activity desired to treat or prevent any above-mentioned disorders associated with the treatment of subjects in need thereof. For instance, one embodiment of the invention can include up to 0.00001 grams of analog per 5 mL of liquid formulation and up to about 10 grams of analog per 5 mL of liquid formulation.
In some embodiments the pharmaceutical compositions of the claimed invention comprise at least one other active agent. in some embodiments, the active agent is a vasoactive agent. In some embodiments the vasoactive agent is chosen from the naturally occurring prostaglandins prostaglandin E0 (PGE0, also referred to 13,14-dihydro-PGE1; hereinafter, the abbreviation “PG” is used for “prostaglandin”), PGE1, 19-hydroxy-PGE1, PGE2, 19-hydroxy-PGE2, PGA1, 19-hydroxy-PGA1, PGA2, 19-hydroxy-PGA2, PGB1, 19-hydroxy-PGB1, PGB2, 19-hydroxy-PGB2, PGB3, PGD2, PGF1α, PGF2α (dinoprost), PGE3, PGF3α, PGI2 (prostacyclin), and combinations thereof. PGE0, PGE1, PGE2, and the hydrolyzable lower alkyl esters thereof (e.g., the methyl, ethyl and isopropyl esters) are, however, particularly suitable. Other suitable prostaglandins are exemplified, without limitation, by arboprostil, carbaprostacyclin, carboprost tromethamine, dinoprost tromethamine, dinoprostone, enprostil, iloprost, lipoprost, gemeprost, metenoprost, sulprostone, tiaprost, viprostil (CL 115,347), viprostil methyl ester, 16,16-dimethyl-Δ2-PGE1 methyl ester, 15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester (misoprostol), 16,16-dimethyl-PGE1, 11-deoxy-15-methyl-PGE1, 16-methyl-18,18,19,19-tetrahydrocarbacyclin, 16(RS)-15-deoxy-16-hydroxy-16-methyl-PGE1 methyl ester, (+)-4,5-didehydro-16-phenoxy-α-tetranor-PGE2 methyl ester, 11-deoxy-11α,16,16-trimethyl-PGE2, (+)-11α,16α,16β-dihydroxy-1-(hydroxymethyl)-16-methyl-trans-prostene, 9-chloro-16,16-dimethyl-PGE2, 16,16-dimethyl-PGE2, 15(S)-15-methyl-PGE2, 9-deoxy-9-methylene-16,16-dimethyl-PGE2, potassium salt, 19(R)-hydroxy-PGE2, and 11-deoxy-16,16-dimethyl-PGE2. Additional vasoactive agents useful as secondary active agents herein include endothelin-derived relaxation factors (“EDRFs”) such as nitric oxide releasing agents, e.g., sodium nitroprusside and diazenium diolates, or “NONOates.” NONOates include, but are not limited to, (Z)-1-{N-methyl-N-{6-(N-methyl-ammoniohexyl)amino}}diazen-1-ium-1,2-diolate (“MAHMA/NO”), (Z)-1-{N-(3-ammoniopropyl)-N-(n-propyl)amino}-diazen-1-ium-1,2-diolate (“PAPA/NO”), (Z)-1-{N-{3-aminopropyl}-N-{4-(3-aminopropylammonio)butyl}amino}diazen-1-ium-1,2-diolate (spermine NONOate or “SPER/NO”) and sodium (Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine NONOate or “DEA/NO”) and derivatives thereof). Still other vasoactive agents include vasoactive intestinal polypeptide analogs and derivatives thereof (particularly derivatives in the form of hydrolyzable lower alkyl esters), smooth muscle relaxants, leukotriene inhibitors, calcium channel blockers, P2-adrenergic agonists, angiotensin-converting enzyme (“ACE”) inhibitors, angiotensin II receptor antagonists, and phosphodiesterase inhibitors. Still other suitable vasoactive agents include, but are not limited to: nitrates and like compounds such as nitroglycerin, isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate, molsidomine, linsidomine chlorhydrate (“SIN-1”), S-nitroso-N-acetyl-d,l-penicillamine (“SNAP”) and S-nitroso-N-glutathione (“SNO-GLU”); long and short acting α-blockers such as phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, tolazoline, prazosin, trimazosin, alfuzosin, tamsulosin and indoramin; ergot alkaloids such as ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride; antihypertensive agents such as diazoxide, hydralazine and minoxidil; nimodepine; pinacidil; cyclandelate; dipyridamole; isoxsuprine; chlorpromazine; haloperidol; yohimbine; and trazodone.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an inhibitor of rho kinase, an enzyme belonging to the rhoA/rho associated kinase pathway, which regulates the state of phosphorylation of myosin phosphatase, in turn leading to the control of smooth muscle contraction. One example of a suitable rho kinase inhibitor has the following structural formula and is identified as Y-27632. Other suitable rho kinase inhibitors are disclosed, for example, in U.S. Pat. No. 6,218,410, which is herein incorporated by reference.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that are peptide analogs of α-melanocyte-stimulating hormone (α-MSH), also referred to as “melanocortin peptides.” Such peptides include the sequence His-Phe-Arg-Trp, His-D-Phe-Arg-Trp, or are homologs thereof, and can be cyclic. A suitable melanocortin peptide is Ac-Nle-cyclo-(-Asp-His-D-Phe-Arg-Trp-Lys)-OH. See U.S. Pat. No. 6,051,555 to Hadley and International Patent Publication No. WO 01/00224 to Blood et al., assigned to Palatin Technologies, Inc. The aforementioned amino acid residues have their conventional meaning as given in Chapter 2422 of the Manual of Patent Examining Procedure (2000). Thus, “Arg” is arginine, “Nle” is norleucine, “His” is histamine, “Phe” is phenylalanine, “D-Phe” is D-phenylalanine, “Trp” is tryptophan, and “Ac” refers to an acetyl moiety, i.e., an acetyl moiety present in a peptide or amino acid sequence that is acetylated.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an endothelin antagonists, including antagonists of any or all of the three isoforms of endothelin, i.e., ET-1, ET-2, and ET-3, and are exemplified by: phenoxyphenylacetic acids and derivatives thereof, such as N-(4-isopropylbenzene-sulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenyl acetamide dipotassium salt, 2-{(2,6-dipropyl-4-hydroxymethyl)-phenoxy}-2-(4-phenoxyphenyl)-acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(4-phenylphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3-carboxyphenyl)-acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-ethylenedioxyphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4,5-trimethoxyphenyl)acetic acid, 2-{(2,6-dipropyl-4-hydroxymethyl)phenoxy}-2-(3,4-methylenedioxyphenyl)acetic acid, N-(4-dimethylaminobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide, N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide, N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-methoxy-carbonyl-2-propylphenoxy)-2-(3,4-methylenedioxy-phenyl)acetamide, N-(2-chlorobenzene-sulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide, and others, as described in U.S. Pat. No. 5,565,485; and certain isooxazoles, oxazoles, thiazoles, isothiazoles and imidazoles, as described, for example, in U.S. Pat. No. 6,136,828.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a peptidyl drug including the peptidyl hormones activin, amylin, angiotensin, atrial natriuretic peptide (ANP), calcitonin, calcitonin gene-related peptide, calcitonin N-terminal flanking peptide, ciliary neurotrophic factor (CNTF), corticotropin (adrenocorticotropin hormone, ACTH), corticotropin-releasing factor (CRF or CRH), epidermal growth factor (EGF), follicle-stimulating hormone (FSH), gastrin, gastrin inhibitory peptide (GIP), gastrin-releasing peptide, gonadotropin-releasing factor (GnRF or GNRH), growth hormone releasing factor (GRF, GRH), human chorionic gonadotropin (hCH), inhibin A, inhibin B, insulin, luteinizing hormone (LH), luteinizing hormone-releasing hormone (LHRH), α-melanocyte-stimulating hormone, β-melanocyte-stimulating hormone, γ-melanocyte-stimulating hormone, melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide, parathyroid hormone (PTH), placental lactogen, prolactin (PRL), prolactin-release inhibiting factor (PIF), prolactin-releasing factor (PRF), secretin, somatotropin (growth hormone, GH), somatostatin (SIF, growth hormone-release inhibiting factor, GIF), thyrotropin (thyroid-stimulating hormone, TSH), thyrotropin-releasing factor (TRH or TRF), thyroxine, and vasopressin. Other peptidyl drugs are the cytokines, e.g., colony stimulating factor 4, heparin binding neurotrophic factor (HBNF), interferon-a, interferon α-2a, interferon α-2b, interferon α-n3, interferon-β, etc., interleukin-1, interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, etc., tumor necrosis factor, tumor necrosis factor-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage colony-stimulating factor, midkine (MD), and thymopoietin.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a selective androgen receptor modulators (SARMs) include LGD2226 and/or LGD1331, both available from Ligand Pharmaceuticals (San Diego, Calif.). See Negro-Villar et al. J. Clin. Endocrinol. & Metabol. 84(10):3459-62 (1999).
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a suitable neuropeptide including bradykinin, kallidin, des-Arg9-bradykinin, des-Arg10-kallidin, des-Arg9-{Leu8}-bradykinin, {D-Phe7}-bradykinin, HOE 140, neuropeptide Y, calcitonin gene-related peptide (cGRP), enkaphalins and related opioid peptides such as Met5enkaphalin, Leu5enkephalin, α-, β- and γ-endorphin, α- and β-neo-endorphin, and dynorphin, as well as the neurotransmitters GABA (γ-aminobutyric acid), glycine, glutamate, acetylcholine, dopamine, epinephrine, 5-hydroxytryptamine, substance P, serotonin, and catecholamines.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a suitable serotonin agonists include, but are not limited to 2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, ergot alkaloids, 8-hydroxy-(2-N,N-dipropyl-amino)-tetraline, 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride, mezacopride, and combinations thereof. Suitable serotonin antagonists include, for example, ondansetron, granisetron, metoclopramide, tropisetron, dolasetron, palonosetron, trimethobenzamide, methysergide, risperidone, ketanserin, ritanserin, clozapine, amitriptyline, MDL 100,907 (R(+)-α-(2,3-dimethoxyphenyl)-1-{2-(4-fluorophenyl)ethyl}-4-piperidine-methanol) (Marion Merrell Dow), azatadine, cyproheptadine, fenclonine, chlorpromazine, mianserin and combinations thereof.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is an ergot alkaloids include ergotamine and ergotamine analogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline, delorgotrile, dihydroergotamine, disulergine, ergonovine, ergonovine maleate, ergotamine tartrate, etisulergine, lergotrile, lysergide, mesulergine, metergoline, metergotamine, nicergoline, pergolide, propisergide, proterguride and terguride.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a calcium channel blockers that are suitable for use according to the present invention include, without limitation, amlodipine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, bepridil, diltiazem, verapamil, and combinations thereof. In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a potassium channel openers include, but are not limited to, pinacidil, diazoxide, cromakalim, nicorandil, minoxidil, (N-cyano-N′-(1,1-dimethylpropyl)-N″-3-pyridyl-guanidine (P-1075), and N-cyano-N′-(2-nitroxyethyl)-3-pridinecarboximidamide monomethanesulfonate (KRN 2391).
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a potassium channel blockers include tedisamil, agitoxin-2, apamin, BDS-I, BDS-II, charybdotoxin, α-dendrotoxin, β-dendrotoxin, γ-dendrotoxin, δ-dendrotoxin, dendrotoxin-I, dendrotoxin-K, E-4031, iberiotoxin, kaliotoxin, MCD-peptide, margatoxin, noxiustoxin, paxilline, penitrem A, stichodactyla, tertiapin, tityustoxin K alpha, verruculogen, and combinations thereof. Although all of the active agents are available commercially, most of the listed potassium channel blockers are available from Alomone Labs (Jerusalem, Israel).
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a dopamine agonist including, for example, levodopa, bromocriptine, pergolide, apomorphine, piribedil, pramipexole, ropinirole, and combinations thereof. Dopamine antagonists include, without limitation, spiroperidol, benperidol, trifluperidol, pimozide, fluphenazine, droperidol, haloperidol, thiothixene, trifluperazine, moperone, prochlorperazine, molindone, thioridazine, clozapine, chlorpromazine, promazine, sulpiride, clebopride, chlorpromazine, spiperone, flupenthixol, and combinations thereof.
In some embodiments, the pharmaceutical compositions of the invention comprise an active agent that is a non-androgenic steroid including progestins and estrogens. Suitable estrogens include synthetic and natural estrogens such as: estradiol (i.e., 1,3,5-estratriene-3,17β-diol, or “17β-estradiol”) and its esters, including estradiol benzoate, valerate, cypionate, heptanoate, decanoate, acetate and diacetate; 17α-estradiol; ethinylestradiol (i.e., 17α-ethinylestradiol) and esters and ethers thereof, including ethinylestradiol 3-acetate and ethinylestradiol 3-benzoate; estriol and estriol succinate; polyestrol phosphate; estrone and its esters and derivatives, including estrone acetate, estrone sulfate, and piperazine estrone sulfate; quinestrol; mestranol; and conjugated equine estrogens. Suitable progestins include acetoxypregnenolone, allylestrenol, anagestone acetate, chlormadinone acetate, cyproterone, cyproterone acetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone (17α-ethinyltestosterone), ethynodiol diacetate, flurogestone acetate, gestadene, hydroxyprogesterone, hydroxyprogesterone acetate, hydroxyprogesterone caproate, hydroxymethylprogesterone, hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel, lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol, megestrol acetate, melengestrol acetate, norethindrone, norethindrone acetate, norethisterone, norethisterone acetate, norethynodrel, norgestimate, norgestrel, norgestrienone, normethisterone, and progesterone. It is generally desirable to co-administer a progestin along with an estrogen so that the estrogen is not “unopposed.” As is well known in the art, estrogen-based therapies are known to increase the risk of endometrial hyperplasia and cancer, as well as the risk of breast cancer, in treated individuals. Co-administration of estrogenic agents with a progestin has been found to decrease the aforementioned risks.
The pharmaceutical compositions of the present invention may also include one or more chemotherapeutic agents. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides.
In one embodiment of the present invention, the chemotherapeutic agent is a platinum coordination compound. The term “platinum coordination compound” refers to any tumor cell growth inhibiting platinum coordination compound that provides the platinum in the form of an ion. Suitable platinum coordination compounds include, but are not limited to, cis-diamminediaquoplatinum (II)-ion; chloro (diethylenetriamine)-platinum (II) chloride; dichloro (ethylenediamine)-platinum (II); diammine (1,1-cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; diammine (2-ethylmalonato)-platinum (II); ethylenediaminemalonatoplatinum (II); aqua (1,2-diaminodyclohexane)-sulfatoplatinum (II); (1,2-diaminocyclohexane) malonatoplatinum (II); (4-caroxyphthalato) (1,2-diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane)-(isocitrato) platinum (II); (1,2-diaminocyclohexane) cis (pyruvato) platinum (II); (1,2-diaminocyclohexane) oxalatoplatinum (II); ormaplatin; and tetraplatin
In some embodiments, the secretin analog and the additional active agent or agents may be incorporated into a single formulation, or they may be administered separately, either simultaneously or sequentially. In one embodiment, an androgenic agent is administered prior to administration of VIP or a VIP agonist, i.e., the androgenic agent is administered as a pretreatment. In some embodiments, such a method involves administration of an androgenic agent, e.g., via oral or topical (vulvar and/or vaginal) administration, followed by topical (again, vulvar and/or vaginal) administration of VIP or a VIP agonist.
In some embodiments, the formulations herein are administered by topical application to the vulvar region and/or by vaginal drug administration. These pharmaceutical formulations may typically contain one or more pharmaceutically acceptable carriers suited to the particular type of formulation, i.e., gel, ointment, suppository, or the like. The vehicles are comprised of materials of naturally occurring or synthetic origin that do not adversely affect the active agent or other components of the formulation. Suitable carriers for use herein include water, silicone, waxes, petroleum jelly, polyethylene glycol, propylene glycol, liposomes, sugars such as mannitol and lactose, and a variety of other materials, again depending, on the specific type of formulation used. As described in Section IV, infra, dosage forms used for administration to the vulvar region and/or vagina may be used to deliver drug on an as-needed, on-demand basis, and/or throughout an extended, sustained release profile.
The pharmaceutical compositions may also include a chemical compound to enhance permeation of the active agent through the mucosal tissue, i.e., a “permeation enhancer.” Suitable permeation enhancers include those generally useful in conjunction with topical, transdermal or transmucosal drug delivery. Examples of suitable permeation enhancers include the following: sulfoxides such as dimethylsulfoxide (DMSO) and decylmethylsulfoxide (C10MSO); ethers such as diethylene glycol monoethyl ether (available commercially as TRANSCUTOL® (Gattefosse S. A., Saint-Priest, France) and diethylene glycol monomethyl ether; surfactants such as sodium laurate, sodium lauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231, 182, 184), TWEEN® (20, 40, 60, 80) (ICI Chemicals, Bridgewater, N.J.), and lecithin (U.S. Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones, particularly 1-n-dodecylcyclazα-cycloheptan-2-one (available under the trademark AZONE® (Durham Pharmaceuticals, LLC, Durham, N.C.); see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934); alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol, and the like; fatty acids such as lauric acid, oleic acid and valeric acid; fatty acid esters such as isopropyl myristate, isopropyl palmitate, methylpropionate, and ethyl oleate; polyols and esters thereof such as propylene glycol, ethylene glycol, glycerol, butanediol, polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see, e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compounds such as urea, dimethylacetamide (DMA), dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones; and organic acids, particularly salicylic acid and salicylates, citric acid and succinic acid. Mixtures of two or more enhancers may also be used.
In some embodiments, the pharmaceutical compositions may include an enzyme inhibitor, i.e., a compound effective to inhibit enzymes present in the vagina or vulvar area that could degrade or metabolize the active agent. That is, inhibitors of enzymes that decrease or eliminate the activity of the active agent may be included in the formulation so as to effectively inhibit the action of those enzymes. Such compounds include, for example, fatty acids, fatty acid esters, and NAD inhibitors.
In some embodiments, the pharmaceutical composition may be in the form of an ointment, cream, emulsion, lotion, gel, solid, solution, suspension, foam or liposomal formulation. Alternatively, the formulations may be contained within avaginal ring (e.g., as disclosed in U.S. Pat. No. 5,188,835 to Lindskoget al., assigned to Kabi Pharmacia AB), or within a tampon, suppository, sponge, pillow, puff, or osmotic pump system; these platforms are useful solely for vaginal delivery. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, as will be appreciated by those skilled in the art, is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, non irritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, supra, at pages 1034-1038, ointment bases may be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (0/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Suitable water-soluble ointment bases are prepared from polyethylene glycols of varying molecular weight; again, reference may be had to Remington: The Science and Practice of Pharmacy for further information.
In one aspect of the invention, a method is provided for treating sexual dysfunction in a female individual comprising administering to the vagina and/or vulvar area a pharmaceutical formulation comprising a secretin family analog. In some embodiments, the secretin family analog is a vasodilator, with vasodilators selected from the group consisting of VIP and vasoactive intestinal polypeptide analogs and combinations of any of the foregoing. Any number of drug delivery platforms may be used, e.g., suppositories, ointments, creams, gels, solutions and the like. Also, one or more additional types of drugs, i.e., pharmacologically active agents may be incorporated into the pharmaceutical formulations. In other aspects of the invention, vaginal administration of a vasoactive agent as just described is used to improve vaginal muscle tone and tissue health, to enhance vaginal lubrication, or to minimize collagen misdeposition resulting from hypoxia as well as the associated lack of elasticity resulting from the collagen misdeposition.
In another embodiment of the invention, a method is provided for improving memory by administering a secretin family analog.
In another aspect of the invention, pharmaceutical compositions and dosage forms are provided for carrying out the aforementioned methods. The compositions and dosage forms contain a vasoactive agent as described above, a pharmaceutically acceptable vehicle, and, optionally, one or more additional pharmacologically active agents. The formulations contain a therapeutically effective amount of the active agent, or a therapeutically effective concentration of the active agent, i.e., a concentration that provides a therapeutically effective amount of active agent upon administration of a selected volume of composition.
The subject can be any animal, including but not necessarily limited to mammals such as a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, monkey, cow, horse, pig, and the like. In some embodiments, the subject is a human
According to some embodiments of the invention, the formulation may be supplied as part of a kit. The kit comprise comprising an analog, wherein the analog comprises an α-amino acid and at least one β-amino acid. In another embodiment, the kit comprises a pharmaceutically acceptable salt of an analog with a rehydration mixture. In another embodiment, the pharmaceutically acceptable salt of an analog are in one container while the rehydration mixture is in a second container. The rehydration mixture may be supplied in dry form, to which water or other liquid solvent may be added to form a suspension or solution prior to administration. Rehydration mixtures are mixtures designed to solubilize a lyophilized, insoluble salt of the invention prior to administration of the composition to a subject takes at least one dose of a purgative. In another embodiment, the kit comprises a pharmaceutically acceptable salt in orally available pill form.
The kit may contain two or more containers, packs, or dispensers together with instructions for preparation and administration. In some embodiments, the kit comprises at least one container comprising the pharmaceutical composition or compositions described herein and a second container comprising a means for delivery of the compositions such as a syringe. In some embodiments, the kit comprises a composition comprising an analog in solution or lyophilized or dried and accompanied by a rehydration mixture. In some embodiments, the analog and rehydration mixture may be in one or more additional containers.
The compositions included in the kit may be supplied in containers of any sort such that the shelf-life of the different components are preserved, and are not adsorbed or altered by the materials of the container. For example, suitable containers include simple bottles that may be fabricated from glass, organic polymers, such as polycarbonate, polystyrene, polypropylene, polyethylene, ceramic, metal or any other material typically employed to hold reagents or food; envelopes, that may consist of foil-lined interiors, such as aluminum or an alloy. Other containers include test tubes, vials, flasks, and syringes. The containers may have two compartments that are separated by a readily removable membrane that upon removal permits the components of the compositions to mix. Removable membranes may be glass, plastic, rubber, or other inert material.
Kits may also be supplied with instructional materials. Instructions may be printed on paper or other substrates, and/or may be supplied as an electronic-readable medium, such as a floppy disc, CD-ROM, DVD-ROM, zip disc, videotape, audio tape, or other readable memory storage device. Detailed instructions may not be physically associated with the kit; instead, a user may be directed to an internet web site specified by the manufacturer or distributor of the kit, or supplied as electronic mail.
In another embodiment, a packaged kit is provided that contains the pharmaceutical formulation to be administered, i.e., a pharmaceutical formulation containing VIP analog or a for enhancing female sexual desire and responsiveness, a container (e.g., a vial, a bottle, a pouch, an envelope, a can, a tube, an atomizer, an aerosol can, etc.), optionally sealed, for housing the formulation during storage and prior to use, and instructions for carrying out drug administration in a manner effective to enhance sexual desire and responsiveness. The instructions will typically be written instructions on a package insert, a label, and/or on other components of the kit.
Depending on the type of formulation and the intended mode of administration, the kit may also include a device for administering the formulation (e.g., a transdermal delivery device). The administration device may be a dropper, a swab, a stick, or the nozzle or outlet of an atomizer or aerosol can. The formulation may be any suitable formulation as described herein. For example, the formulation may be an oral dosage form containing a unit dosage of the active agent, or a gel or ointment contained within a tube. The kit may contain multiple formulations of different dosages of the same agent. The kit may also contain multiple formulations of different active agents.
The present kits will also typically include means for packaging the individual kit components, i.e., the pharmaceutical dosage forms, the administration device (if included), and the written instructions for use. Such packaging means may take the form of a cardboard or paper box, a plastic or foil pouch, etc.
The invention relates to the use of an analog in the preparation of a medicament for treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. In some embodiments, the invention relates to compositions comprising a secretin family analog for treatment or prevention of chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof.
The present invention relates to inhibiting secretion of TNF-α in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting binding of VIP to a VIP receptor in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting biological effect of GHRH in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting chemotaxis of T cells in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to inhibiting expression of LPS in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to modulating the amount of cyclic cAMP in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog. The present invention relates to increasing the activity or expression of adenylate cyclase in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a secretin family analog and a VPAC1 antagonist. In some embodiments the analog is a secretin family analog. and a VPAC2 agonist. In some embodiments the analog is a VIP analog. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR1 agonist, and has substantially reduced selectivity or no selectivity for VIPR2 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a PAC1 agonist, and has substantially reduced selectivity or no selectivity for VIPR2 or VIPR1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR2 agonist, and has substantially reduced selectivity or no selectivity for VIPR1 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR2 antagonist, but does not antagonize VIPR1 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a VIPR1 antagonist, but does not antagonize VIPR2 or PAC1 receptors. In some embodiments, the composition or pharmaceutical composition of the claimed invention comprises a VIP analog, wherein the VIP analog is a PAC1 antagonist, but does not antagonize VIPR2 or VIPR1 receptors. Any of the above-mentioned selective agonist or antagonists may be used in any of the method claims provided herein.
The present invention relates to modulating the amount of PLD in the nervous system of a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.
The present invention relates to modulating the amount of antibody production of a B cell in a subject comprising administering a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.
The present invention relates to modulating the amount of antibody production of a B cell or a B cell hybridoma cell in vitro comprising treating a culture containing B cells or a hybridomas with a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.
The present invention relates to modulating the immune response of a subject comprising administering a subject with a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.
The present invention relates to modulating the activation of cystic fibrosis transmembrane conductance regulator (CFTR) in a subject comprising administering a subject with a composition comprising an analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid. In some embodiments the analog is a secretin family analog. In some embodiments the analog is a VIP analog.
The present invention also relates measuring the modulation of activity of a secretin receptor molecule by measuring receptor activity comprising:
a) contacting a human secretin family receptor with a secretin family analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the secretin family analog to the secretin receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the secretin family analog to the human secretin receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human secretin receptor in the absence of an unknown compound.
The present invention also relates identifying a modulator of activity of a secretin receptor molecule by measuring receptor activity comprising:
a) contacting a human secretin family receptor with a secretin family analog, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the secretin family analog to the secretin receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the secretin family analog to the human secretin receptor in the presence of an unknown compound to the rate of association of the secretin analog to the human secretin receptor in the absence of an unknown compound.
The present invention also relates to a method of measuring the modulation of activity of a human VIP receptor molecule by measuring receptor activity comprising:
a) contacting a human VIP family receptor with a VIP analog, wherein the analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.
The present invention also relates identifying a modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising:
a) contacting a human VIP family receptor with a VIP analog, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC1, VPAC₂or PAC1.
The present invention also relates identifying a modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising:
a) contacting a VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the binding affinity of the VIP analog to the VIP family receptor in the presence and absence of a compound that binds to the VIP family receptor; and
c) comparing the binding affinity of the VIP analog to the VIP receptor in the presence of a compound that binds to the VIP family receptor to the binding affinity of the VIP analog to the VIP receptor in the absence of a compound that binds to the VIP family receptor. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC1, VPAC2 or PAC1.
The invention also relates to the use of an analog with selectivity for VPAC1, PAC1, or VPAC2 in the preparation of a medicament for treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood glucose levels, elevated blood pressure, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction due to administration of a medication that causes onset of or exacerbates symptoms of pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof. In some embodiments, the invention relates to compositions comprising a secretin family analog with selectivity for VPAC1, PAC1, or VPAC2 for treatment or prevention of chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung carcinoma, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction in a subject in need thereof.
The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising administering a VIP analog to the subject, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for the VPAC1, VPAC2, or PAC1 receptor as compared to the other receptors. In some embodiments, the cancer is chosen from the following: non-small cell lung carcinoma, small cell lung carcinoma, colorectal carcinoma, breast carcinoma, gastric carcinoma, prostate carcinoma, liver carcinoma, ductal pancreatic carcinoma, bladder carcinoma, Non-Hodgkin's lymphoma, maningioma, leiomyoma, endometrial carcinoma, pheochromocytoma, paraganglioma. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for the VPAC1, VPAC2, or PAC1 receptor as compared to the other receptors. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising administering a VIP analog to the subject, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor antagonist with increased selectivity for the VPAC1 receptor. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor antagonist with increased selectivity for the VPAC1 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing small cell lung carcinoma comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one VPAC1, VPAC2, or PAC1 receptor. The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one of the following: VPAC1, VPAC2, or PAC1 receptors. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing primary arterial hypertension (PAH) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one VPAC1, VPAC2, or PAC1 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1, VPAC2, or PAC1 receptor antagonist or agonist with increased selectivity for at least one of the following: VPAC1, VPAC2, or PAC1 receptors as compared to its selectivity for the other receptors. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor agonist with increased selectivity for the VPAC1 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor agonist with increased selectivity for the VPAC1 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. The present invention relates to a method of treating or preventing inflammatory disease comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments the inflammatory disease is rheumatoid arthritis. In some embodiments, the VIP analog is administered at a therapeutically effective dose.
The present invention also relates to a method of treating or preventing chronic obstructive pulmonary disease, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension comprising administering a VIP analog with selectivity for VPAC2 to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses.
The present invention relates to a method of treating or preventing chronic obstructive pulmonary disease (COPD) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. The present invention relates to a method of treating or preventing COPD comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.
The invention also relates to a method of preventing or inhibiting activation of alveolar macrophages comprising administering a VIP analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC1 receptor antagonist or agonist with increased selectivity for the VPAC1 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.
The present invention relates to a method of treating or preventing chronic obstructive pulmonary disease (COPD) comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. The present invention relates to a method of treating or preventing COPD comprising administering a VIP analog to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler. The invention relates to a method of preventing or inhibiting activation of alveolar macrophages comprising administering a VIP analog to a subject, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist with increased selectivity for the VPAC2 receptor. In some embodiments, the VIP analog is administered at a therapeutically effective dose via nebulizer or inhaler.
The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising:
a) contacting a human VIP family receptor with a VIP analog, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the association of the VIP analog to the VIP receptor in the presence and absence of an unknown compound; and
c) comparing the rate of association of the VIP analog to the human VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the human VIP receptor in the absence of an unknown compound.
The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising:
a) contacting a first and a second VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the rate association of the VIP analog to the first and second VIP receptors in the presence and absence of an unknown compound; and
c) comparing the rate of association of the VIP analog to the first VIP receptor in the presence of an unknown compound to the rate of association of the VIP analog to the the second VIP receptor in the absence of an unknown compound.
The present invention also relates to methods of identifying a selective modulator of activity of a VIP family receptor molecule by measuring receptor activity comprising:
a) contacting a first and a second VIP family receptor with a VIP analog in a known concentration, wherein said analog comprises an α-amino acid and at least one β-amino acid;
b) measuring the binding affinity of the VIP analog to the first and second VIP receptors in the presence and absence of an unknown compound; and
c) comparing the binding affinity of the VIP analog to the first VIP receptor in the presence of an unknown compound to the binding affinity of the VIP analog to the the second VIP receptor in the absence of an unknown compound. In some embodiments, the VIP family receptor is chosen from VIPR1, VIPR2, VPAC₁, VPAC₂or PAC₁.
The present invention also relates to methods of inhibiting the immune response against a transplanted organ in a subject, wherein the subject is an organ donor recipient. in some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a human experiencing organ rejection after transplantation.
In another embodiment, the present invention also relates to a method for inhibiting the growth of a tumor cell, the method comprising: contacting the tumor cell with an effective amount of a secretin family analog, wherein the secretin family analog or functional fragment thereof comprises at least one β-amino acid. In some embodiments, the method comprises contacting the tumor cell with an effective amount of a combination of a chemotherapeutic agent and a secretin family analog. In some embodiments, the secretin analog is a VIP analog. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides. In some embodiments, the secretin analog is a VPAC1 antagonist with selectivity for VPAC1. In some embodiments, the tumor cell is a tumor cell derived from a breast cancer, a lung cancer, a colon cancer, a prostate cancer, or a pancreatic cancer.
In another embodiment, the present invention also relates to a method of inhibiting the growth of a tumor cell in a mammalian subject in need thereof, the method comprising: administering to the subject an effective amount of a secretin family analog or functional fragment thereof, wherein the secretin family analog or functional fragment thereof comprises at least one β-amino acid. In some embodiments, the method comprises administering to the subject an effective amount of a combination of a chemotherapeutic agent and a secretin family analog. In some embodiments, the secretin analog is a VIP analog. In some embodiments, the tumor cell is a tumor cell derived from a breast cancer, a lung cancer, a colon cancer, a prostate cancer, hepatic cancer (HCC) or a pancreatic cancer. Suitable chemotherapeutic agents include, but are not limited to, platinum coordination compounds, topoisomerase inhibitors, antibiotics, antimitotic alkaloids and difluoronucleosides.
The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC₁; wherein the VIP analog is a VPAC₁antagonist; and wherein the cancer cell is a bladder, breast, colon, liver, lung, prostate, stomach, thyroid or uterine cancer cell. The present invention relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC₁; wherein the VIP analog is a VPAC₁antagonist; and wherein the cancer is a bladder, breast, colon, liver, lung, prostate, stomach, thyroid, hepatocellular, or uterine cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.
The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC₂; wherein the VIP analog is a VPAC₂antagonist; and wherein the cancer cell is a lung, breast, stomach cancer cell. In some embodiments the cancer cell is derived from a stomach leiomyoma.
The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to VPAC₂; wherein the VIP analog is a VPAC₂antagonist; and wherein the cancer a lung, breast, stomach, or heptocellular cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.
The present invention also relates to a method of treating or preventing airway constriction comprising administering a VIP analog or functional fragment thereof to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist. In some embodiments, the VIP analog or functional fragment thereof has increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses.
The present invention also relates to a method of treating or preventing asthma, comprising administering a VIP analog or functional fragment thereof to a subject in need thereof, wherein said analog comprises an α-amino acid and at least one β-amino acid and wherein said analog is a VPAC2 receptor agonist. In some embodiments, the VIP analog or functional fragment thereof has increased selectivity to VPAC2 receptor. In all methods of treatment or prevention, analogs of the present invention may be administered in therapeutically effective doses. In some embodiments, the VIP analog or functional fragment thereof may be administered via an inhaler or nebulizer.
The present invention also relates to a method of treating or preventing cancer cell growth in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to PAC₁; wherein the VIP analog is a PAC₁antagonist; and wherein the cancer cell is a nerve cell, adrenal cell, pituitary cell, or breast cell. The present invention also relates to a method of treating or preventing cancer in a subject in need thereof comprising the steps of: administering a VIP analog or functional fragment thereof the subject, wherein the VIP analog or functional fragment comprises at least one β-amino acid, wherein the VIP analog or functional fragment thereof is selective or has increased selectivity to PAC₁; wherein the VIP analog is a PAC₁antagonist; and wherein the cancer is a glioblastoma, neuroblastoma, adrenal, pituitary, catecholamine-secreting tumors, pheochromocytomas, paragangliomas, endometrial cancers, or breast cancer. In some embodiments, the cancer has been diagnosed as being malignant. In some embodiments, the subject may have an increased risk or increased susceptibility to contracting a malignant cancer.
The invention also relates to methods of treating or preventing the aforementioned diseases using the analogs of the present invention. Any analog described in the present invention may or may not have preferred selectivity of one of its receptors versus another. The invention relates to analogs based upon the polypeptide sequences identified in Tables 1, 2, 3, and 4. All modified and unmodified variants of the sequences listed in Table 4 are contemplated as being part of the invention. For instance, the sequence of Biotin-Bombesin is listed in Table 4 as Biotin—EQRLGNQWAVGHLM—NH2 (SEQ ID NO:67). Not only do analogs of the claimed invention include biotinylated sequence above with an amidated methionine, but the analogs of the present invention also relate to the unmodified or modified polypeptide backbone EQRLGNQWAVGHLM as well as functional fragments thereof. In some embodiments the polypeptide analog is derived from one of the following amino acid sequences of Table 4:

TABLE 4

Targets from which the Analogs are derived

1.	Galanin	2.	neurokinin A
3.	neurokinin B	4.	RGD
5.	Osteogenic growth peptide	6.	Parathyroid hormone
7.	Kallidin	8.	T cell receptor peptide
9.	PDGF	10.	Amylin
11.	Calcitonin	12.	GHRH
13.	Thymopoietin	14.	cecropin
15.	TRH	16.	EPO
17.	FGF	18.	Stem Cell Factor
19.	Gp120	20.	Gp160
21.	CD4	22.	IGF
23.	IGF receptor	24.	Insulin
25.	GMCSF	26.	GCSF
27.	MCSF	28.	Kentsin
29.	LAP	30.	Tuftsin
31.	Prolactin	32.	Angiotensin II
33.	Angiotensin II receptor	34.	Dynorphin
35.	Calcitonin	36.	Cholecystokinin
37.	Pepstatin	38.	Bestatin
		39.	Leupeptin
40.	Luteinizing hormone	41.	Neurotensin
42.	Motilin	43.	TGF-alpha
44.	TGF-beta	45.	BMP-1
46.	BMP-2	47.	BMP-3
48.	BMP-4	49.	BMP-5
50.	BMP-7	51.	BMP-8
52.	BMP-9	53.	Bombesin
54.	Enterostatin	55.	Glucagon
56.	GLP-1	57.	Beta-Endorphin
58.	ACTH	59.	Alpha-MSH
60.	γ-MSH	61.	adrenal peptide E
62.	alpha casein fragment	63.	beta casomorphin
64.	dermorphin	65.	kyotorphin
66.	metophamide	67.	neuropeptide FF (NPFF)
68.	melanocyte inhibiting factor	69.	vasotocin
70.	Protein kinase C	71.	Amyloid
72.	Amyloid fibrin	73.	Calpain
74.	Charybdotoxin	75.	Apamin
76.	Phospholipase A2	77.	Phospholipase A2 receptor
78.	ENaC-alpha	79.	ENaC-beta
80.	ENaC-gamma	81.	IgG subunit
82.	Endotoxin	83.	ADNF
84.	Adrenomedullin	85.	Apelin
86.	Ghrelin	87.	Mastoparan (MCD peptides)
88.	Melanin concentrating hormone	89.	Nociceptin
90.	Nocistatin	91.	Orexin
92.	Receptor activity modulating protein,	93.	Urotensin
94.	Glycoprotein IIb/IIIa inhibitors	95.	c7E3 Fab
96.	Apo-lipoprotein A-I	97.	IL-1
98.	IL-2	99.	IL-3
100.	IL-4	101.	IL-5
102.	IL-6	103.	IL-7
104.	IL-8	105.	IL-9
106.	IL-10	107.	IL-12
108.	IL-15	109.	IL-18
110.	IL-22	111.	IL-23
112.	IL-24	113.	IL-26
114.	IL-27	115.	IL-28
116.	brain-derived neurotrophic factor	117.	nerve growth factor
	(BDNF)
118.	neurotrophin 3	119.	Corticotropin releasing factor
120.	MHC I bind protei	121.	P-selectin
122.	LFA-1	123.	LFA-3
124.	EPGF	125.	EPGF receptor
126.	Oxytocin	127.	Vasopressin
128.	Defensin, alpha 1	129.	Neutrophil defensin 3
130.	Neutrophil defensin 4	131.	Defensin-5
132.	Defesin-6	133.	Beta-defensin 1
134.	Beta-defensin-3	135.	Beta defensin 103
136.	Beta-defensin 107	137.	Beta-defensin 110
138.	Beta-defensin 136	139.	RK-1
			(MPCSCKKYCDPWEVIDGSCGLFNSKYICCREK)
140.	dermaseptin S4	141.	magainin 1
142.	magainin 2	143.	magainin A
144.	magainin B	145.	magainin G
146.	MSI-78	147.	MSI-99
148.	MSI-130	149.	MSI-511
150.	Myp30	151.	Pexiganan
152.	Laminin	153.	YIGSR
154.	Gastrin	155.	Gastrin releasing peptide
156.	GnRH	157.	Secretin
158.	Bradykinin	159.	Substance P
160.	RANTES	161.	MCP-1
162.	MIP-1 alpha	163.	MIP-1beta
164.	PDWHF	165.	CRF
166.	Endothelin	167.	Integrin
168.	Neuropeptide Y	169.	LHRH
170.	Enkephilin	171.	alpha-neo-endorphin, porcine
172.	beta-neoendorphin	173.	Ac-beta-endorphin, camel, bovine, ovine
174.	Ac-beta-endorphin 1-27, camel,	175.	Ac-beta-endorphin, human
	bovine, ovine
176.	Ac-beta-endorphin 1-26, human	177.	Ac-beta-endorphin 1-27, human
178.	Ac-gamma-endorphin (Ac-beta-	179.	acetyl-alpha-endorphin
	lipotropin 61-77)
180.	alpha-endorphin (beta-lipotropin 61-	181.	alpha-neo-endorphin analog
	76)
182.	alpha-neo-endorphin 1-7	183.	{Arg⁸}-alpha-neoendorphin 1-8
184.	beta-endorphin (beta-lipotropin 61-	185.	beta-endorphin 1-27, camel, bovine,
	91), camel, bovine, ovine		ovine
186.	beta-endorphin, equine	187.	beta-endorphin (beta-lipotropin 61-91),
			human
188.	beta-endorphin (1-5) + (16-31), human	189.	beta-endorphin 1-26, human
190.	beta-endorphin 1-27, human	191.	beta-endorphin 6-31, human
192.	beta-endorphin 18-31, human	193.	beta-endorphin, porcine
194.	beta-endorphin, rat	195.	beta-lipotropin 1-10, porcine
196.	beta-lipotropin 60-65	197.	beta-lipotropin 61-64
198.	beta-lipotropin 61-69	199.	beta-lipotropin 88-91
200.	biotinyl-beta-endorphin (biotinyl-	201.	biocytin-beta-endorphin, human
	bets-lipotropin 61-91)
202.	gamma-endorphin (beta-lipotropin	203.	{DAla²}-alpha-neo-endorphin 1-2, amide
	61-77)
204.	{DAla²}-beta-lipotropin 61-69	205.	{DAla²}-gamma-endorphin
206.	{Des-Tyr¹}-beta-endorphin, human	207.	{Des-Tyr¹}-gamma-endorphin (beta-
			lipotropin 62-77)
208.	{Leu⁵}-beta-endorphin, camel,	209.	{Met⁵,Lys⁶}-alpha-neo-endorphin 1-6
	bovine, ovine
210.	{Met⁵,Lys^6,7}-alpha-neo-endorphin	211.	{Met⁵,Lys⁶,Arg⁷}-alpha-neo-endorphin
	1-7		1-7
212.	endothelin-1 (ET-1)	213.	endothelin-1 {Biotin-Lys⁹}
214.	endothelin-1 (1-15), human	215.	endothelin-1 (1-15), amide, human
216.	Ac-endothelin-1 (16-21), human	217.	Ac-{DTrp¹⁶}-endothelin-1 (16-21),
			human
218.	{Ala^3,11}-endothelin-1	219.	{Dpr1,Asp¹⁵}-endothelin-1
220.	{Ala²}-endothelin-3, human	221.	{Ala¹⁸}-endothelin-1, human
222.	{Asn¹⁸}-endothelin-1, human	223
224.	{Res-701-1}-endothelin B receptor	225.	Suc-{Glu⁹,Ala^11,15}-endothelin-1 (8-21),
	antagonist		IRL-1620
226.	endothelin-C-terminal hexapeptide	227.	{D-Val²²}-big endothelin-1 (16-38),
			human
228.	endothelin-2 (ET-2), human, canine	229.	endothelin-3 (ET-3), human, rat, porcine,
			rabbit
230.	biotinyl-endothelin-3 (biotinyl-ET-3)	231.	prepro-endothelin-1 (94-109), porcine
232.	BQ-518	233.	BQ-610
234.	BQ-788	235.	endothelium-dependent relaxation
			antagonist
236.	FR139317	237.	IRL-1038
238.	JKC-30 1	239.	JKC-302
240.	PD-145065	241.	PD-142893
242.	sarafotoxin S6a (atractaspis	243.	sarafotoxin S6b (atractaspis engaddensis)
	engaddensis)
244.	sarafotoxin S6c (atractaspis	245.	{Lys⁴}-sarafotoxin S6c
	engaddensis)
246.	sarafotoxin S6d	247.	big endothelin-1, human
248.	biotinyl-big endothelin-1, human	249.	big endothelin-1 (1-39), porcine
250.	big endothelin-3 (22-41), amide,	251.	big endothelin-1 (22-39), rat
	human
252.	big endothelin-1 (1-39), bovine	253.	big endothelin-1 (22-39), bovine
254.	big endothelin-1 (19-38), human	255.	big endothelin-1 (22-38), human
256.	big endothelin-2, human	257.	big endothelin-2 (22-37), human
258.	big endothelin-3, human	259.	big endothelin-1, porcine
260.	big endothelin-1 (22-39) (prepro-	261.	big endothelin-1, rat
	endothelin-1 (74-91))
262.	big endothelin-2 (1-38), human	263.	big endothelin-2 (22-38), human
264.	big endothelin-3, rat	265.	biotinyl-big endothelin-1, human
266.	{Tyr¹²³}-prepro-endothelin (110-	267.	{BQ-123}
	130), amide, human
268.	{BE18257B}	269.	{BE-18257A}/{W-7338A}
270.	{BQ-485}	271.	FR139317
272.	PD-151242 and TTA-386	273.	{BQ-3020} {RES-701-3} and {IRL-
			1720}
274.	adrenorphin	275.	free acid amidorphin (proenkephalin A
			(104-129)-NII2)
276.	bovine BAM-12P	277.	bovine adrenal medulla enkephalin
278.	{D-Ala²,D-Leu⁵}-enkephalin	279.	{D-Ala²,D-Met⁵}-enkephalin
280.	{DAla²}-Leu-enkephalin	281.	amide {DAla²,Leu⁵,Arg⁶}-enkephalin
282.	{Des-Tyr¹,DPen^2,5}-enkephalin	283.	{Des-Tyr¹,DPen²,Pen⁵}-enkephalin
284.	{Des-Tyr¹}-Leu-enkephalin	285.	{D-Pen^2,5}-enkephalin
286.	{DPen²,Pen⁵}-enkephalin	287.	enkephalinase substrate
288.	{D-Pen²,pCI-Phe⁴,D-Pen⁵}-	289.	Leu-enkephalin
	enkephalin
290.	amide biotinyl-Leu-enkephalin	291.	{D-Ser²}-Leu-enkephalin-Thr (delta-
			receptor peptide) (DSLET)
292.	{D-Thr²}-Leu-enkephalin-Thr	293.	{Lys⁶}-Leu-enkephalin
	(DTLET)
294.	{Met⁵,Arg⁶}-enkephalin	295.	{Met⁵,Arg⁶-enkephalin-Arg
			{Met⁵,Arg⁶,Phe⁷}-enkephalin
296.	amide Met-enkephalin biotinyl-Met-	297.	{D-Ala²}-Met-enkephalin
	enkephalin
298.	amide Met-enkephalin-Arg-Phe Met-	299.	amide {Ala²}-Met-enkephalin
	enkephalin
300.	amide {DMet²,Pro⁵}-enkephalin	301.	amide {DTrp²}-Met-enkephalin, amide,
			metorphinamide (adrenorphin) peptide B
302.	bovine 3200-Dalton adrenal peptide E	303.	bovine peptide F
304.	bovine preproenkephalin B 186-204	305.	human spinorphin
306.	bovine and thiorphan (D,L,3-	307.	platelet factor-4 (58-70)
	mercapto-2-benzylpropanoyl-glycine)
308.	human echistatin (Echis carinatus) E	309.	human echistatin (Echis carinatus) P
310.	L selectin conserved region	311.	fibrinopeptide A
	fibronectin
312.	human {Tyr⁰}-fibrinopeptide A	313.	human fibrinopeptide B
314.	human {Glu¹}-fibrinopeptide B	315.	human {Tyr¹⁵}-fibrinopeptide B
316.	human fibrinogen beta-chain	317.	fibrinolysis inhibiting factor FN-C/H-1
	fragment of 24-42 fibrinogen binding		(fibronectin heparin-binding fragment)
	inhibitor peptide
318.	FN-C/H-V (fibronectin heparin-	319.	heparin-binding peptide laminin penta
	binding fragment)		peptide, amide Leu-Asp-Val-NH₂(LDV—NH₂),
320.	human, bovine, rat,	321.	chicken necrofibrin
322.	human necrofibrin, rat	323.	platelet membrane glycoprotein IIB
			peptide 296-306
324.	human galanin 1-19	325.	human preprogalanin 1-30
326.	human preprogalanin 65-88	327.	human preprogalanin 89-123
328.	human galanin	329.	porcine galanin 1-16
330.	porcine, rat galanin	331.	rat biotinyl-galanin
332.	rat preprogalanin 28-67	333.	rat galanin 1-13-bradykinin 2-9
334.	amide M40	335.	galanin 1-13-Pro-Pro-(Ala-Leu) 2-Ala-
			amide C7
336.	galanin 1-13-spantide-amide GMAP	337.	amide GMAP 16-41
	1-41
338.	amide GMAP 25-41	339.	amide galantide and entero-kassinin
340.	gastrin	341.	chicken gastric inhibitory peptide (GIP)
342.	human gastrin I	343.	human biotinyl-gastrin I
344.	human big gastrin-1	345.	human gastrin releasing peptide
346.	human gastrin releasing peptide 1-16	347.	human gastric inhibitory polypeptide
			(GIP)
348.	porcine gastrin releasing peptide	349.	porcine biotinyl-gastrin releasing peptide
350.	porcine gastrin releasing peptide 14-	351.	porcine, human little gastrin
	27
352.	rat pentagastrin gastric inhibitory	353.	porcine gastric inhibitory peptide 1-30,
	peptide 1-30		amide
354.	porcine {Tyr⁰-gastric inhibitory	355.	human and gastric inhibitory peptide, rat
	peptide 23-42
356.	{Des-His′-Glu⁹}-glucagon	357.	exendin-4
358.	glucagon	359.	human biotinyl-glucagon
360.	human glucagon 19-29	361.	human glucagon 22-29
362.	human {Des-His¹-Glu⁹}-glucagon	363.	amide glucagon-like peptide 1
364.	amide glucagon-like peptide 1	365.	human glucagon-like peptide 1 (7-36)
			glucagon-like peptide 2
366.	rat biotinyl-glucagon-like peptide-1	367.	(biofinyl-preproglucagon 78-107, amide)
	(7-36)
368.	glucagon-like peptide 2	369.	human intervening peptide-2
			oxyntomodulin/glucagon 37
370.	valosin (peptide VQY), porcine	371.	Gn-RH associated peptide 25-53
372.	human Gn-RH associated peptide 1-	373.	human Gn-RH associated peptide 1-13
	24
374.	human Gn-RH associated peptide 1-	375.	rat gonadotropin releasing peptide
	13
376.	human {Tyr⁰}-GAP({Tyr⁰}-Gn-RH	377.	proopiomelanocortin (POMC) precursor
	Precursor Peptide 14-69)		27-52, porcine
378.	TGF-d	379.	TGF beta
380.	TF alpha	381.	TGF 34-43
382.	EGF, any mammalian version	383.	human acidic fibroblast growth factor
			basic
384.	fibroblast growth factor	385.	basic fibroblast growth factor 13-18
386.	basic fibroblast growth factor 120-	387.	brain derived acidic fibroblast growth
	125		factor 1-11
388.	brain derived basic fibroblast growth	389.	brain derived acidic fibroblast growth
	factor 1-24		factor 102-111
390.	{Cys(Acm^20,31)}-epidermal growth	391.	epidermal growth factor receptor peptide
	factor 20-31		985-996
392.	insulin-like growth factor (IGF)-I	393.	chicken IGF-I
394.	rat IGF-I	395.	human Des (1-3) IGF-I
396.	human R3 IGF-I	397.	human R3 IGF-I
398.	human long R3 IGF-I	399.	human adjuvant peptide analog
400.	anorexigenic peptide Des (1-6)	401.	IGF-II
402.	human R6 IGF-II	403.	human IGF-I analogue IGF 1 (24-41)
404.	IGF 1 (57-70)	405.	IGF I (30-41)
406.	IGF II IGF II (33-40)	407.	{Tyr⁰}-IGF II (33-40)
408.	liver cell growth factor midkine	409.	midkine 60-121
410.	alpha-TGF 34-43	411.	human alpha-TGF 34-43
412.	human alpha-TGF 34-43	413.	rat nerve growth factor (NGF)
414.	mouse platelet-derived growth factor	415.	platelet-derived growth factor
416.	transforming growth factor-α	417.	human and rat transforming growth
			factor-I
418.	growth hormone (hGH)	419.	human growth hormone 1-43
420.	human growth hormone 6-13	421.	human growth hormone releasing factor
422.	murine growth hormone releasing	423.	bovine growth hormone releasing factor
	factor
424.	porcine growth hormone releasing	425.	rat growth hormone pro-releasing factor
	factor 1-29, amide
426.	human biotinyl-growth hormone	427.	human growth hormone releasing factor
	releasing factor		1-29, amide
428.	human {D-Ala²}-growth hormone	429.	human {N-Ac-Tyr¹,D-Arg²}-GRF 1-29,
	releasing factor 1-29, amide		amide
430.	{His¹,Nle²⁷}-growth hormone	431.	growth hormone releasing factor 1-37
	releasing factor 1-32, amide
432.	human growth hormone releasing	433.	human growth hormone releasing factor
	factor 140		1-40, amide
434.	human growth hormone releasing	435.	human growth hormone releasing factor
	factor 30-44, amide
436.	mouse growth hormone releasing	437.	ovine growth hormone releasing factor
	factor
438.	rat biotinyl-growth hormone releasing	439.	rat GHRP-6({His¹,Lys⁶}-GHRP)
	factor
440.	hexarelin (growth hormone releasing	441.	{D-Lys3}-GHRP-6
	hexapeptide)
442.	{Arg⁸}-GTP-binding protein	443.	Gs alpha GTP-binding protein fragment
	fragment
445.	G beta GTP-binding protein fragment	446.	GAlpha GTP-binding protein fragment
447.	Go Alpha GTP-binding protein	448.	Gs Alpha and GTP-binding protein
	fragment		fragment
449.	G Alpha i2	450.	guanylin
451.	human guanylin	452.	rat uroguanylin
453.	human uroguanylin	454.	inhibin
455.	bovine inhibin	456.	alpha-subunit 1-32
457.	human {Tyr⁰}-inhibin, alpha-subunit	458.	human seminal plasma inhibin-like
	1-32		peptide
459.	human {Tyr⁰}- seminal plasma	460.	human inhibin
	inhibin-like peptide
461.	alpha-subunit 1-32	462.	porcine and {Tyr⁰}-inhibin, alpha-subunit
			1-32, porcine
463.	human insulin	464.	porcine IGF-I
465.	human insulin-like growth factor II	466.	pro-insulin-like growth factor 11 (68-
	(69-84)		102)
467.	human pro-insulin-like growth factor	468.	human {Asp^B28}-insulin
	II (105-128)
469.	human {Lys^B28}-insulin	470.	human {Leu^B28}-insulin
471.	human {Val^B28}-insulin	472.	human {Ala^B28}-insulin
473.	human {Asp^B28,Pro^B29}-insulin	474.	human {Lys^B28,Pro^B29}-insulin
475.	human {Leu^B28Pro^B29}-insulin	476.	human {Val^B28,Pro^B29}-insulin
477.	human {Ala^B28,Pro^B29}-insulin	478.	human {Gly^A21}-insulin
479.	human {Gly^A21Gln^B30}-insulin	480.	human {Ala^A21}-insulin
481.	human {Ala^A21Gln^B30}insulin	482.	human {Gln^B30}-insulin
483.	human {Gln^B30}-insulin	484.	human {Gly^A21Glu^B30}-insulin
485.	human {Gly^A21Gln^B3Glu^B30}-insulin	486.	human {Gln^B3Glu^B30}-insulin
487.	human B22-B30 insulin	488.	human B23-B30 insulin
489.	human B25-B30 insulin	490.	human B26-B30 insulin
491.	human B27-B30 insulin	492.	human B29-B30 insulin
493.	A chain of human insulin	494.	B chain of human insulin
495.	interleukin-1 beta 165-181, rat	496.	rat IL-8
497.	laminin alpha1 (I)-CB3 435-438, rat	498.	laminin binding inhibitor
499.	leptin 93-105	500.	human leptin 22-56, rat
501.	Tyr-leptin 26-39, human	502.	leptin 116-130, amide, mouse
503.	leucomyosuppressin (LMS)	504.	leucopyrokinin (LPK)
505.	leucokinin I	506.	leucokinin II
507.	leucokinin III	508.	leucokinin IV
509.	leucokinin VI	510.	leucokinin VII
511.	leucokinin VIII	512.	antide Gn-RH II
513.	chicken luteinizing hormone-	514.	(GnRH) biotinyl-LH-RH
	releasing hormone (LH-RH)
515.	cetrorelix (D-20761)	516.	{D-Ala⁶}-LH-RH
517.	{Gln⁸}-LH-RH (Chicken LH-RH)	518.	{DLeu⁶,Val⁷}LH-RH 1-9
519.	ethyl amide {D-Lys⁶}-LH-RH	520.	{D-Phe²,Pro³,D-Phe⁶}-LH-RH
521.	{DPhe²,DAla⁶} LH-RH	522.	{Des-Gly¹⁰}-LH-RH, ethyl amide
523.	{D-Ala⁶,Des-Gly¹⁰}-LH-RH, ethyl	524.	{DTrp⁶}-LH-RH, ethyl amide
	amide
525.	{D-Trp⁶,Des-Gly¹⁰}-LH-RH, ethyl	526.	{DSer(But)₆,Des-Gly¹⁰}-LH-RH, ethyl
	amide (Deslorelin)		amide ethyl amide leuprolide
527.	LH-RH 4-10	528.	LH-RH 7-10 LH-RH
529.	free acid LH-RH	530.	lanprey LH-RH
531.	salmon {Lys⁸}-LH-RH	532.	{Trp⁷,Leu⁸} LH-RH, free acid
533.	{(t-Bu)DSer⁶,(Aza)Gly¹⁰}-LH-RH	534.	{(t-Bu)DSer⁶,(Aza)Gly¹⁰}-LH-RH
	free acid
535.	mastoparan	536.	mas7
537.	mas8	538.	mas17
539.	mastoparan X	540.	mast cell degranulating peptide HR-1
541.	mast cell degranulating peptide HR-2	542.	{Ac-Cys⁴,DPhe⁷,Cys¹⁰⁰} alpha-MSH 4-
			13
543.	amide alpha-melanocyte stimulating	544.	free acid beta-MSH, porcine
	hormone alpha-MSH
545.	biotinyl-alpha-melanocyte	546.	biotinyl-{Nle⁴,D-Phe⁷}
	stimulating hormone
547.	alpha-melanocyte stimulating	548.	{Des-Acetyl}-alpha-MSH {DPhe⁷}-
	hormone		alpha-MSH, amide
549.	gamma-1-MSH, amide	550.	{Lys⁰}-gamma-1-MSH, amide
551.	MSH release inhibiting factor, amide	552.	{Nle⁴}-alpha-MSH, amide
553.	{Nle⁴,D-Phe⁷}-alpha-MSH N-Acetyl	554.	{Nle⁴,DPhe⁷} alpha-MSH 4-10, amide
555.	beta-MSH, human	556.	gamma-MSH
557.	morphiceptin (beta-casomorphin 14	558.	{D-Pro⁴}-morphiceptin
	amide)
559.	{N-MePhe³,D-Pro⁴}-morphiceptin	560.	motilin
561.	canine motilin	562.	porcine biotinyl-motilin
563.	porcine {Leu¹³}-motilin	564.	Ac-Asp-Glu achatina cardio-excitatory
			peptide-1 (ACEP-1) (Achatina fulica)
565.	adipokinetic hormone (AKH)	566.	adipokinetic hormone (Heliothis zea and
	(Locust)		Manduca sexta)
567.	alytesin Tabanus atratus	568.	adipokinetic hormone (Taa-AKH)
569.	adipokinetic hormone II (Locusta	570.	adipokinetic hormone II (Schistocera
	migratoria)		gregaria)
571.	adipokinetic hormone III (AKH-3)	572.	adipokinetic hormone G (AKH-G)
			(Gryllus bimaculatus)
573.	allatotropin (AT) (Manduca sexta)	574.	allatotropin 6-13 (Manduca sexta)
575.	APGW amide (Lymnaea stagnalis)	576.	buccalin
577.	{Des-Ser¹}-cerebellin corazonin	578.	crustacean cardioactive peptide (CCAP)
	(American Cockroach Periplaneta
	americana)
579.	crustacean erythrophore DF2	580.	diazepam-binding inhibitor fragment
	(Procambarus clarkii)
581.	human diazepam binding inhibitor	582.	eledoisin related peptide FMRF amide
	fragment (ODN)		(molluscan cardioexcitatory neuropeptide)
583.	cerebellin	584.	human granuliberin R head activator
			neuropeptide {His⁷}-corazonin
585.	stick insect hypertrehalosaemic factor	586.	Tabanus atratus hypotrehalosemic
	II		hormone (Taa-HoTH)
587.	rat NGE (prepro-MCH 110-128)	588.	methiodide piperidine-4-sulphonic acid
	neuropeptide		joining peptide of proopiomelanocortin
589.	(POMC)	590.	bovine joining peptide
591.	rat KSAYMRF amide (P. reclivivus)	592.	kassinin kinetensin levitide
593.	litorin LUQ 81-91 (Aplysia	594.	LUQ 83-91 (Aplysia californica)
	californica)
595.	myoactive peptide I (Periplanetin CC-	596.	myoactive peptide II (Periplanetin CC-2)
	1)
597.	myomodulin neuron specific peptide	598.	neuron specific enolase 404-443
599.	rat neuropeptide FF neuropeptide K	600.	porcine NEI (prepro-MCH 131-143)
			neuropeptide
601.	rat NGE (prepro-MCH 110-128)	602.	rat NFI (Procambarus clarkii)
	neuropeptide
603.	PBAN-1 (Bombyx mori)	604.	Hez-PBAN (Heliothis zea)
605.	SCPB (cardioactive peptide from	606.	secretoneurin, rat uperolein
	aplysia)
607.	urechistachykinin I	608.	urechistachykinin II
609.	xenopsin-related peptide I	610.	xenopsin-related peptide II
611.	pedal peptide (Pep)	612.	aplysia peptide F1
613.	lobster, phyllomedusin	614.	polistes mastoparan
615.	proctolin	616.	ranatensin Ro I (Lubber Grasshopper,
			Romalea microptera)
617.	Ro II (Lubber Grasshopper, Romalea	618.	SALMF amide 1 (S1)
	microptera)
619.	SALMF amide 2 (S2)	620.	SCPA
621.	{Leu³¹,Pro³⁴} neuropeptide Y,	622.	B1BP3226 NPY antagonist Bis (31/31′)
	human neuropeptide F (Moniezia expansa)		{{Cys³¹,Trp³²,Nva³⁴} NPY 31-36}.
			neuropeptide Y, human
623.	rat neuropeptide Y 1-24 amide	624.	human biotinyl-neuropeptide Y
625.	{D-Tyr^27,36,D-Thr³²}-NPY 27-36	626.	Des 10-17 (cyclo 7-21) {Cys^7,21,Pro³⁴}-
			NPY C2-NPY
627.	{Leu³¹,Pro³⁴} neuropeptide Y	628.	human neuropeptide Y
629.	porcine prepro NPY 68-97	630.	human N-acetyl-{Leu²⁸,Leu³¹} NPY 24-
			36 neuropeptide Y
631.	porcine {D-Trp³²}-neuropeptide Y	632.	porcine {D-Trp³²} NPY 1-36
633.	human {Leu¹⁷,DTrp³²} neuropeptide	634.	human {Leu³¹,Pro³⁴}-NPY
	Y
635.	porcine NPY 2-36	636.	porcine NPY 3-36
637.	human NPY 3-36	638.	porcine NPY 13-36
639.	human NPY 13-36	640.	porcine NPY 16-36
641.	porcine NPY 18-36	642.	porcine NPY 20-36
643.	FY 22-36 NPY 26-36	644.	Pro³⁴}-NPY 1-36
645.	human {Pro³⁴}-neuropeptide Y	646.	porcine PYX-1
647.	PYX-2	648.	T4- {NPY(33-36)}4
649.	Tyr(OMe)²¹}-neuropeptide Y, human	650.	glial derived neurotropic factor (GDNF)
651.	brain derived neurotropic factor	652.	ciliary neurotropic factor (CNTF)
	(BDNF)
653.	orexin A	654.	human orexin B
655.	rat orexin B	656.	mouse orexin B
657.	alpha-casein fragment 90-95	658.	BAM-18P
659.	casomokinin L	660.	casoxin D
661.	crystalline DALDA	662.	dermenkephalin (deltorphin)
			(Phylomedusa sauvagei)
663.	{D-Ala²}-deltorphin I	664.	{D-Ala²}-deltorphin II
665.	endomorphin-1	666.	endomorphin-2
667.	kyotorphin	668.	{DArg²}-kyotorphin
669.	morphine tolerance peptide	670.	morphine modulating peptide
671.	C-terminal fragment morphine	672.	nociceptin {orphanin FQ} (ORL1
	modulating neuropeptide (A-18-F—NH2)		agonist)
673.	TIPP	674.	Tyr-MIF-1
675.	Tyr-W-MIF-1	676.	valorphin LW-hemorphin-6
677.	human Leu-valorphin-Arg	678.	Z-Pro-D-Leu
679.	{Asu⁶}-oxytocin	680.	oxytocin
681.	biotinyl-oxytocin	682.	{Thr⁴,Gly⁷}-oxytocin
683.	tocinoic acid ({Ile³}-pressinoic acid)	684.	PACAP 1-27, human, ovine, rat
685.	PACAP (1-27)-Gly-Lys-Arg-NH₂	686.	human {Des-Gln¹⁶}-PACAP 6-27
687.	human, ovine, rat PACAP38	688.	frog PACAP27-NH₂
689.	human, ovine, rat biotinyl-PACAP27-	690.	human, ovine, rat PACAP 6-27
	NH2
691.	human, ovine, rat PACAP38	692.	human, ovine, rat biotinyl-PACAP38
693.	human, ovine, rat PACAP 6-38	694.	human, ovine, rat PACAP27-NH₂
695.	human, ovine, rat biotinyl-PACAP27-	696.	human, ovine, rat PACAP 6-27
	NH₂
697.	human, ovine, rat PACAP38	698.	human, ovine, rat biotinyl-PACAP38
699.	human, ovine, rat PACAP 6-38	700.	human, ovine, rat PACAP38 16-38
701.	human, ovine, rat PACAP38 31-38	702.	human, ovine, rat PACAP38 31-38
703.	human, ovine, rat PACAP-related	704.	human
	peptide (PRP)
705.	PACAP-related peptide (PRP), rat	706.	chromostatin
707.	bovine pancreastatin (hPST-52)	708.	pancreastatin 24-52 (hPST-29)
	(chromogranin A 250-301, amide)
709.	human chromogranin A 286-301,	710.	human pancreastatin
	amide
711.	porcine biotinyl-pancreastatin	712.	porcine {Nle⁸}-pancreastatin
713.	porcine {Tyr⁰,Nle⁸}-pancreastatin	714.	porcine {Tyr⁰}-pancreastatin
715.	porcine parastatin 1-19	716.	porcine pancreastatin
	(chromogranin A 347-365)
717.	chromogranin A 264-314-amide	718.	rat biotinyl-pancreastatin
719.	biotinyl-chromogranin A 264-314-	720.	{Tyr⁰}-pancreastatin
	amide
721.	rat pancreastatin 26-51	722.	pancreastatin 33-49, porcine
723.	pancreatic polypeptide	724.	avian pancreatic polypeptide
725.	human C-fragment pancreatic	726.	human C-fragment pancreatic
	polypeptide acid		polypeptide amide
727.	human pancreatic polypeptide (Rana	728.	ancreatic polypeptide
	temporaria)
729.	salmon pancreatic polypeptide	730.	{Asp⁷⁶-parathyroid hormone 39-84
731.	human {Asp⁷⁶}-parathyroid hormone	732.	human {Asn⁷⁶}-parathyroid hormone 1-
	53-84		84
733.	hormone {Asn⁷⁶}-parathyroid	734.	human {Asn⁸, Leu¹⁸}-parathyroid
	hormone 64-84		hormone 1-34
735.	human {Cys^5,28}-parathyroid	736.	human hypercalcemia malignancy factor
	hormone 1-34		1-40
737.	{Leu¹⁸}-parathyroid hormone 1-34	738.	human {Lys(biotinyl) ¹³
739.	{Nle^8,18,Tyr³⁴}-parathyroid hormone	740.	{Nle^8,18,Tyr³⁴}-parathyroid hormone 3-
	1-34 amide		34 amide
741.	bovine {Nle^8,18,Tyr³⁴}-parathyroid	742.	human {Nle^8,18,Tyr³⁴}-parathyroid
	hormone 1-34		hormone 1-34 amide
743.	human {Nle^8,18,Tyr³⁴}-parathyroid	744.	human {Nle^8,18,Tyr³⁴}-parathyroid
	hormone 3-34 amide		hormone 7-34 amide
745.	bovine {Nle^8,21,Tyr³⁴}-parathyroid	746.	rat parathyroid hormone 44-68
	hormone 1-34 amide
747.	human parathyroid hormone 1-34	748.	bovine parathyroid hormone 3-34
749.	bovine parathyroid hormone 1-31	750.	human parathyroid hormone 1-34
	amide
751.	human parathyroid hormone 13-34	752.	human parathyroid hormone 1-34
753.	rat parathyroid hormone 1-38	754.	human parathyroid hormone 1-44
755.	human parathyroid hormone 28-48	756.	human parathyroid hormone 39-68
757.	human parathyroid hormone 39-84	758.	human parathyroid hormone 53-84
759.	human parathyroid hormone 69-84	760.	human parathyroid hormone 70-84
761.	human {Pro³⁴}-peptide YY (PYY)	762.	human {Tyr⁰}-hypercalcemia malignancy
			factor 1-40
763.	{Tyr⁰}-parathyroid hormone 1-44	764.	human {Tyr⁰}-parathyroid hormone 1-34
765.	human {Tyr¹}-parathyroid hormone	766.	human {Tyr²⁷}-parathyroid hormone 27-
	1-34		48
767.	human {Tyr³⁴}-parathyroid hormone	768.	bovine {Tyr⁴³}-parathyroid hormone 43-
	7-34 amide		68
769.	human {Tyr⁵²,Asn⁷⁶}-parathyroid	770.	{Tyr⁶³}-parathyroid hormone 63-84,
	hormone 52-84		human
771.	PTHrP ({Tyr³⁶}-PTHrP 1-36 amide)	772.	chicken hHCF-(1-34)-NH2 (humoral
			hypercalcemic factor)
773.	human PTH-related protein 1-34	774.	human biotinyl-PTH-related protein 1-34
775.	human {Tyr⁰}-PTH-related protein 1-	776.	human {Tyr³⁴}-PTH-related protein 1-34
	34		amide
777.	human PTH-related protein 1-37	778.	human PTH-related protein 7-34 amide
779.	human PTH-related protein 38-64	780.	human PTH-related protein 67-86 amide
	amide
781.	human PTH-related protein 107-111	782.	human, rat, mouse PTH-related protein
			107-111 free acid
783.	PTH-related protein 107-138	784.	human and PTH-related protein 109-111
785.	peptide T {D-Ala¹}-peptide T	786.	{D-Ala¹}-peptide T amide
787.	prolactin-releasing peptide 31	788.	human prolactin-releasing peptide 20
789.	human prolactin-releasing peptide 31	790.	rat prolactin-releasing peptide 20
791.	rat prolactin-releasing peptide 31	792.	bovine prolactin-releasing peptide 20
793.	human PYY 3-36	794.	human biotinyl-PYY
795.	human PYY	796.	human {Leu³¹,Pro³⁴}-PYY
797.	porcine PYY	798.	rat PYY
799.	acetyl	800.	angiotensinogen 1-14
801.	human angiotensinogen 1-14	802.	porcine renin substrate tetradecapeptide
803.	rat {Cys⁸}-renin substrate	804.	rat {Leu⁸}-renin substrate
	tetradecapeptide		tetradecapeptide
805.	rat {Val⁸}-renin substrate	806.	canine secretin
	tetradecapeptide, rat.
807.	chicken secretin	808.	human biotinyl-secretin
809.	human secretin	810.	porcine secretin
811.	rat secretin	812.	BIM-23027
813.	biotinyl-somatostatin biotinylated	814.	human cortistatin 14
	cortistatin 17
815.	rat cortistatin 17	816.	human {Tyr⁰}-cortistatin 17
817.	human cortistatin 29	818.	rat {D-Trp⁸}-somatostatin
819.	{DTrp⁸,DCys¹⁴}-somatostatin	820.	{DTrp⁸,Tyr¹¹}-somatostatin
821.	{D-Trp¹¹}-somatostatin NTB	822.	{Nle⁸}-somatostatin 1-28
	(Naltriben)
823.	octreotide (SMS 201-995)	824.	prosomatostatin 1-32
825.	porcine {Tyr⁰}-somatostatin	826.	{Tyr⁰}-somatostatin
827.	{Tyr¹}-somatostatin 28 (1-14)	828.	{Tyr¹¹}-somatostatin {Tyr⁰}
829.	{D-Trp⁸}-somatostatin	830.	somatostatin
831.	somatostatin antagonist	832.	somatostatin-25
833.	somatostatin-28	834.	somatostatin 28 (1-12)
835.	biotinyl-somatostatin-28	836.	{Tyr⁰}-somatostatin-28
837.	{Leu⁸,D-Trp²²,Tyr²⁵}-somatostatin-	838.	biotinyl-{Leu⁸,D-Trp²²,Tyr²⁵}-
	28		somatostatin-28
839.	somatostatin-28 (1-14)	840.	RC-160
841.	G protein antagonist-2 Ac-{Arg⁶,	842.	Ac-Trp-3,5-bis(trifluoromethyl)benzyl
	Sar⁹, Met(02)¹¹}-substance P 6-11 {Arg³}-		ester Ac-{Arg⁶,Sar⁹,Met(O2)¹¹}-substance P
	substance P
843.	6-11 {D-Ala⁴}-substance P	844.	4-11 {Tyr⁶,D-Phe⁷,D-His⁹}-substance P
845.	6-11 (sendide) biotinyl-substance P	846.	{Tyr⁸}-substance P
	biotinyl-NTE{Arg³}-substance P
847.	{Sar⁹,Met(O2)¹¹}-substance P	848.	{D-Pro²,DTrP^7,9}-substance P
849.	{D-Pro⁴,O-TrP^7,9}-substance P	850.	4-11 substance P
851.	4-11 {DTrp^2,7,9}-substance P	852.	{(Dehydro)Pro^2,4,Pro⁹}-substance P
853.	{Dehydro-Pro⁴}-substance P	854.	4-11 {Glp⁵,(Me)Phe⁸,Sar⁹}-substance P
855.	5-11 {Glp⁵,Sar⁹}-substance P	856.	5-11 {Glp⁵}-substance P
857.	5-11 hepta-substance P (substance P	858.	{MePhe⁸,Sar⁹}-substance P
	5-11) hexa-substance P(substance P6-11)
859.	{Nle¹¹}-substance P	860.	Octa-substance P(substance P4-11)
861.	{pGlu¹}-hexa-substance P	862.	({pGlu⁶}-substance P6-11)
863.	{pGlu⁶,D-Pro⁹}-substance P 6-11	864.	{(pNO₂)Phe⁷Nle¹¹}-substance P
865.	penta-substance P (substance P7-11)	866.	{Pro⁹}-substance P GR73632
867.	substance P7-11	868.	{Sar⁴}-substance P4-11
869.	{Sar⁹}-substance P septide	870.	({pGlu⁶,Pro⁹}-substance P 6-11)
871.	spantide I	872.	spantide II
873.	cod substance P	874.	trout substance P
875.	antagonist substance P-Gly-Lys-Arg	876.	substance P 1-4
877.	substance P 1-6	878.	substance P 1-7
879.	substance P 1-9	880.	deca-substance P (substance P 2-11)
881.	nona-substance P (substance P 3-11)	882.	substance P tetrapeptide (substance P 8-
			11)
883.	substance P tripeptide (substance P 9-	884.	substance P, free acid
	11)
885.	substance P methyl ester	886.	{Tyr⁸,Nle¹¹} substance P
887.	{Ala⁵,beta-Ala⁸} neurokinin A	888.	4-10 eledoisin
889.	locustatachykinin I (Lom-TK-I)	890.	locustatachykinin II (Lom-TK-II)
	(Locusta migratoria)		(Locusta migratoria)
891.	neurokinin A 4-10	892.	neurokinin A (neuromedin L, substance
			K)
893.	cod neurokinin A	894.	biotinyl-neurokinin A (biotinyl-
			neuromedin L, biotinyl-substance K)
895.	{Tyr⁰}-neurokinin A	896.	{Tyr⁶}-substance K
897.	FR64349	898.	{Lys³,Gly⁸-(R)-gamma-lactam-Leu⁹}-
			neurokinin A 3-10
899.	GR83074	900.	GR87389
901.	GR94800	902.	{Beta-Ala⁸}-neurokinin A 4-10
903.	{Nle¹⁰}-neurokinin A 4-10	904.	{Trp⁷,beta-Ala⁸}-neurokinin A 4-10
905.	neurokinin B (neuromedin K)	906.	biotinyl-neurokinin B (biotinyl-
			neuromedin K)
907.	{MePhe⁷}-neurokinin B	908.	{Pro⁷}-neurokinin B
909.	{Tyr⁰}-neurokinin B	910.	neuromedin B
911.	porcine biotinyl-neuromedin B	912.	porcine neuromedin B-30
913.	porcine neuromedin B-32	914.	porcine neuromedin B
915.	receptor antagonist neuromedin C	916.	porcine neuromedin N
917.	porcine neuromedin (U-8)	918.	porcine neuromedin (U-25)
919.	porcine neuromedin U	920.	rat neuropeptide-gamma (gamma-
			preprotachykinin 72-92)
921.	PG-KII phyllolitorin	922.	{Leu⁸}-phyllolitorin (Phyllomedusa
			sauvagei)
923.	physalaemin	924.	physalaemin 1-11
925.	scyliorhinin II, amide	926.	dogfish senktide
927.	selective neurokinin B receptor	928.	{Ser²}-neuromeclin C
	peptide
929.	beta-preprotachykinin 69-91	930.	human beta-preprotachykinin 111-129
931.	human tachyplesin I	932.	xenopsin
933.	human xenopsin 25 (xenin 25)	934.	biotinyl-thyrotropin-releasing hormone
935.	{Glu¹}-TRH	936.	His-Pro-diketopiperazine
937.	{3-Me-His²}-TRH	938.	pGlu-Gln-Pro-amide pGlu-His {Phe²}-
			TRH
939.	prepro TRH 53-74	940.	prepro TRH 83-106
941.	prepro-TRH 160-169	942.	Ps4, TRH-potentiating peptide
943.	prepro-TRH 178-199	944.	thyrotropin-releasing hormone (TRH)
945.	TRH, free acid	946.	TRH-SH Pro
947.	TRH precursor peptide	948.	omega-agatoxin TK agelenin, (spider,
			Agelena opulenta)
949.	apamin (honeybee, Apis mellifera)	950.	calcicudine (CaC) (green mamba,
			Dedroaspis angusticeps)
951.	calciseptine (black mamba,	952.	charybdotoxin (ChTX) (scorpion, Leiurus
	Dendroaspis polylepis polylepis)		quinquestriatus var. hebraeus)
953.	chlorotoxin conotoxin GI (marine	954.	conotoxin GS (marine snail, Conus
	snail, Conus geographus)		geographus)
955.	conotoxin MI (Marine Conus magus)	956.	alpha-conotoxin EI, Conus ermineus
957.	alpha-conotoxin SIA	958.	alpha-conotoxin ImI alpha-conotoxin SI
			(cone snail, Conus striatus)
959.	micro-conotoxin GIIIB (marine snail,	960.	omega-conotoxin GVIA (marine snail,
	Conus geographus)		Conus geographus)
961.	omega-conotoxin MVIIA (Conus	962.	omega-conotoxin MVIIC (Conus magus)
	magus)
963.	omega-conotoxin SVIB, (cone snail,	964.	endotoxin inhibitor geographutoxin I
	Conus striatus)		(GTX-I) (.mu.-Conotoxin GIIIA)
965.	iberiotoxin (IbTX) (scorpion, Buthus	967.	kaliotoxin 1-37 kaliotoxin (scorpion,
	tamulus)		Androctonus mauretanicus mauretanicus)
968.	mast cell-degranulating peptide	969.	margatoxin (MgTX) (scorpion,
	(MCD-peptide, peptide 401)		Centruriodes Margaritatus)
970.	neurotoxin NSTX-3 (Papua New	971.	PLTX-II (spider, Plectreurys tristes)
	Guinean spider, Nephilia maculata)
972.	scyllatoxin (leiurotoxin I)	973.	stichodactyla sheep VIP toxin (ShK)
974.	stichodactyla porcine VIP toxin	975.	stichodactyla rat VIP toxin (ShK)
	(ShK)
976.	VIP-Gly-Lys-Arg-NH₂biotinyl-PHI	977.	porcine {Glp¹⁶} VIP 16-28
	(biotinyl-PHI-27)
978.	porcine PHI (PHI-27)	979.	porcine PHI (PHI-27)
980.	rat PHM-27 (PHI)	981.	human prepro VIP 81-122
982.	human preproVIP/PHM 111-122	983.	prepro VIP/PHM 156-170
984.	biotinyl-PHM-27 (biotinyl-PHI)	985.	human vasoactive intestinal contractor
			(endothelin-beta)
986.	vasoactive intestinal octacosa-peptide	987.	chicken vasoactive intestinal peptide
988.	guinea pig biotinyl-VIP	989.	human VIP peptide 1-12
990.	porcine VIP peptide 1-12	991.	rat VIP peptide 1-12
992.	sheep VIP peptide 1-12	993.	human VIP peptide 10-28
994.	porcine VIP peptide 10-28	995.	rat VIP peptide 10-28
996.	sheep VIP peptide 10-28	997.	human VIP peptide 11-28
998.	porcine VIP peptide 11-28	999.	rat VIP peptide 11-28
1000.	sheep VIP peptide 11-28	1001.	human VIP peptide 6-28
1002.	porcine VIP peptide 6-28	1003.	rat VIP peptide 6-28
1004.	sheep VIP peptide 6-28	1005.	vasoactive intestinal peptide antagonist
1006.	vasoactive intestinal peptide	1007.	vasoactive intestinal peptide receptor
	antagonist ({Ac-Tyr¹,D-Phe²}-GHRF 1-29		antagonist (4-Cl-D-Phe⁶,Leu¹⁷}-VIP)
	amide)
1008.	vasoactive intestinal peptide	1009.	Ala{^11,22,28}VIP
	receptor binding inhibitor, L-8-K
1010.	Ala{^{2,8,9,11,19,22,24,25,27,28}} VIP	1011.	{K¹⁵,R¹⁶,L²⁷}-VIP(1-7)/GRF(8-27)
1012.	Ro25-1553	1013.	Ro25-1392
1014.	BAY55-9837	1015.	R3P65
1016.	Maxadilan	1017.	PG97-269
1018.	PG99-465	1019.	Max.d.4.
1020.	M65 (Dickson & Finlayson,	1021.	{Asu^1,6,Arg⁸}-vasopressin
	Pharmacology & Therapeutics, Volume
	121, Issue 3, March 2009, Pages 294-316).
1022.	vasotocin	1023.	{Asu^1,6,Arg⁸}-vasotocin
1024.	{Lys⁸}-vasopressin	1025.	{Arg⁸}-desamino vasopressin
1026.	desglycinamide	1027.	{Arg⁸}-vasopressin (AVP)
1028.	{Arg⁸}-vasopressin desglycinamide	1029.	biotinyl-{Arg⁸}-vasopressin (biotinyl-
			AVP)
1030.	{D-Arg⁸}-vasopressin	1031.	desamino-Arg⁸-vasopressin
1032.	desamino-{D-Arg⁸}-vasopressin	1033.	{deamino-{D-3-(3′-pyridyl-Ala)}-
	(DDAVP)		{Arg⁸}-vasopressin
1034.	{1-(beta-Mercapto-beta,beta-	1035.	vasopressin metabolite neuropeptide
	cyclopentamethylene propionic acid), 2-(O-
	methyl)tyrosine}-{Arg⁸}-vasopressin
1036.	{pGlu⁴,Cys⁶} vasopressin	1037.	{pGlu⁴,Cys⁶} {Lys⁸}-deamino
	metabolite neuropeptide		vasopressin desglycinamide
1038.	{Lys⁸}-vasopressin	1039.	{Mpr¹,Val⁴,DArg⁸}-vasopressin
1040.	{Phe²,Ile³,Orn⁸}-vasopressin	1041.	({Phe²,Orn⁸}-vasotocin)
1042.	{Arg⁸}-vasotocin	1043.	{d(CH₂)₅,Tyr(Me)₂,Orn⁸}-vasotocin
1044.	human CMV protease substrate	1045.	HCV core protein 59-68
1046.	HCV NS4A	1047.	protein 1840 (JT strain)
1048.	HCV NS4A protein 21-34 (JT	1049.	hepatitis B virus receptor binding
	strain)		fragment
1050.	hepatitis B virus pre-S region 120-	1051.	{Ala¹²⁷}-hepatitis B virus pre-S region
	145		120-131
1052.	herpes virus inhibitor 2	1053.	HIV envelope protein fragment 254-274
1054.	HIV gag fragment 129-135	1055.	HIV substrate P 18 peptide
1056.	peptide T	1057.	{3,5 diiodo-Tyr⁷} peptide T
1058.	R15K	1059.	HIV-1 inhibitory peptide T20
1060.	T21	1061.	V3
1062.	decapeptide P 18-110	1063.	virus replication inhibiting peptide
1064.	buforin I	1065.	buforin II
1066.	cecropin A	1067.	cecropin B
1068.	cecropin P1	1069.	porcine gaegurin 2 (Rana rugosa)
1070.	gaegurin 5 (Rana rugosa)	1071.	indolicidin
1072.	protegrin-(PG)-I	1073.	magainin 1
1074.	magainin 2	1075.	T-22
1076.	{Tyr^5,12,Lys⁷}-poly-phemusin II	1077.	Alzheimer′s disease beta-protein (SP28)
	peptide
1078.	calpain inhibitor peptide	1079.	capsase-1 inhibitor V
1080.	capsase-3	1081.	substrate IV caspase-1 inhibitor I
1082.	cell-permeable caspase-1 inhibitor	1083.	caspase-3 substrate III
	VI
1084.	caspase-1 substrate V	1085.	fluorogenic caspase-3 inhibitor I
1086.	cell-permeable caspase-6	1087.	ICE inhibitor III
1088.	{Des-Ac,biotin}-ICE inhibitor III	1089.	IL-1B converting enzyme (ICE)
			inhibitor II
1090.	IL-1 B converting enzyme (ICE)	1091.	MDL 28170
	substrate IV
1092.	MG-132	1093.	alpha-ANP (alpha-chANP)
1094.	chicken anantin ANP 1-11	1095.	rat ANP 8-30
1096.	frog ANP 11-30	1097.	frog ANP-21 (fANP-21)
1098.	frog ANP-24 (fANP-24)	1099.	frog ANP-30
1100.	frog ANP fragment 5-28	1101.	human ANP 7-23
1102.	canine ANP 7-23	1103.	human ANP fragment 7-28
1104.	human alpha-atrial natriuretic	1105.	canine alpha-atrial natriuretic
	polypeptide 1-28		polypeptide 1-28
1106.	human A71915	1107.	canine A71915
1108.	rat atrial natriuretic factor 8-33	1109.	rat atrial natriuretic polypeptide 3-28
1110.	human atrial natriuretic polypeptide	1111.	human atrial natriuretic polypeptide 5-
	4-28		27
1112.	canine atrial natriuretic polypeptide	1113.	human atrial natriuretic aeptide (ANP)
	5-27
1114.	eel atriopeptin I	1115.	rat atriopeptin II
1116.	rabbit atriopeptin II	1117.	mouse atriopeptin II
1118.	rat atriopeptin III	1119.	rabbit atriopeptin III
1120.	mouse atriopeptin III	1121.	rat atrial natriuretic factor (rANF),
1122.	rabbit atrial natriuretic factor	1123.	mouse atrial natriuretic factor (rANF),
	(rANF),
1124.	rat, auriculin A (rat ANF 126-149)	1125.	auriculin B (rat ANF 126-150)
1126.	beta-ANP (1-28, dimer, antiparallel)	1127.	biotinyl-alpha-ANP 1-28
	beta-rANF 17-48
1128.	human biotinyl-atrial natriuretic	1129.	canine biotinyl-atrial natriuretic factor
	factor (biotinyl-rANF)		(biotinyl-rANF)
1130.	rat cardiodilatin 1-16	1131.	human C-ANF 4-23
1132.	rat Des-{Cys¹⁰⁵,Cys¹²¹}-atrial	1133.	rat {Met(O)¹²} ANP 1-28
	natriuretic factor 104-126
1134.	human {Mpr⁷,DAla⁹}ANP 7-28,	1135.	rat prepro-ANF 104-116
	amide
1136.	human prepro-ANF 26-55 (proANF	1137.	human prepro-ANF 56-92 (proANF 31-
	1-30)		67)
1138.	human prepro-ANF 104-123	1139.	human {Tyr⁰}-atriopeptin I
1140.	rat {Tyr⁰}-atriopeptin II	1141.	rabbit {Tyr⁰}-atriopeptin II
1142.	mouse {Tyr⁰}-atriopeptin II	1143.	rat {Tyr⁰-prepro ANF 104-123}
1144.	rabbit {Tyr⁰-prepro ANF 104-123}	1145.	mouse {Tyr⁰-prepro ANF 104-123}
1146.	human urodilatin (CDD/ANP 95-	1147.	ventricular natriuretic peptide (VNP),
	126)		eel
1148.	ventricular natriuretic peptide	1149.	alpha bag cell peptide
	(VNP), rainbow trout
1150.	alpha-bag cell peptide 1-9	1151.	alpha-bag cell peptide 1-8
1152.	alpba-bag cell peptide 1-7	1153.	beta-bag cell factor
1154.	gamma-bag cell factor	1155.	alpha-s1
1156.	casein 101-123 (bovine milk)	1157.	biotinyl-bombesin
1158.	bombesin 8-14	1159.	{Leu¹³-psi (CH₂NH)Leu¹⁴}-bombesin
1160.	{D-Phe⁶,Des-Met¹⁴}-bombesin	1161.	6-14 ethylamide {DPhe¹²} bombesin
1162.	{DPhe¹²,Leu¹⁴}-bombesin	1163.	{Tyr⁴}-bombesin
1164.	{Tyr⁴,DPhe¹²}-bombesin	1165.	bone GLA protein
1166.	bone GLA protein 45-49	1167.	{Glu¹⁷,Gla^21,24}-osteocalcin 1-49
1168.	human myclopeptide-2 (MP-2)	1169.	osteocalcin 1-49
1170.	human osteocalcin 37-49	1171.	{Tyr³⁸,Phe^42,46} bone GLA protein 38-
			49
1172.	{Ala^2,6,des-Pro³}-bradykinin	1173.	bradykinin bradykinin (Bowfin. Gar)
1174.	bradykinin potentiating peptide	1175.	bradykinin 1-3
1176.	bradykinin 1-5	1177.	bradykinin 1-6
1178.	bradykinin 1-7	1179.	bradykinin 2-7
1180.	bradykinin 2-9	1181.	{DPhe⁷} bradykinin
1182.	{Des-Arg⁹}-bradykinin	1183.	{Des-Arg¹⁰}-Lys-bradykinin
1184.	({Des-Arg¹⁰}-kallidin)	1185.	{D-N—Me-Phe⁷}-bradykinin
1186.	{Des-Arg⁹,Leu⁸}-bradykinin	1187.	Lys-bradykinin (kallidin)
1188.	Lys-(Des-Arg⁹,Leu⁸}-bradykinin	1189.	({Des-Arg¹⁰,Leu⁹}-kallidin)
1190.	{Lys⁰-Hyp³}-bradykinin	1191.	ovokinin
1192.	{Lys⁰,Ala³}-bradykinin	1193.	Met-Lys-bradykinin
1194.	peptide K12	1195.	bradykinin potentiating peptide
1196.	{(pCl)Phe^5,8}-bradykinin	1197.	T-kinin (Ile-Ser-bradykinin)
1198.	{Thi.^5,8,D-Phe⁷}-bradykinin	1199.	{Tyr⁰}-bradykinin {Tyr⁵}-bradykinin
1200.	{Tyr⁸}-bradykinin	1201.	kallikrein
1202.	BNP 32	1203.	canine BNP-like Peptide
1204.	eel BNP-32	1205.	human BNP-45
1206.	mouse BNP-26	1207.	porcine BNP-32
1208.	porcine biotinyl-BNP-32	1209.	porcine BNP-32
1210.	rat biotinyl-BNP-32	1211.	rat BNP45 (BNP 51-95, 5K cardiac
			natriuretic peptide)
1212.	human {Tyr⁰}-BNP 1-32	1213.	C-peptide
1214.	human {Tyr⁰}-C-peptide	1215.	C-type natriuretic peptide
1216.	chicken C-type natriuretic peptide-	1217.	porcine C-type natriuretic peptide-53
	22 (CNP-22)		(CNP-53)
1218.	rat C-type natriuretic peptide-53	1219.	human C-type natriuretic peptide-53
	(CNP-53)		(CNP-53)
1220.	porcine C-type natriuretic peptide-	1221.	rat C-type natriuretic peptide-53
	53
1222.	(porcine) 1-29 (CNP-531-29)	1223.	(rat) 1-29 (CNP-531-29)
1224.	prepro-CNP 1-27	1225.	rat prepro-CNP 30-50
1226.	porcine vasonatrin peptide (VNP)	1227.	rat vasonatrin peptide (VNP)
1228.	{Tyr⁰}-C-type natriuretic peptide-22	1229.	biotinyl-calcitonin
	({Tyr⁰}-CNP-22)
1230.	human biotinyl-calcitonin	1231.	rat biotinyl-calcitonin
1232.	salmon calcitonin	1233.	chicken calcitonin
1234.	eel calcitonin	1235.	human calcitonin
1236.	porcine calcitonin	1237.	rat calcitonin
1238.	salmon calcitonin 1-7	1239.	human calcitonin 8-32
1240.	salmon katacalcin (PDN-21) (C-	1241.	human N-proCT (amino-terminal
	procalcitonin)		procalcitonin cleavage peptide)
1242.	acetyl-alpha-CGRP 19-37	1243.	human alpha-CGRP 19-37
1244.	human alpha-CGRP 23-37	1245.	human biotinyl-CGRP
1246.	human biotinyl-CGRP II	1247.	human biotinyl-CGRP
1248.	rat beta-CGRP	1249.	rat biotinyl-beta-CGRP
1250.	rat CGRP	1251.	human calcitonin C-terminal adjacent
			peptide CGRP 1-19
1252.	human CGRP 20-37	1253.	human CGRP 8-37
1254.	human CGRP II	1255.	human CGRP
1256.	rat CGRP 8-37	1257.	rat CGRP 29-37
1258.	rat CGRP 30-37	1259.	rat CGRP 31-37
1260.	rat CGRP 32-37	1261.	rat CGRP 33-37
1262.	rat CGRP 31-37	1263.	rat ({Cys(Acm)^2,7}-CGRP elcatonin
1264.	{Tyr⁰}-CGRP,human {Tyr⁰}-	1265.	human {Tyr⁰}-CGRP 28-37
	CGRP II
1266.	rat {Tyr⁰}-CGRP	1267.	{Tyr²²}-CGRP 22-37, rat
1268.	human CART 55-102	1269.	human CART
1270.	rat CART 55-102	1271.	beta-casomorphin
1272.	human beta-casomorphin 1-3	1273.	beta-casomorphin 1-3, amide
1274.	beta-casomorphin, bovine	1275.	beta-casomorphin 1-4
1276.	bovine beta-casomorphin 1-5	1277.	bovine beta-casomorphin 1-5, amide
1278.	bovine beta-casomorphin 1-6	1279.	bovine {DAla²}-beta-casomorphin 1-3,
			amide
1280.	bovine {DAla²,Hyp⁴,Tyr⁵}-beta-	1281.	{DAla²,DPro⁴,Tyr⁵}-beta-casomorphin
	casomorphin 1-5 amide		1-5, amide
1282.	{DAla²,Tyr⁵}-beta-casomorphin 1-	1283.	bovine {DAla^2,4,Tyr⁵}-beta-
	5, amide		casomorphin 1-5, amide
1284.	bovine {DAla²,(pCl)Phe³}-beta-	1285.	bovine {DAla²}-beta-casomorphin 1-4,
	casomorphin, amide		amide
1286.	bovine {DAla²}-beta-casomorphin	1287.	bovine {DAla²}-beta-casomorphin 1-5,
	1-5		amide
1288.	bovine {DAla²,Met⁵}-beta-	1289.	bovine {DPro²}-beta-casomorphin 1-5,
	casomorphin 1-5		amide
1290.	bovine {DAla²}-beta-casomorphin	1291.	bovine {DPro²}-beta-casomorphin 1-4,
	1-6		amide
1292.	{Des-Tyr¹}-beta-casomorphin	1293.	bovine {DAla^2,4,Tyr⁵}-beta-
			casomorphin 1-5, amide
1294.	bovine {DAla²,(pCl)Phe³}-beta-	1295.	bovine {DAla²}-beta-casomorphin 1-4,
	casomorphin, amide		amide
1296.	bovine {DAla²}-beta-casomorphin	1297.	bovine {DAla²}-beta-casomorphin 1-5,
	1-5		amide
1298.	bovine {DAla²,Met⁵}-beta-	1299.	bovine {DPro²}-beta-casomorphin 1-5,
	casomorphin 1-5		amide
1300.	bovine {DAla²}-beta-casomorphin	1301.	bovine {DPro²}-beta-casomorphin 14,
	1-6		amide
1302.	{Des-Tyr¹}-beta-casomorphin	1303.	bovine {Val³}-beta-casomorphin 1-4,
			amide
1304.	defensin 1 (human)	1305.	HNP-1 (human neutrophil peptide-1)
1306.	N-formyl-Met-Leu-Phe	1307.	caerulein
1308.	cholecystokinin	1309.	cholecystokinin-pancreozymin CCK-33
1310.	human cholecystokinin octapeptide	1311.	cholecystokinin octapeptide (CCK 26-
	14 (non-sulfated) (CCK 26-29, unsulfated)		33)
1312.	cholecystokinin octapeptide (non-	1313.	cholecystokinin heptapeptide (CCK 27-
	sulfated) (CCK 26-33, unsulfated)		33)
1314.	cholecystokinin tetrapeptide (CCK	1315.	porcine CR 1409
	30-33) CCK-33
1316.	cholecystokinin antagonist CCK	1317.	N-acetyl cholecystokinin, CCK 26-30
	flanking peptide (unsulfated)
1318.	sulfated N-acetyl cholecystokinin,	1319.	sulfated N-acetyl cholecystokinin, CCK
	CCK 26-31		26-31
1320.	non-sulfated prepro CCK fragment	1321.	proglumide
	V-9-M
1322.	colony-stimulating factor (CSF)	1323.	GMCSF
1324.	MCSF	1325.	G-CSF
1326.	astressin alpha-helical CRF 12-41	1327.	biotinyl-CRF
1328.	ovine biotinyl-CRF	1329.	porcine CRF
1330.	human CRF	1331.	rat CRF
1332.	bovine CRF	1333.	ovine CRF
1334.	porcine {Cys²¹}-CRF	1335.	CRF antagonist human (alpha-helical
			CRF 9-41)
1336.	CRF antagonist rat (alpha-helical	1337.	CRF 6-33
	CRF 9-41)
1338.	human {DPro⁵}-CRF	1339.	rat {DPro⁵}-CRF
1340.	human {D-Phe¹²,Nle^21,38}-CRF 12-	1341.	rat {D-Phe¹²,Nle^21,38}-CRF 12-41
	41
1342.	human eosinophilotactic peptide	1343.	rat eosinophilotactic peptide {Met(0)²¹}-
	{Met(0)²¹}-CRF		CRF
1344.	ovine {Nle²¹,Tyr³²}-CRF	1345.	ovine prepro CRF 125-151
1346.	human sauvagine	1347.	frog {Tyr⁰}-CRF
1348.	human {Tyr⁰}-CRF	1349.	rat {Tyr⁰}-CRF
1350.	ovine {Tyr⁰}-CRF 34-41	1351.	ovine {Tyr⁰}-urocortin urocortin amide
1352.	human urocortin	1353.	rat urotensin I (Catostomus
			commersoni)
1354.	urotensin II	1355.	urotensin II (Rana ridibunda
1356.	cortistatin 29	1357.	cortistatin 29 (1-13)
1358.	{Tyr⁰}-cortistatin 29	1359.	pro-cortistatin 28-47
1360.	pro-cortistatin 51-81	1361.	tumor necrosis factor
1362.	TNF-r3	1363.	dermorphin
1364.	dermorphin analog 1-4	1365.	big dynorphin (prodynorphin 209-240)
1366.	porcine biotinyl-dynorphin A	1367.	{DAla²,DArg⁶}dynorphin A 1-13
	(biotinyl-prodynorphin 209-225)
1368.	porcine {D-Ala²}-dynorphin A	1369.	porcine {D-Ala²}-dynorphin A amide
1370.	porcine {D-Ala²}-dynorphin A 1-13,	1371.	porcine {D-Ala²}-dynorphin A 1-9
	amide
1372.	porcine {DArg⁶}-dynorphin A 1-13	1373.	porcine {DArg⁸}-dynorphin A 1-13
1374.	porcine {Des-Tyr¹}-dynorphin A 1-	1375.	{D-Pro¹⁰}-dynorphin A 1-11
	8
1376.	porcine dynorphin A amide	1377.	porcine dynorphin A 1-6
1378.	porcine dynorphin A 1-7	1379.	porcine dynorphin A 1-8
1380.	porcine dynorphin A 1-9	1381.	porcine dynorphin A 1-10
1382.	porcine dynorphin A 1-10 amide	1383.	porcine dynorphin A 1-11
1384.	porcine dynorphin A 1-12	1385.	porcine dynorphin A 1-13
1386.	porcine dynorphin A 1-13 amide	1387.	porcine DAKLI (dynorphin A-analogue
			kappa ligand)
1388.	DAKLI-biotin	1389.	({Arg^11,13}-dynorphin A (1-13)-Gly-
			NH(CH₂)₅NH-biotin) dynorphin A 2-17
1390.	porcine dynorphin 2-17, amide	1391.	porcine dynorphin A 2-12
1392.	porcine dynorphin A 3-17, amide	1393.	porcine dynorphin A 3-8
1394.	porcine dynorphin A 3-13	1395.	porcine dynorphin A 3-17
1396.	porcine dynorphin A 7-17	1397.	porcine dynorphin A 8-17
1398.	porcine dynorphin A 6-17	1399.	porcine dynorphin A 13-17
1400.	porcine dynorphin A (prodynorphin	1401.	porcine dynorphin B 1-9
	209-225)
1402.	{MeTyr¹,MeArg⁷,D-Leu⁸}-	1404.	porcine {Phe⁷}-dynorphin A 1-7
	dynorphin 1-8 ethyl amide {(nMe)Tyr¹}
	dynorphin A 1-13, 1403.amide
1405.	porcine {Phe⁷}-dynorphin A 1-7,	1406.	prodynorphin 228-256 (dynorphin B 29)
	amide		(leumorphin)
1407.	human ACTH 1-10	1408.	ACTH 1-13
1409.	human ACTH 1-16	1410.	human ACTH 1-17
1411.	ACTH 1-24	1412.	human ACTH 4-10
1413.	ACTH 4-11	1414.	ACTH 6-24
1415.	ACTH 7-38	1416.	human ACTH 18-39
1417.	human ACTH	1418.	rat ACTH 12-39
1419.	rat beta-cell tropin (ACTH 22-39)	1420.	biotinyl-ACTH 1-24
1421.	human biotinyl-ACTH 7-38	1422.	human corticostatin
1423.	rabbit {Met(02)⁴,DLys⁸,Phe⁹}	1424.	human {Met(0)⁴,DLys⁸,Phe⁹}ACTH 4-
	ACTH 4-9		9
1425.	human N-acetyl, ACTH 1-17	1426.	ebiratide
1427.	adrenomedullin	1428.	adrenomedullin 1-52
1429.	human adrenomedullin 1-12	1430.	human adrenomedullin 13-52
1431.	human adrenomedullin 22-52	1432.	human pro-adrenomedullin 45-92
1433.	human pro-adrenomedullin 153-185	1434.	human adrenomedullin 1-52
1435.	porcine pro-adrenomedullin (N-20)	1436.	porcine adrenomedullin 1-50
1437.	rat adrenomedullin 11-50	1438.	rat proAM-N20 (proadrenomedullin N-
			terminal 20 peptide
1439.	allatostatin I	1440.	allatostatin II
1441.	allatostatin III	1442.	allatostatin IV
1443.	acetyl-amylin 8-37	1444.	human acetylated amylin 8-37
1445.	rat AC187 amylin antagonist AC253	1446.	amylin antagonist AC625
1447.	amylin antagonist amylin 8-37	1448.	human amylin (IAPP)
1449.	cat amylin (insulinoma or islet	1450.	human amylin 1-13 (diabetes-associated
	amyloid polypeptide(IAPP)) amylin amide		peptide 1-13)
1451.	human amylin 20-29 (IAPP 20-29)	1452.	human AC625 amylin antagonist
1453.	amylin 8-37	1454.	human amylin (IAPP)
1455.	cat amylin	1456.	rat amylin 8-37
1457.	rat biotinyl-amylin	1458.	rat biotinyl-amylin amide
1459.	human biotinyl-amylin amide	1460.	Alzheimer′s disease beta-protein 12-28
			(SP17)
1461.	amyloid beta-protein 25-35	1462.	amyloid beta/A4-protein precursor 328-
			332
1463.	amyloid beta/A4 protein precursor	1464.	amyloid beta-protein 1-43 amyloid beta-
	(APP) 319-335		protein 1-42
1465.	amyloid beta-protein 1-40	1466.	amyloid beta-protein 10-20
1467.	amyloid beta-protein 22-35	1468.	Alzheimer′s disease beta-protein (SP28)
1469.	beta-amyloid peptide 1-42	1470.	rat beta-amyloid peptide 1-40
1471.	rat beta-amyloid 1-11	1472.	beta-amyloid 31-35
1473.	beta-amyloid 32-35	1474.	beta-amyloid 35-25
1475.	beta-amyloid/A4 protein precursor	1476.	beta-amyloid precursor protein 657-676
	96-110
1477.	beta-amyloid 1-38	1478.	{Gln¹¹}-Alzheimer's disease beta-
			protein
1479.	{Gln¹¹}-beta-amyloid 1-40	1480.	{Gln²²}-beta-amyloid 6-40
1481.	non-A beta component of	1482.	Alzheimer's disease amyloid β-peptide
	Alzheimer's disease amyloid (NAC) P3, (A
	beta 17-40)
1483.	SAP (serum amyloid P component)	1484.	A-779 Ala-Pro-Gly-angiotensin II
	194-204
1485.	{Ile³,Val⁵}-angiotensin II	1486.	angiotensin III
1487.	antipeptide angiogenin fragment	1488.	angiogenin fragment 108-123
	108-122
1489.	angiotensin I converting enzyme	1490.	human angiotensin I converting enzyme
	inhibitor angiotensin I		substrate angiotensin I 1-7
1491.	human angiopeptin angiotensin II	1492.	human angiotensin II antipeptide
			angiotensin II 1-4
1493.	human angiotensin II 3-8	1494.	human angiotensin II 4-8
1495.	human angiotensin II 5-8	1496.	human angiotensin III ({Des-Asp¹}-
			angiotensin II)
1497.	human angiotensin III inhibitor	1498.	angiotensin-converting enzyme inhibitor
	({Ile⁷}-angiotensin III)		(Neothunnus macropterus)
1499.	{Asn¹,Val⁵}-angiotensin I	1500.	goosefish {Asn¹,Val⁵,Asn⁹}-
			angiotensin I
1501.	salmon {Asn¹,Val⁵, Gly⁹}-	1502.	eel {Asn¹,Val⁵}-angiotensin 11-7
	angiotensin I
1503.	eel {Asn¹,Val⁵}-angiotensin II	1504.	goosefish {Asn¹,Val⁵}-angiotensin II
1505.	salmon {Asn¹,Val⁵}-angiotensin II	1506.	biotinyl-angiotensin I
1507.	human biotinyl-angiotensin II	1508.	human biotinyl-Ala-Ala-Ala-angiotensin
			II
1509.	{Des-Asp¹}-angiotensin I	1510.	human {p-aminophenylalanine⁶}-
			angiotensin II
1511.	renin substrate (angiotensinogen 1-	1512.	human preangiotensinogen 1-14 (renin
	13)		substrate tetradecapeptide)
1513.	human renin substrate	1514.	porcine {Sar¹}-angiotensin II
	tetradecapeptide (angiotensinogen 1-14)
1515.	{Sar¹}-angiotensin II 1-7 amide	1516.	{Sar¹,Ala⁸}-angiotensin II
1517.	{Sar¹,Ile⁸}-angiotensin II {Sar¹,	1518.	{Sar¹,Tyr(Me)⁴}-angiotensin II
	Thr⁸}-angiotensin II		(Sarmesin)
1519.	{Sar¹,Val⁵,Ala⁸}-angiotensin II	1520.	{Sar¹,Ile⁷}-angiotensin III
1521.	synthetic tetradecapeptide renin	1522.	{Val⁴}-angiotensin III
	substrate (No. 2)
1523.	{Val⁵}-angiotensin II	1524.	{Val⁵}-angiotensin I
1525.	human {Val⁵}-angiotensin I	1526.	bullfrog {Val⁵,Asn⁹}-angiotensin I
1527.	fowl {Val⁵,Ser⁹}-angiotensin I	1528.	Ac-SQNY
1529.	bovine bactenecin	1530.	CAP 37 (20-44)
1531.	carbormethoxycarbonyl-DPro-	1532.	CD36 peptide P 139-155
	DPhe-OBzl
1533.	CD36 peptide P93-110	1534.	cecropin A-melittin hybrid peptide
1535.	{CA(1-7)M(2-9)NH₂} cecropin B,	1536.	CYS(Bzl)84 CD fragment 81-92
	free acid
1537.	defensin (human)	1538.	HNP-2
1539.	dermaseptin immunostimulating	1540.	human lactoferricin
	peptide
1541.	bovine lactoferricin	1542.	Hepatocyte Growth Factor (HGF)
1543.	HGFR

(SEQ ID NO:42)
α-Bag Cell Peptide (1-9)
APRLREYSL

(SEQ ID NO:43)
γ-Bag Cell Peptide
RLRFD

(SEQ ID NO:44)
β-Bag Cell Peptide
RLRFH

(SEQ ID NO:45)
BAM 3200 Peptide E
YGGFMRRVGPEWWMDYQKRYGGFL

(SEQ ID NO:46)
BAM-18P
YGGFMRRVGRPEWWMDYQ

(SEQ ID NO:47)
BAM-12P, Bovine Adrenal Medulla Docosapeptide
YGGFMRRVGRPE

(SEQ ID NO:48)
BAM-12P (7-12)
RVGRPE

(SEQ ID NO:49)
bFGF (119-126), Basic Fibroblast Growth Factor, human, bovine
KRTGQYKL

(SEQ ID NO:50)
bFGF Inhibitory Peptide
APSGHYKG

(SEQ ID NO:51)
bFGF Inhibitory Peptide II
MWYRPDLDERKQQKRE

(SEQ ID NO:52)
(Glu63) Bax BH3, mutant
STKKLSECEKRIGDELDSNM

(SEQ ID NO:53)
BAD (103-126), human
NLWAAQRYGRELRRMSDEFVDSFK

(SEQ ID NO:54)
BAD (103-127), human
NLWAAQRYGRELRRMSDEFVDSFKK

(SEQ ID NO:55)
BAD(NT-1)
PEFEPSEQEDSSSAERC-NE12

(SEQ ID NO:56)
Bak-BH3, TAMRA-labeled
GQVGRQLAIIGDDINR-K(TAMRA)-NH2

(SEQ ID NO:57)
Bax BH3 peptide (55-74), wild type
STKKLSECLKRIGDELDSNM

(SEQ ID NO:58)
Bcl 9-2
GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2

(SEQ ID NO:59)
BMf-BH3
LQHRAEVQIARKLQCIADQFHRLHT

(SEQ ID NO:60)
Noxa BH3, Peptide I
PAELEVECATQLRRFGDKLNFRQKLL

(SEQ ID NO:61)
{D-Phe12, Leu14}-Bombesin
Pyr-QRLGNQWAVGfLL-NH2

(SEQ ID NO:62)
{D-Phe12}-Bombesin
Pyr-QRLGNQWAVGfLM-NH2

(SEQ ID NO:63)
{D-Tyr6, β-Ala11, Phe13, Nle14}-Bombesin (6-14)
yQWAV-(β-A)-HF-Nle- NH2

(SEQ ID NO:64)
{D-Tyr6, β-Ala11, β-Phe13, Nle14}-Bombesin (1-14)
Pyr-QRLGyQWAV-(β-A)-H-(β-F)-Nle-NH2

(SEQ ID NO:65)
{Lys3}-Bombesin
Pyr-QKLGNQWAVGHLM-NH2

(SEQ ID NO:66)
{Tyr4, D-Phe12}-Bombesin
Pyr-QRYGNQWAVGfLM-NH2

(SEQ ID NO:66)
{Tyr4}-Bombesin
Pyr-QRYGNQWAVGHLM-NH2

(SEQ ID NO:68)
Biotin-Bombesin
Biotin-EQRLGNQWAVGHLM-NH2

(SEQ ID NO:68)
Biotin-LC-LC-Bombesin
Biotin-LC-LC-EQRLGNQWAVGHLM-NH2

(SEQ ID NO:65)
Bombesin
Pyr-QRLGNQWAVGHLM-NH2

(SEQ ID NO:68)
Bombesin, FAM-labeled
FAM-EQRLGNQWAVGHLM-NH2

(SEQ ID NO:69)
{D-Phe7}-Bradykinin
RPPGFSfFR

(SEQ ID NO:70)
{Des-Arg1}-Bradykinin
PPGFSPFR

{Des-Arg10}-HOE I40
rRP-Hyp-G-Thi-S-(D-Tic)-Oic

(SEQ ID NO:71)
{Ile-Ser}-Bradykinin (T-Kinin)
ISRPPGFSPFR

(SEQ ID NO:73)
{Leu8, Des-Arg9}-Bradykinin
RPPGFSPL

(SEQ ID NO:73)
{Lys0}-Bradykinin (Kallidin)
KRPPGFSPFR

(SEQ ID NO:74)
Angiotensin Converting Enzyme Inhibitor BPP 9a
Pyr-WPRPQIPP

(SEQ ID NO:75)
Biotin-Bradykinin
Biotin-RPPGFSPFR

(SEQ ID NO:76)
Bradykinin
RPPGFSPFR

(SEQ ID NO:77)
Bradykinin Potentiator B, Angiotensin I Converting Enzyme Inhibitor
Pyr-GLPPRPKIPP

(SEQ ID NO:78)
Bradykinin Potentiator C, Angiotensin I Converting Enzyme Inhibitor
Pyr-GLPPGPPIPP

(SEQ ID NO:79)
Hemopressin
PVNFKLLSHHOE I40
rRP-(Hyp)-G-(Thi)-S-(D-Tic)-(Oic)-R

(SEQ ID NO:80)
C-peptide (57-87), human
EAEDLQVGQVELGGGPGAGSLQPLALEGSLQ

(SEQ ID NO:81)
Proinsulin C-peptide (55-89), human
RREAEDLQVGQVELGGGPGAGSLQPLALEGSLQKR

(SEQ ID NO:82)
{Trp63, 64}-C3a(63-77)
WWGKKYRASKLGLAR

(SEQ ID NO:83)
C3a (70-77)
ASHLGLAR

(SEQ ID NO:84)
C3f fragment, Human c3 (1286-1297)
THRIHWESASLL

(SEQ ID NO:85)
C3f, Human c3 (1282-1298)
SSKITHRIHWESASLLR

(SEQ ID NO:86)
Complement anaphylatoxin C5a (37-53), human
RAARISLGPRCIKAFTE

(SEQ ID NO:87)
α-CGRP (19-37), human
SGGVVKNNFVPTNVGSKAF-NH2

(SEQ ID NO:88)
{Tyr0}-α-CGRP, human
YACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 (Disulfide bridge: between
amino acids 3 and 8)

(SEQ ID NO:89)
Biotin-Calcitonin, human
Biotin-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 (Disulfide bridge: between amino
acids 1-7)

(SEQ ID NO:90)
Calcitonin Gene Related Peptide, CGRP (8-37), human
VTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2

(SEQ ID NO:91)
Calcitonin Gene Related Peptide, CGRP (8-37), rat
VTHRLAGLLSRSGGVVKDNFVPTNVGSEAF-NH2

(SEQ ID NO:92)
Calcitonin Gene Related Peptide, CGRP, chicken
ACNTATCVTHRLADFLSRSGGVGKNNFVPTNVGSKAF-NH2 (Disulfide bridge: 2-7)

(SEQ ID NO:93)
Calcitonin Gene Related Peptide, CGRP, human
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2 (Disulfide bridge: 2-7)

(SEQ ID NO:94)
Calcitonin N-Terminal Flanking Peptide, human, N-Procalcitonin
APFRSALESSPADPATLSEDEARLLLAALVQDYVQMKASELEQEQEREGSSLDSPRS

(SEQ ID NO:95)
Calcitonin, chicken
CASLSTCVLGKLSQELHKLQTYPRTDVGAGTP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:96)
Calcitonin, eel
CSNLSTCVLGKLSQELHKLQTYPRTDVGAGTP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:102)
Calcitonin, human
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:97)
Calcitonin, human, FAM-labeled
FAM-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:98)
Calcitonin, porcine
CSNLSTCVLSAYWRNLNNFHRFSGMGFGPETP-NH2 (Disulfide bridge: 1-

(SEQ ID NO:99)
Calcitonin, rat
CGNLSTCMLGTYTQDLNKFHTFPQTSIGVGAP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:100)
Calcitonin, salmon
CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP-NH2 (Disulfide bridge: 1-7)

(SEQ ID NO:101)
Calcitonin-Lys(Biotin), human
CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAPK(Biotin (Disulfide bridge: 1-7)

Calcitonin-Lys(Biotin), human, FAM-labeled
FAM-CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAPK(Biotin)
(Disulfide bridge: 1-7)

(SEQ ID NO:103)
{-2}pPSA, Prostate-Specific Antigen, truncated
SRIVGGWECEK

(SEQ ID NO:104)
{-4}pPSA
ILSRIVGGWECEK

(SEQ ID NO:105)
{A90,95}Bid BH3 (77-100), mouse
ESQEEIIHNIARHAAQIGAEMDHN

(SEQ ID NO:106)
{Ala6, Va115} MUC5AC Analog 2
GTTPSAVPTTSTTSVP

(SEQ ID NO:107)
{APLILSR}pPSA
APLILSRIVGGWECEK

(SEQ ID NO:108)
{Arg67}Bax H2-H3 (53-86), {R67} Helix 2-3 (53-86), mutant
DASTKKLSECLKRIRDELDSNMELQRMIAAVDTD

(SEQ ID NO:109)
{Asn370} tyrosinase (368-376)
YMNGTMSQV

(SEQ ID NO:110)
{Asp370}-Tyrosinase (368-376)
YMDGTMSQV

(SEQ ID NO:111)
{Cys(Acm)33}-Endostatin (6-49)
FQPVLHLVALNSPLSGGMRGIRGADFQ-C(Acm)-FQQARAVGLAGTFRAF

(SEQ ID NO:112)
{Gln340}-Maspin, Reactive Site Loop (RSL), (330-345)
GGDSIEVPGAQILQHK

(SEQ ID NO:57)
{Glu63} Bax BH3, mutant
STKKLSECEKRIGDELDSNM

(SEQ ID NO:113)
{Ile12, Val15} MUC5AC Analog 3
GTTPSPVPTTSITSVP

(SEQ ID NO:114)
{Ile161} IMAGE-A2 (157-166)
YLQLIFGIEV

(SEQ ID NO:115)
{p5er155}-BAD BH3 (146-159)
RYGRELRRM-pS-DEFE

(SEQ ID NO:116)
{pThr145}-p21 (140-147)
RKRRQ-pT-SM

(SEQ ID NO:117)
{Ser244} Tyrosinase (240-251)
DAEKSDICTDEY

(SEQ ID NO:118)
{Val165+56NY-ESO-1(157-165)
SLLMWITQV

(SEQ ID NO:119)
234 CM
KYICNSSCM

(SEQ ID NO:120)
234 CW
KYMCNSSCM

(SEQ ID NO:121)
53BP2 (490-498), p53-Binding Loop (CDB3)
REDEDEIEW

(SEQ ID NO:122)
Adipophilin
SVASTITGV

(SEQ ID NO:123)
Amphoterin (150-183)
KLKEKYEKDIAAYRAKGKPDAAKKGVVKAEKSKK

(SEQ ID NO:124)
Antennapedia Bak BH3 (Ant-BH3) (71-89) Fusion peptide
RQIKIVVFQNRRMKWKKMGQVGRQLAIIGDDINRRY

(SEQ ID NO:1366)
Anti-Flt1 Peptide
GNQWFI

Bad (103-127), human, all d-isomers
nlwaaqrygrelrrmsdefydsfkk

(SEQ ID NO:126)
BAD (CT-1)
KKGLPRPKSAGTATQMRQSSSWTC-NH2

(SEQ ID NO:127)
BAD BH3 (103-123)
NLWAAQRYGRELRRMSDEFVD

(SEQ ID NO:128)
BAD BH3 (146-159)
RYGRELRRMSDEFE

(SEQ ID NO:129)
BAD Peptide, biotin-labeled
Biotin-LC-AGAGRSRHSSYPAGT

(SEQ ID NO:130)
BAFF-R (160-183)
SVPVPATELGSTELVTTKTAGPEQ

(SEQ ID NO:131)
BAGE (2-10)
AARAVFLAL

(SEQ ID NO:132)
Bak BH3
GQVGRQLAIIGDDINR

(SEQ ID NO:133)
Bak BH3 (67-87)
PSSTMGQVGRQLAIIGDDINR

(SEQ ID NO:134)
Bak BH3 (69-93)
STMGQVGRQLAIIGDDINRRYDSEF

(SEQ ID NO:135)
Bak BH3 (71-89)
MGQVGRQLAIIGDDINRRY

(SEQ ID NO:136)
Bak BH3(73-87)
QVGRQLAIIGDDINR

Bak BH3 peptide, Mca labeled
7-methoxycoumarine-4-yl acetyl (Mca)-GQVGRQLAIIGDDINR

(SEQ ID NO:137)
Bax BH3
KKLSECLKRIGDELDS

(SEQ ID NO:138)
Bax BH3 (58-71)
KLSECLKRIGDELD

Bax BH3 peptide (55-74), wild type
STKKLSECLKRIGDELDSNM

(SEQ ID NO:139)
Bax BH3L63A
KKLSECAKRIGDELDS

(SEQ ID NO:140)
Bax H2-H3 (53-86), Helix 2-3
DASTKKLSECLKRIGDELDSNMELQRMIAAVDTD

(SEQ ID NO:141)
Bax H3 (71-86), Helix 3 (71-86)
DSNMELQRMIAAVDTD

(SEQ ID NO:142)
Bax I
PQDASTKKLSECLKRIGDELDSNMEL

(SEQ ID NO:58)
Bcl 9-2
GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2

(SEQ ID NO:143)
Bcl-2 BH3 (85-105)
ALSPVPVVHLTLRQAGDFSRR

(SEQ ID NO:144)
Bcl-2 BH3 Peptide II
LSPVPPVVHLALRQAGDDFSRRYRG

(SEQ ID NO:145)
Bcl-2 Binding Peptide, Bad BH3 Peptide
LWAAQRYGRELRRMSDEFEGSFKGL

(SEQ ID NO:146)
Bcl-XL BH3 (85-98)
AVKQALREAGDEFE

(SEQ ID NO:147)
Bcl9-2, mutant
GSEGLSKEQLEHRERSFQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2

(SEQ ID NO:148)
BDC25(A)
GKKVAAPAWARMG

(SEQ ID NO:159)
BH3 BIM Peptide (52-71), human
Ac-MRPEIVVIAQELRRIGDEFNA

(SEQ ID NO:150)
Bid BH3 (77-100), mouse
ESQEEIIHNIARHLAQIGDEMDHN

(SEQ ID NO:151)
Bid BH3 (79-99)
QEDIIRNIARHLAQVGDSMDR

(SEQ ID NO:152)
Bid BH3 (85-98)
NIARHLAQVGDSMD

(SEQ ID NO:153)
Bid BH3 Peptide
EDIIRNIARHLAQVGDSMDR

(SEQ ID NO:153)
Bid BH3, FAM labeled
5-FAM-EDIIRNIARHLAQVGDSMDR

(SEQ ID NO:153)
Bid BH3, Peptide II, TAMRA labeled
5-TAMRA-EDIIRNIARHLAQVGDSMDR

Bid BH3-r8
_dR _dR _dR vR _dR _dR _dR _dR - GEDIIRNIARHLAQVGDSMDR

(SEQ ID NO:156)
Bid BH3-R8
RRRRRRRRGEDIIRNIARHLAQVGDSMDR

(SEQ ID NO:157)
Bid BH3-R9
RRRRRRRRRGEDIIRNIARHLAQVGDSMDR

(SEQ ID NO:158)
Bid-BH3
RNIARHLAQVGDSMDR

Bik BH3 (50-70)

(SEQ ID NO:159)
Bik BH3 (56-69)
ALALRLACIGDEMD

(SEQ ID NO:160)
BIK BH3 Peptide
MEGSDALALRLACIGDEMDV

(SEQ ID NO:161)
Bim BH3 (87-100)
WIAQELRRIGDEFN

(SEQ ID NO:162)
Bim BH3 Fragment I, TAMRA labeled
5-TAMRA-DNRPEIVVIAQELRRIGDEFNAYYAR

(SEQ ID NO:163)
Bim BH3, Fragment II, TAMRA labeled
5-TAMRA-MRPEIWIAQELRRIGDEFNA

(SEQ ID NO:164)
Bim BH3, Peptide III
DMRPEIWIAQELRRIGDEFNAYYAR

(SEQ ID NO:165)
Bim BH3, Peptide IV
DMRPEIWIAQELRRIGDEFNAYYARR

(SEQ ID NO:166)
Bim-23056
fFYwKVFnal-NH2

(SEQ ID NO:167)
BMF BH3 peptide
HQAEVQIARKLQLIADQFHR

(SEQ ID NO:168)
BNIP3-α BH3 peptide
VVEGEKEVEALKKSADWVSD

(SEQ ID NO:169)
BRCAA1 (610-619)
SSKKQKRSHK

(SEQ ID NO:170)
c-Myc peptide epitope
EQKLISEEDL

(SEQ ID NO:171)
CEA, CAP-1, Carcinoembryonic Antigen
YLSGANLNL

(SEQ ID NO:172)
CEA Related, QYSWFVNGTF
QYSWFVNGTF

(SEQ ID NO:173)
CEA Related, TYACFVSNL
TYACFVSNL

(SEQ ID NO:174)
CEA, CAP-1-6-D, {Asp6}-Carcinoembryonic Antigen
YLSGADLNL

(SEQ ID NO:175)
Cell Penetrating ARF Peptide (26-44)
_dR _dR _dR _dR _dR _dR _dR _dR _dR KFVRSRRPRTASCALAFVN

(SEQ ID NO:176)
Cell Penetrating Mutant ARF (37-44) Peptide
_dR _dR _dR _dR _dR _dR _dR _dR _dR SCALAFVN

(SEQ ID NO:177)
Cripto-1, CR-1
CPPSFYGRNCEHDVRKE

(SEQ ID NO:178)
CTT, Gelatinase Inhibitor
CTTHWGFTLC (Disulfide Bridge: 1-10)

(SEQ ID NO:179)
Cys-p21 (139-154)
CGRKRRQTSMTDFYHSK

(SEQ ID NO:180)
E7 (43-62), HPV Oncoprotein
GQAEPDRAHYNIVTFCCKCD

(SEQ ID NO:181)
E7 (43-77), HPV Oncoprotein
GQAEPDRAHYNIVTFCCKCDSTLRLCVQSTHVDIR

(SEQ ID NO:182)
EGFR (662-681)
RRELVEPLTPSGEAPNQALLR

(SEQ ID NO:183)
Ep-CAM (263-271)
GLKAGVIAV

(SEQ ID NO:184)
Epidermal Mitosis Inhibiting Pentapeptide
Pyr-EDSG

(SEQ ID NO:185)
F42, Gastric Signet Ring Cell Carcinoma Derived Peptide
YSWMDISCWI

(SEQ ID NO:186)
G154, gp100 (154-162)
KTWGQYWQV

(SEQ ID NO:187)
G209, gp100 (209-217)
ITDQVPFSV

(SEQ ID NO:188)
G209-2M, gp100 (209-217)
IMDQVPFSV

(SEQ ID NO:189)
G280-9, gp100 (280-288), Lys (biotin)
YLEPGPVTA-K(Biotin)

(SEQ ID NO:190)
G280-9V, 100(280-288) Lys(biotin)
YLEPGPVTV-K(Biotin)

(SEQ ID NO:191)
GAD65 (206-220)
TYEIAPVFVLLEYVT

(SEQ ID NO:192)
GAD65 (78-97)
KPCNCPKGDVNYAFLHATDL

(SEQ ID NO:193)
GnT-V (nt38-67)
VLPDVFIRCV

(SEQ ID NO:194)
gp100 (177-186)
AMLGTHTMEV

(SEQ ID NO:195)
gp100 (178-187)
MLGTHTMEV

(SEQ ID NO:196)
gp100 (25-33), human
KVPRNQDWL

(SEQ ID NO:197)
gp100 (457-466)
LLDGTATLRL

(SEQ ID NO:198)
gp100 (476-485)
VLYRYGSFSV

(SEQ ID NO:199)
gp100 (570-579)
SLADTNSLAV

(SEQ ID NO:200)
gp100 (614-622)
LIYRRRLMK

(SEQ ID NO:201)
gp100 (619-627)
RLMKQDFSV

(SEQ ID NO:202)
gp100 (639-647)
RLPRIFCSC

(SEQ ID NO:203)
GPC3 (144-152)
FVGEFFTDV

(SEQ ID NO:204)
GPC3 (298-306), mouse
EYILSLEEL

(SEQ ID NO:205)
GRP78 Binding Chimeric Peptide Motif
WIFPWIQL-GG-klaklakklaklak-NH2

(SEQ ID NO:206)
hACC1 (1258-1271), phosphorylated
DSPPQ-pS-PTFPEAGH

(SEQ ID NO:207)
HB-1(18-41)
WKSELVEVDDVYLRHSSSLTYRL

(SEQ ID NO:208)
HB-1(26-41)
EDDVYLRHSSSLTYRL

(SEQ ID NO:209)
HER-2/Neu (654-662), GP2
IISAVVGIL

(SEQ ID NO:210)
HIF-1 {alpha} (556-574)
DLDLEMLAPYIPMDDDFQL

(SEQ ID NO:211)
HIF-2 (66-84)
SLEAQGIKADRETVAVKPT

(SEQ ID NO:212)
HPV16 E7(86-93)
TLGIVCPI

(SEQ ID NO:213)
HRK BH Peptide
SSAAQLTAARLKALGDELHQ

(SEQ ID NO:214)
IL-11R- alpha Binding Peptide II
CGRRAGGSC (S-S bonded)

(SEQ ID NO:215)
iLRP1, iLRP, Immature Laminin Receptor Protein (58-66)
LLLAARAIV

(SEQ ID NO:216)
iLRP2, iLRP (60-68)
LAARAIVAI

(SEQ ID NO:217)
iLRP3, iLRP(146-154)
ALCNTDSPL

(SEQ ID NO:218)
iLRP4, iLRP(7-15)
VLQMKEEDV

(SEQ ID NO:219)
IP3 peptide, (Lys)TAMRA labeled
MPRFMDYWEGLN-K(5/6-TMR)

(SEQ ID NO:220)
IP3 peptide, Acetylated and Biotinylated
Ac-MPRFMDYWEGLNK-K(Biotin)

(SEQ ID NO:221)
IP3 Truncated Peptide, Acetylated
Ac-FMDYWEGLN

(SEQ ID NO:222)
Kisspeptin-10, Metastin (45-54)
YNWNSFGLRF-NH2

(SEQ ID NO:223)
KM-HN-1(107-116)
VFGTRIEKDL

(SEQ ID NO:224)
KM-HN-1(196-204)
NYNNFYRFL

(SEQ ID NO:225)
KM-HN-1(335-343)
HFCRKCKKL

(SEQ ID NO:226)
KM-HN-1(499-508)
EYSKECLKEF

(SEQ ID NO:227)
KM-HN-1(65-74)
SFQALRMQTL

(SEQ ID NO:228)
KM-HN-1(770-778)
EYLSLSDKI

(SEQ ID NO:229)
Laminin Peptide (CDPGYIGSR) NEW
CDPGYIGSR-NH2

(SEQ ID NO:230)
Livin7, ML-IAP
KWFPSCQFLL

(SEQ ID NO:231)
LyP-1, Peptide 1 NEW
CGNKRTRGC (S-S Bonded)

(SEQ ID NO:232)
LyP-1, Peptide 2
CGNKRTRGC

(SEQ ID NO:233)
MAGE-1(161-169)
EADPTGHSY

(SEQ ID NO:234)
MAGE-1 (230-238)
STAPPAHGV

(SEQ ID NO:235)
MAGE-3 (112-120)
KVAELVHFL

(SEQ ID NO:236)
MAGE-3 (114-127)
AELVHFLLLKYRAR

(SEQ ID NO:237)
MAGE-3 (121-134)
LLKYRAREPVTKAE

(SEQ ID NO:238)
MAGE-3 (161-169)
EVDPIGHLY

(SEQ ID NO:239)
MAGE-3 (271-279)
FLWGPRALV

(SEQ ID NO:240)
MAGE-A1(96-104)
SLFRAVITK

(SEQ ID NO:241)
MAGE-A1 (237-245)
KLLTQDLVQ

(SEQ ID NO:242)
MAGE-A1 Antigen (278-286), human
KVLEYVIKV

(SEQ ID NO:43)
MAGE-A10 (183-191)
MLLVFGIDV

(SEQ ID NO:244)
MAGE-A10 (254-262)
GLYDGMEHL

(SEQ ID NO:245)
MAGE-A2 (112-120)
KMVELVHFL

(SEQ ID NO:246)
MAGE-A2 (157-166)
YLQLVFGIEV

(SEQ ID NO:247)
MAGE-A3 (167-176)
MEVDPIGHLY

(SEQ ID NO:248)
MAGE-A3 (195-203)
IMPKAGLLI

(SEQ ID NO:249)
MAGE-A4 Antigen (230-239), human
GVYDGREHTV

(SEQ ID NO:251)
MAGE-C2 (336-344)
ALKDVEERV

(SEQ ID NO:251)
Malaria CSP (334-342)
YLKKIKNSL

(SEQ ID NO:252)
Maspin Reactive Site Loop (RSL), (330-345)
GGDSIEVPGARILQHK

(SEQ ID NO:253)
Melan-A/MART-1 (24-34)
AEEAAGIGILT

(SEQ ID NO:254)
Melanoma Antigen Family A 3 (196-204); MAGE-3 (196-204)
MPKAGLLII

(SEQ ID NO:255)
Melanoma Antigen Family A 8 (115-123); MAGE-8 (115-123)
KVAELVRFL

(SEQ ID NO:256)
Melanoma Antigen Family A 9B (223-231), MAGE-9B (223-231)
ALSVMGVYV

(SEQ ID NO:257)
Melanosomal Antigen II
DAEKCDKTDEY

(SEQ ID NO:234)
MUC-1 (9-17)
STAPPAHGV

(SEQ ID NO:258)
MUC1, tandem repeat fragment
PDTRPAPGSTAPPAHGVTSA

(SEQ ID NO:259)
MUC5AC3
GT-T*-PSPVPTTSTTSAP

(SEQ ID NO:260)
MUC5AC, Analog 1
GTTPSPVPTTSTTSAP

(SEQ ID NO:261)
MUC5AC, Analog B
TTSTTSAPTTS

(SEQ ID NO:262)
MUC5AC-13
GTTPSPVPTTST-T*-SAP

(SEQ ID NO:263)
MUC5AC-3/13
GT-T-PSPVPTTST-T-SAP

(SEQ ID NO:264)
MUM-1(261-69)
EEKLIVVLF

(SEQ ID NO:265)
MycC Peptide
YEQLRNSRA

(SEQ ID NO:266)
MZ2-F
YRPRPRRY

(SEQ ID NO:267)
NES Adenoviral E1A
VMLAVQEGIDL

(SEQ ID NO:268)
NES Nmd3p (491-500)
INIDELLDEL

(SEQ ID NO:269)
NES p120ctn
CSLEEELDVLVLDDEGG

(SEQ ID NO:270)
NES Topoisomerase II alpha (1054-1066)
FILEKIDGKIIIE

(SEQ ID NO:271)
Noxa A BH3 peptide
AELPPEFAAQLRKIGDKVYC

(SEQ ID NO:272)
Noxa A BH3 peptide, cell permeable
_sR _dR _dR _dR _dR _dR _dR _dR GAELPPEFAAQLRKIGDKVYC

(SEQ ID NO:273)
NuBCP- A
FSRSLHSLL

(SEQ ID NO:274)
Nuclear Export Signal, NES HIV Rev
LQLPPLERLTLD

(SEQ ID NO:275)
Nuclear Export Signal, NES MAPKK
ALQKKLEELELD

(SEQ ID NO:276)
Nuclear Export Signal, NES p53
FRELNEALELKD

(SEQ ID NO:277)
NY-ESO-1(53-62)
ASGPGGGAPR

(SEQ ID NO:278)
ORF5 fragment
PASKKTDPQK

(SEQ ID NO:279)
p21 (140-147)
RKRRQTSM

(SEQ ID NO:280)
p53 (12-20)
PPLSQETFS

(SEQ ID NO:281)
p53 (17-26)
ETFSDLWKLL

(SEQ ID NO:282)
p53 (17-26), FITC labeled
FITC-LC-ETFSDLWKLL-NH2

(SEQ ID NO:283)
p53 (65-73)
RMPEAAPPV

(SEQ ID NO:284)
p53 Mutant Form (361-371), Pab 421
KKGQSTSRHKK-NH2

(SEQ ID NO:285)
p53 Tumor Suppressor (361-393), human
GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD

(SEQ ID NO:286)
p53 Tumor Suppressor (361-393), LC-Biotin, human
Biotin-LC-GSRAHSSHLKSKKGQSTSRHKKLMFKTEGPDSD-NH2

(SEQ ID NO:287)
p53, (12-26)
PPLSQETFSDLWKLL

(SEQ ID NO:288)
Pirh2-Derived Peptide (CDB62) (120-137)
LKCNLCLTTNLRGKHKCI

(SEQ ID NO:289)
PNC-28, MDM Binding Domain
ETFSDLWKLLKKWKMRRNQFWVKVQRG

(SEQ ID NO:290)
PRAME epitope (PRA300-309) Tumor-associated antigen
ALYVDSLFFL

(SEQ ID NO:291)
Pro-TGF-α
HADLLAVVAASQ

(SEQ ID NO:292)
Pro-TGF-α
HADLLAVVAASQ

(SEQ ID NO:293)
Prostate Vasculature Marker, biotin-labeled
SMSIARL-K(epsilon-LC-Biotin)

(SEQ ID NO:294)
Prostate-Specific Antigen, PSA propeptide
APLILSR

(SEQ ID NO:295)
PSA1(141-150)
FLTPKKLQCV

(SEQ ID NO:296)
PSA2 (146-154)
KLQCVDLHV

(SEQ ID NO:297)
Rab24 (179-199)
QVMTEDKGVDLSQKANPYFYS

(SEQ ID NO:298)
Rad51 (175-190) (CDB55)
AERYGLSGSDVLDNVA

(SEQ ID NO:299)
Rad51 (179-190)
GLSGSDVLDNVA

(SEQ ID NO:300)
RAGE derived peptide
SPSSNRIRNT

(SEQ ID NO:301)
Shepherdin (79-87)
KHSSGCAFL

(SEQ ID NO:302)
Stromal Target Antigen
SIYYYRYGL

(SEQ ID NO:303)
STT Gelatinase Inhibitor modification, negative control
STTHWGFTLS

(SEQ ID NO:304)
Survivin
ELTLGEFLKL

(SEQ ID NO:305)
Survivin (85-93)
AFLSVKKQF

(SEQ ID NO:306)
Survivin 2B (80-88)
AYACNTSTL

(SEQ ID NO:307)
Telomerase Reverse Transcriptase p572Y (TERT572Y)
RLFFYRKSV

(SEQ ID NO:308)
TP53 Q9NP68, p53 Mutant Form (361-377), Lys371 (Ac)
KKGQSTSRHK-K(Ac)-LMFKTEG

(SEQ ID NO:309)
TRP-1, Fragment
MSLQRQFL

(SEQ ID NO:310)
TRP-2 (180-188) NEW
SVYDFFVVVL

(SEQ ID NO:311)
TRP-2 coding region fragment
LLPGGRPYR

(SEQ ID NO:312)
Tumor Necrosis Factor-a Converting Enzyme, TACE (807-823), human
ASFKLQRQNRVDSKETE

(SEQ ID NO:313)
Tyrosinase (146-156)
SSDYVIPIGTY

(SEQ ID NO:314)
Tyrosinase (192-200)
SEIVVRDIDF

(SEQ ID NO:315)
Tyrosinase (206-214), T9206
AFLPWHRLF

(SEQ ID NO:316)
Tyrosinase (240-251)
DAEKCDICTDEY

(SEQ ID NO:317)
Tyrosinase (450-462)
SYLQDSDPDSFQD

(SEQ ID NO:318)
Tyrosinase (56-70)
QNILLSNAPLGPQFP

(SEQ ID NO:319)
Tyrosinase(243-251), core nonamer sequence
KCDICTDEY

(SEQ ID NO:320)
VEGFR-2/KDR I, murine
FSNSTNDILI

(SEQ ID NO:321)
VEGFR-2/KDR II, murine
VILTNPISM

(SEQ ID NO:322)
VEGFR2/KDR Antagonist
ATWLPPR

(SEQ ID NO:323)
WP9QY, TNF-alpha Antagonist
YCWSQYLCY (Disulfide bridge: 2-8)

(SEQ ID NO:324)
Human Cardiac Troponin I (hcTnI) (39-58)
SKISASRKLQLKTLLLQIAK

(SEQ ID NO:325)
CART (55-102), human
VPIYEKKYGQVPMCDAGEQCAVRKGARIGKLCDCPRGTSCNSFLL
KCL (Disulfide bridge: 74-94, 68-86, and 88-101)

(SEQ ID NO:326)
β- Casomorphin (1-7), human
YPFVEPI

Caspase Related Peptides
Ac-AEVD-pNA
Ac-AEVD-pNA

Biotin-Caspase 1 Inhibitor II
Biotin-YVAD-CMK
Biotin-Caspase 1 Substrate V

(SEQ ID NO:327)
Caspase 1 (ICE) Inhibitor I
Ac-YVAD-CHO

(SEQ ID NO:328)
Caspase 1 (ICE) Substrate 1, chromogenic
Ac-YEVD-pNA

(SEQ ID NO:329)
Caspase 1 (ICE) Substrate 1m, fluorogenic
Ac-YEVD-AMC

(SEQ ID NO:330)
Caspase 1 (ICE) Substrate 2, chromogenic
Ac-YVAD-pNA

Caspase 1 (ICE) Substrate 2f, fluorogenic
Ac-YVAD-AFC

Caspase 1 (ICE) Substrate 2f, fluorogenic
Ac-YVAD-AFC

Caspase 1 (ICE) Substrate 2m, fluorogenic
Ac-YVAD-AMC

Caspase 1 (ICE) Substrate 2r, fluorogenic
(Ac-YVAD)2-Rh110

(SEQ ID NO:331)
Caspase 1 (ICE) Substrate 3f, fluorogenic
Ac-WEHD-AFC

Caspase 1 (ICE) Substrate 3f, fluorogenic
Ac-WEHD- AFC

(SEQ ID NO:332)
Caspase 1 (ICE) Substrate 3m, fluorogenic
Ac-WEHD- AMC

Caspase 1 (ICE) Substrate 3r, fluorogenic
(Ac-WEHD)2-Rh110

Caspase 1 (ICE) substrate for FRET assays
DABCYL- YVADAPV-EDANS

Caspase 1 Inhibitor
Caspase
1 Inhibitor I

Caspase 1 Inhibitor II
Ac-YVAD-CMK

Caspase 1 Inhibitor IV, Boc-D-CMK
Boc-D(OBz1)-CMK

Caspase 1 Inhibitor VIII
Ac-WEHD-CHO

(SEQ ID NO:334)
Caspase 1 Substrate III
Ac-WEHD- pNA

(SEQ ID NO:335)
Caspase 2 (ICH-1) Substrate 1, chromogenic
Ac-VDVAD-pNA

Caspase 2 (ICH-1) Substrate 1, chromogenic
Ac-VDVAD-pNA

Caspase 2 (ICH-1) Substrate 1f, fluorogenic
Ac-VDVAD-AFC

Caspase 2 (ICH-1) Substrate 1m, fluorogenic
Ac-VDVAD-AMC

(SEQ ID NO:336)
Caspase 2 (ICH-1) Substrate 2, fluorogenic
Mca-VDVADGWK(Dnp)- NH2

(SEQ ID NO:337)
Caspase 2 Inhibitor
Ac-VDVAD-CHO

(SEQ ID NO:338)
Caspase 2 Substrate 3r
(D)2-Rh110

Caspase 2 Substrate, chromogenic
Ac-VDQQD-pNA

(SEQ ID NO:339)
Caspase 3 (163-175)
CRGTELDCGIETD

(SEQ ID NO:340)
Caspase 3 (Apopain) Inhibitor 1
Ac-DEVD-CHO

(SEQ ID NO:341)
Caspase 3 (Apopain) Inhibitor 1b
Biotin-DEVD-CHO

Caspase 3 (Apopain) Substrate 1, chromogenic
Ac-DEVD-pNA

Caspase 3 (Apopain) Substrate 1f, fluorogenic
Ac-DEVD- AFC

Caspase 3 (Apopain) Substrate 1m, fluorogenic
Ac-DEVD- AMC

Caspase 3 (Apopain) Substrate 1m, fluorogenic
Ac-DEVD- AMC

Caspase 3 (Apopain) Substrate 1r-z, fluorogenic
(Z-DEVD)2-Rh110

Caspase 3 (Apopain) Substrate 1z, chromogenic
Z-DEVD-pNA

(SEQ ID NO:342)
Caspase 3 (Apopain) Substrate 2, chromogenic
Ac-DQMD-pNA

(SEQ ID NO:343)
Caspase 3 Inhibitor 1
Ac-DMQD-CHO

(SEQ ID NO:344)
Caspase 3 Substrate 1, chromogenic
Ac-DMQD-pNA

Caspase
3 Substrate 1f, fluorogenic
Ac-DMQD-AFC

Caspase 3 Substrate 1m, fluorogenic
Ac-DMQD-AMC

Caspase 3 Substrate 1r, fluorogenic
(Ac-DMQD)2-Rh110

(SEQ ID NO:345)
Caspase 3 Substrate, chromogenic
Ac-VQVD-pNA

(SEQ ID NO:346)
Caspase 4 (ICH-2) Substrate 1, chromogenic
Ac-LEVD-pNA

Caspase 4 (ICH-2) Substrate 1f, fluorogenic
Ac-LEVD-AFC

Caspase 4 (ICH-2) Substrate 1m, fluorogenic
Ac-LEVD- AMC

Caspase 4 (ICH-2) Substrate 1r, fluorogenic
(Ac-LEVD)2-Rh110

(SEQ ID NO:347)
Caspase 6 (Mch 2) Inhibitor 1
Ac-VEID-CHO

(SEQ ID NO:348)
Caspase 6 (Mch2) Substrate 1, chromogenic
Ac-VEID-pNA

Caspase 6 (Mch2) Substrate 1f, fluorogenic
Ac-VEID-AFC

Caspase 6 (Mch2) Substrate 1m, fluorogenic
Ac-VEID-AMC

Caspase 6 (Mch2) Substrate 1r, fluorogenic
(Ac-VEID)2-Rh110

Caspase 6 (Mch2) Substrate 2, fluorogenic
Mca-VQVDGW-K(Dnp)-NH2

Caspase 6 Substrate V, fluorogenic
Ac-VEHD- AFC

Caspase 8 Inhibitor 1
Ac-IETD-CHO

Caspase 8 Substrate 1, chromogenic
Ac-IETD-pNA

Caspase 8 Substrate 1f, fluorogenic
Ac-IETD-AFC

Caspase 8 Substrate 1f-z, fluorogenic
Z-IETD-AFC

Caspase 8 Substrate 1m, fluorogenic
Ac-IETD-AMC

Caspase 8 Substrate 1r-z, fluorogenic
(Z-IEHD)2-Rh110

Caspase 8 Substrate 1r-z, fluorogenic
(Z-IETD)2-Rh110

Caspase 9 Substrate 1, chromogenic
Ac-LEHD-pNA

Caspase 9 Substrate 1f, fluorogenic
Ac-LEHD-AFC

Caspase 9 Substrate 1r, fluorogenic
(Ac-LEHD)2-Rh110

Caspase 9 Substrate 2m, fluorogenic
Ac-LEHD-AMC

Caspase Inhibitor II CHO
Ac-VAD-CHO

Caspase Inhibitor II CMK
Ac-VAD-CMK

Caspase-1 Substrate V, Fluorogenic
Mca-YVADAP-K(Dnp)

Caspase-1/Caspase-4 Substrate II, Fluorogenic
Ac-WVAD-AMC

(SEQ ID NO:349)
ICE Inhibitor I, cell permeable
Ac-AAVLPAVLLALLAPYVAD-CHO

(SEQ ID NO:350)
Smac N7 Protein
AVPIAQK
Z-DEVD-AFC
Z-DEVD-AMC

(SEQ ID NO:351)
37,43Gap 27, Connexin Mimetic
SRPTEKTIFII

(SEQ ID NO:352)
37, 40 GAP26, Connexin Mimetic
VCYDQAFPISHIR

(SEQ ID NO:353)
40Gap 27, Connexin Mimetic
SRPTEKNVFIV

(SEQ ID NO:354)
43Gap 26, Connexin Mimetic
VCYDKSFPISHVR

(SEQ ID NO:355)
43Gap 36, Connexin Mimetic
KRDPCHQVDCFLSRPTEK

(SEQ ID NO:356)
Alpha B-Crystallin (73-92)
DRFSVNLDVKHFSPEELKVK

(SEQ ID NO:357)
Calreticulin (CRT) Binding Peptide 1
GQPMYGQPMY

Calreticulin (CRT) Binding Peptide 1, biotin-labeled
BIOTIN-GQPMYGQPMY

(SEQ ID NO:358)
DAM1 (221-241)
SFVLNPTNIGMSKSSQGHVTK

(SEQ ID NO:359)
Hyaluronan Inhibitor
GAHWQFNALTVR

(SEQ ID NO:360)
L1CD cell adhesion molecule (1144-1163)
KRSKGGKYSVKDKEDTQVDS

(SEQ ID NO:361)
L1FLCD (1173-1185)
FGEYRSLESDNEE

(SEQ ID NO:362)
pALA, Polyalanine Peptide
AAADAAAAL

(SEQ ID NO:363)
S1P1
VSTSIPEVKALRSSVSDYGNYDIIVRHYNYTGKLNIGAEKDHGIK

(SEQ ID NO:364)
Pen2W2F, FAM Labeled
5-FAM-RQIKIFFQNRRMKFKK-NH2

(SEQ ID NO:365)
Hel 11-7 NEW
KLLKLLLKLWLKLLKLLL

(SEQ ID NO:366)
HIV-1 Rev (34-0)
TRQARRNRRRRWRERQR

(SEQ ID NO:367)
HIV-1 Tat (48-60)
GRKKRRQRRRPPQ

(SEQ ID NO:368)
Human T-cell Lymphotrophic Virus (HTLV)-II Rex, (4-16)
TRRQRTRRARRNR

(SEQ ID NO:369)
Lipid Membrane Translocating Peptide
KKAAAVLLPVLLAAP

(SEQ ID NO:370)
Lipid Membrane Translocating Peptide, D-isomer
kkaaavilpyllaap

(SEQ ID NO:371)
Mastoparan
INLKALAALAKKIL-NH2

(SEQ ID NO:372)
Mastoparan 7
INLKALAALAKALL-NH2

(SEQ ID NO:373)
Mastoparan X
INVVKGIAAMAKKLL-NH2

(SEQ ID NO:374)
MEK1 Derived Peptide Inhibitor 1
MPKKKPTPIQLNP

(SEQ ID NO:375)
Membrane-Permeable Sequence, MPS
AAVALLPAVLLALLAK

(SEQ ID NO:376)
MPGΔNLS, HIV related;
GALFLGFLGAAGSTMGAWSQPKSKRKV

(SEQ ID NO:377)
MPS-Gαi2
AAVALLPAVLLALLAKNNLKDCGLF

(SEQ ID NO:378)
MPS-Gαi3
AAVALLPAVLLALLAKNNLKECGLY

Myristoyl-MEK1 Derived Peptide Inhibitor 1
Myr-MPKKKPTPIQLNP

(SEQ ID NO:379)
NGR Peptide 1
CNGRCGGklaklakklaklak-NH2 (Disulfide bridge: 1-5)

(SEQ ID NO:380)
NGR Peptide 2
CNGRCGGLVTT (Disulfide bridge: 1-5)

(SEQ ID NO:381)
NGR Peptide 3
CNGRC-NH2 (Disulfide bridge: 1-5)

(SEQ ID NO:382)
NGR Peptide 4
CNGRCGGkklklllkll (Disulfide bridge: 1-5)

(SEQ ID NO:383)
Nuclear Localiation Signal Peptide
PKKKRKV

(SEQ ID NO:384)
P22 N (14-30)
NAKTRRHERRRKLAIER

(SEQ ID NO:385)
PenArg,FAM Labeled
5-FAM-RQIRIVVFQNRRMRWRR-NH2

(SEQ ID NO:386)
Pep-1-Cysteamine
Ac-KETWWETVVWTEWSQPKKKRKV-cysteamine

(SEQ ID NO:387)
Pep-1: Chariot (Non-Covalent Delivery of Peptides and Proteins)
KETWWETVVWTEWSQPKKKRKV

(SEQ ID NO:388)
phi 21 N Peptide (12-29)
TAKTRYKARRAELIAERR

(SEQ ID NO:389)
Phospho-IkBa-derived peptide, FAM labeled
5-FAM-GRHDSGLD-pS-MK-NH2

(SEQ ID NO:390)
Rabies Virus Glycoprotein (RVG)
YTIVVMPENPRPGTPCDIFTNSRGKRASNG

(SEQ ID NO:391)
Rabies Virus Matrix Protein Fragment (RV-MAT)
MNLLRKIVKNRRDEDTQKSSPASAPLDDG

(SEQ ID NO:392)
Stearyl-MEK-1 Derived Peptide Inhibitor 1, amide
Ste-MPKKKPTPIQLNP-NH2

(SEQ ID NO:393)
SV-40 Large T-antigen Nuclear Localization Signal (NLS)
CGGGPKKKRKVED

(SEQ ID NO:394)
SV40 T-Ag-derived Nuclear Localization Signal (NLS) Peptide
PKKKRKVEDPYC

(SEQ ID NO:395)
SynB1
RGGRLSYSRRRFSTSTGRA

(SEQ ID NO:396)
TAT (47-57)
YGRKKRRQRRR

TAT (47-57)
YGRKKRRQRRR

TAT (47-57) GGG-Cys(Npys)
YGRKKRRQRRRGGG-C(Npys)-NH2

TAT (47-57), FAM-labeled
FAM-YGRKKRRQRRR

TAT (47-57), TAMRA-labeled
TAMRA-YGRKKRRQRRR

TAT (47-57)-Lys(TAMRA)
YGRKKRRQRRR-K(TAMRA)

(SEQ ID NO:397)
Tat (48-57)
GRKKRRQRRR

(SEQ ID NO:398)
Tat-C (48-57)
CGRKKRRQRRR

(SEQ ID NO:399)
Tat-NR2Bct
YGRKKRRQRRRKLSSIESDV

(SEQ ID NO:400)
TAT-N5F222 Fusion Peptide
YGRKKRRQRRR-GGG-LDKEFNSIFRRAFASRVFPPE

(SEQ ID NO:401)
TAT-NSF700 Fusion Peptide
YGRKKRRQRRR-GGG-LLDYVPIGPRFSNLVLQALLVL

(SEQ ID NO:402)
Transdermal Peptide
ACSSSPSKHCG

(SEQ ID NO:403)
Transportan
GWTLNSAGYLLGKINLKALAALAKKIL

(SEQ ID NO:404)
Yeast PRP6 (129-144)
TRRNKRNRIQEQLNRK

(SEQ ID NO:405)
{Cys58}105Y, Cell Penetrating Peptide, α1-antitrypsin (358-374)
CSIPPEVKFNKPFVYLI

(SEQ ID NO:406)
105Y, α1-antitrypsin (359-374)
SIPPEVKFNKPFVYLI

(SEQ ID NO:407)
Aminopeptidase N Ligand (CD13), NGR peptide
CNGRCG (Disulfide bridge: 1-5)

(SEQ ID NO:408)
Antennapedia Leader Peptide (CT)
KKWKMRRNQFVVVKVQRG

(SEQ ID NO:409)
Antennapedia Peptide, acid
RQIKIVVFQNRRMKWKK

(SEQ ID NO:410)
Antennapedia Peptide, amide
RQIKIVVFQNRRMKWKK-NH2

(SEQ ID NO:411)
Antennapedia Peptide, FAM-labeled
5-FAM-RQIKIVVFQNRRMKWKK-NH2

(SEQ ID NO:412)
Anti-BetaGamma (MPS-Phosducin-like protein C terminus)
AAVALLPAVLLALLAVTDQLGEDFFAVDLEAFLQEFGLLPEKE

(SEQ ID NO:413)
Bcl-2 Binding Peptide, cell permeable
Decanoyl-KNLWAAQRYGRELRRMSDEFEGSFKGL

(SEQ ID NO:414)
Alpha-A-Crystallin (70-88)
KFVIFLDVKHFSPEDLTVK

(SEQ ID NO:415)
Hsc70-binding Peptide II
NIVRKKK

(SEQ ID NO:416)
Cholecystokinin-Pancreozymin Peptides
{Thr28, Nle31}-Cholecystokinin (25-33), sulfated
RD-Y(SO3H)-TGW-Nle-DF-NH2

(SEQ ID NO:417)
Caerulein
Pyr-QD-Y(SO3H)-TGWMDF-NH2

(SEQ ID NO:418)
Cholecystokinin (1-21)
KAPSGRVSMIKNLQSLDPSHR

(SEQ ID NO:419)
Cholecystokinin (10-20)
IKNLQSLDPSH

(SEQ ID NO:420)
Cholecystokinin (26-33), CCK Octapeptide, sulfated
D-Y(SO3H)-MGWMDF-NH2

(SEQ ID NO:421)
Cholecystokinin (26-33), CCK8
DYMGWMDF-NH2

Cholecystokinin (26-33), free acid
DYMGWMDF

(SEQ ID NO:422)
Cholecystokinin Flanking Peptide, non-sulfated
SAEEYEYPS

(SEQ ID NO:423)
Cholecystokinin, CCK (27-33), CCK7
YMGWMDF-NH2

(SEQ ID NO:424)
Prepro CCK fragment, V-9-M
VPVEAVDPM

(SEQ ID NO:425)
CRF
{Tyr0}-Corticotropin Releasing Factor, {Tyr0}-CRF, human, rat
YSEEPPISLDLTFHLLREVLEEMARAEQLAQQAHSNRKLMEII-NH2

(SEQ ID NO:426)
{Tyr0}-Corticotropin Releasing Factor, {Tyr0}-CRF, ovine
YSQEPPISLDLTFHLLREVLEMTKADQLAQQAHSNRKLLDIA-NH2

Biotin-Corticotropin Releasing Factor, Biotin-CRF, human, rat
Biotin-SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH2

(SEQ ID NO:427)
Corticotropin Releasing Factor, CRF, human, rat
SEEPPISLDLTFHLLREVLEMARAEQLAQQAHSNRKLMEII-NH2

(SEQ ID NO:428)
Somatostatin
{Tyr0}-Somatostatin 28
YSANSNPAMAPRERKAGCKNFFVVKTFTSC (Disulfide bridge: 18-29

(SEQ ID NO:429)
{Tyr1}-Somatostatin 14
YGCKNFFWKTFTSC (Disulfide bridge: 3-14)

(SEQ ID NO:430)
Big Endothelin-1 (1-38), human
CSCSSLMDKECVYFCHLDIIVVVNTPEHVVPYGLGSPRS (Disulfide bridge: 1-15 and 3-1)

(SEQ ID NO:431)
1: VIP vasoactive intestinal peptide isoform 1 preprotein
>gi\|4507897\|ref\|NP_0033721\| VIP peptides isoform 1 preproprotein {Homo
sapiens} MDTRNKAQLLVLLTLLSVLFSQTSAWPLYRAPSALRLGDRIPFEGANEPDQVSLKEDIDMLQ
NALAENDTPYYDVSRNARHADGVFTSDFSKLLGQLSAKKYLESLMGKRVSSNISEDPVPVKR
HSDAVFTDNYTRLRKQMAVKKYLNSILNGKRSSEGESPDFPEELEK

Residues 125-152 constitute the active form:
HSDAVFTDNYTRLRKQMAVKKYLNSILN
VPAC₁Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, F6, R14, K15, K21, Y22, L23, N24, and I26
VPAC₂Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, T11, R14, K15, K21, Y22, L23, I26 and N28

(SEQ ID NO:432)
2: VIP vasoactive intestinal peptide isoform 2 preprotein
>gi\|37588853\|ref\|NP_9194161\| VIP peptides isoform 2 preproprotein {Homo
sapiens} MDTRNKAQLLVLLTLLSVLFSQTSAWPLYRAPSALRLGDRIPFEGANEPDQVSLKEDIDMLQ
NALAENDTPYYDVSRNARHADGVFTSDFSKLLGQLSAKKYLESLMGKRVSNISEDPVPVKR
HSDAVFTDNYTRLRKQMAVKKYLNSILNGKRSSEGESPDFPEELEK

Residues 124-151 constitute the active form:
HSDAVFTDNYTRLRKQMAVKKYLNSILN

VPAC₁Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, F6, R14, K15, K21, Y22, L23, N24, and I26
VPAC₂Interacting residues are likely (numbered from 1 using the active
sequence): H1, V5, T11, R14, K15, K21, Y22, L23, I26 and N28

(SEQ ID NO:433)
3 VIP Synthetic sequence 1
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY(Bay55-9837)

(SEQ ID NO:434)
4 VIP Synthetic sequence 2
HADAVFTAAYARIAKQMAAKKALAAIAA (10Ala)

(SEQ ID NO:435)
5 VIP Synthetic sequence 3
HSDAVFTDNYARLRKQMAVKKALNSILA (3Ala)

(SEQ ID NO:436)
6 VIP Synthetic sequence 1
YFDAIFTNSYRKVLGQLSARKLLQDIMSR AcYF-GRF1-29

(SEQ ID NO:437)
7, VIP Synthetic sequence 2
FTDNYTRLRKQMAVKKYLNSILN VIP 6-28

(SEQ ID NO:438)
8 VIP Synthetic sequence 3
HSDAVFTDNYTRLRKQLAVKKYLNSILN (F-6+32p-Cl-dF)

(SEQ ID NO:439)
9 VIP Synthetic sequence
Ac-HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRY

(SEQ ID NO:440)
10 VIP Synthetic sequence
HTDAVFTDNYTRLRKQVAAKKYLQSIKNKRY

(SEQ ID NO:441)
11 VIP Synthetic sequence
HSEAVFTDNYTRLRKQVAAKKYLQSIKNKRY

(SEQ ID NO:442)
12 VIP Synthetic sequence
HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRY

(SEQ ID NO:443)
13 VIP Synthetic sequence
HTEAVFTDNYTRLRKQVAAKKYLQSIKNKRY

(SEQ ID NO:444)
14 VIP Synthetic sequence
HTEAVFTDQYTRLRKQVAAKKYLQSIKQKRY

(SEQ ID NO:445)
15 VIP Synthetic sequence
Ac-HTDAVFTDQYTRLRKQVAAKKYLQSIKQKRY

(SEQ ID NO:446)
16 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC

(SEQ ID NO:447)
17 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC-PEG22kD

(SEQ ID NO:448)
18 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYC-PEG43kD

(SEQ ID NO:449)
19 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC

(SEQ ID NO:450)
20 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC-PEG22kD

(SEQ ID NO:451)
21 VIP Synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSIKNKRYSWC-PEG43kD

(SEQ ID NO:452)
22 VIP Synthetic sequence
HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC

(SEQ ID NO:453)
23 VIP Synthetic sequence
HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC-PEG22kD

(SEQ ID NO:454)
24 VIP Synthetic sequence
HSDAVFTDQYTRLRKQVAAKKYLQSIKQKRYC-PEG43kD

(SEQ ID NO:455)
25 VIP Synthetic sequence
Ac-HSDAVFTENYTKLRKQN_leAAKK*YLNDIKKGGT(Ro25-1553)

(SEQ ID NO:456)
26 VIP Synthetic sequence
Ac-HSDAVFTENY_MTKLRKQN_leAAKKYLNDLKK (Ro 25-1392)

(SEQ ID NO:457)
27 VIP Synthetic sequence
HSDAVFTDNYTRLRRQLAVRRYLNSILNGRR (LK312532)

(SEQ ID NO:458)
28 VIP Synthetic sequence
Ac-H_dFDAVFTNSYRKVLKRLSARKLLQDIL (PG 97-269)

(SEQ ID NO:459)
29 VIP Synthetic sequence
HSDAVFTNSYRKVLKRLSARKLLQDIL(k15r16127VIP GFR)

(SEQ ID NO:460)
30 VIP Synthetic sequence
H_dADAIFTA_ibAYRKVLAALA_ibARKALAAAG_ab(GER-6)

(SEQ ID NO:461)
31 VIP Synthetic sequence
HSDGITTSEYSKMRGRAQVQKFIQNLM (R16-chicken)

(SEQ ID NO:462)
32 VIP Synthetic sequence
HSDAVFTDYYTRLRKQMD_ipVKKYLNSILN (y9Dip18-VIP)

(SEQ ID NO:463)
33 VIP Synthetic sequence
FTDYYTRLRKQMD_ipVKKYLNSILN (y9Dip18-VIP)

(SEQ ID NO:464)
34 VIP Synthetic sequence
HSDAVFTDNYTK_mLRKQMAVKKYLNSIKKGGT

(SEQ ID NO:465)
35 VIP Synthetic sequence
Ac-HSDAVFTNSYRKVLKRLSARKLLQDIL (PG 97-268)

(SEQ ID NO:466)
36 VIP Synthetic sequence
Ac-HDAI_dRTNSYRKVLKRLSAKKYLQDN_ledR_hR (JV-1-53?)

(SEQ ID NO:467)
37 VIP Synthetic sequence
AC-H_dFDAIF_4clTNRYRKVLA_buQLSARKLLQDINleDR_hR (JV-1-51)

(SEQ ID NO:468)
38 VIP synthetic sequence
HSDAVFTDQYTRLRKQLAAKKYLQSLKKKRY (RBAYL)

(SEQ ID NO:469)
39 VIP synthetic sequence
HSDAVFTDNYTRLRKQVAAKKYLQSLKNKRY (rBAY)

(SEQ ID NO:470)
40 VIP synthetic sequence
Hexanoyl-HSDAVFTDNYTRLRKQMAVKKYLNSILN (c6VIP)

(SEQ ID NO:471)
41 VIP synthetic sequence
Hexanoyl-HSDAVETDNYTRLRKQMAAKKYLNSIKK (c6a19k27k28-VIP)

(SEQ ID NO:472)
HSDAVFTEQY(OMe)TRAibRAibQLAAAibOrnY(OMe)LQSIK AibOrn

(SEQ ID NO:473)
HSDAVFTEK(CO(CH2)2SH)Y(OMe)TOrnLRAibQVAAAibOrn YLQSIOrnOrn

(SEQ ID NO:474)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLOSIOrnK(W) Orn

(SEQ ID NO:475)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibK(CO(CH₂)₂SH)YLQ SIOrnOrn

(SEQ ID NO:476)
HSDAVFTEQY(OMe)TOrnLRAibQVAAK CO(CH₂)₂SH)OrnYLQ SIOrnOrn

(SEQ ID NO:477)
HSDAVFTEQY(OMe)TOrnLRAibQVCAAibOrnYLOSIOrnOrn

(SEQ ID NO:478)
HSDAVFTEQY(OMe)TOrnLRCQVAAAibOrnYLOSIOrnOrn

(SEQ ID NO:479)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQSIOrnOrn

(SEQ ID NO:480)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYAibQSIOrnOrn

(SEQ ID NO:481)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQAibIOrnOrn

(SEQ ID NO:482)
HSDAVFTEQY(OMe)TOrnLRAibQVAAbuAibOrnYLQAibIOrnOrn

(SEQ ID NO:483)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQAibIOrnOrn

(SEQ ID NO:484)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYAibQAibIOrnOrn

(SEQ ID NO:485)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYAibQSIOrnOrn

(SEQ ID NO:486)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnOrn

(SEQ ID NO:487)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYAibQAibIOrn Orn

(SEQ ID NO:488)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYAibQSIOrnOrn

(SEQ ID NO:489)
HSDAVFTEQY(OMe)TOrnLRK(W)QVAAAibOrnYLQSIOrnOrn

(SEQ ID NO:490)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLK(W)SIOrnOrn

(SEQ ID NO:491)
HSDAVFTEQY(OMe)TOrnLRAibQK(W)AAAibOrnYLQSIOrnOrn

(SEQ ID NO:492)
HSDAVFTEQY(OMe)TOrnLRK CO(CH₂)₂SH)QVAAAibOrnYLQ SIOrnOrn

(SEQ ID NO:493)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibK(W)YLQSIOrnOrn

(SEQ ID NO:494)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibCYLQSIOrnOrn

(SEQ ID NO:495)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrnOrn

(SEQ ID NO:496)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQSK(W)OrnOrn

(SEQ ID NO:497)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrnC Orn

(SEQ ID NO:498)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibCOrn Orn

(SEQ ID NO:499)
HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnYLQAibIOrnOrn

(SEQ ID NO:500)
HSDAVFTEQY(OMe)TOrnLRCQLAAbuAibOrnYLQAibIOrnOrn

(SEQ ID NO:501)
HSDAVFTEQY(OMe)TOrnLRAibQVK CO(CH₂)₂SH)AAibOrn YLQSIOrnOrn

(SEQ ID NO:502)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnCOrn

(SEQ ID NO:503)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSCOrnOrn

(SEQ ID NO:504)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrn K CO(CH₂)₂SH)Orn

(SEQ ID NO:505)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrn K CO(CH₂)₂SH)Orn

(SEQ ID NO:506)
HSDAVFTEQY(OMe)TOrnLRK(W)QLAAbuAibOrnYLQAibIOrn Orn

(SEQ ID NO:507)
HSDAVFTEQY(OMe)TOrnLRAibQLAAAibOrnYLQSIOrnOrnC

(SEQ ID NO:508)
HSDAVFTEQY(OMe)TOrnLRAibQVAAAibOrnYLQSIOrnOrnC

(SEQ ID NO:509)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQSIOrnOrnC

(SEQ ID NO:510)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQAibI OrnOrn

(SEQ ID NO:511)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQAibI OrnCOrn

(SEQ ID NO:512)
HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnY(OMe)LQAibI OrnOrn

(SEQ ID NO:513)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnYLQAibIOrn OrnC

(SEQ ID NO:514)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQSI OrnOrn

(SEQ ID NO:515)
HSDAVFTEQY(OMe)TOrnLRAibQCAAbuAibOrnY(OMe)LQSI OrnOrn

(SEQ ID NO:516)
HSDAVFTEQY(OMe)TOrnLRAibQLAAbuAibOrnY(OMe)LQSI OrnCOrn

(SEQ ID NO:517)
HSDAVFTEQY(OMe)TOrnLRAibQLAbuAAibOrnYLQSIOrnOrn

(SEQ ID NO:518)
HSDAVFTEQY(OMe)TOrnLRAibQK CO(CH₂)₂SH)AAbu AibOrnYLQAibIOrnOrn

(SEQ ID NO:519)
HSDAVFTEQY(OMe)TOrnLRAibQK(W)AAbuAibOrnYLQ AibIOrnOrn

3 pituitary adenylate cyclase-activating polypeptide precursor {Homosapiens}
>gi\|153266792\|ref\|NP_0010932031\|pituitary adenylate cyclase-activating
polypeptide precursor {Homosapiens}

(SEQ ID NO:520)
MTMCSGARLALLVYGIIMHSSVYSSPAAAGLRFPGIRPEEEAYGEDGNPLPDFDGSEPPGAGS
PASAPRAAAAWYRPAGRRDVAHGILNEAYRKVLDQLSAGKHLQSLVARGVGGSLGGGAGD
DAEPLSKRHSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNKGRRIAYL

Residues 132-158 constitute the active form PACAP-27:
HSDGIFTDSYSRYRKQMAVKKYLAAVL
Residues 132-158 constitute the active form PACAP-38:
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK

4 pituitary adenylate cyclase-activating polypeptide precursor {Homosapiens}

(SEQ ID NO:521)
>gi\|153266795\|ref\|NP_0011082\| pituitary adenylate cyclase-activating
polypeptide precursor {Homosapiens }
MTMCSGARLALLVYGIIMHSSVYSSPAAAGLRFPGIRPEEEAYGEDGNPLPDFDGSEPPGAGS
PASAPRAAAAWYRPAGRRDVAHGILNEAYRKVLDQLSAGKHLQSLVARGVGGSLGGGAGD
DAEPLSKRHSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNKGRRIAYL

Residues 132-158 constitute the active form PACAP-27:
HSDGIFTDSYSRYRKQMAVKKYLAAVL
Residues 132-158 constitute the active form PACAP-38:
HSDGIFTDSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK

(SEQ ID NO:522)
39 PACAP-Antagonist
FTSYSRYRKQMAVKKYLAAVLGKRYKQRVKNK

(SEQ ID NO:523)
40 Maxadilan peptide
>US6462016_1 Sequence 1 from Patent US 6462016 inClaims gi: 27279414
CDATCQERKAIDDCQKQAHHSNVLQTSVQTTATETSMDTSQLPGNSVEKECMKQKKKEEKA

(SEQ ID NO:525)
40 Maxadilan peptide 2
CDATCQERKAIDDCQKQAHHSNVLQTSVQTTATETSMDTSQLPGNSVEKECMKQKKKEESS
GK

(SEQ ID NO:525)
40 M65 peptide
CDATCQERKAIDDCQKQAHHSNVLPGNSVEKECMKQKKKEEKA

(SEQ ID NO:526)
40 M65 peptide v2
CDATCQERKAIDDCQKQAHHSNVLGNSVEKECMKQKKKEEKA

(SEQ ID NO:527)
41 M65 peptide
>U56462016_10 Sequence 10 from Patent US 6462016 inClaims gi: 27279423
GSCDATCQERKAIDDCQKQAHHSNVPGNSVEKECMKQKKKEEKAGK

The contents of this Table 4 also include relate to analogs comprising any
agonist listed in US2009-US Application Serial \10/586124, filed on
Jun 24, 2008

5 glucagon preproprotein

gi\|4503945\|ref\|NP_0020451\| glucagon preproprotein {Homosapiens}

(SEQ ID NO:528)
MKSIYEVAGLEVMLVQGSWQRSLQDTEEKSRSESASQADPLSDPDQMNEDKRHSQGTETSD
YSKYLDSRRAQDEVQWLMNTKRNRNNIAKRHDEFERHAEGTETSDVSSYLEGQAAKEFIAW
LVKGRGRRDEPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDEINWLIQTKITDRK

(SEQ ID NO:529)
Residues 21-50 constitute an active form Glicentin-related polypeptide
(GRPP): RSLQDTEEKSRSFSASQADPLSDPDQMNED

(SEQ ID NO:530)
Residues 53-81 constitute an active form Glucagon:
HSQGTFTSDYSKYLDSRRAQDFVQWLMNT

(SEQ ID NO:531)
Residues 92-128 constitute the pro-form of GLP-1
HDEFERHAEGTFTSDVSSYLEGQAAKEFIAWLVKGRG
Residues 98 - 128 constitute an active form of GLP-1
HAEGTETSDVSSYLEGQAAKEFIAWLVKGRG
Residues 98-125 constitute an active form of GLP-1
HAEGTETSDVSSYLEGQAAKEFIAWLVK

(SEQ ID NO:532)
Residues 146-178 constitute an active form GLP-2:
HADGSFSDEMNTILDNLAARDEINWLIQTKITD

(SEQ ID NO:533)
6 Apolipoprotein-mimetic peptide (D4F, DWFKAFYDKVAEKFKEAF) and
other family members:

(SEQ ID NO:534)
3F-2 (Ac-DKWKAVYDKFAEAFKEFL-NH2)
(SEQ ID NO:535)
3F14 (Ac-DWLKAFYDKVAEKFREAF-NH2

The baseline sequence of 18A is DWLKAFYDKVAEKLKEAF
Ac-18A-NH2
Ac-{F318A}NH2
Ac-{F1418A}NH2
Ac-}F3,1418A}NH2
Ac-{F11,14,1718A}NH2
Ac-{F10,11,14,1718A}NH2
Ac-{F3,10,11,14,1718A}NH2

4F=Ac-DWEKAFYDKVAEKEKEAF-NH2 (18 mer)
4F-KVEPIRA-4F (43 mer)
4F-P-4F (37 mer)
4F-A-4F (37 mer)

apoA-IMilano (R173C) and apoA-IParis (R151C)

apolipoprotein A-I {Homosapiens

(SEQ ID NO:536)
gi\|4557321\|ref\|NP_0000301\| apolipoprotein A-I preproprotein {Homosapiens}
MKAAVLTLAVLFLTGSQARHFVVQQDEPPQSPWDRVKDLATVYVDVLKDSGRDYVSQFEGS
ALGKQLNLKLLDNWDSVTSTFSKLREQLGPVTQEFVVDNLEKETEGLRQEMSKDLEEVKAKV
QPYLDDFQKKWQEEMELYRQKVEPLRAELQEGARQKLHELQEKLSPLGEEMRDRARAHVD
ALRTHLAPYSDELRQRLAARLEALKENGGARLAEYHAKATEHLSTLSEKAKPALEDLRQGL
LPVLESFKVSFLSALEEYTKKLNTQ

I apolipoprotein E {Homosapiens}

(SEQ ID NO:537)
>gi\|178853\|gb\|AAB593971\| apolipoprotein E {Homosapiens}
MKVLWAALLVTFLAGCQAKVEQAVETEPEPELRQQTEWQSGQRWELALGRFWDYLRWVQ
TLSEQVQEELLSSQVTQELRALMDETMKELKAYKSELEEQLTPVAEETRARLSKELQAAQAR
LGADMEDVRGRLVQYRGEVQAMLGQSTEELRVRLASHLRKLRKRLLRDADDLQKRLAVY
QAGAREGAERGLSAIRERLGPLVEQGRVRAATVGSLAGQPLQERAQAWGERLRARMEEMG
SRTRDRLDEVKEQVAEVRAKLEEQAQQIRLQAEAFQARLKSWFEPLVEDMQRQWAGLVEK
VQAAVGTSAAPVPSDNH

II Ac-L V GRQLEEFL-NH
III Ac-LLEQLNEQFNWVSRLANLTQGE-NH2
Ac--PSGVTEVVVKLFDS-NHsub2
IV Ac-Q QTHMLDVMQD-NHsub2

V Apolipoprotein C-I {Homosapiens}

(SEQ ID NO:538)
>gi\|32822890\|gb\|AAH550931\| Apolipoprotein C-I {Homosapiens}
MRLFLSLPVLVVVLSIVLEGPAPAQGTPDVSSALDKLKEFGNTLEDKARELISRIKQSELSAK
MREWFSETFQKVKEKLKIDS

VI apolipoprotein I {Homosapiens}

(SEQ ID NO:539)
>gi\|27373753\|gb\|AAN873471\| apolipoprotein J {Homosapiens}
CSTNNPSQAKLRRELDESLQVAERLTRKYNELLKSYQWKMLNTSSLLEQLNEQFNVVVSRLA
NLTQGEDQYYLRVTT

apoJ peptide 336--D-J336+32Ac-LLEQLNEQFNVVVSRLANTQGE-NH₂

(SEQ ID NO:540)
ANP
>gi\|23510319\|ref\|NP_0061631\| atrial natriuretic factor preproprotein {Homo
sapiens} MSSFSTTTVSFLLLLAFQLLGQTRANPMYNAVSNADLMDFKNLLDHLEEKMPLEDEVVPPQ
VLSEPNEEAGAALSPLPEVPPWTGEVSPAQRDGGALGRGPWDSSDRSALLKSKLRALLTAPR
SLRRSSCFGGRMDRIGAQSGLGCNSFRY

(SEQ ID NO:541)
Active form: RSLRRSSCFGGRMDRIGAQSGLGC

(SEQ ID NO:542)
Active form: RSLRRSSCFGGRMDRIGAQSGLGCNSFRY

(SEQ ID NO:543)
Active form: SLRRSSCFGGRMDRIGAQSGLGCNSFRY

(SEQ ID NO:544)
cardiodilatin
>gi\|23510319:26-92 atrial natriuretic factor preproprotein {Homosapiens}
NPMYNAVSNADLMDFKNLLDHLEEKMPLEDEVVPPQVLSEPNEEAGAALSPLPEVPPWTGE
VSPAQR

(SEQ ID NO:545)
BNP
natriuretic peptides B preproprotein {Homosapiens}
>gi\|4505433\|ref\|NP_0025121\| natriuretic peptides B preproprotein {Homo
sapiens} MDPQTAPSRALLLLLFLHLAFLGGRSHPLGSPGSASDLETSGLQEQRNHLQGKLSELQVEQTS
LEPLQESPRPTGVVVKSREVATEGIRGHRKMVLYTLRAPRSPKMVQGSGCFGRKMDRISSSSG
LGCKVLRRH

(SEQ ID NO:546)
Active form: SPKMVQGSGCFGRKMDRISSSSGLGCKVLRRH

(SEQ ID NO:547)
CNP
natriuretic peptide precursor C precursor {Homosapiens}
>gi\|13249346\|ref\|NP_0777201\| natriuretic peptide precursor C precursor {Homo
sapiens} MHLSQLLACALLLTLLSLRPSEAKPGAPPKVPRTPPAEELAEPQAAGGGQKKGDKAPGGGG
ANLKGDRSRLLRDLRVDTKSRAAWARLLQEHPNARKYKGANKKGLSKGCFGLKLDRIGSM
SGLGC

(SEQ ID NO:548)
Active form: GLSKGCFGLKLDRIGSMSGLGC

(SEQ ID NO:549)
urodilatin
>gi\|226320\|prf\|\|1506430A urodilatin
TAPRSLRRSSCFGGRMDRIGAQSGLGCNSFRY

(SEQ ID NO:550)
Urodilatin
RPATSLRRSSCFGGRMDRIGAQSGLGCNSFRY

(SEQ ID NO:551)
neuropeptide Y preproprotein {Homosapiens}
>gi\|4505449\|ref\|NP_0008961\| neuropeptide Y preproprotein {Homosapiens}
MLGNKRLGLSGLTLALSLLVCLGALAEAYPSKPDNPGEDAPAEDMARYYSALRHYINLITRQ

(SEQ ID NO:552)
RYGKRSSP

(SEQ ID NO:553)
ETLISDLLMRESTENVPRTRLEDPAMW

(SEQ ID NO:554)
Active form:
>gi\|4505449:29-64 neuropeptide Y preproprotein {Homosapiens}
YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY

PYY
peptide YY precursor {Homosapiens}

(SEQ ID NO:555)
>gi\|71361686\|ref\|NP_0041512\| Human peptide YY precursor
MVFVRRPWPALTTVLLALLVCLGALVDAYPIKPEAPREDASPEELNRYYASLRHYLNLVTRQ

(SEQ ID NO:556)
RYGKRDGP

(SEQ ID NO:557)
DTLLSKTFFPDGEDRPVRSRSEGPDLW

(SEQ ID NO:558)
Active form: IKPEAPREDASPEELNRYYASLRHYLNLVTRQRY

(SEQ ID NO:559)
Active form: IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY

(SEQ ID NO:560)
Active form: YPIKPEAPREDASPEELNRYYASLRHYLNLVTRQRY

(SEQ ID NO:561)
Active form: YPIKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY

adrenomedullin {Homosapiens}

(SEQ ID NO:562)
Active form: YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY

(SEQ ID NO:563)
Pro-Adrenomedullin (N-20): ARLDVAAEFRKKWNKWALSR

(SEQ ID NO:564)
PrePro-Adrenornedullin:
ELRMSSSYPTGLADVKAGPAQTLIRPQDMKGASRSPEDSSPDAARTRV

(SEQ ID NO:565)
Ghrelin analog, sequences
{Ala1, D-Trp2,4, Leu6}-Ghrelin Receptor Agonist
AwFwLL

(SEQ ID NO:566)
{D-Trp1,3, Leu5}-Ghrelin Core-Ligand
wFwLL

(SEQ ID NO:567)
{Des-octanoyl}-Ghrelin, human
GSSFLSPEHQRVQQRKESKKPPAKLQPR

(SEQ ID NO:568)
Biotin-GS-S (n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR

FAM-GS-S(n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR

TAMRA-GS-S(n-octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR

(SEQ ID NO:569)
human Obestatin analog seteteences
FNAPFDVGIKLSGVQYQQHSQAL-NH2

(SEQ ID NO:570)
PTH analog sequences
Parathyroid Hormone (1-34), human
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVIINF

(SEQ ID NO:571)
Parathyroid Hormone (1-34), human, biotinylated
Biotin-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNF

Parathyroid Hormone (1-34 human, C-Terminal FAM-labeled
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(FAM)

Parathyroid Hormone (1-34)-Lys(Biotin), human
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(Biotin)

Parathyroid Hormone (1-34)-Lys(Biotin), human, FAM-labeled
FAM-SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHNFK(Biotin)

(SEQ ID NO:572)
Parathyroid Hormone-Related Protein, PTHrP (107-111)
TRSAW

(SEQ ID NO:573)
TIP 39, Tuberoinfundibular Neuropeptide
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP

(SEQ ID NO:574)
Hypercalcemia Malignancy Factor (1-40)
AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS

(SEQ ID NO:575)
Acetalin analog sequences
Acetalin
1, Opioid Receptor Antagonist 1
Ac-RFMWMR-NH2

(SEQ ID NO:576)
Acetalin 2, Opioid Receptor Antagonist 2
Ac-RFMWMK-NH2

(SEQ ID NO:577)
Acetalin 3, Opioid Receptor Antagonist 3
Ac-RFMWMT-NH2

(SEQ ID NO:578)
ACTH analog sequences
{Glu10}-ACTH (1-17)
SYSMEHFRWEKPVGKKR

(SEQ ID NO:579)
{Phe2, Nle4}-ACTH (1-24)
SFS-Nle-EHFRWGKPVGKKRRPVKVYP

(SEQ ID NO:580)
ACTH (1-10)
SYSMEHFRWG

(SEQ ID NO:581)
ACTH (1-13), human
SYSMEHFRWGKPV

(SEQ ID NO:582)
ACTH (1-24), human
SYSMEHFRWGKPVGKKRRPVKVYP

(SEQ ID NO:583)
ACTH (1-39), human
SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF

(SEQ ID NO:584)
ACTH (18-39), human (CLIP)
RPVKVYPNGAEDESAEAFPLEF

(SEQ ID NO:585)
ACTH (22-39)
VYPNGAEDESAEAFPLEF

(SEQ ID NO:586)
ACTH (7-38), human
FRWGKPVGKKRRPVKVYPNGAEDESAEAFPLE
Biotin-ACTH (1-39), human
Biotin-SYSMEHFRWGKPVGKKRRPVKVYPNGAEDESAEAFPLEF

(SEQ ID NO:587)
Sauvagine
Pyr-GPPISIDLSLELLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2

(SEQ ID NO:588)
AGRP (25-51)
LAPMEGIRRPDQALLPELPGLGLRAPL

(SEQ ID NO:589)
AGRP (54-82)
TTAEQAEEDLLQEAQALAEVLDLQDREPR

(SEQ ID NO:590)
AGRP (87-132), human
Ac-CVRLHESCLGQQVPCCDPCATCYCRFFNAFCYCRKLGTAMNPCSRT

(SEQ ID NO:591)
AGRP fragment (83-132), amide
SSRRCVRLHESCLGQQVPCCDPCATCYCRFFNAFCYCRKLGTAMNPCSRT-NH2
(5 disulfide bridges

(SEQ ID NO:592)
Allatostatin I (free acid)
APSGAQRLYGFGL

(SEQ ID NO:593)
Allatostatin I, Dip-AST7, cockroach
APSGAQRLYGFGL-NH2

(SEQ ID NO:594)
Allatostatin II
GDGRLYAFGL-NH2

(SEQ ID NO:595)
Allatostatin III
GGSLYSFGL-NH2

(SEQ ID NO:596)
Altatostatin IV
DRLYSFGL-NH2

(SEQ ID NO:597)
Allatostatin VI
YPQEHRFSFGL-NH2

(SEQ ID NO:598)
Allatostatin VII
DGRMYSFGL-NH2

(SEQ ID NO:599)
Allatotropin, Mas-AT
GFKNVEMMTARGF-NH2

(SEQ ID NO:600)
{Ala16, 17, 20}-beta- Amyloid (1-28)
DAEFRHDSGYEVHHQAAVFAAEDVGSN

(SEQ ID NO:601)
{Gln22}-beta-Amyloid (15-23)
QKLVFFAQD

(SEQ ID NO:602)
{NMeG24, NMeI26} Human Islet Amyloid Polypeptide (IAPP) (22-27)
NF-(NMe-G)-A-(NMe-I)-L

(SEQ ID NO:603)
Amylin (1-13), human
KCNTATCATQRLA (Disulfide bridge: 2-7)

(SEQ ID NO:604)
Amylin (1-37), human
KCNTATCATQRLANFLVHSSNNFGAILSSTVGSNTY (Disulfide bridge: 2-7)

(SEQ ID NO:605)
Amylin (20-29), human
SNNFGAILSS

(SEQ ID NO:606)
Amylin (8-37), human
ATQRLANFLVHSSNNFGAILSSTNVGSNTY-NH2

(SEQ ID NO:607)
Beta-Amyloid (12-24)
VHHQKLVFFAEDV

(SEQ ID NO:608)
Beta-Amyloid (13-23)
HHQKLVFFAED

(SEQ ID NO:609)
Beta-Amyloid (7-29)
DSGYEVHHQKLVFFAEDVGSNKG

(SEQ ID NO:610)
Angiotensin
{Des-Asp1}-Angiotensin I, human
RVYIHPFHL

(SEQ ID NO:611)
{Sar1, Ala8}-Angiotensin II
Sar-RVYIHPA

(SEQ ID NO:612)
{Sar1, Va15, A1a8}-Angiotensin II, Saralasin
Sar-RVYVHPA

Angiotensin Converting Enzyme Inhibitor, BPP 9a
Pyr-WPRPQIPP

(SEQ ID NO:613)
Angiotensin I Converting Enzyme 2, ACE-2/Caspase-1 Substrate
Mca-YVADAPK(Dnp)

(SEQ ID NO:614)
Angiotensin I human
DRVYIHPFHL

(SEQ ID NO:615)
Angiotensin II Antipeptide
EGVYVHPV

(SEQ ID NO:616)
Angiotensin I/II (3-8)
VYIHPF

(SEQ ID NO:617)
Angiotensin I/II (4-8)
YIHPF

(SEQ ID NO:618)
Angiotensin I/II (5-8)
IHPF

(SEQ ID NO:619)
Angiotensin II Substrate
DRV-pY-IHPF

(SEQ ID NO:620)
Angiotensin II, human
DRVYIHPF

(SEQ ID NO:621)
Angiotensin III
RVYIHPF

(SEQ ID NO:622)
Prorenin Peptide (33-42)
RIFLKRMPSI

(SEQ ID NO:623)
Renin Substrate, human
DRVYIHPFHLVIHN

(SEQ ID NO:624)
Renin Inhibitor III
RRPFH-Sta-IHK-NH2

(SEQ ID NO:625)
Annexin 1 (ANXA-1, Ac 2-12)
Ac-AMVSEFLKQAW

(SEQ ID NO:626)
Anti-Inflammatory Peptide 1
MQMKKVLDS

(SEQ ID NO:627)
Anti-Inflavornatory Peptide 2
HDMNKVLDL

(SEQ ID NO:628)
Anti-Inflammatory Peptide 3
MQMNKVLDS

(SEQ ID NO:629)
Interleukin-6 Receptor Peptide
TSLPVQDSSSVP

WP9QY, TNF-alpha Antagonist
YCWSQYLCY (Disulfide bridge: between amino acid numbers between 2 8)

(SEQ ID NO:630)
{A1a13}-Apelin-13
QRPRLSHKGPMPA

(SEQ ID NO:631)
{Phe17}-Apelin 17
KFRRQRPRLSHKGPMPF

(SEQ ID NO:632)
{Pyr1}-Apelin-13
Pyr-RPRLSHKGPMPF-OH

(SEQ ID NO:633)
Apelin 12
RPRLSHKGPMPF

(SEQ ID NO:634)
Apelin-15 (63-75)
RRQRPRLSHKGPM

(SEQ ID NO:635)
Apelin-16, human, bovine
FRRQRPRLSHKGPMPF

(SEQ ID NO:636)
Apelin-36, human
LVQPRGSRNGPGPWQGGRRKFRRQRPRLSHKGPMPF

(SEQ ID NO:637)
Bak BH3, Bcl2 (72-87)
KGGGQVGRQLAIIGDDINR)

Bcl 9-2
GSEGLSKEQLEHRERSLQTLRDIERLLLRSGETEPFLKGPPGGAG-NH2

(SEQ ID NO:638)
PR39, Anti-Apoptotic Factor
RRRPRPPYLPRPRPPPFFPPRLPPRIPPGFPPRFPPRFP

(SEQ ID NO:639)
Proapoptotic Peptide, (klaklak)2
klaklakklaklak-NH2, wherein all amino acid residues are D-amino acid residues

(SEQ ID NO:640)
PUMA BH3
EEQWAREIGAQLRRMADDLNAQYER

(SEQ ID NO:641)
RGD-targeted Proapoptotic Peptide
ACDCRGDCFC-GG-klaklakklakak-NH2 (S-S bonded C1-C4 & C2-C3)

(SEQ ID NO:642)
26Rfa, Hpothalamic Peptide, human
TSGPLGNLAEELNGYSRKKGGFSFRF-NH2

(SEQ ID NO:643)
Catch-Relaxing Peptide (CARP)
AMPMLRL-NH2

(SEQ ID NO:644)
Neuropeptide AF (hNPAF), Human
AGEGLNSQFWSLAAPQRF-NH2

(SEQ ID NO:646)
NPSF (1-37), Neuropeptide SF (1-37)
SLNFEELKDWGPKNVIKMSTPAVNKMPHSFANLPLRF-NH2

(SEQ ID NO:646)
AKH/RPCH family of arthropod neuropeptides
LOCUST (AKH-I): pELNFTPNWGT
(SEQ ID NO:647)
CARAUSIUS (HTF-II): pELTFTPNWGT
(SEQ ID NO:648)
SYNTHETIC: LTFTPNWGT
(SEQ ID NO:649)
SYNTHETIC: pELTFTPNWG

Mandauca/Heliothis (AKH)
pELTFTSSWG

(SEQ ID NO:650)
CRUSTACEAN (RPCH)
pELNFSPGW

(SEQ ID NO:651)
LOCUSTA (AKH-II)
pELNFSAGW

(SEQ ID NO:652)
SCHISTOCERCA
pELNFSTGW

(SEQ ID NO:653)
PERIPLANETA M-I
pEVNFSPNW

(SEQ ID NO:654)
PERIPLANETA M-II
pELTFTPNW

(SEQ ID NO:655)
NEUPHOETA/BLABERUS HTH
pEVNFS PGWT

(SEQ ID NO:656)
ROMALEA-I
pEVNFTPNWGT

(SEQ ID NO:657)
ROMALEA-II/Gryllus
pEVNFS AGW

insulin receptor substrate 1 {Homosapiens}

(SEQ ID NO:658)
>gi\|5031805\|ref\|NP_0055351\| insulin receptor substrate 1 {Homosapiens}
MASPPESDGFSDVRKVGYLRKPKSMHKRFFVLRAASEAGGPARLEYYENEKKWRHKSSAPK
RSIPLESCFNINKRADSKNKHLVALYTRDEHFAIAADSEAEQDSWYQALLQLHNRAKGHHD
GAAALGAGGGGGSCSGSSGLGEAGEDLSYGDVPPGPAFKEVWQVILKPKGLGQTKNLIGIYR
LCLTSKTISFVKLNSEAAAVVLQLMNIRRCGHSENFFFIEVGRSAVTGPGEFWMQVDDSVVA
QNMHETILEAMRAMSDEFRPRSKSQSSSNCSNPISVPLRRHHLNNPPPSQVGLTRRSRTESITA
TSPASMVGGKPGSFRVRASSDGEGTMSRPASVDGSPVSPSTNRTHAHRHRGSARLHPPLNHS
RSIPMPASRCSPSATSPVSLSSSSTSGHGSTSDCLFPRRSSASVSGSPSDGGFISSDEYGSSPCDF
RSSFRSVTPDSLGHTPPARGEEELSNYICMGGKGPSTLTAPNGHYILSRGGNGHRCTPGTGLG
TSPALAGDEAASAADLDNRFRKRTHSAGTSPTITHQKTPSQSSVASIEEYTEMMPAYPPGGGS
GGRLPGHRHSAFVPTRSYPEEGLEMHPLERRGGHHRPDSSTLHTDDGYMPMSPGVAPVPSG
RKGSGDYMPMSPKSVSAPQQIINPIRRHPQRVDPNGYMMMSPSGGCSPDIGGGPSSSSSSSNA
VPSGTSYGKLWTNGVGGHHSHVLPHPKPPVESSGGKLLPCTGDYMNMSPVGDSNTSSPSDC
YYGPEDPQHKPVLSYYSLPRSFKHTQRPGEPEEGARHQHLRLSTSSGRLLYAATADDSSSSTS
SDSLGGGYCGARLEPSLPHPHHQVLQPHLPRKVDTAAQTNSRLARPTRLSLGDPKASTLPRA
REQQQQQQPLLHPPEPKSPGEYVNIEFGSDQSGYLSGPVAFHSSPSVRCPSQLQPAPREEETGT
EEYMKMDLGPGRRAAWQESTGVEMGRLGPAPPGAASICRPTRAVPSSRGDYMTMQMSCPR
QSYVDTSPAAPVSYADMRTGIAAEEVSLPRATMAAASSSSAASASPTGPQGAAELAAHSSLL
GGPQGPGGMSAFTRVNLSPNRNQSAKVIRADPQGCRRRHSSETFSSTPSATRVGNTVPFGAG
AAVGGGGGSSSSSEDVKRHSSASFENVWLRPGELGGAPKEPAKLCGAAGGLENGLNYIDLD
LVKDFKQCPQECTPEPQPPPPPPPHQPLGSGESSSTRRSSEDLSAYASISFQKQPEDRQ

(SEQ ID NO:659)
insulin {Homosapiens}
>gi\|386828\|gb\|AAA591721\| insulin {Homosapiens }
MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED
LQVGQVELGGGPGAGSLQPLALEGSLQKRGIVEQCCTSICSLYQLENYCN

(SEQ ID NO:660)
ACTIVE (human) INSULIN fragment:
Chain A: GIVEQCCTSICSLYQLENYCN
(SEQ ID NO:661)
Chain B: FVNQHLCGSHLVEALYLVCGERGFFYTPKT
(Modifications: Disulfide bridge between amino acid numbers
6-11, 7 -7, 20-19)

(SEQ ID NO:662)
Insulin Glargine
>A chain
GIVEQCCTSICSLYQLENYCG
(SEQ ID NO:666)
>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR
In some embodiments the C-terminus is amidated In some embodiments the N
terminus is acylated

(SEQ ID NO:670)
Insulin Lispro
>A chain
GIVEQCCTSICSLYQLENYCN
(SEQ ID NO:673)
>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTKPT
In some embodiments the C-terminus is amidated in some embodiments the N
terminus is acylated

(SEQ ID NO:677)
Insulin Aspart
>A chain
GIVEQCCTSICSLYQLENYCN
>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTDKT
In some embodiments the C-terminus is amidated in some embodiments the N
terminus is acylated
Oxyntomodulin
>gi\|125987831\|sp\|P012753\|

MKSIYFVAGLFVMLVQGSWQRSLQDTEEKSRSFSASQADPLSDPDQMNEDKRHSQGTFTSD
YSKYLDSRRAQDFVQWLMNTKRNRNNIAKRHDEFERHAEGTFTSDVSSYLEGQAAKEFIAW
LVKGRGRRDFPEEVAIVEELGRRHADGSFSDEMNTILDNLAARDFINWLIQTKITDRK

(SEQ ID NO:681)
Oxm HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGln
TrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:682)
DHis1-Oxm
dHisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTr
pLeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:683)
Ala2-Oxm
HisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:684)
DHis1-Ala2-Oxm
dHisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTrpL
euMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:686)
Oxm(ex15-18)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaAlaGlnAspPheValGlnTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:687)
Oxm(ex15-21)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheValG1nTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:688)
Oxm(ex15-23)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGlnTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:689)
Oxm(ex15-24)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGluTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:690)
Oxm(ex27-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrp
LeuLysAsnGlyGlyProSerSerAsnAsnIleAla

(SEQ ID NO:691)
Oxm(ex29-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrp
LeuMetAsnGlyGlyProSerSerAsnAsnIleAla

(SEQ ID NO:692)
Oxm(ex30-33)
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrp
LeuMetAsnThrGlyProSerSerAsnAsnIleAla

(SEQ ID NO:693)
Oxm(ex27-30) His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr
Leu Asp Ser Arg Arg AlaGln Asp Phe Val Gln Trp Leu Lys Asn Gly Gly Arg
Asn Arg Asn Asn Ile Ala

(SEQ ID NO:694)
Oxm19-37 AlaGlnAspPheValG1nTrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAla

(SEQ ID NO:695)
Oxm30-37 LysArgAsnArgAsnAsnIleAla

(SEQ ID NO:698)
Oxm-Ala38
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTr
pLeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAla

(SEQ ID NO:699)
Oxm-Ala38,39
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla

(SEQ ID NO:700)
Oxm-Ala38-42
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValG1nTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAlaAlaAlaAla

(SEQ ID NO:701)
Oxm-Lys38-Laur
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGlnTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla(LysLAUROYL)

(SEQ ID NO:702)
Oxm-Lys38-Palm
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAla(LysPALMITOYL)

(SEQ ID NO:703)
Oxm-Ala38,39-Lys40Laur
HisSerGlnGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGinTrp
LeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla(LysLAUROYL)

(SEQ ID NO:704)
Oxm-Ala38,39-Lys40Palm
HisSerGinGlyThrPheThrSerAspTyrSerLysTyrLeuAspSerArgArgAlaGlnAspPheValGin
TrpLeuMetAsnThrLysArgAsnArgAsnAsnIleAlaAlaAla(LysPALMITOYL)-(D-His1)-Ala2-

(SEQ ID NO:705)
Oxm(ex15-23)
dHisAlaGinGlyThrPheThrSerAspTyrSerLysTyrLeuGluGluGluAlaValArgLeuPheIleGinTr
pLysAsnGlyGlyProSerSerArgAsnAsnIleAlaAlaAla(LysLAUROYL)(ex27-33)-Ala38,39-
Lys40-LAUROYL

(SEQ ID NO:706)
MC-4R Agonist (Cyclo (B-Ala-His-D-Phe-Arg-Trp-Glu)-NH₂)
Ac-Nle-Asp-His-D-Tyr-Arg-Trp-Lys-NH2
(SEQ ID NO:707)
Ac-Lys-Tyr-Val-Nle-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-NH₂
(SEQ ID NO:709)
Ac- Ser Tyr Ser Met Glu His Phe Arg Trp Gly Lys Pro Val NH₂

(SEQ ID NO:710)
Biotin-β- Endomorphin, human
Biotin-YGGFMTSEKSQTPLVTLFKNAIIKNAYKKGE

(SEQ ID NO:711)
{Ala1,3, 11, 16}-Endothelin 1, human
ASASSLMDKEAVYFAHLDIIW

Big Endothelin-1 (1-38), human
CSCSSLMDKECVYFCHLDIIVVVNTPEHVVPYGLGSPRS (Disulfide bridge: 1-15 and 3-11)

(SEQ ID NO:713)
Endothelin 1, human, porcine
CSCSSLMDKECVYFCHLDIIW (Disulfide bridge: 1-15 and 3-11

(SEQ ID NO:714)
Endothelin 2, human
CSCSSWLDKECVYFCHLDIIW (Disulfide bridge: 1-15 and 3-11)

(SEQ ID NO:715)
Orphanin FQ2, (OFQ2, NOCII)
FSEFMRQYLVLSMQSSQ

(SEQ ID NO:716)
{Des-His1, Glu8}-Exendin-4
GEGTPTSELSKQMEEEAVRLPIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:718)
Biotin-Exendin 4
Biotin-HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:718)
Exendin (10-39)
LSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:719)
Exendin (4-39)
GTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:720)
Exendin (5-39)
TFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:721)
Exendin (7-39)
TSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:722)
Exendin (9-39)
DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:723)
Exendin (9-39)
DLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:724)
Exendin 3
HSDGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS-NH2

(SEQ ID NO:725)
Glicentin-Related Peptide (21-50), human RSLQDTEEKSRSFSASQADPLSDPDQMNED-NH2

(SEQ ID NO:726)
α1 (I) Collagen (614-639), Type I Collagen α1 (I) C-Telopeptide, human
SAGFDFSFLPQPPQEKAHDGGRYYRA

(SEQ ID NO:727)
FDC-SP (30-85), human
SISDSDELASGFFVFPYPYPFRPLPPIPFPRFPWFRRNFPIPIPESAPTTPLPSEK

(SEQ ID NO:728)
FDC-SP (61-85), human
FPWFRRNFPIPIPESAPTTPLPSEK

(SEQ ID NO:729)
Fibrinopeptide A, human
ADSGEGDFLAEGGGVR

(SEQ ID NO:730)
Fibrinopeptide B, human
Pyr-GVNDNEEGFFSAR

(SEQ ID NO:731)
Gamma-Fibrinogen (377-395)
YSMKETTMKIIPFNRLSIG

(SEQ ID NO:732)
{Glu1}-Fibrinopeptide B Glufib
EGVNDNEEGFFSAR

(SEQ ID NO:733)
EAK16-II
AEAEAKAKAEAEAKAK-NH2

(SEQ ID NO:734)
Elastin-Like Octapeptide
GVGVPGVGVPGVGVPGVG

(SEQ ID NO:735)
Fibrinogen β-Chain (24-42)
EEAPSLRPAPPPISGGGYR

(SEQ ID NO:736)
Fibrinogen γ-Chain (117-133)
NNQKIVNLKEKVAQLEA

(SEQ ID NO:737)
Fibrinogen γ-Chain (397-411)
GQQHHLGGAKQAGDV

(SEQ ID NO:738)
Fibrinogen Binding Inhibitor Peptide
HHLGGAKQAGDV

(SEQ ID NO:739)
Fibrinogen-Binding Peptide
EHIPA

(SEQ ID NO:740)
{Ala6,D-Trp8}-Galanin (1-15)-ol
GWTLNAAwYLLGPHA-ol

(SEQ ID NO:741)
{D-Trp6,8,9}-Galanin (1-15)-ol
GWTLNwAwwLLGPHA-ol

(SEQ ID NO:742)
Biotin-Galanin, human
Biotin-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS

Biotin-Galanin, human
Biotin-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS

(SEQ ID NO:743)
Galanin (1-13)-Bradykinin (2-9), amide, M35
GWTLNSAGYLLGPPPGFSPFR-NH2

(SEQ ID NO:744)
Galanin (1-13)-Neuropeptide Y (25-36), amide, M32
GWTLNSAGYLLGPRHYINLITRQRY-NH2

(SEQ ID NO:745)
Galanin (1-13)-Pro-Pro-(Ala-Leu)2-Ala, amide
GWTLNSAGYLLGPPPALALA- NH2

(SEQ ID NO:746)
Galanin (1-13)-Spantide I, C7
GWTLNSAGYLLGPrPKPQQwFwLL-NH2

(SEQ ID NO:747)
Galanin (1-13)-Spantide I, C8
GWTLNSAGYLLGPrPKPQQwFwLL-NH2

(SEQ ID NO:748)
Galanin (1-13)-Substance P (5-11), amide, Galantide
GWTLNSAGYLLGPQQFFGLM-NH2

(SEQ ID NO:749)
Galanin (1-13)/Galanin Like Peptide (GALP) (9-21), common
GWTLNSAGYLLGP

(SEQ ID NO:750)
Galanin Message Associated Peptide, GMAP (1-41), amide
ELEPEDEARPGGFDRLQSEDKAIRTIMEFLAFLHLKEAGAL-NH2

(SEQ ID NO:751)
Galanin Message Associated Peptide, GMAP (16-41), amide
LQSEDKAIRTIMEFLAFLHLKEAGAL-NH2

(SEQ ID NO:752)
Galanin Message Associated Peptide, GMAP (25-41), amide
TIMEFLAFLHLKEAGAL-NH2

(SEQ ID NO:753)
Galanin Message Associated Peptide, GMAP (44-59), amide
LPGLPSAASSEDAGQS-NH2

Galanin, human
GWTLNSAGYLLGPHAVGNHRSFSDKNGLTS

(SEQ ID NO:754)
Galanin-Lys(Biotin), human
GWTLNSAGYLLGPHAVGNHRSFSDKNGLTSK(Biotin)

Galanin-Lys(Biotin), human, FAM-labeled
FAM-GWTLNSAGYLLGPHAVGNHRSFSDKNGLTSK(Biotin)

(SEQ ID NO:755)
Leptin (57-74)
VTGLDFIPGLHPILTLSK

GIP (1-42), human
YAEGTFISDYSIAMDKIHQQDFVNVVLLAQKGKKNDWKHNITQ

(SEQ ID NO:756)
GIP (3-42), human
EGTFISDYSIAMDKIHQQDFVNVVLLAQKGKKNDWKHNITQ

(SEQ ID NO:757)
(Leu15)-Gastrin-1, human
Pyr-GPWLEEEEEAYGWLDF-NH2

(SEQ ID NO:758)
Big Gastrin-1, human
Pyr-LGPQGPPHLVADPSKKQGPWLEEEEEAYGWMDF-NH2

(SEQ ID NO:759)
Biotin-Gastrin (1-17)
Biotin-EGPWLEEEEEAYGWMDF-NH2

(SEQ ID NO:760)
Biotin-Gastrin (1-17), phosphorylated
Biotin-EGPWLEEEEEA-pY-GWMDF-NH2

(SEQ ID NO:761)
Biotin-Gastrin Releasing Peptide, human
Biotin-VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2

(SEQ ID NO:762)
Gastrin derived peptide
GPWLEEEEEAYGWMDFK-NH2

(SEQ ID NO:763)
Gastrin Releasing Peptide (14-27), porcine and human
MYPRGNHWAVGHLM-NH2

(SEQ ID NO:764)
Gastrin Releasing Peptide (20-27), porcine and human, acetylated
Ac-HWAVGHLM-NH2

(SEQ ID NO:765)
Gastrin Releasing Peptide, human
VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2

Gastrin Releasing Peptide-Lys(Biotin), human
VPLPAGGGTVLTKMYPRGNHWAVGHLMK(Biotin)

(SEQ ID NO:766)
Gastrin-1, human
Pyr-GPWLEEEEEAYGWMDF-NH2

(SEQ ID NO:767)
Gastrin-Releasing Peptide (1-17)
VPLPAGGGTVLTKMYPR

(SEQ ID NO:768)
GRP10, Gastrin-releasing Peptide 10/Neuromedin C, amidated
GNHWAVGHLM-NH2

(SEQ ID NO:769)
{Des-His1, Glu9}-Glucagon (1-29), amide
SQGTFTSEYSKYLDSRRAQDFVQWLMNT-NH2

Glucagon-like Peptide-2, GLP-2 (146-178), human
HADGSFSDEMNTILDNLAARDFINWLIQTKITD

(SEQ ID NO:770)
Peptide Histidine Isoleucinamide (PHI), Porcine (1-27)
HADGVFTSDFSRLLGQLSAKKYLESLI-NH2

(SEQ ID NO:771)
Glucagon-Like Peptide 1, GLP-1 (7-17)-Cys
HAEGTFTSDVSC

(SEQ ID NO:772)
{GalNAc-Ser}-Erythropoietin (Epo) (117-131)
EAISPPDAA-S-AAPLR (S=GalNAc-Ser)

(SEQ ID NO:773)
EGFR-1148, EGFR (1140-1152)
QISLDNPDYQQDF

(SEQ ID NO:774)
Growth Hormone Releasing Factor, GRF (1-29), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2

(SEQ ID NO:775)
Growth Hormone Releasing Factor, GRF (1-40), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGA-NH2

(SEQ ID NO:776)
Growth Hormone Releasing Factor, GRF (1-44), amide, human
YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL-NH2

(SEQ ID NO:777)
{D-Ala2}-Growth Hormone Releasing Factor, GRF (1-29), amide, human
YaDAIFTNSYRKVLGQLSARKLLQDIMSR-NH2

(SEQ ID NO:778)
PEP1--inhibits membrane association of NS5A, hence impairing HCV replication
SGSWLRDVVVDWICTVLTDFKTWLQSKLDYKD-NH2

(SEQ ID NO:779)
Pep 4A
GSVVIVGRIILSGR-NH2

(SEQ ID NO:780)
Pep 4AK
KKKGSVVIVGRIILSGR-NH2

(SEQ ID NO:781)
HMGA N-Terminal Fragment
GAGQPSTSAQGQ

(SEQ ID NO:782)
AKT/PKB/Rac-Protein Kinase Substrate {ARKRERTYSFGHHA}, Biotinylated
Biotin-ARKRERTYSFGHHA

(SEQ ID NO:783)
5-TMR-ARKRERTYSFGHHA Competitively inhibits histone H2B phosphorylation (Ki=12 μM)
by AKT
5-TMR-ARKRERTYSFGHHA

(SEQ ID NO:784)
T20
Ac-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-NH2

(SEQ ID NO:785)
T22 ({Tyr5,12, Lys7}-polyphemusin II)
RRWCYRKCYKGYCYRKCR

(SEQ ID NO:786)
Skeletal Dihydropyridine Receptor (671-690)
TSAQKAKAEERKRRKMSRGL

(SEQ ID NO:787)
Luteinizing Hormone-Releasing Hormone (LH-RH), human,
Pyr-HWSYGLRPG-NH2

(SEQ ID NO:788)
β- MSH, human
AEKKDEGPYRMEHFRWGSPPKD

(SEQ ID NO:789)
γ-2-MSH (41-58)
YVMGHFRWDRFG

(SEQ ID NO:790)
{D-Phe7}-ACTH, α-MSH (1-13), amide
SYSMEHfRWGKPV-NH2

(SEQ ID NO:791)
{Nle4, D-Phe7}-α-MSH, amide
Ac-SYS-Nle-EHfRWGKPV-NH2

(SEQ ID NO:792)
Melanin Concentrating Hormone, human, mouse, rat
DFDMLRCMLGRVYRPCWQV (Disulfide bridge: 7-16)

(SEQ ID NO:793)
VA-β- MSH, Lipotropin-γ, Proopiomelanocortin-derived
VAAEKKDEGPYRMEHFRWGSPPKD

(SEQ ID NO:794)
Apolipoprotein B-100 (3136-3155), human
KTTKQSFDLSVKAQYKKNKH

(SEQ ID NO:795)
alpha-9 Gliadin Peptide
QVLQQSTYQLLQELCCQHLW

(SEQ ID NO:796)
MOG (8-21)
PGYPIRALVGDEAE

(SEQ ID NO:797)
MOG (97-108)
TCFFRDHSYQEE

(SEQ ID NO:798)
MOG (14-39), human
ALVGDEVELPCRISPGKNATGMELGW

(SEQ ID NO:799)
MOG (50-74), human
LYRNGKDQDGDAPEYRGRTELLKD

(SEQ ID NO:800)
MOG (27-50), human
SPGKNATGMELGWYRPPFSRVVHL

(SEQ ID NO:801)
MOG (76-100), human
IGEGKVTLRIRNVRFSDEGGFTCFF

(SEQ ID NO:802)
MOG (89-113), human
RFSDEGGFTCFFRDHSYQEEAAMEL

(SEQ ID NO:803)
MOG (35-51)
MEVGWYRSPFSRVVHLY

(SEQ ID NO:804)
MOG (35-52)
MEVGWYRSPFSRVVHLYR

(SEQ ID NO:805)
MOG (35-53)
MEVGWYRSPFSRVVHLYRN

(SEQ ID NO:806)
MOG (35-55), human
MEVGWYRPPFSRVVHLYRNGK

(SEQ ID NO:807)
MOG (101-120), human, mouse
RDHSYQEEAAMELKVEDPFY

(SEQ ID NO:808)
{A1a4}-MBP (1-11)
Ac-ASQARPSQRHG

(SEQ ID NO:809)
{Tyr4}-MBP (1-11)
Ac-ASQYRPSQRHG

(SEQ ID NO:810)
MBP (1-17)
ASQKRPSQRSKYLATAS

(SEQ ID NO:811)
MBP (1-20), Myelin Basic Protein (1-20)
ASQKRPSQRSKYLATASTMD

(SEQ ID NO:812)
MBP (111-129)
LSRFSWGAEGQRPGFGYGG

(SEQ ID NO:813)
MBP (131-155)
ASDYKSAHKGLKGVDAQGTLSKIFK

(SEQ ID NO:814)
Vasonatrin Peptide (1-27)
GLSKGCFGLKLDRIGSMSGLGCNSFRY (Disulfide bridge: 6-22)

(SEQ ID NO:815)
{Ala5, β-Ala8}-Neurokinin A (4-10)
DAFV-(β-A)-LM-NH2

(SEQ ID NO:816)
{D-Pro2, D-Trp6,8, Nle10}-Neurokinin B
DpHDFwVwL-NIe-NH2

(SEQ ID NO:817)
{Lys5, NMeLeu9, NIe10}-Neurokinin A (4-10)
DKFVG-(NMeL)-NIe-NH2

(SEQ ID NO:818)
Neurokinin A, Substance K, Neuromedin L, NKA
HKTDSFVGLM-NH2

(SEQ ID NO:819)
Neuromedin (B-30)
LSWDLPEPRSRAGKIRVHPRGNLWATGHFM-NH2

(SEQ ID NO:820)
{Ser2}-Neuromedin C
GSHWAVGHLM-NH2

(SEQ ID NO:821)
β-Neuroprotectin (D-Ala1)
aDLIAYL-NH2

(SEQ ID NO:822)
{Ala16,17,20}-beta-Amyloid (1-28)
DAEFRHDSGYEVHHQAAVFAAEDVGSNK

26Rfa, Hypothalamic Peptide, human
TSGPLGNLAEELNGYSRKKGGFSFRF-NH2

(SEQ ID NO:823)
Brain Neuropeptide I
AGEGLSSPFWSLAAPQRF-NH2

(SEQ ID NO:824)
Erythropoietin, Human (hEPO) Fragment
MEVGQQAVEVWQGLALLSEAVLR

(SEQ ID NO:825)
Neuropeptide NPW-23 (Human)
WYKHVASPRYHTVGRAAGLLMGL

(SEQ ID NO:826)
VGF Protein Precursor (491-507)
PPEPVPPPRAAPAPTHV

(SEQ ID NO:827)
{Gln4}-Neurotensin
Pyr-LYQNKPRRPYIL

(SEQ ID NO:828)
{D-Tyr11}-Neurotensin
Pyr-LYENKPRRPyIL

(SEQ ID NO:829)
{D-Trp11}-Neurotensin
Pyr-LYENKPRRPwIL

(SEQ ID NO:830)
{D-Phe11}-Neurotensin
Pyr-LYENKPRRPfIL

(SEQ ID NO:831)
Neurotensin
Pyr-LYENKPRRPYIL

(SEQ ID NO:832)
Neuropeptide F
PDKDFIVNPSDLVLDNKAALRDYLRQINEYFAIIGRPRF-NH2

(SEQ ID NO:833)
PTD-p50 (NLS) Inhibitory Peptide
DRQIKIVVFQNRRMKWKKVQRKRQKLMP

(SEQ ID NO:834)
PTD-p65-P1 Peptide
DRQIKIVVFQNRRMKWKKQLRRPSDRELSE

(SEQ ID NO:835)
PTD-p65-P6 (Ser529/536) Inhibitory Peptide
DRQIKIVVFQNRRMKWKKNGLLSGDEDFSS

(SEQ ID NO:836)
PTD-TRAF6 Inhibitory Peptide
DRQIKIFQNRRMKWKKRKIPTEDEY

(SEQ ID NO:837)
RNase S Complex Peptide
Ac-KETAAAKFERQHMDSSTSA-NH2

(SEQ ID NO:838)
IKKγ NEMO Binding Domain (NBD) Inhibitory Peptide
DRQIKIVVFQNRRMKWKKTALDWSWLQTE

(SEQ ID NO:839)
{Trp5}-Oryzatensin (5-9), rice
WPLPR

(SEQ ID NO:840)
LVV-Hemorphin-6, Leu-Valorphin-Arg
LVVYPWTQR

(SEQ ID NO:841)
LVV-Hemorphin-7
LVVYPWTQRF

(SEQ ID NO:842)
Nociceptin (1-11), (Orphanin FQ, or OFQ/N) (1-11)
FGGFTGARKSA

(SEQ ID NO:843)
Nociceptin (1-13), amide
FGGFTGARKSARK

(SEQ ID NO:844)
Nociceptin (1-7), (Orphanin FQ, or OFQ/N) (1-7)
FGGFTGA

(SEQ ID NO:845)
Prepronociceptin (169-176), human
TLHQNGNV

(SEQ ID NO:846)
Serorphin, BSA (399-404)
YGFQNA

(SEQ ID NO:847)
Valorphin
VVYPWTQ

(SEQ ID NO:848)
Orexin A, bovine, human, mouse, rat
Pyr-PLPDCCRQKTCSCRLYELLHGAGNHAAGILTL-NH2 (Disulfide bridge: 6-12 and 7-14)

(SEQ ID NO:849)
Orexin B, human
RSGPPGLQGRLQRLLQASGNHAAGILTM-NH2

(SEQ ID NO:851)
{Gla17,21,24}-Osteocalcin (1-49)
YLYQWLGAPVPYPDPL-Gla-PRR-Gla-VC-Gla-LNPDCDELDHIGFQEAYRRFYGPV
(Gla=γ-Carboxyglutamic Acid; Disulfide bridge: 23-29)

(SEQ ID NO:852)
Osteocalcin (37-49), human
GFQEAYRRFYGPV

(SEQ ID NO:853)
Osteocalcin (7-19), human
GAPVPYPDPLEPR

(SEQ ID NO:854)
Lys-OVA (257-264), KSIINFEKL
KSIINFEKL

(SEQ ID NO:855)
{Arg8}-Vasopressin (AVP)
CYFQNCPRG-NH2 (Disulfide bridge: 1-6)

(SEQ ID NO:856)
{Deamino-Cys1, D-Arg8}-Vasopressin, free acid
3-Mercaptopropionyl-YFQNCPrG (Disulfide bridge: 1-6)

(SEQ ID NO:857)
Oxytocin
CYIQNCPLG-NH2 (Disulfide bridge: 1-6)

(SEQ ID NO:858)
Serum Albumin (102-226)
ADDKETCFAEEGKKLVAASQAALGL

(SEQ ID NO:859)
Apolipoprotein J (215-222)
RPHFFFPK

(SEQ ID NO:860)
Apolipoprotein L (306-316)
VNEPSILEMSR

(SEQ ID NO:861)
Catestatin, human
SSMKLSFRARAYGFRGPGPL

(SEQ ID NO:862)
Pancreastatin (37-52), Human
EEEEEMAVVPQGLFRG-NH2

(SEQ ID NO:863)
Pancreatic Polypeptide (30-53), human
APLEPVYPGDNATPEQMAQYAADL

(SEQ ID NO:864)
{Tyr0}-Hypercalcemia Malignancy Factor (1-40)
YAVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTAEIRATS

(SEQ ID NO:865)
Hypercalcemia Malignancy Factor (1-34), (PLP) amide, human
AVSEHQLLHDKGKSIQDLRRRFFLHHLIAEIHTA-NH2

(SEQ ID NO:866)
TIP 39, Tuberoinfundibular Neuropeptide
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP

(SEQ ID NO:867)
PACAP-Related Peptide (PRP), human
DVAHGILNEAYRKVLDQLSAGKHLQSLVA

(SEQ ID NO:868)
Prolactin Releasing Peptide (1-31), human
SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH2

(SEQ ID NO:869)
Prolactin Releasing Peptide (12-31), human
TPDINPAWYASRGIRPVGRF-NH2

(SEQ ID NO:870)
Calpain Inhibitor Peptide, B27-WT
DPMSSTYIEELGKREVTIPPKYRELLA

105Y, α1-antitrypsin (359-374)
SIPPEVKFNKPFVYLI

(SEQ ID NO:871)
Acetyl-Calpastatin (184-210), CS peptide, human
Ac-DPMSSTYIEELGKREVTIPPKYRELLA-NH2

(SEQ ID NO:872)
{Ala144}-PLP (139-151) A144-PLP(139-151)
HSLGKALGHPDKF

(SEQ ID NO:873)
PLP (190-209)
SKTSASIGSLCADARMYGVL

(SEQ ID NO:874)
PLP (48-70)
TYFSKNYQDYEYLINIHAFQYV

(SEQ ID NO:875)
Acetyl-Tetradecapeptide Renin Substrate, Acetyl-Angiotensinogen (1-14), human
Ac-DRVYIHPFHLVIHN

(SEQ ID NO:876)
TP508, Thrombin-derived Peptide
AGYKPDEGKRGDACEGDSGGPFV

(SEQ ID NO:877)
Salusin-alpha
SGALPPAPAAPRPALRAQRAGPAGPGAK-NH2

(SEQ ID NO:878)
Salusin-beta
AIFIFIRWLLKLGHHGRAPP

(SEQ ID NO:879)
Prosaptide 769P (D-Ala2)
CaFLVKEVTKLIDNNKTEKEIL

(SEQ ID NO:880)
Prosaptide TX14(A) (D-Ala2)
TaLIDNNATEEILY

(SEQ ID NO:881)
Prosaptide, wild type
TKLIDNNKTEKEIL

(SEQ ID NO:882)
Saposin C12
LIDNNKTEKEIL

(SEQ ID NO:883)
Saposin C18
VKEVTKLIDNNKTEKEIL

(SEQ ID NO:884)
Saposin C22
CEFLVKEVTKLIDNNKTEKEIL

(SEQ ID NO:885)
Secretin, human
HSDGTFTSELSRLREGARLQRLLQGLV-NH2

(SEQ ID NO:886)
CC Chemokine Receptor 3 Fragment I, amide
MTTSLDTVETFGTTSYYDDVGLLCEKADTR-NH2

(SEQ ID NO:887)
CC Chemokine Receptor 3 Fragment II
MTTSLDTVETFGTTSYYDDVGLLC

(SEQ ID NO:888)
DAP10 Signaling Fragment
PAQEDGKVYINMPGRG

(SEQ ID NO:889)
Erythropoietin-Mimetic Peptide 17 (EMP17)
TYSCHFGPLTWVCKPQGG

(SEQ ID NO:890)
Hsp Heat shock protein (3-13)
KTIAYDEEARR

(SEQ ID NO:891)
iNOS (507-531), human
RPKRREIPLKVLVKAVLFACMLMRK

(SEQ ID NO:892)
Notch 1(1735-1752)
VLLFFVGCGVLLSRKRRR

(SEQ ID NO:893)
SmMLCKp, Smooth-Muscle Myosin Light-Chain Kinase (796-815), Calmodulin
Binding ARRKWQKTGHAVRAIGRLSS

(SEQ ID NO:894)
Tau-Protein (1-16)
MAEPRQEFEVMEDHAG

(SEQ ID NO:895)
Tau-Protein (323-335)
GSLGNIHHKPGGG

(SEQ ID NO:896)
Caveolin-1 Scaffolding Domain (82-101)
DGIVVKASFTTFTVTKYWFYR

(SEQ ID NO:897)
Caveolin-3 (Cay-3), (55-74)
DGVWRVSYTTFTVSKYVVCYR

(SEQ ID NO:898)
{Gly35, Asp37}-beta-Amyloid (1-42)
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLGVDGVVIA

(SEQ ID NO:899)
{Cys7}-beta-Amyloid (1-40)
DAEFRHCSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV

(SEQ ID NO:900)
beta-Amyloid (1-40)
DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVV

(SEQ ID NO:901)
{Cys3,6, Tyr8, Pro9}-Substance P
RPCPQCFYPLM-NH2 (Disulfide bridge: 3-6)

(SEQ ID NO:902)
{4-Chloro-Phe}7,8-Substance P
RPKPQQ-F(4-Cl-F)-GLM-NH2

(SEQ ID NO:903)
{Cys3,6, Tyr8, Pro10}-Substance P
RPCPQCFYGPM-NH2 (Disulfide bridge: 3-6)

(SEQ ID NO:904)
Ranakinin
KPNPERFYGLM-NH2

(SEQ ID NO:905)
Scyliorhinin I, Scy I, Shark Substance P Related Peptide
AKFDKFYGLM

(SEQ ID NO:906)
Substance P
RPKPQQFFGLM-NH2

(SEQ ID NO:907)
SFLLRNPNDKYEPF, human Thrombin Receptor 42-55
SFLLRNPNDKYEPF

(SEQ ID NO:908)
Tumor Necrosis Factor Receptor, TNFR (159-178) Analog
QEKQNTVATAHGFFLRENEG

(SEQ ID NO:909)
CDIP2
KISLQRLKSYVITTSRCPQ

(SEQ ID NO:910)
Pro-TNF-α+0(71-82), human
SPLAQAVRSSSR

(SEQ ID NO:911)
TNF-α (10-36), human
DKPVAHVVANPQAEGQLQWLNRRANAL

(SEQ ID NO:912)
TNF-α (31-5), human
RRANALLANGVELRD

(SEQ ID NO:913)
Brevinin-2Eg
GIMDTLKNLAKTAGKGALQSLLNHASCKLSGQC (Disulfide bridge 27-33)

(SEQ ID NO:914)
Brevinin-2Eh
GIMDTLKNLAKTAGKGALQSLLNHASCKLSKQC (Disulfide bridge 27-33)

(SEQ ID NO:915)
Caloxin 1b1
TAWSEVLHLLSRGGG

(SEQ ID NO:916)
Caloxin 2A1
VSNSNWPSFPSSGGG

(SEQ ID NO:917)
Caloxin 3A1
WSSTSSVSAPLEFGGGGSAK

(SEQ ID NO:918)
Delta-Toxin (1-26), Staphylococcus aureus
MAQDIISTIGDLVKWIIDTVNKFTKK

(SEQ ID NO:919)
Delta-Toxin (5-20), Staphylococcus aureus
IISTIGDLVKWIIDTV

(SEQ ID NO:920)
Sarafotoxin 6c
CTCNDMTDEECLNFCHQDVIVV (Disulfide bridge: 1-15 and 3-11)

(SEQ ID NO:921)
Vesicle-Associated Membrane Protein, VAMP (60-94)
LSELDDRADALQAGASQFETSAAKLKRKYWWKNLK

(SEQ ID NO:922
Vesicle-Associated Membrane Protein, VAMP (77-94)
SQFETSAAKLKRKYWWKNLK

(SEQ ID NO:923)
Helodermin
HSDAIFTQQYSKLLAKLALQKYLASILGSRTSPPP

(SEQ ID NO:924)
highly selective CRF2 receptor antagonist K41498
dFHLLRKNleIEIEKQEKEKQQAANNRLLLDTI-NH2

(SEQ ID NO:925)
Corticotrooin-releasing factor receptor antagonist
DLTFHLLREMLEMAKAEQEAEQAALNRLLLEEA-NH2

(SEQ ID NO:926)
Astressin CAS No: {170809-51-5}
Potent cortieotropin-releasing factor (CRF) receptor antagonist (K_ivalues
are 2, 15 and 1 nM at CRF₁, CRF₂α and CRF₂β) Reduces ACTH secretion, blocks
delayed gastric emptying and is neuroprotective in vivo
dFfHLLREVLENleARAEQLAQEAHKgNRKLNleEII-NH2 E-Kg are cyclized The
cyclic structure has been fixed by amide bond between gamma-COOH group of
glutamicacid and alpha-NH2 group of glycine coupled to the epsilon-NH2 group
of lysine

(SEQ ID NO:927)
Stressin I
Potent and selective corticotropin releasing factor receptor-1 (CRF₁) agonist
(K_ivalues are15 and 224 nM for CRF₁and CRF₂receptors respectively) Increases
ACTH levels andincreases faecal pellet output in vivo following ip
administration Ac-PPISLDLTFHLIREVLENleARAEQIAQQEHSKAKLNleEII-NH2 E-K are
cyclized The cyclic structure has been fixed by amide bond between gamma-COOH
groupof glutamic acid and epsilon-NH2 group of lysine

(SEQ ID NO:928)
Human urocortin III ?+0like sequences
MLMPVHFLLLLLLLLGGPRTGLPHKFYKAKPIFSCLNTALSEAEKGQWEDASLLSKR
SFHYLRSRDASSGEEEEGKEKKTFPISGARGGAGGTRYRYVSQAQPRGKPRQDTAKS
PHRTKFTLSLDVPTNIMNLLFNIAKAKNLRAQAAANAHLMAQIGRKK

(SEQ ID NO:929)
Active Form: 120-137 urocortin III {Homosapiens}
FTLSLDVPTNIMNLLFNI
FTLSLDVPTNIMNLLFNIAKAKNLRAQAAANAHLMAQI

(SEQ ID NO:930)
Human urocortin-2
IVLSLDVPIGLLQILLEQARARAAREQATTNARILARV

Human Growth Hormone Releasing Factor (GHRF), GRF
YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2

JI-22 {Dat1, Orn12,21, Abu15, Nle27, Agm29} GHRF-(1-29)
JI-34 {Dat1, Orn12,21 ,Abu15, N1e27, Asp28, Agm29} GHRF-(1-29)
JI-36 {Dat1, Thr8, Orn12,21, Abu15, N1e27, Asp28, Agm29} GHRF-(1-29)
JI-38 {Dat1, Gln8, Orn12,21, Abu15, N1e27, Asp28, Agm29} GHRF-(1-29)
Dat=desaminotyrosine
Agm=agmatine

α-CGRP (human)
ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF-NH2
Optional Disulfide bridge between C2 and C7

(SEQ ID NO:931)
CGRP (rat)
SCNTATCVTHRLAGLLSRSFFVKDNFVPTNVGSEAF-NH2
Optional Disulfide bridge between C2 and C7

(SEQ ID NO:932)
PTHrP (Human) 1-37
AVSEHQLLHDKGKSIQDLRRFFLHHLIAEIHTAEIR

(SEQ ID NO:933)
PTH (human) 1-34
SVSEIQLMHNLGKHLNSMERVEWLRKKLQDVHN

(SEQ ID NO:934)
TIP 39, Tuberoinfundibular Neuropeptide (human)
SLALADDAAFRERARLLAALERRHWLNSYMHKLLVLDAP

TIP 39, Tuberoinfundibular Neuropeptide (mouse)
SLALADDAAFRERARLLAALERRRWLDSYMQKLLLLDAP

PTH2 Agonists
{His5}-PTH 1-34 (human)
{Ile5}-PTHrP 1-36
{Ile5,Trp23}-PTHrP 1-36 (human)
{Ile5,Trp23}-PTHrP 2-36 (human)
{Ile5,Trp23}-PTHrP 3-36 (human)
{Ile5,Trp23}-PTHrP 4-36 (human)
{Ile5,Trp23}-PTHrP 5-36 (human)
{Ile5,Trp23,Tyr36}-PTHrP 1-36-NH2 (human)1-34 (human)
{Phe23}-PTH (human)
PTH 1-34
PTH 1-34 (rat)
PTHrP 1-34
PTHrP 1-36 (human)
{125I} {Nle8,21,Tyr34}-PTH 1-34-NH2 (rat)
TIP39 (human/bovine)
TIP39 (mouse)
{Trp23}-PTHrP 1-36 (human)
{Trp23,Tyr36}-PTHrP1-36-NH2 (human)

PTH2 Antagonists
{D-Trp12+56-PTH 7-34 (bovine
{D-Trp12,Tyr34}-PTH 7-34 (bovine)
{Ile5,Trp23}-PTHrP 5-36
PTHrP 1-21/PTH 22-34
PTHrP 7-34
TIP39 7-39 (human/bovine)
TIP39 7-39 (mouse)

(SEQ ID NO:935)
AF 12198
(Potent and selective antagonist for the human type I interleukin-1 (IL-1)
receptor)Ac-FEWTPGWYQXYALPL-NH2 X=2-Carboxyazetidine

(SEQ ID NO:936)
human epidermal growth factor
>gi\|46242544\|gb\|AAS833951\| epidermal growth factor {Homosapiens }
NSDSECPLSHDGYCLHDGVCMYIEALDKYACNCVVGYIGERCQYRDLKWWELR

(SEQ ID NO:937)
{cPP1-7,NPY19-23,A1a31,Aib32,G1n34}-hPancreatic Polypeptide
GPSQPTYPGDNATPEQMARYYSALRRYINMAXRQRY-NH X=Aib

(SEQ ID NO:938)
Xenin 8 C-Terminal fragment of xenin, a neurotensin-like peptide; modulates
pancreatic insulin and glucagon secretion/effects HPKRPWIL

(SEQ ID NO:939)
>gi\|29725609\|ref\|NP_0052192\| epidermal growth factor receptor isoform a
precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP
NCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQE
RELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELRE
ATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGS
QYLLNVVCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHA
EGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLP
QPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNF
YRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPI
KEDSFLQRYSSDPTGALTEDSIDDTFLPVPEYINQSVPKRPAGSVQNPVYHNQPLNPAPSRDP
HYQDPHSTAVGNPEYLNTVQPTCVNSTFDSPAHWAQKGSHQISLDNPDYQQDFFPKEAKPN
GIFKGSTAENAEYLRVAPQSSEFIGA

(SEQ ID NO:940)
>gi\|41327736\|ref\|NP_9584411\| epidermal growth factor receptor isoform d
precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP
NCTYGPGNESLKAMLFCLFKLSSCNQSNDGSVSHQSGSPAAQESCLGWIPSLLPSEFQLGWG
GCSHLHAWPSASVIITASSCH

(SEQ ID NO:941)
>gi\|41327732\|ref\|NP_9584391\| epidermal growth factor receptor isoform b
precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQ
FSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCK
ATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPEC
LPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHP
NCTYGS

(SEQ ID NO:942)
>gi\|41327734\|ref\|NP_9584401\| epidermal growth factor receptor isoform c
precursor {Homosapiens}
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVV
LGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSN
YDANKTGLKELPMRNLQEILHGAVRFSNNPALCNVESIQWRDIVSSDFLSNMSMDFQNHLGS
CQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESD
CLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSC
VRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLH
ILPVAFRGDSFTHTPPLDPQELDILKTVKEITGLS

(SEQ ID NO:943)
PHM 27 (human) Endogenous peptide product of human prepro-VIP and analog of
porcine PHI-27; potent agonist for the human calcitonin receptor (EC50=11 nM)
HADGVFTSDFSKLLGQLSAKKYLESLM-NH2

(SEQ ID NO:944)
Calcitoninreceptor-stimulating peptide-1
(Endogenous central calcitonin (CT) receptor agonist
agonist that stimulates cAMP formation at a potency
350-fold greater than CT (ED50 values are 02 and 71 nM respectively) Displays
no activity at calcitonin-gene related peptide (CGRP) and adrenomedullin
receptors Inhibits formation of multinuclear osteoclasts with similar
efficacy to CT in vitro Suppresses food intake and increases body temperature
in free-feeding rats, and significantly decreases plasma calcium levels in
vivo) SCNTATCMTHRLVGLLSRSGSMVRSNLLPTKMGFKVFG-NH2

(SEQ ID NO:945)
AC 187
(Orally active, potent amylin receptor antagonist (IC50=048 nM) that displays
38-fold and 400-foldselectivity over calcitonin and CGRP receptors
respectively Blocks amyloid β-induced neurotoxicity by attenuating
the activation of initiator and effector caspases in vitro Increases glucagon
secretion, accelerates gastric emptying, alters plasma glucose levels
and increases food intake in vivo) Ac-VLGKLSQQLHKLQTYPRTNTGSNTY-NH2

(SEQ ID NO:946)
VIP (guinea pig)
(Neuropeptide with many biological actions; plays a role in
neurotransmission, smooth musclerelaxation and has trophic and mitogenic
actions)HSDALFTDTYTRLRKQMAMKKYLNSVLN-NH2

(SEQ ID NO:947)
{Ala2,8,9,11,19,22,24,25,27,28}-VIP
(Highly selective agonist for the VPAC1 receptor (IC50 values are~115-132
and >30000 nM for VPAC1 and VPAC2 receptors respectively)))
HADAVFTAAYARLRKQMAAKKALAAIAA-NH2

(SEQ ID NO:948)
{Ac-Tyr1,D-Phe2}GRF 1-29, amide (human)
(VIP antagonist; inhibits {125I}iodo-VIP binding and selectively inhibits
VIP- and GRF-induced effects on adenylyl cyclase)
Ac-YdFDAIFTNSYRKVLGQLSARKLLQDIMSR-NH2

(SEQ ID NO:949)
VIP (6-28) (human, rat, porcine, bovine) (VIP antagonist)
FTDNYTRLRKQMAVKKYLNSILN-NH2

(SEQ ID NO:950)
{D-p-Cl-Phe6,Leu17}-VIP
(Selective vasoactive intestinal peptide (VIP) antagonist (IC50=1258 nM)
Displays no activity on glucagon, secretin or GRF receptors)
HSDAVFTDNYTRLRKQLAVKKYLNSILN-NH2 Phe-6=p-Cl-D-Phe

(SEQ ID NO:951)
Neurotensin
XLYENKPRRPYIL X=Pyroglutamic acid (Pyr) (pGlu)
N-stearyl-{Nle17} neurotensin(6-11)/VIP (7-28)
neurotensin(6-11)/P ACAP (6-38)

(SEQ ID NO:952)
human pancreatic polypeptide
APLEPVYPGDNATPEQMAQYAADLRRYINMLTRPRY

(SEQ ID NO:953)
Kinetensin (human) (Endogenous neurotensin-like peptide, originally isolated
from pepsin-treatedhuman plasma Induces histamine release from rat peritoneal
mast cells in vitro (ED50~10 mM))IARRHPYFL

(SEQ ID NO:954)
JMV 449
(Potent, metabolically stable neurotensin receptor agonist peptide (IC50=015
nM for inhibition of{125I}-NT binding to neonatal mouse brain; EC50=19 nM for
contraction of guinea pigleum)Produces long-lasting hypothermic,
neuroprotective and analgesic effects in mice following central
administration in vivo)KKPYIL(Note: Lys-1-Lys-2 peptide bond replace with
Psi(CH2-NH)))

(SEQ ID NO:955)
Neuromedin N (rat, mouse, porcine, canine)
(Endogenous neurotensin-like neuropeptide, originally isolated from porcine
spinal cord. Binds toneurotensin receptors (IC50=167 nM for inhibition of
{Trp11}-NT bindingto rat brain receptors)
Regulates guinea pig intestinal smooth muscle contraction and produces
hypotension inrats Alsoinduces hypothermia following central administration
in rats in vivo) KIPYIL

(SEQ ID NO:956)
des-His1-{Glu9}-Glucagon (1-29) amide
(Glucagon receptor antagonist (pA2=72 for inhibition of glucagon-induced
adenylyl cyclaseactivation in rat liver membranes); displays no agonist
activity Enhances glucose-stimulatedpancreatic insulin release in vitro In
vivo, blocks added glucagon-induced hyperglycemia in normal
rabbits without affecting glycogenolysis Also blocks endogenous glucagon-
induced hyperglycemia in streptozocin diabetic rats)
SQGTFTSEYSKYLDSRRAQDFVQWLMNT-NH2

(SEQ ID NO:957)
Antisauvagine-30
(Potent, selective and competitive corticotropin-releasing factor CRF2
receptor antagonist (Kd valuesare 14 and 1536 nM for binding to mouse CRF2β
and rat CRF1 receptors respectively) Inhibitssauvagine-stimulated cAMP
accumulation in HEK-mCRF2β cells (pA2=849) Prevents stress-
enhanced fear conditioning and MEK 1/2-dependent activation of ERK1/2 in mice
in vivo) dFHLLRKMIEIEKQEKEKQQAANNRLLLDTI-NH2

(SEQ ID NO:958)
>gi\|76781480\|ref\|NP_0010205372\| vascular endothelial growth factor A isoform
a {Homosapiens} TDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFV
QLLGCSRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVYVGARCCLMPWSLPGPHPCGPC
SERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDKPRR

(SEQ ID NO:959)
>gi\|76781481\|ref\|NP_0033674\| vascular endothelial growth factor A isoform b
{Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRYKSWSVPCGPCSERRKHLFVQDPQTCKC
SCKNTDSRCKARQLELNERTCRCDKPRR

(SEQ ID NO:960)
gi\|76781482\|ref\|NP_0010205382\| vascular endothelial growth factor A isoform c
{Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKKSVRGKGKGQKRKRKKSRPCGPCSERRKHLFVQDPQTCKCSCKNTDS
RCKARQLELNERTCRCDKPRR

>gi\|76781483\|ref\|NP_0010205392\| vascular endothelial growth factor A isoform
d {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRCDK
PRR

(SEQ ID NO:961)
>gi\|76781487\|ref\|NP_0010289281\| vascular endothelial growth factor A isoform
g {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKARQLELNERTCRSLTR
KD

(SEQ ID NO:962)
>gi\|76781484\|ref\|NP_0010205402\| vascular endothelial growth factor A isoform
e {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQENPCGPCSERRKHLFVQDPQTCKCSCKNTDSRCKM

(SEQ ID NO:963)
>gi\|76781485\|ref\|NP_0010205412\| vascular endothelial growth factor A isoform
f {Homosapiens}
MTDRQTDTAPSPSYHLLPGRRRTVDAAASRGQGPEPAPGGGVEGVGARGVALKLFVQLLGC
SRFGGAVVRAGEAEPSGAARSASSGREEPQPEEGEEEEEKEEERGPQWRLGARKPGSWTGEA
AVCADSAPAARAPQALARASGRGGRVARRGAEESGPPHSPSRRGSASRAGPGRASETMNFL
LSWVHWSLALLLYLHHAKWSQAAPMAEGGGQNHHEVVKFMDVYQRSYCHPIETLVDIFQE
YPDEIEYIFKPSCVPLMRCGGCCNDEGLECVPTEESNITMQIMRIKPHQGQHIGEMSFLQHNK
CECRPKKDRARQEKCDKPRR

(SEQ ID NO:964)
>gi\|4507887\|ref\|NP_0033681\| vascular endothelial growth factor B precursor
{Homosapiens}
MSPLLRRLLLAALLQLAPAQAPVSQPDAPGHQRKVVSWIDVYTRATCQPREVVVPLTVELM
GTVAKQLVPSCVTVQRCGGCCPDDGLECVPTGQHQVRMQILMIRYPSSQLGEMSLEEHSQC
ECRPKKKDSAVKPDRAATPHHRPQPRSVPGWDSAPGAPSPADITHPTPAPGPSAHAAPSTTSA
LTPGPAAAAADAAASSVAKGGA

(SEQ ID NO:965)
>gi\|4885653\|ref\|NP_0054201\| vascular endothelial growth factor C
preproprotein {Homosapiens}
MHLLGFFSVACSLLAAALLPGPREAPAAAAAFESGLDLSDAEPDAGEATAYASKDLEEQLRS
VSSVDELMTVLYPEYWKMYKCQLRKGGWQHNREQANLNSRTEETIKFAAAHYNTEILKSID
NEWRKTQCMPREVCIDVGKEFGVATNTFFKPPCVSVYRCGGCCNSEGLQCMNTSTSYLSKT
LFEITVPLSQGPKPVTISFANHTSCRCMSKLDVYRQVHSIIRRSLPATLPQCQAANKTCPTNYM
WNNHICRCLAQEDFMFSSDAGDDSTDGFHDICGPNKELDEETCQCVCRAGLRPASCGPHKEL
DRNSCQCVCKNKLFPSQCGANREFDENTCQCVCKRTCPRNQPLNPGKCACECTESPQKCLL
KGKKFHHQTCSCYRRPCTNRQKACEPGFSYSEEVCRCVPSYVVKRPQMS

(SEQ ID NO:966)
A-71623
(Potent CCK1 agonist (IC50=37 nM) with 1200-fold selectivity over the CCK2
receptor
Suppresses food intake following central or peripheral administration)
XWKDF-NH2 Trp-1=Boc-Trp, Lys-3=Lys(Tac), Phe-5=N-methyl-Phe

(SEQ ID NO:967)
Enterostatin
(N′ terminal peptide fragment of procolipase that binds to the β-subunit of
F1-ATPase Activates the ERK and cAMP signaling pathways,
and downregulates expression of Krtippel-like factor 4 (KLF4)
and agouti-related peptide (AgRP) in vitro Inhibits insulin secretion from
pancreatic β-cells bydownregulating expression of dynamin2 and altering
via activation of CCK1, induces satiety, enhances memory-consolidation and
exhibits hypocholesterolemic activity in vivo Orally active))
APGPR

Ac2-12
(Annexin/lipocortin 1-mimetic peptide; inhibits leukocyte extravasation
Reduces neutrophil adhesion and emigration, and promotes
detachment of neutrophils from activated mesenteric endothelium in
mice in vivo) Ac-AMVSEFLKQAW

(SEQ ID NO:968)
Ac2-26
(Annexin/lipocortin 1-mimetic peptide; inhibits leukocyte extravasation
Reduces neutrophil adhesion and emigration, and promotes detachment
of neutrophils from activated mesenteric
endothelium in mice in vivo Anti-inflammatory)
Ac-AMVSEFLKQAWFIENEEQEYVQTVK

(SEQ ID NO:969)
Peptide F9
(Peptide derived from the heparin-binding domain in the B1 chain of laminin
Binds to heparin, promotes cell adhesion, and inhibits the migration
towards, and adhesion of metastatic fibrosarcoma
cells to laminin)
RYVVLPRPVCFEKGMNYTVR

(SEQ ID NO:970)
R18
(Antagonist of 1433 proteins (KD ≈80 nM) Competitively inhibits 1433-ligand
interactions
without requiring phosphorylation Blocks the ability of 1433 to bind to target proteins
such as Raf-1, Bad, ASK1 and exoenzyme S Induces apoptosis)
PHCVPRDLSWLDLEANMCLP

(SEQ ID NO:971)
Thymosin β34
(Naturally occuring, potent regulator of actin polymerization present in
human platelets at a concentration of 200-500 μM
Sequesters G-actin monomers in a 1:1 ratio (Kd=07−10 μM) and
allows rapid filament polymerization in the presence of profilin Implicated in wound healing,MMPs, chemotaxis, angiogenesis, inflammatory processes and
tumor progression induction of
Ac-SDKPDMAEIEKFDKSKLKKTETQEKNPLPSKETIEQEKQAGES

(SEQ ID NO:972)
Anti-GluR4 blocking peptide
(Synthetic peptide ({K}-HTGTAIRQSSGLAVIASDLP) corresponding to the C-terminal
amino acids883-902 of rat precursor GluR4 (Accession No P19493) with a lysine
added at the N-terminus of the peptide Immunogen used for anti-GluR4)
KHTGTAIRQSSGLAVIASDLP

(SEQ ID NO:973)
Anti-phospho-GluR1(Ser831) phosphorylated blocking peptide 826-836 of rat
mature(Synthetic peptide (LIPQQ(pS)INEA1{K}) corresponding to amino acids
GluR1 (Accession No P19490), with a phosphorylated serine at position 831,
and a lysine added to the C-terminus for conjugation Immunogen used for anti-
phospho-GluR1 (5er831)) LIPQQSINEAI Ser-6=phosphorylated Ser

(SEQ ID NO:974)
PHV (1-42)
HADGVFTSDFSKLLGQLSAKKYLESLMGKRVSSNISEDPVPV

(SEQ ID NO:975)
PRP
DVAHGILNQAYRKVLDQLSAGKHLQSLVA

PHM
HADGVFTSDFSKLLGQLSAKKYLESLM

(SEQ ID NO:976)
>gi\|4501947\|ref\|NP_0006651\| adenosine receptor A1 {Homosapiens}
MPPSISAFQAAYIGIEVLIALVSVPGNVLVIVVAVKVNQALRDATFCFIVSLAVADVAVGALVI
PLAILINIGPQTYFHTCLMVACPVLILTQSSILALLAIAVDRYLRVKIPLRYKMVVTPRRAAVAI
AGCWILSFVVGLTPMFGWNNLSAVERAWAANGSMGEPVIKCEFEKVISMEYMVYFNFFVW
VLPPLLLMVLIYLEVFYLIRKQLNKKVSASSGDPQKYYGKELKIAKSLALILFLFALSWLPLHI
LNCITLFCPSCHKPSILTYIAIFLTHGNSAMNPIVYAFRIQKFRVTFLKIVVNDHFRCQPAPPIDED
LPEERPDD

(SEQ ID NO:977)
>gi\|4501951\|ref\|NP_0006671\| adenosine receptor A2b {Homosapiens}
MLLETQDALYVALELVIAALSVAGNVLVCAAVGTANTLQTPTNYFLVSLAAADVAVGLFAI
PFAITISLGFCTDFYGCLFLACFVLVLTQSSIFSLLAVAVDRYLAICVPLRYKSLVTGTRARGVI
AVLWVLAFGIGLTPFLGWNSKDSATNNCTEPWDGTTNESCCLVKCLFENVVPMSYMVYFNF
FGCVLPPLLIMLVIYIKIFLVACRQLQRTELMDHSRTTLQREIHAAKSLAMIVGIFALCWLPVH
AVNCVTLFQPAQGKNKPKWAMNMAILLSHANSVVNPIVYAYRNRDFRYTFHKIISRYLLCQ
ADVKSGNGQAGVQPALGVGL

(SEQ ID NO:978)
>gi\|4501953\|ref\|NP_0006681\| adenosine receptor A3 isoform 2 {Homosapiens}
MPNNSTALSLANVTYITMEIFIGLCAIVGNVLVICVVKLNPSLQTTTFYFIVSLALADIAVGVL
VMPLAIVVSLGITIHFYSCLFMTCLLLIFTHASIMSLLAIAVDRYLRVKLTVRYKRVTTHRRIVV
LALGLCWLVSFLVGLTPMFGWNMKLTSEYHRNVTFLSCQFVSVMRMDYMVYFSFLTWIFIP
LVVMCAIYLDIFYIIRNKLSLNLSNSKETGAFYGREFKTAKSLFLVLFLFALSWLPLSHNCIIYF
NGEVPQLVLYMGILLSHANSMMNPIVYAYKIKKFKETYLLILKACVVCHPSDSLDTSIEKNSE

(SEQ ID NO:979)
>gi\|4501957\|ref\|NP_0006691\| alpha-1D adrenergic receptor {Homosapiens}
MTFRDLLSVSFEGPRPDSSAGGSSAGGGGGSAGGAAPSEGPAVGGVPGGAGGGGGVVGAGS
GEDNRSSAGEPGSAGAGGDVNGTAAVGGLVVSAQGVGVGVFLAAFILMAVAGNLLVILSV
ACNRHLQTVTNYFIVNLAVADLLLSATVLPFSATMEVLGFWAFGRAFCDVWAAVDVLCCT
ASILSLCTISVDRYVGVRHSLKYPAIMTERKAAAILALLWVVALVVSVGPLLGWKEPVPPDE
RFCGITEEAGYAVFSSVCSFYLPMAVIVVMYCRVYVVARSTTRSLEAGVKRERGKASEVVLR
IHCRGAATGADGAHGMRSAKGHTFRSSLSVRLLKFSREKKAAKTLAIVVGVFVLCWFPFFFV
LPLGSLFPQLKPSEGVFKVIFWLGYFNSCVNPLIYPCSSREFKRAFLRLLRCQCRRRRRRRPLW
RVYGHHWRASTSGLRQDCAPSSGDAPPGAPLALTALPDPDPEPPGTPEMQAPVASRRKPPSA
FREWRLLGPFRRPTTQLRAKVSSLSHKIRAGGAQRAEAACAQRSEVEAVSLGVPHEVAEGAT
CQAYELADYSNLRETDI

(SEQ ID NO:980)
>gi\|4501959\|ref\|NP_0006701\| alpha-1B adrenergic receptor {Homosapiens}
MNPDLDTGHNTSAPAHWGELKNANFTGPNQTSSNSTLPQLDITRAISVGLVLGAFILFAIVGN
ILVILSVACNRHLRTPTNYFIVNLAMADLLLSFTVLPFSAALEVLGYWVLGRIFCDIVVAAVDV
LCCTASILSLCAISIDRYIGVRYSLQYPTLVTRRKAILALLSVWVLSTVISIGPLLGWKEPAPND
DKECGVTEEPFYALFSSLGSFYIPLAVILVMYCRVYIVAKRTTKNLEAGVMKEMSNSKELTL
RIHSKNFHEDTLSSTKAKGHNPRSSIAVKLFKFSREKKAAKTLGIVVGMFILCWLPFFIALPLG
SLFSTLKPPDAVFKVVFWLGYFNSCLNPIIYPCSSKEFKRAFVRILGCQCRGRGRRRRRRRRRL
GGCAYTYRPWTRGGSLERSQSRKDSLDDSGSCLSGSQRTLPSASPSPGYLGRGAPPPVELCAF
PEWKAPGALLSLPAPEPPGRRGRHDSGPLFTFKLLTEPESPGTDGGASNGGCEAAADVANGQ
PGFKSNMPLAPGQF

(SEQ ID NO:981)
>gi\|4501969\|ref\|NP_0000151\| adrenergic, beta-2-, receptor, surface
{Homosapiens}
MGQPGNGSAFLLAPNRSHAPDHDVTQQRDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAKFE
RLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTASIETL
CVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQEAINCYAN
ETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRFHVQNLSQVEQ
DGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQDNLIRKEVYILLNWI
GYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNTGEQSGYHVEQEKENKLL
CEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL

(SEQ ID NO:982)
>gi\|4501997\|ref\|NP_0006761\| type-1 angiotensin II receptor {Homosapiens}
MILNSSTEDGIKRIQDDCPKAGRHNYIFVMIPTLYSIIFVVGIFGNSLVVIVIYFYMKLKTVASV
FLLNLALADLCFLLTLPLWAVYTAMEYRWPFGNYLCKIASASVSFNLYASVFLLTCLSIDRYL
AIVHPMKSRLRRTMLVAKVTCIIIVVLLAGLASLPAIIHRNVFFIENTNITVCAFHYESQNSTLPI
GLGLTKNILGFLFPFLIILTSYTLIVVKALKKAYEIQKNKPRNDDIFKIIMAIVLFFFFSWIPHQIFT
FLDVLIQLGIIRDCRIADIVDTAMPITICIAYFNNCLNPLFYGFLGKKFKRYFLQLLKYIPPKAKS
HSNLSTKMSTLSYRPSDNVSSSTKKPAPCFEVE

(SEQ ID NO:983)
>gi\|4502331\|ref\|NP_0006971\| vasopressin V1a receptor {Homosapiens}
MRLSAGPDAGPSGNSSPWWPLATGAGNTSREAEALGEGNGPPRDVRNEELAKLEIAVLAVT
FAVAVLGNSSVLLALHRTPRKTSRMHLFIRHLSLADLAVAFFQVLPQMCWDITYRFRGPDWL
CRVVKHLQVFGMFASAYMLVVMTADRYIAVCHPLKTLQQPARRSRLMIAAAWVLSFVLST
PQYFVFSMIEVNNVTKARDCWATFIQPWGSRAYVTWMTGGIFVAPVVILGTCYGFICYNIVVC
NVRGKTASRQSKGAEQAGVAFQKGFLLAPCVSSVKSISRAKIRTVKMTFVIVTAYIVCWAPF
FIIQMWSVWDPMSVVVTESENPTITITALLGSLNSCCNPWIYMFFSGHLLQDCVQSFPCCQNM
KEKFNKEDTDSMSRRQTFYSNNRSPTNSTGMWKDSPKSSKSIKFIPVST

(SEQ ID NO:984)
>gi\|4502333\|ref\|NP_0006981\| vasopressin V1b receptor {Homosapiens}
MDSGPLWDANPTPRGTLSAPNATTPWLGRDEELAKVEIGVLATVLVLATGGNLAVLLTLGQ
LGRKRSRMHLFVLHLALTDLAVALFQVLPQLLWDITYRFQGPDLLCRAVKYLQVLSMFAST
YMLLAMTLDRYLAVCHPLRSLQQPGQSTYLLIAAPWLLAAIFSLPQVFIFSLREVIQGSGVLD
CWADFGFPWGPRAYLTWTTLAIFVLPVTMLTACYSLICHEICKNLKVKTQAWRVGGGGWR
TWDRPSPS TLAATTRGLPSRVSSINTISRAKIRTVKMTFVIVLAYIACWAPFFSVQMWSVVVDK
NAPDEDSTNVAFTISMLLGNLNSCCNPWIYMGFNSHLLPRPLRHLACCGGPQPRMRRRLSDG
SLSSRHTTLLTRSSCPATLSLSLSLTLSGRPRPEESPRDLELADGEGTAETIIF

(SEQ ID NO:985)
>gi\|4502359\|ref\|NP_0016951\| brain-specific angiogenesis inhibitor 3 precursor
{Homosapiens}
MKAVRNLLIYIFSTYLLVMFGFNAAQDFWCSTLVKGVIYGSYSVSEMFPKNFTNCTVVTLENP
DPTKYSIYLKFSKKDLSCSNFSLLAYQFDHFSHEKIKDLLRKNHSIMQLCNSKNAFVFLQYDK
NFIQIRRVFPTNFPGLQKKGEEDQKSFFEFLVLNKVSPSQFGCHVLCTVVLESCLKSENGRTESC
GIMYTKCTCPQHLGEWGIDDQSLILLNNVVLPLNEQTEGCLTQELQTTQVCNLTREAKRPPK
EEFGMMGDHTIKSQRPRSVHEKRVPQEQADAAKFMAQTGESGVEEWSQWSTCSVTCGQGS
QVRTRTCVSPYGTHCSGPLRESRVCNNTALCPVHGVWEEWSPWSLCSFTCGRGQRTRTRSC
TPPQYGGRPCEGPETHHKPCNIALCPVDGQWQEWSSWSQCSVTCSNGTQQRSRQCTAAAHG
GSECRGPWAESRECYNPECTANGQWNQWGHWSGCSKSCDGGWERRIRTCQGAVITGQQCE
GTGEEVRRCSEQRCPAPYEICPEDYLMSMVWKRTPAGDLAFNQCPLNATGTTSRRCSLSLHG
VAFWEQPSFARCISNEYRHLQHSIKEHLAKGQRMLAGDGMSQVTKTLLDLTQRKNFYAGDL
LMSVEILRNVTDTFKRASYIPASDGVQNFFQIVSNLLDEENKEKWEDAQQIYPGSIELMQVIE
DFIHIVGMGMMDFQNSYLMTGNVVASIQKLPAASVLTDINFPMKGRKGMVDWARNSEDRV
VIPKSIFTPVSSKELDESSVFVLGAVLYKNLDLILPTLRNYTVINSKIIVVTIRPEPKTTDSFLEIE
LAHLANGTLNPYCVLWDDSKTNESLGTWSTQGCKTVLTDASHTKCLCDRLSTFAILAQQPR
EIIMESSGTPSVTLIVGSGLSCLALITLAVVYAALWRYIRSERSIILINFCLSIISSNILILVGQTQT
HNKSICTTTTAFLHFFFLASFCWVLTEAWQSYMAVTGKIRTRLIRKRFLCLGWGLPALVVAT
SVGFTRTKGYGTDHYCWLSLEGGLLYAFVGPAAAVVLVNMVIGILVFNKLVSRDGILDKKL
KHRAGQMSEPHSGLTLKCAKCGVVSTTALSATTASNAMASLWSSCVVLPLLALTWMSAVL
AMTDKRSILFQILFAVFDSLQGFVIVMVHCILRREVQDAFRCRLRNCQDPINADSSSSFPNGH
AQIMTDFEKDVDIACRSVLHKDIGPCRAATITGTLSRISLNDDEEEKGTNPEGLSYSTLPGNVI
SKVIIQQPTGLHMPMSMNELSNPCLKKENSELRRTVYLCTDDNLRGADMDIVHPQERMMES
DYIVMPRSSVNNQPSMKEESKMNIGMETLPHERLLHYKVNPEFNMNPPVMDQFNMNLEQH
LAPQEHMQNLPFEPRTAVKNFMASELDDNAGLSRSETGSTISMSSLERRKSRYSDLDFEKVM
HTRKRHMELFQELNQKFQTLDRFRDIPNTSSMENPAPNKNPWDTFKNPSEYPHYTTINVLDT
EAKDALELRPAEWEKCLNLPLDVQEGDFQTEV

(SEQ ID NO:986)
>gi\|4502415\|ref\|NP_0017071\|Burkitt lymphoma receptor 1 isoform 1
{Homosapiens}
MNYPLTLEMDLENLEDLFVVELDRLDNYNDTSLVENHLCPATEGPLMASFKAVFVPVAYSLIF
LLGVIGNVLVLVILERHRQTRSSTETFLFHLAVADLLLVFILPFAVAEGSVGWVLGTFLCKTVI
ALHKVNFYCSSLLLACIAVDRYLAIVHAVHAYRHRRLLSIHITCGTIVVLVGFLLALPEILFAKV
SQGHHNNSLPRCTFSQENQAETHAWFTSRFLYHVAGFLLPMLVMGWCYVGVVHRLRQAQR
RPQRQKAVRVAILVTSIFFLCWSPYHIVIFLDTLARLKAVDNTCKLNGSLPVAITMCEFLGLA
HCCLNPMLYTFAGVKFRSDLSRLLTKLGCTGPASLCQLFPSWRRSSLSESENATSLTTF

(SEQ ID NO:987)
>gi\|4502455\|ref\|NP_0017181\| bombesin receptor subtype-3 {Homosapiens}
MAQRQPHSPNQTLISITNDTESSSSVVSNDNTNKGWSGDNSPGIEALCAIYITYAVIISVGILGN
AILIKVFFKTKSMQTVPNIFITSLAFGDLLLLLTCVPVDATHYLAEGWLFGRIGCKVLSFIRLTS
VGVSVFTLTILSADRYKAVVKPLERQPSNAILKTCVKAGCVWIVSMIFALPEAIFSNVYTFRD
IPNKNMTFESCTSYPVSKKLLQEIHSLLCFLVFYIIPLSIISVYYSLIARTLYKSTLNIPTEEQSHAR
KQIESRKRIARTVLVLVALFALCWLPNHLLYLYHSFTSQTYVDPSAMHFIFTIFSRVLAFSNSC
VNPFALYWLSKSFQKHFKAQLFCCKAERPEPPVADTSLTTLAVMGTVPGTGSIQMSEISVTSF
TGCSVKQAEDRF

(SEQ ID NO:988)
>gi\|4502509\|ref\| NP_0017271\| C5a anaphylatoxin chemotactic receptor
{Homosapiens}
MNSFNYTTPDYGHYDDKDTLDLNTPVDKTSNTLRVPDILALVIFAVVFLVGVLGNALVVWV
TAFEAKRTINAIWFLNLAVADFLSCLALPILFTSIVQHHHWPFGGAACSILPSLILLNMYASILL
LATISADRFLLVFKPIVVCQNFRGAGLAWIACAVAWGLALLLTIPSFLYRVVREEYFPPKVLCG
VDYSHDKRRERAVAIVRLVLGFLWPLLTLTICYTFILLRTWSRRATRSTKTLKVVVAVVASFF
IIFVVLPYQVTGIMMSFLEPSSPTFLLLNKLDSLCVSFAYINCCINPIIYVVAGQGFQGRLRKSLPS
LLRNVLTEESVVRESKSFTRSTVDTMAQKTQAV

(SEQ ID NO:989)
>gi\|4502547\|ref\|NP_0017331\| calcitonin receptor isoform 2 precursor
{Homosapiens}
MRFTFTSRCLALFLLLNHPTPILPAFSNQTYPTIEPKPFLYVVGRKKMMDAQYKCYDRMQQL
PAYQGEGPYCNRTWDGWLCWDDTPAGVLSYQFCPDYFPDFDPSEKVTKYCDEKGVVVFKHP
ENNRTWSNYTMCNAFTPEKLKNAYVLYYLAIVGHSLSIFTLVISLGIFVFFRSLGCQRVTLHK
NMFLTYILNSMIIIIHLVEVVPNGELVRRDPVSCKILHFFHQYMMACNYFVVMLCEGIYLHTLI
VVAVFTEKQRLRWYYLLGWGFPLVPTTIHAITRAVYFNDNCWLSVETHLLYIIHGPVMAAL
VVNFFFLLNIVRVLVTKMRETHEAESHMYLKAVKATMILVPLLGIQFVVFPWRPSNKMLGKI
IYDYVMHSLIHFQGFFVATIYCFCNNEVQTTVKRQWAQFKIQWNQRWGRRPSNRSARAAAA
AAEAGDIPIYICHQELRNEPANNQGEESAEIIPLNIIEQESSA

(SEQ ID NO:990)
>gi\|4502607\|ref\|NP_0007211\| cholecystokinin receptor type A {Homosapiens}
MDVVDSLLVNGSNITPPCELGLENETLFCLDQPRPSKEWQPAVQILLYSLIFLLSVLGNTLVIT
VLIRNKRMRTVTNIFLLSLAVSDLMLCLFCMPFNLIPNLLKDFIFGSAVCKTTTYFMGTSVSVS
TFNLVAISLERYGAICKPLQSRVVVQTKSHALKVIAATWCLSFTIMTPYPIYSNLVPFTKNNNQ
TANMCRFLLPNDVMQQSWHTFLLLILFLIPGIVMMVAYGLISLELYQGIKFEASQKKSAKERK
PSTTSSGKYEDSDGCYLQKTRPPRKLELRQLSTGSSSRANRIRSNSSAANLMAKKRVIRMLIVI
VVLFFLCWMPIFSANAWRAYDTASAERRLSGTPISFILLLSYTSSCVNPIIYCFMNKRFRLGFM
IATFPCCPNPGPPGARGEVGEEEEGGTTGASLSRFSYSHMSASVPPQ

(SEQ ID NO:991)
>gi\|4502631\|ref\|NP_0012861\| C-C chemokine receptor type 1 {Homosapiens}
METPNTTEDYDTTTEFDYGDATPCQKVNERAFGAQLLPPLYSLVFVIGLVGNILVVLVLVQY
KRLKNMTSIYLLNLAISDLLFLFTLPFWIDYKLKDDWVFGDAMCKILSGFYYTGLYSEIFFIIL
LTIDRYLAIVHAVFALRARTVTFGVITSIIIVVALAILASMPGLYFSKTQWEFTHHTCSLHFPHES
LREWKLFQALKLNLFGLVLPLLVMIICYTGIIKILLRRPNEKKSKAVRLIFVIMIIFFLFVVTPYN
LTILISVFQDFLFTHECEQSRHLDLAVQVTEVIAYTHCCVNPVIYAFVGERFRKYLRQLFHRR
VAVHLVKWLPFLSVDRLERVSSTSPSTGEHELSAGF

(SEQ ID NO:992)
>gi\|4502637\|ref\|NP_0018281\| C-C chemokine receptor type 3 isoform 1
{Homosapiens}
MTTSLDTVETFGTTSYYDDVGLLCEKADTRALMAQFVPPLYSLVFTVGLLGNVVVVMILIKY
RRLRIMTNIYLLNLAISDLLFLVTLPFWIHYVRGHNVVVFGHGMCKLLSGFYHTGLYSEIFFIIL
LTIDRYLAIVHAVFALRARTVTFGVITSIVTWGLAVLAALPEFIFYETEELFEETLCSALYPEDT
VYSWRHFHTLRMTIFCLVLPLLVMAICYTGIIKTLLRCPSKKKYKAIRLIFVIMAVFFIFVVTPY
NVAILLSSYQSILFGNDCERSKHLDLVMLVTEVIAYSHCCMNPVIYAFVGERFRKYLRHFFHR
HLLMHLGRYIPFLPSEKLERTSSVSPSTAEPELSIVF

(SEQ ID NO:993)
>gi\|4502639\|ref\|NP_0005701\| chemokine (C-C motif) receptor 5 {Homosapiens}
MDYQVSSPIYDINYYTSEPCQKINVKQIAARLLPPLYSLVFIFGFVGNMLVILILINCKRLKSMT
DIYLLNLAISDLFFLLTVPFWAHYAAAQWDFGNTMCQLLTGLYFIGFFSGIFFIILLTIDRYLAV
VHAVFALKARTVTFGVVTSVITWVVAVFASLPGIIFTRSQKEGLHYTCSSHFPYSQYQFVVKN
FQTLKIVILGLVLPLLVMVICYSGILKTLLRCRNEKKRHRAVRLIFTIMIVYFLFWAPYNIVLLL
NTFQEFFGLNNCSSSNRLDQAMQVTETLGMTHCCINPIIYAFVGEKFRNYLLVFFQKHIAKRF
CKCCSIFQQEAPERASSVYTRSTGEQEISVGL

(SEQ ID NO:994)
>gi\|4502641\|ref\|NP_0018291\| chemokine (C-C motif) receptor 7 precursor
{Homosapiens}
MDLGKPMKSVLVVALLVIFQVCLCQDEVTDDYIGDNTTVDYTLFESLCSKKDVRNFKAWFL
PIMYSIICFVGLLGNGLVVLTYIYFKRLKTMTDTYLLNLAVADILFLLTLPFVVAYSAAKSWVF
GVHFCKLIFAIYKMSFFSGMLLLLCISIDRYVAIVQAVSAHRHRARVLLISKLSCVGIVVILATV
LSIPELLYSDLQRSSSEQAMRCSLITEHVEAFITIQVAQMVIGFLVPLLAMSFCYLVIIRTLLQA
RNFERNKAIKVIIAVVVVFIVFQLPYNGVVLAQTVANFNITSSTCELSKQLNIAYDVTYSLACV
RCCVNPFLYAFIGVKFRNDLFKLFKDLGCLSQEQLRQWSSCRHIRRSSMSVEAETTTTFSP

(SEQ ID NO:995)
>gi\|4502817\|ref\|NP_0007301\| cholinergic receptor, muscarinic 2 {Homosapiens}
MNNSTNSSNNSLALTSPYKTFEVVFIVLVAGSLSLVTIIGNILVMVSIKVNRHLQTVNNYFLFS
LACADLIIGVFSMNLYTLYTVIGYWPLGPVVCDLWLALDYVVSNASVMNLLIISFDRYFCVT
KPLTYPVKRTTKMAGMMIAAAWVLSFILWAPAILFVVQFIVGVRTVEDGECYIQFFSNAAVTF
GTAIAAFYLPVIIMTVLYWHISRASKSRIKKDKKEPVANQDPVSPSLVQGRIVKPNNNNMPSS
DDGLEHNKIQNGKAPRDPVTENCVQGEEKESSNDSTSVSAVASNMRDDEITQDENTVSTSLG
HSKDENSKQTCIRIGTKTPKSDSCTPTNTTVEVVGSSGQNGDEKQNIVARKIVKMTKQPAKK
KPPPSREKKVTRTILAILLAFIITWAPYNVMVLINTFCAPCIPNTVVVTIGYWLCYINSTINPACY
ALCNATFKKTFKHLLMCHYKNIGATR

(SEQ ID NO:996)
>gi\|4502819\|ref\|NP_0007311\| cholinergic receptor, muscarinic 3 {Homosapiens}
MTLHNNSTTSPLFPNISSSWIHSPSDAGLPPGTVTHFGSYNVSRAAGNFSSPDGTTDDPLGGHT
VWQVVFIAFLTGILALVTIIGNILVIVSFKVNKQLKTVNNYFLLSLACADLIIGVISMNLFTTYII
MNRWALGNLACDLWLAIDYVASNASVMNLLVISFDRYFSITRPLTYRAKRTTKRAGVMIGL
AWVISFVLWAPAILFWQYFVGKRTVPPGECFIQFLSEPTITFGTAIAAFYMPVTIMTILYWRIY
KETEKRTKELAGLQASGTEAETENFVHPTGSSRSCSSYELQQQSMKRSNRRKYGRCHFVVFTT
KSWKPSSEQMDQDHSSSDSWNNNDAAASLENSASSDEEDIGSETRAIYSIVLKLPGHSTILNS
TKLPSSDNLQVPEEELGMVDLERKADKLQAQKSVDDGGSFPKSFSKLPIQLESAVDTAKTSD
VNSSVGKSTATLPLSFKEATLAKRFALKTRSQITKRKRMSLVKEKKAAQTLSAILLAFIITWTP
YNIMVLVNTFCDSCIPKTFVVNLGYWLCYINSTVNPVCYALCNKTFRTTFKMLLL
CQCDKKKRRKQQYQQRQSVIFHKRAPEQAL

(SEQ ID NO:997)
>gi\|4502929\|ref\|NP_0018321\| cannabinoid receptor 2 {Homosapiens}
MEECWVTEIANGSKDGLDSNPMKDYMILSGPQKTAVAVLCTLLGLLSALENVAVLYLILSSH
QLRRKPSYLFIGSLAGADFLASVVFACSFVNFHVFHGVDSKAVFLLKIGSVTMTFTASVGSLL
LTAIDRYLCLRYPPSYKALLTRGRALVTLGIMWVLSALVSYLPLMGWTCCPRPCSELFPLIPN
DYLLSWLLFIAFLFSGIIYTYGHVLWKAHQHVASLSGHQDRQVPGMARMRLDVRLAKTLGL
VLAVLLICWFPVLALMAHSLATTLSDQVKKAFAFCSMLCLINSMVNPVIYALRSGEIRSSAHH
CLAHWKKCVRGLGSEAKEEAPRSSVTETEADGKITPWPDSRDLDLSDC

(SEQ ID NO:998)
>gi\|4503171\|ref\|NP_0013281\| CX3C chemokine receptor 1 isoform b
{Homosapiens}
MDQFPESVTENFEYDDLAEACYIGDIVVFGTVFLSIFYSVIFAIGLVGNLLVVFALTNSKKPKS
VTDIYLLNLALSDLLFVATLPFWTHYLINEKGLHNAMCKFTTAFFFIGFFGSIFFITVISIDRYL
AIVLAANSMNNRTVQHGVTISLGVWAAAILVAAPQFMFTKQKENECLGDYPEVLQEIVVPVL
RNVETNFLGFLLPLLIMSYCYFRIIQTLFSCKNHKKAKAIKLILLVVIVFFLFVVTPYNVMIFLET
LKLYDFFPSCDMRKDLRLALSVTETVAFSHCCLNPLIYAFAGEKFRRYLYHLYGKCLAVLCG
RSVHVDFSSSESQRSRHGSVLSSNFTYHTSDGDALLLL

(SEQ ID NO:999)
>gi\|4503175\|ref\|NP_0034581\| chemokine (C-X-C motif) receptor 4 isoform b
{Homosapiens}
MEGISIYTSDNYTEEMGSGDYDSMKEPCFREENANFNKIFLPTIYSIIFLTGIVGNGLVILVMG
YQKKLRSMTDKYRLHLSVADLLFVITLPFVVAVDAVANWYFGNFLCKAVHVIYTVNLYSSVL
ILAFISLDRYLAIVHATNSQRPRKLLAEKVVYVGVWIPALLLTIPDFIFANVSEADDRYICDRF
YPNDLWVVVFQFQHIMVGLILPGIVILSCYCIIISKLSHSKGHQKRKALKTTVILILAFFACWLP
YYIGISIDSFILLEIIKQGCEFENTVHKWISITEALAFFHCCLNPILYAFLGAKFKTSAQHALTSV
SRGSSLKILSKGKRGGHSSVSTESESSSFHSS

(SEQ ID NO:1000)
>gi\|4503383\|ref\|NP_0007851\| d(1A) dopamine receptor {Homosapiens}
MRTLNTSAMDGTGLVVERDFSVRILTACFLSLLILSTLLGNTLVCAAVIRFRHLRSKVTNFFVI
SLAVSDLLVAVLVMPWKAVAEIAGFWPFGSFCNIWVAFDIMCSTASILNLCVISVDRYWAISS
PFRYERKMTPKAAFILISVAWTLSVLISFIPVQLSWHKAKPTSPSDGNATSLAETIDNCDSSLSR
TYAISSSVISFYIPVAIMIVTYTRIYRIAQKQIRRIAALERAAVHAKNCQTTTGNGKPVECSQPE
SSFKMSFKRETKVLKTLSVIMGVFVCCWLPFFILNCILPFCGSGETQPFCIDSNTFDVFVVVFGW
ANSSLNPIIYAFNADFRKAFSTLLGCYRLCPATNNAIETVSINNNGAAMFSSHHEPRGSISKEC
NLVYLIPHAVGSSEDLKKEEAAGIARPLEKLSPALSVILDYDTDVSLEKIQPITQNGQHPT

(SEQ ID NO:1001)
>gi\|4503385\|ref\|NP_0007861\| d(2) dopamine receptor isoform long
{Homosapiens}
MDPLNLSWYDDDLERQNWSRPFNGSDGKADRPHYNYYATLLTLLIAVIVFGNVLVCMAVS
REKALQTTTNYLIVSLAVADLLVATLVMPWVVYLEVVGEWKFSRIHCDIFVTLDVMMCTAS
ILNLCAISIDRYTAVAMPMLYNTRYSSKRRVTVMISIVWVLSFTISCPLLFGLNNADQNECIIA
NPAFVVYSSIVSFYVPFIVTLLVYIKIYIVLRRRRKRVNTKRSSRAFRAHLRAPLKGNCTHPED
MKLCTVIMKSNGSFPVNRRRVEAARRAQELEMEMLSSTSPPERTRYSPIPPSHHQLTLPDPSH
HGLHSTPDSPAKPEKNGHAKDHPKIAKIFEIQTMPNGKTRTSLKTMSRRKLSQQKEKKATQM
LAIVLGVFIICWLPFFITHILNIHCDCNIPPVLYSAFTWLGYVNSAVNPHYTTFNIEFRKAFLKIL
HC

(SEQ ID NO:1002)
>gi\|4503391\|ref\|NP_0007891\| d(1B) dopamine receptor {Homosapiens}
MLPPGSNGTAYPGQFALYQQLAQGNAVGGSAGAPPLGPSQVVTACLLTLLIIVVTLLGNVLVC
AAIVRSRHLRANMTNVFIVSLAVSDLFVALLVMPWKAVAEVAGYWPFGAFCDVWVAFDIM
CSTASILNLCVISVDRYVVAISRPFRYKRKMTQRMALVMVGLAWTLSILISFIPVQLNWHRDQ
AASWGGLDLPNNLANVVTPWEEDFWEPDVNAENCDSSLNRTYAISSSLISFYIPVAIMIVTYTR
IYRIAQVQIRRISSLERAAEHAQSCRSSAACAPDTSLRASIKKETKVLKTLSVIMGVFVCCWLP
FFILNCMVPFCSGHPEGPPAGFPCVSETTFDVFVVVFGWANSSLNPVIYAFNADFQKVFAQLLG
CSHFCSRTPVETVNISNELISYNQDIVFHKEIAAAYIHMMPNAVTPGNREVDNDEEEGPFDRM
FQIYQTSPDGDPVAESVWELDCEGEISLDKITPFTPNGFH

(SEQ ID NO:1003)
>gi\|4503459\|ref\|NP_0037661\| sphingosine-1-phosphate receptor 4 precursor
{Homosapiens}
MNATGTPVAPESCQQLAAGGHSRLIVLHYNHSGRLAGRGGPEDGGLGALRGLSVAASCLVV
LENLLVLAAITSHMRSRRWVYYCLVNITLSDLLTGAAYLANVLLSGARTFRLAPAQWFLREG
LLFTALAASTFSLLFTAGERFATMVRPVAESGATKTSRVYGFIGLCWLLAALLGMLPLLGWN
CLCAFDRCSSLLPLYSKRYILFCLVIFAGVLATIMGLYGAIFRLVQASGQKAPRPAARRKARR
LLKTVLMILLAFLVCWGPLFGLLLADVFGSNLWAQEYLRGMDWILALAVLNSAVNPIIYSFR
SREVCRAVLSFLCCGCLRLGMRGPGDCLARAVEAHSGASTTDSSLRPRDSFRGSRSLSFRMR
EPLSSISSVRSI

(SEQ ID NO:1004)
>gi\|4503465\|ref\|NP_0019481\| endothelin-1 receptor isoform a precursor
{Homosapiens}
METLCLRASFVVLALVGCVISDNPERYSTNLSNHVDDFTTFRGTELSFLVTTHQPTNLVLPSNG
SMHNYCPQQTKITSAFKYINTVISCTIFIVGMVGNATLLRIIYQNKCMRNGPNALIASLALGDL
IYVVIDLPINVFKLLAGRWPFDHNDFGVFLCKLFPFLQKSSVGITVLNLCALSVDRYRAVASW
SRVQGIGIPLVTAIEIVSIVVILSFILAIPEAIGFVMVPFEYRGEQHKTCMLNATSKFMEFYQDVK
DWWLFGFYFCMPLVCTAIFYTLMTCEMLNRRNGSLRIALSEHLKQRREVAKTVFCLVVIFAL
CWFPLHLSRILKKTVYNEMDKNRCELLSFLLLMDYIGINLATMNSCINPIALYFVSKKFKNCF
QSCLCCCCYQSKSLMTSVPMNGTSIQWKNHDQNNHNTDRSSHKDSMN

(SEQ ID NO:1005)
>gi\|4503779\|ref\|NP_0020201\| fMet-Leu-Phe receptor {Homosapiens}
METNSSLPTNISGGTPAVSAGYLFLDIITYLVFAVTFVLGVLGNGLVIWVAGFRMTHTVTTIS
YLNLAVADFCFTSTLPFFMVRKAMGGHWPFGWFLCKFVFTIVDINLFGSVFLIALIALDRCVC
VLHPVWTQNHRTVSLAKKVIIGPWVMALLLTLPVIIRVTTVPGKTGTVACTFNFSPWTNDPK
ERINVAVAMLTVRGIIRFIIGFSAPMSIVAVSYGLIATKIHKQGLIKSSRPLRVLSFVAAAFFLC
WSPYQVVALIATVRIRELLQGMYKEIGIAVDVTSALAFFNSCLNPMLYVFMGQDFRERLIHA
LPASLERALTEDSTQTSDTATNSTLPSAEVELQAK

(SEQ ID NO:1006)
>gi\|4503781\|ref\|NP_0014531\| N-formyl peptide receptor 2 {Homosapiens}
METNFSTPLNEYEEVSYESAGYTVLRILPLVVLGVTFVLGVLGNGLVIVVVAGFRMTRTVTTI
CYLNLALADFSFTATLPFLIVSMAMGEKWPFGWFLCKLIHIVVDINLFGSVFLIGFIALDRCIC
VLHPVWAQNHRTVSLAMKVIVGPWILALVLTLPVFLFLTTVTIPNGDTYCTFNFASWGGTPE
ERLKVAITMLTARGIIRFVIGFSLPMSIVAICYGLIAAKIHKKGMIKSSRPLRVLTAVVASFFIC
WFPFQLVALLGTVWLKEMLFYGKYKIIDILVNPTSSLAFFNSCLNPMLYVFVGQDFRERLIHS
LPTSLERALSEDSAPTNDTAANSASPPAETELQAM

(SEQ ID NO:1007)
>gi\|4503905\|ref\|NP_0038481\| galanin receptor type 2 {Homosapiens}
MNVSGCPGAGNASQAGGGGGWHPEAVIVPLLFALIFLVGTVGNTLVLAVLLRGGQAVSTTN
LFILNLGVADLCFILCCVPFQATIYTLDGWVFGSLLCKAVHFLIFLTMHASSFTLAAVSLDRYL
AIRYPLHSRELRTPRNALAAIGLIVVGLSLLFSGPYLSYYRQSQLANLTVCHPAWSAPRRRAM
DICTFVFSYLLPVLVLGLTYARTLRYLWRAVDPVAAGSGARRAKRKVTRMILIVAALFCLCW
MPHHALILCVWFGQFPLTRATYALRILSHLVSYANSCVNPIVYALVSKHFRKGFRTICAGLLG
RAPGRASGRVCAAARGTHSGSVLERESSDLLHMSEAAGALRPCPGASQPCILEPCPGPSWQG
PKAGDSILTVDVA

(SEQ ID NO:1008)
>gi\|4503907\|ref\|NP_0036051\| galanin receptor type 3 {Homosapiens}
MADAQNISLDSPGSVGAVAVPVVFALIFLLGTVGNGLVLAVLLQPGPSAWQEPGSTTDLFIL
NLAVADLCFILCCVPFQATIYTLDAWLFGALVCKAVHLLIYLTMYASSFTLAAVSVDRYLAV
RHPLRSRALRTPRNARAAVGLVWLLAALFSAPYLSYYGTVRYGALELCVPAWEDARRRAL
DVATFAAGYLLPVAVVSLAYGRTLRFLWAAVGPAGAAAAEARRRATGRAGRAMLAVAAL
YALCWGPHHALILCFWYGRFAFSPATYACRLASHCLAYANSCLNPLVYALASRHFRARFRR
LWPCGRRRRHRARRALRRVRPASSGPPGCPGDARPSGRLLAGGGQGPEPREGPVHGGEAAR
GPE

(SEQ ID NO:1009)
>gi\|4503947\|ref\|NP_0001511\| glucagon receptor precursor {Homosapiens}
MPPCQPQRPLLLLLLLLACQPQVPSAQVMDFLFEKWKLYGDQCHHNLSLLPPPTELVCNRTF
DKYSCWPDTPANTTANISCPWYLPWHHKVQHRFVFKRCGPDGQWVRGPRGQPWRDASQC
QMDGEEIEVQKEVAKMYSSFQVMYTVGYSLSLGALLLALAILGGLSKLHCTRNAIHANLFAS
FVLKASSVLVIDGLLRTRYSQKIGDDLSVSTWLSDGAVAGCRVAAVFMQYGIVANYCWLLV
EGLYLHNLLGLATLPERSFFSLYLGIGWGAPMLFVVPWAVVKCLFENVQCWTSNDNMGFVV
WILRFPVFLAILINFFIFVRIVQLLVAKLRARQMHHTDYKFRLAKSTLTLIPLLGVHEVVFAFV
TDEHAQGTLRSAKLFFDLFLSSFQGLLVAVLYCFLNKEVQSELRRRWHRWRLGKVLWEERN
TSNHRASSSPGHGPPSKELQFGRGGGSQDSSAETPLAGGLPRLAESPF

(SEQ ID NO:1010)
>gi\|4503999\|ref\|NP_0001551\| gastric inhibitory polypeptide receptor precursor
{Homosapiens}
MTTSPILQLLLRLSLCGLLLQRAETGSKGQTAGELYQRWERYRRECQETLAAAEPPSGLACN
GSFDMYVCWDYAAPNATARASCPWYLPWHHHVAAGFVLRQCGSDGQWGLWRDHTQCEN
PEKNEAFLDQRLILERLQVMYTVGYSLSLATLLLALLILSLFRRLHCTRNYIHINLFTSFMLRA
AAILSRDRLLPRPGPYLGDQALALWNQALAACRTAQIVTQYCVGANYTWLLVEGVYLHSLL
VLVGGSEEGHFRYYLLLGWGAPALFVIPWVIVRYLYENTQCWERNEVKAIWWIIRTPILMTI
LINFLIFIRILGILLSKLRTRQMRCRDYRLRLARSTLTLVPLLGVHEVVFAPVTEEQARGALRF
AKLGFEIFLSSFQGFLVSVLYCFINKEVQSEIRRGWHHCRLRRSLGEEQRQLPERAFRALPSGS
GPGEVPTSRGLSSGTLPGPGNEASRELESYC

(SEQ ID NO:1011)
>gi\|4504059\|ref\|NP_0003971\| gonadotropin-releasing hormone receptor isoform 1 {Homosapiens}
MANSASPEQNQNHCSAINNSIPLMQGNLPTLTLSGKIRVTVTFFLFLLSATFNASFLLKLQKW
TQKKEKGKKLSRMKLLLKHLTLANLLETLIVMPLDGMWNITVQWYAGELLCKVLSYLKLFS
MYAPAFMMVVISLDRSLAITRPLALKSNSKVGQSMVGLAWILSSVFAGPQLYIFRMIHLADSS
GQTKVFSQCVTHCSFSQWWHQAFYNFFTFSCLFHPLFIMLICNAKIIFTLTRVLHQDPHELQL
NQSKNNIPRARLKTLKMTVAFATSFTVCWTPYYVLGIVVYWFDPEMLNRLSDPVNHFFFLFAF
LNPCFDPLIYGYFSL

(SEQ ID NO:1012)
>gi\|4504091\|ref\|NP_0014961\| G-protein coupled estrogen receptor 1
{Homosapiens}
MDVTSQARGVGLEMYPGTAQPAAPNTTSPELNLSHPLLGTALANGTGELSEHQQYVIGLFLS
CLYTIFLFPIGFVGNILILVVNISFREKMTIPDLYFINLAVADLILVADSLIEVFNLHERYYDIAV
LCTFMSLFLQVNMYSSVFFLTVVMSFDRYIALARAMRCSLFRTKHHARLSCGLIVVMASVSAT
LVPFTAVHLQHTDEACFCFADVREVQWLEVTLGFIVPFAIIGLCYSLIVRVLVRAHRHRGLRP
RRQKALRMILAVVLVFFVCWLPENVFISVHLLQRTQPGAAPCKQSFRHAHPLTGHIVNLAAF
SNSCLNPLIYSFLGETFRDKLRLYIEQKTNLPALNRFCHAALKAVIPDSTEQSDVRFSSAV

(SEQ ID NO:1013)
>gi\|4504093\|ref\|NP_0014971\| G protein-coupled receptor 32 {Homosapiens}
MNGVSEGTRGCSDRQPGVLTRDRSCSRKMNSSGCLSEEVGSLRPLTVVILSASIVVGVLGNG
LVLWMTVFRMARTVSTVCFFHLALADFMLSLSLPIAMYYIVSRQWLLGEWACKLYITFVFLS
YFASNCLLVFISVDRCISVLYPVVVALNHRTVQRASWLAFGVWLLAAALCSAHLKFRTTRKW
NGCTHCYLAFNSDNETAQIVVIEGVVEGHIIGTIGHFLLGFLGPLAIIGTCAHLIRAKLLREGWV
HANRPKRLLLVLVSAFFIFVVSPFNVVLLVHLWRRVMLKEIYHPRMLLILQASFALGCVNSSL
NPFLYVFVGRDFQEKFFQSLTSALARAFGEEEFLSSCPRGNAPRE

(SEQ ID NO:1014)
>gi\|4504095\|ref\|NP_0014981\| motilin receptor {Homosapiens}
MGSPWNGSDGPEGAREPPWPALPPCDERRCSPFPLGALVPVTAVCLCLFVVGVSGNVVTVM
LIGRYRDMRTTTNLYLGSMAVSDLLILLGLPFDLYRLWRSRPWVFGPLLCRLSLYVGEGCTY
ATLLHMTALSVERYLAICRPLRARVLVTRRRVRALIAVLWAVALLSAGPFLFLVGVEQDPGI
SVVPGLNGTARIASSPLASSPPLWLSRAPPPSPPSGPETAEAAALFSRECRPSPAQLGALRVML
WVTTAYFFLPFLCLSILYGLIGRELWSSRRPLRGPAASGRERGHRQTVRVLLVVVLAFIICWL
PFHVGRIIYINTEDSRMMYFSQYFNIVALQLFYLSASINPILYNLISKKYRAAAFKLLLARKSRP
RGFHRSRDTAGEVAGDTGGDTVGYTETSANVKTMG

(SEQ ID NO:1015)
>gi\|4504097\|ref\|NP_0014991\| G-protein coupled receptor 39 {Homosapiens}
MASPSLPGSDCSQIIDHSHVPEFEVATWIKITLILVYLIIFVMGLLGNSATIRVTQVLQKKGYLQ
KEVTDHMVSLACSDILVFLIGMPMEFYSIIVVNPLTTSSYTLSCKLHTFLFEACSYATLLHVLTL
SFERYIAICHPFRYKAVSGPCQVKLLIGFVWVTSALVALPLLFAMGTEYPLVNVPSHRGLTCN
RSSTRHHEQPETSNMSICTNLSSRWTVFQSSIFGAFVVYLVVLLSVAFMCWNMMQVLMKSQ
KGSLAGGTRPPQLRKSESEESRTARRQTIIFLRLIVVTLAVCWMPNQIRRIMAAAKPKHDWTR
SYFRAYMILLPFSETFFYLSSVINPLLYTVSSQQFRRVFVQVLCCRLSLQHANHEKRLRVHAH
STTDSARFVQRPLLFASRRQSSARRTEKIFLSTFQSEAEPQSKSQSLSLESLEPNSGAKPANSAA
ENGFQEHEV

(SEQ ID NO:1016)
>gi\|4504099\|ref\|NP_0014951\| C-X-C chemokine receptor type 3 isoform A
{Homosapiens}
MVLEVSDHQVLNDAEVAALLENFSSSYDYGENESDSCCTSPPCPQDFSLNFDRAFLPALYSLL
FLLGLLGNGAVAAVLLSRRTALSSTDTFLLHLAVADTLLVLTLPLWAVDAAVQWVFGSGLC
KVAGALFNINFYAGALLLACISFDRYLNIVHATQLYRRGPPARVTLTCLAVWGLCLLFALPD
FIFLSAHHDERLNATHCQYNFPQVGRTALRVLQLVAGFLLPLLVMAYCYAHILAVLLVS RGQ
RRLRAMRLVVVVVVAFALCWTPYHLVVLVDILMDLGALARNCGRESRVDVAKSVTSGLGY
MHCCLNPLLYAFVGVKFRERMWMLLLRLGCPNQRGLQRQPSSSRRDSSWSETSEASYSGL

(SEQ ID NO:1017)
>gi\|4504141\|ref\|NP_0008321\| metabotropic glutamate receptor 4 precursor
{Homosapiens}
MPGKRGLGWWWARLPLCLLLSLYGPWMPSSLGKPKGHPHMNSIRIDGDITLGGLFPVHGRG
SEGKPCGELKKEKGIHRLEAMLFALDRINNDPDLLPNITLGARILDTCSRDTHALEQSLTFVQ
ALIEKDGTEVRCGSGGPPIITKPERVVGVIGASGSSVSIMVANILRLFKIPQISYASTAPDLSDNS
RYDFFSRVVPSDTYQAQAMVDIVRALKWNYVSTVASEGSYGESGVEAFIQKSREDGGVCIA
QSVKIPREPKAGEFDKIIRRLLETSNARAVIIFANEDDIRRVLEAARRANQTGHFFVVMGSDSW
GSKIAPVLHLEEVAEGAVTILPKRMSVRGFDRYFSSRTLDNNRRNIVVFAEFVVEDNFHCKLSR
HALKKGSHVKKCTNRERIGQDSAYEQEGKVQFVIDAVYAMGHALHAMHRDLCPGRVGLCP
RMDPVDGTQLLKYIRNVNFSGIAGNPVTFNENGDAPGRYDIYQYQLRNDSAEYKVIGSWTD
HLHLRIERMHWPGSGQQLPRSICSLPCQPGERKKTVKGMPCCWHCEPCTGYQYQVDRYTCK
TCPYDMRPTENRTGCRPIPIIKLEWGSPWAVLPLFLAVVGIAATLFVVITFVRYNDTPIVKASG
RELSYVLLAGIFLCYATTFLMIAEPDLGTCSLRRIFLGLGMSISYAALLTKTNRIYRIFEQGKRS
VSAPRFISPASQLAITFSLISLQLLGICVWFVVDPSHSVVDFQDQRTLDPRFARGVLKCDISDLS
LICLLGYSMLLMVTCTVYAIKTRGVPETFNEAKPIGFTMYTTCIVWLAFIPIFFGTSQSADKLY
IQTTTLTVSVSLSASVSLGMLYMPKVYIILFHPEQNVPKRKRSLKAVVTAATMSNKFTQKGN
FRPNGEAKSELCENLEAPALATKQTYVTYTNHAI

(SEQ ID NO:1018)
>gi\|4504143\|ref\|NP_0008331\| metabotropic glutamate receptor 5 isoform b
precursor {Homosapiens}
MVLLLILSVLLLKEDVRGSAQSSERRVVAHMPGDIIIGALFSVHHQPTVDKVHERKCGAVRE
QYGIQRVEAMLHTLERINSDPTLLPNITLGCEIRDSCWHSAVALEQSIEFIRDSLISSEEEEGLV
RCVDGSSSSFRSKKPIVGVIGPGSSSVAIQVQNLLQLFNIPQIAYSATSMDLSDKTLFKYFMRV
VPSDAQQARAMVDIVKRYNWTYVSAVHTEGNYGESGMEAFKDMSAKEGICIAHSYKIYSN
AGEQSFDKLLKKLTSHLPKARVVACFCEGMTVRGLLMAMRRLGLAGEFLLLGSDGWADRY
DVTDGYQREAVGGITIKLQSPDVKWFDDYYLKLRPETNHRNPWFQEFVVQHRFQCRLEGFPQ
ENSKYNKTCNSSLTLKTHHVQDSKMGFVINAIYSMAYGLHNMQMSLCPGYAGLCDAMKPI
DGRKLLESLMKTNFTGVSGDTILFDENGDSPGRYEIMNFKEMGKDYFDYINVGSWDNGELK
MDDDEVWSKKSNIIRSVCSEPCEKGQIKVIRKGEVSCCWTCTPCKENEYVFDEYTCKACQLG
SWPTDDLTGCDLIPVQYLRWGDPEPIAAVVFACLGLLATLFVTVVFIIYRDTPVVKSSSRELC
YIILAGICLGYLCTFCLIAKPKQIYCYLQRIGIGLSPAMSYSALVTKTNRIARILAGSKKKICTK
KPRFMSACAQLVIAFILICIQLGIIVALFIMEPPDIMHDYPSIREVYLICNTTNLGVVTPLGYNGL
LILSCTFYAFKTRNVPANFNEAKYIAFTMYTTCHWLAFVPIYFGSNYKIITMCFSVSLSATVAL
GCMFVPKVYIILAKPERNVRSAFTTSTVVRMHVGDGKSSSAASRSSSLVNLWKRRGSSGETL
SSNGKSVTWAQNEKSSRGQHLWQRLSIHINKKENPNQTAVIKPFPKSTESRGLGAGAGAGGS
AGGVGATGGAGCAGAGPGGPESPDAGPKALYDVAEAEEHFPAPARPRSPSPISTLSHRAGSA
SRTDDDVPSLHSEPVARSSSSQGSLMEQISSVVTRFTANISELNSMMLSTAAPSPGVGAPLCSS
YLIPKEIQLPTTMTTFAEIQPLPAIEVTGGAQPAAGAQAAGDAARESPAAGPEAAAAKPDLEE
LVALTPPSPFRDSVDSGSTTPNSPVSESALCIPSSPKYDTLIIRDYTQSSSSL

(SEQ ID NO:1019)
>gi\|4504147\|ref\|NP_0008351\| metabotropic glutamate receptor 7 isoform a
precursor {Homosapiens}
MVQLRKLLRVLTLMKFPCCVLEVLLCALAAAARGQEMYAPHSIRIEGDVTLGGLFPVHAKG
PSGVPCGDIKRENGIHRLEAMLYALDQINSDPNLLPNVTLGARILDTCSRDTYALEQSLTFVQ
ALIQKDTSDVRCTNGE PVFVKPEKVVGVIGASGSSVSIMVANILRLFQIPQISYASTAPELSD
DRRYDFFSRVVPPDSFQAQAMVDIVKALGWNYVSTLASEGSYGEKGVESFTQISKEAGGLCI
AQSVRIPQERKDRTIDFDRIIKQLLDTPNSRAVVIFANDEDIKQILAAAKRADQVGHFLWVGS
DSWGSKINPLHQHEDIAEGAITIQPKRATVEGFDAYFTSRTLENNRRNVVVFAEYWEENFNCK
LTISGSKKEDTDRKCTGQERIGKDSNYEQEGKVQFVIDAVYAMAHALHHMNKDLCADYRG
VCPEMEQAGGKKLLKYIRNVNFNGSAGTPVMFNKNGDAPGRYDIFQYQTTNTSNPGYRLIG
QWTDELQLNIEDMQWGKGVREIPASVCTLPCKPGQRKKTQKGTPCCWTCEPCDGYQYQFD
EMTCQHCPYDQRPNENRTGCQDIPIIKLEWHSPWAVIPVFLAMLGIIATIFVMATFIRYNDTPI
VRASGRELSYVLLTGIFLCYIITFLMIAKPDVAVCSFRRVFLGLGMCISYAALLTKTNRIYRIFE
QGKKSVTAPRLISPTSQLAITSSLISVQLLGVFIVVFGVDPPNIIIDYDEHKTMNPEQARGVLKCD
ITDLQIICSLGYSILLMVTCTVYAIKTRGVPENFNEAKPIGFTMYTTCIVWLAFIPIFFGTAQSAE
KLYIQTTTLTISMNLSASVALGMLYMPKVYIIIFHPELNVQKRKRSFKAVVTAATMSSRLSHK
PSDRPNGEAKTELCENVDPNSPAAKKKYVSYNNLVI

(SEQ ID NO:1020)
>gi\|4504379\|ref\|NP_0036581\| leucine-rich repeat-containing G protein-coupled
receptor 5 precursor{Homosapiens}
MDTSRLGVLLSLPVLLQLATGGSSPRSGVLLRGCPTHCHCEPDGRMLLRVDCSDLGLSELPS
NLSVFTSYLDLSMNNISQLLPNPLPSLRFLEELRLAGNALTYIPKGAFTGLYSLKVLMLQNNQ
LRHVPTEALQNLRSLQSLRLDANHISYVPPSCFSGLHSLRHLWLDDNALTEIPVQAFRSLSAL
QAMTLALNKIHHIPDYAFGNLSSLVVLHLHNNRIHSLGKKCFDGLHSLETLDLNYNNLDEFP
TAIRTLSNLKELGFHSNNIRSIPEKAFVGNPSLITIHFYDNPIQFVGRSAFQHLPELRTLTLNGAS
QITEFPDLTGTANLESLTLTGAQISSLPQTVCNQLPNLQVLDLSYNLLEDLPSFSVCQKLQKID
LRHNEIYEIKVDTFQQLLSLRSLNLAWNKIAIIHPNAFSTLPSLIKLDLSSNLLSSFPITGLHGLT
HLKLTGNHALQSLISSENFPELKVIEMPYAYQCCAFGVCENAYKISNQWNKGDNSSMDDLH
KKDAGMFQAQDERDLEDFLLDFEEDLKALHSVQCSPSPGPFKPCEHLLDGWLIRIGVWTIAV
LALTCNALVTSTVFRSPLYISPIKLLIGVIAAVNMLTGVSSAVLAGVDAFTFGSFARHGAWWE
NGVGCHVIGFLSIFASESSVFLLTLAALERGFSVKYSAKFETKAPFSSLKVIILLCALLALTMA
AVPLLGGSKYGASPLCLPLPFGEPSTMGYMVALILLNSLCFLMMTIAYTKLYCNLDKGDLEN
IVVDCSMVKHIALLLFTNCILNCPVAFLSFSSLINLTFISPEVIKFILLVVVPLPACLNPLLYILFNP
HFKEDLVSLRKQTYVWTRSKHPSLMSINSDDVEKQSCDSTQALVTFTSSSITYDLPPSSVPSPA
YPVTESCHLSSVAFVPCL

(SEQ ID NO:1021)
>gi\|4504491\|ref\|NP_0008521\| histamine H1 receptor {Homosapiens}
MSLPNSSCLLEDKMCEGNKTTMASPQLMPLVVVLSTICLVTVGLNLLVLYAVRSERKLHTV
GNLYIVSLSVADLIVGAVVMPMNILYLLMSKWSLGRPLCLFVVLSMDYVASTASIFSVFILCID
RYRSVQQPLRYLKYRTKTRASATILGAWFLSFLWVIPILGWNHFMQQTSVRREDKCETDFYD
VTWFKVMTAIINFYLPTLLMLWFYAKIYKAVRQHCQHRELINRSLPSFSEIKLRPENPKGDAK
KPGKESPWEVLKRKPKDAGGGSVLKSPSQTPKEMKSPVVFSQEDDREVDKLYCFPLDIVHM
QAAAEGSSRDYVAVNRSHGQLKTDEQGLNTHGASEISEDQMLGDSQSFSRTDSDTTTETAPG
KGKLRSGSNTGLDYIKFTVVKRLRSHSRQYVSGLHMNRERKAAKQLGFIMAAFILCWIPYFIFF
MVIAFCKNCCNEHLHMFTIVVLGYINSTLNPLIYPLCNENFKKTFKRILHIRS

(SEQ ID NO:1022)
>gi\|4504533 \|ref\|NP_000854 1\| 5-hydroxytryptamine receptor 1B {Homosapiens }
MEEPGAQCAPPPPAGSETWVPQANLSSAPSQNCSAKDYIYQDSISLPWKVLLVMLLALITLAT
TLSNAFVIATVYRTRKLHTPANYLIASLAVTDLLVSILVMPISTMYTVTGRWTLGQVVCDFVV
LSSDITCCTASILHLCVIALDRYWAITDAVEYSAKRTPKRAAVMIALVWVFSISISLPPFFVVRQ
AKAEEEVSECVVNTDHILYTVYSTVGAFYFPTLLLIALYGRIYVEARSRILKQTPNRTGKRLT
RAQLITDSPGSTSSVTSINSRVPDVPSESGSPVYVNQVKVRVSDALLEKKKLMAARERKATKT
LGIILGAFIVCWLPFFIISLVMPICKDACWFHLAIFDFFTVVLGYLNSLINPIIYTMSNEDFKQAFH
KLIRFKCTS

(SEQ ID NO:1023)
>gi\|4504535\|ref\|NP_0008551\| 5-hydroxytryptamine receptor 1D {Homosapiens}
MSPLNQSAEGLPQEASNRSLNATETSEAWDPRTLQALKISLAVVLSVITLATVLSNAFVLTTIL
LTRKLHTPANYLIGSLATTDLLVSILVMPISIAYTITHTWNFGQILCDIVVLSSDITCCTASILHLC
VIALDRYWAITDALEYSKRRTAGHAATMIAIVWAISICISIPPLFVVRQAKAQEEMSCLVNTS
QISYTIYSTCGAFYIPSVLLIILYGRIYRAARNRILNPPSLYGKRFTTAHLITGSAGSSLCSLNSSL
HEGHSHSAGSPLFFNHVKIKLADSALERKRISAARERKATKILGIILGAFIICWLPFFVVSLVLPI
CRDSCWIHPALFDFFTVVLGYLNSLINPHYTVFNEEFRQAFQKIVPFRKAS

(SEQ ID NO:1024)
>gi\|4504537\|ref\|NP_0008561\| 5-hydroxytryptamine receptor 1E {Homosapiens}
MNITNCTTEASMAIRPKTITEKMLICMTLVVITTLTTLLNLAVIMAIGTTKKLHQPANYLICSL
AVTDLLVAVLVMPLSIIYIVMDRWKLGYFLCEVVVLSVDMTCCTCSILHLCVIALDRYWAITN
AIEYARKRTAKRAALMILTVWTISIFISMPPLFWRSHRRLSPPPSQCTIQHDHVIYTIYSTLGAF
YIPLTLILILYYRIYHAAKSLYQKRGSSRHLSNRSTDSQNSFASCKLTQTFCVSDFSTSDPTTEF
EKFHASIRIPPFDNDLDHPGERQQISSTRERKAARILGLILGAFILSWLPFFIKELIVGLSIYTVSS
EVADFLTWLGYVNSLINPLLYTSFNEDFKLAFKKLIRCREHT

(SEQ ID NO:1025)
>gi\|4504541\|ref\|NP_0008591\| 5-hydroxytryptamine receptor 2C {Homosapiens}
MVNLRNAVHSFLVHLIGLLVWQCDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSIVIII
IMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVWPLPRYL
CPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHS RFNS RTKAIMKIAIVWAISIGVSVPIPVI
GLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYVLRRQALMLLHGHTEEP
PGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTMQAINNERKASKVLGIVFF
VFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVCSGINPLVYTLFNKIYRRAFSN
YLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTNEPVIEKASDNEPGIEMQVENLELP
VNPSSVVSERISSV

(SEQ ID NO:1026)
>gi\|4504545\|ref\|NP_0008621\| 5-hydroxytryptamine receptor 6 {Homosapiens}
MVPEPGPTANSTPAWGAGPPSAPGGSGWVAAALCVVIALTAAANSLLIALICTQPALRNTSN
FFLVSLFTSDLMVGLVVMPPAMLNALYGRWVLARGLCLLWTAFDVMCCSASILNLCLISLD
RYLLILSPLRYKLRMTPLRALALVLGAWSLAALASFLPLLLGWHELGHARPPVPGQCRLLAS
LPFVLVASGLTFFLPSGAICFTYCRILLAARKQAVQVASLTTGMASQASETLQVPRTPRPGVE
SADSRRLATKHSRKALKASLTLGILLGMFFVTWLPFFVANIVQAVCDCISPGLFDVLTWLGY
CNSTMNPIIYPLFMRDFKRALGRFLPCPRCPRERQASLASPSLRTSHSGPRPGLSLQQVLPLPLP
PDSDSDSDAGSGGSSGLRLTAQLLLPGEATQDPPLPTRAAAAVNFFNIDPAEPELRPHPLGIPT
N

(SEQ ID NO:1027)
>gi\|4504547\|ref\|NP_0008631\| 5-hydroxytryptamine receptor 7 isoform a {Homosapiens}
MMDVNSSGRPDLYGHLRSFLLPEVGRGLPDLSPDGGADPVAGSWAPHLLSEVTASPAPTWD
APPDNASGCGEQINYGRVEKVVIGSILTLITLLTIAGNCLVVISVCFVKKLRQPSNYLIVSLALA
DLSVAVAVMPFVSVTDLIGGKWIFGHFFCNVFIAMDVMCCTASIMTLCVISIDRYLGITRPLT
YPVRQNGKCMAKMILSVWLLSASITLPPLFGWAQNVNDDKVCLISQDFGYTIYSTAVAFYIP
MSVMLFMYYQIYKAARKSAAKHKFPGFPRVEPDSVIALNGIVKLQKEVEECANLSRLLKHER
KNISIFKREQKAATTLGIIVGAFTVCWLPFFLLSTARPFICGTSCSCIPLWVERTFLWLGYANSL
INPFIYAFFNRDLRTTYRSLLQCQYRNINRKLSAAGMHEALKLAERPERPEFVLQNADYCRK
KGHDS

(SEQ ID NO:1028)
>gi\|4504681\|ref\|NP_0006251\| C-X-C chemokine receptor type 1 {Homosapiens}
MSNITDPQMWDFDDLNFTGMPPADEDYSPCMLETETLNKYVVIIAYALVFLLSLLGNSLVML
VILYSRVGRSVTDVYLLNLALADLLFALTLPIVVAASKVNGWIFGTFLCKVVSLLKEVNFYSGI
LLLACISVDRYLAIVHATRTLTQKRHLVKFVCLGCWGLSMNLSLPFFLFRQAYHPNNSSPVC
YEVLGNDTAKWRMVLRILPHTFGFIVPLFVMLFCYGFTLRTLFKAHMGQKHRAMRVIFAVV
LIFLLCWLPYNLVLLADTLMRTQVIQESCERRNNIGRALDATEILGFLHSCLNPIIYAFIGQNFR
HGFLKILAMHGLVSKEFLARHRVTSYTSSSVNVSSNL

(SEQ ID NO:1029)
>gi\|4504683\|ref\|NP_0015481\| C-X-C chemokine receptor type 2 {Homosapiens}
MEDFNMESDSFEDFVVKGEDLSNYSYSSTLPPFLLDAAPCEPESLEINKYFVVIIYALVFLLSLL
GNSLVMLVILYSRVGRSVTDVYLLNLALADLLFALTLPIVVAASKVNGWIFGTFLCKVVSLLK
EVNFYSGILLLACISVDRYLAIVHATRTLTQKRYLVKFICLSIVVGLSLLLALPVLLFRRTVYSS
NVSPACYEDMGNNTANVVRMLLRILPQSFGFIVPLLIMLFCYGFTLRTLFKAHMGQKHRAMR
VIFAVVLIFLLCWLPYNLVLLADTLMRTQVIQETCERRNHIDRALDATEILGILHSCLNPLIYA
FIGQKFRHGLLKILAIHGLISKDSLPKDSRPSFVGSSSGHTSTTL

(SEQ ID NO:1030)
>gi\|4505127\|ref\|NP_0005201\| adrenocorticotropic hormone receptor
{Homosapiens}
MKHIINSYENINNTARNNSDCPRVVLPEEIFFTISIVGVLENLIVLLAVFKNKNLQAPMYFFICS
LAISDMLGSLYKILENILIILRNMGYLKPRGSFETTADDIIDSLFVLSLLGSIFSLSVIAADRYITIF
HALRYHSIVTMRRTVVVLTVIVVTFCTGTGITMVIFSHHVPTVITFTSLFPLMLVFILCLYVHMF
LLARSHTRKISTLPRANMKGAITLTILLGVFIFCWAPFVLHVLLMTFCPSNPYCACYMS LFQV
NGMLIMCNAVIDPFIYAFRSPELRDAFKKMIFCSRYW

(SEQ ID NO:1031)
>gi\|4505445\|ref\|NP_0009001\| neuropeptide Y receptor type 1 {Homosapiens}
MNSTLFSQVENHSVHSNFSEKNAQLLAFENDDCHLPLAMIFTLALAYGAVIILGVSGNLALIII
ILKQKEMRNVTNILIVNLSFSDLLVAIMCLPFTFVYTLMDHWVFGEAMCKLNPFVQCVSITVS
IFSLVLIAVERHQLIINPRGWRPNNRHAYVGIAVIWVLAVASSLPFLIYQVMTDEPFQNVTLD
AYKDKYVCFDQFPSDSHRLSYTTLLLVLQYFGPLCFIFICYFKIYIRLKRRNNMMDKMRDNK
YRSSETKRINIMLLSIVVAFAVCWLPLTIFNTVFDWNHQIIATCNHNLLFLLCHLTAMISTCVN
PIFYGFLNKNFQRDLQFFFNFCDFRSRDDDYETIAMSTMHTDVSKTSLKQASPVAFKKINNND
DNEKI

(SEQ ID NO:1032)
>gi\|4505447\|ref\|NP_0009011\| neuropeptide Y receptor Y2 {Homosapiens}
MGPIGAEADENQTVEEMKVEQYGPQTTPRGELVPDPEPELIDSTKLIEVQVVLILAYCSIILLG
VIGNSLVIHVVIKFKSMRTVTNFFIANLAVADLLVNTLCLPFTLTYTLMGEWKMGPVLCHLV
PYAQGLAVQVSTITLTVIALDRHRCIVYHLESKISKRISFLIIGLAWGISALLASPLAIFREYSLIE
IIPDFEIVACTEKWPGEEKSIYGTVYSLSSLLILYVLPLGIISFSYTRIVVSKLKNHVSPGAANDH
YHQRRQKTTKMLVCVVVVFAVSWLPLHAFQLAVDIDSQVLDLKEYKLIFTVFHIIAMCSTFA
NPLLYGWMNSNYRKAFLSAFRCEQRLDAIHSEVSVTFKAKKNLEVRKNSGPNDSFTEATNV

(SEQ ID NO:1033)
>gi\|4505513\|ref\|NP_0009041\| opiate receptor-like 1 {Homosapiens}
MEPLFPAPFVVEVIYGSHLQGNLSLLSPNHSLLPPHLLLNASHGAFLPLGLKVTIVGLYLAVCV
GGLLGNCLVMYVILRHTKMKTATNIYIFNLALADTLVLLTLPFQGTDILLGFVVPFGNALCKT
VIAIDYYNMFTSTFTLTAMSVDRYVAICHPIRALDVRTSSKAQAVNVAIVVALASVVGVPVAI
MGSAQVEDEEIECLVEIPTPQDYWGPVFAICIFLFSFIVPVLVISVCYSLMIRRLRGVRLLSGSR
EKDRNLRRITRLVLVVVAVFVGCWTPVQVFVLAQGLGVQPSSETAVAILRFCTALGYVNSCL
NPILYAFLDENFKACFRKFCCASALRRDVQVSDRVRSIAKDVALACKTSETVPRPA

(SEQ ID NO:1034)
>gi\|4505557\|ref\|NP_0025541\| P2Y purinoceptor 1 {Homosapiens}
MTEVLWPAVPNGTDAAFLAGPGSSWGNSTVASTAAVSSSFKCALTKTGFQFYYLPAVYILVF
IIGFLGNSVAIWMFVFHMKPWSGISVYMFNLALADFLYVLTLPALIFYYFNKTDWIFGDAMC
KLQRFIFHVNLYGSILFLTCISAHRYSGVVYPLKSLGRLKKKNAICISVLVWLIVVVAISPILFY
SGTGVRKNKTITCYDTTSDEYLRSYFIYSMCTTVAMFCVPLVLILGCYGLIVRALIYKDLDNS
PLRRKSIYLVIIVLTVFAVSYIPFHVMKTMNLRARLDFQTPAMCAFNDRVYATYQVTRGLAS
LNSCVDPILYFLAGDTFRRRLSRATRKASRRSEANLQSKSEDMTLNILPEFKQNGDTSL

(SEQ ID NO:1035)
>gi\|4505561\|ref\|NP_0025561\| pyrimidinergic receptor P2Y4 {Homosapiens}
MASTESSLLRSLGLSPGPGSSEVELDCWFDEDFKFILLPVSYAVVFVLGLGLNAPTLWLFIFRL
RPWDATATYMFHLALSDTLYVLSLPTLIYYYAAHNHWPFGTEICKFVRFLFYVVNLYCSVLFL
TCISVHRYLGICHPLRALRWGRPRLAGLLCLAVWLVVAGCLVPNLFFVTTSNKGTTVLCHDT
TRPEEFDHYVHFSSAVMGLLFGVPCLVTLVCYGLMARRLYQPLPGSAQSSSRLRSLRTIAVV
LTVFAVCFVPFHITRTIYYLARLLEADCRVLNIVNVVYKVTRPLASANSCLDPVLYLLTGDKY
RRQLRQLCGGGKPQPRTAASSLALVSLPEDSSCRWAATPQDSSCSTPRADRL

(SEQ ID NO:1036)
>gi\|4506241\|ref\|NP_0009431\| platelet-activating factor receptor {Homosapiens}
MEPHDSSHMDSEFRYTLFPIVYSIIFVLGVIANGYVLWVFARLYPCKKFNEIKIFMVNLTMAD
MLFLITLPLWIVYYQNQGNWILPKFLCNVAGCLFFINTYCSVAFLGVITYNRFQAVTRPIKTA
QANTRKRGISLSLVIVVVAIVGAASYFLILDSTNTVPDSAGSGNVTRCFEHYEKGSVPVLIIHIFI
VFSFFLVFLIILFCNLVIIRTLLMQPVQQQRNAEVKRRALWMVCTVLAVFIICFVPHHVVQLP
WTLAELGFQDSKFHQAINDAHQVTLCLLSTNCVLDPVIYCFLTKKFRKHLTEKFYSMRSSRK
CSRATTDTVTEVVVPFNQIPGNSLKN

(SEQ ID NO:1037)
>gi\|4506259\|ref\|NP_0009491\| prostaglandin E2 receptor EP4 subtype
{Homosapiens}
MSTPGVNSSASLSPDRLNSPVTIPAVMFIFGVVGNLVAIVVLCKSRKEQKETTFYTLVC GLAV
TDLLGTLLVSPVTIATYMKGQWPGGQPLCEYSTFILLFFSLSGLSIICAMSVERYLAINHAYFY
SHYVDKRLAGLTLFAVYASNVLFCALPNMGLGSSRLQYPDTVVCFIDWTTNVTAHAAYSYM
YAGFSSFLILATVLCNVLVCGALLRMHRQFMRRTSLGTEQHHAAAAASVASRGHPAASPAL
PRLSDFRRRRSFRRIAGAEIQMVILLIATSLVVLICSIPLVVRVFVNQLYQPSLEREVSKNPDLQ
AIRIASVNPILDPWIYILLRKTVLSKAIEKIKCLFCRIGGSRRERSGQHCSDSQRTSSAMSGHSR
SFISRELKEISSTSQTLLPDLSLPDLSENGLGGRNLLPGVPGMGLAQEDTTSLRTLRISETSDSS
QGQDSESVLLVDEAGGSGRAGPAPKGSSLQVTFPSETLNLSEKCI

(SEQ ID NO:1038)
>gi\|4506261\|ref\|NP_0009501\| prostaglandin F2-alpha receptor isoform a
precursor {Homosapiens}
MSMNNSKQLVSPAAALLSNTTCQTENRLSVFFSVIFMTVGILSNSLAIAILMKAYQRFRQKSK
ASFLLLASGLVITDFFGHLINGAIAVFVYASDKEWIRFDQSNVLCSIFGICMVFSGLCPLLLGSV
MAIERCIGVTKPIFHSTKITSKHVKMMLSGVCLFAVFIALLPILGHRDYKIQASRTWCFYNTED
IKDWEDRFYLLLFSFLGLLALGVSLLCNAITGITLLRVKFKSQQHRQGRSHHLEMVIQLLAIM
CVSCICWSPFLVTMANIGINGNHSLETCETTLFALRMATWNQILDPWVYILLRKAVLKNLYK
LASQCCGVHVISLHIVVELSSIKNSLKVAAISESPVAEKSAST

(SEQ ID NO:1039)
>gi\|4506263\|ref\|NP_0009511\| prostaglandin 12 (prostacyclin) receptor (IP)
{Homosapiens}
MADSCRNLTYVRGSVGPATSTLMFVAGVVGNGLALGILSARRPARPSAFAVLVTGLAATDL
LGTSFLSPAVFVAYARNSSLLGLARGGPALCDAFAFAMTFFGLASMLILFAMAVERCLALSH
PYLYAQLDGPRCARLALPAIYAFCVLFCALPLLGLGQHQQYCPGSWCFLRMRWAQPGGAAF
SLAYAGLVALLVAAIFLCNGSVTLSLCRMYRQQKRHQGSLGPRPRTGEDEVDHLILLALMTV
VMAVCSLPLTIRCFTQAVAPDSSSEMGDLLAFRFYAFNPILDPWVFILFRKAVFQRLKLWVCC
LCLGPAHGDSQTPLSQLASGRRDPRAPSAPVGKEGSCVPLSAWGEGQVEPLPPTQQSSGSAV
GTSSKAEASVACSLC

(SEQ ID NO:1040)
>gi\|4506271\|ref\|NP_0003071\| parathyroid hormone receptor 1 precursor
{Homosapiens}
MGTARIAPGLALLLCCPVLSSAYALVDADDVMTKEEQIFLLHRAQAQCEKRLKEVLQRPASI
MESDKGWTSASTSGKPRKDKASGKLYPESEEDKEAPTGSRYRGRPCLPEWDHILCWPLGAP
GEVVAVPCPDYIYDFNHKGHAYRRCDRNGSWELVPGHNRTWANYSECVKFLTNETREREV
FDRLGMIYTVGYSVSLASLTVAVLILAYFRRLHCTRNYIHMHLFLSFMLRAVSIFVKDAVLYS
GATLDEAERLTEEELRAIAQAPPPPATAAAGYAGCRVAVTFFLYFLATNYYWILVEGLYLHS
LIFMAFFSEKKYLWGFTVFGWGLPAVFVAVWVSVRATLANTGCWDLSSGNKKWIIQVPILA
SIVLNFILFINIVRVLATKLRETNAGRCDTRQQYRKLLKSTLVLMPLFGVHYIVFMATPYTEVS
GTLWQVQMHYEMLFNSFQGFFVAIIYCFCNGEVQAEIKKSWSRWTLALDFKRKARSGSSSY
SYGPMVSHTSVTNVGPRVGLGLPLSPRLLPTATTNGHPQLPGHAKPGTPALETLETTPPAMA
APKDDGFLNGSCSGLDEEASGPERPPALLQEEWETVM

(SEQ ID NO:1041)
>gi\|4506403\|ref\|NP_0039701\| retinoic acid-induced protein 3 {Homosapiens}
MATTVPDGCRNGLKSKYYRLCDKAEAWGIVLETVATAGVVTSVAFMLTLPILVCKVQDSNR
RKMLPTQFLFLLGVLGIFGLTFAFIIGLDGSTGPTRFFLFGILFSICFSCLLAHAVSLTKLVRGRK
PLSLLVILGLAVGFSLVQDVIAIEYIVLTMNRTNVNVFSELSAPRRNEDFVLLLTYVLFLMALT
FLMSSFTFCGSFTGWKRHGAHIYLTMLLSIAIWVAWITLLMLPDFDRRWDDTILSSALAANG
WVFLLAYVSPEFWLLTKQRNPMDYPVEDAFCKPQLVKKSYGVENRAYSQEEITQGFEETGD
TLYAPYSTHFQLQNQPPQKEFSIPRAHAWPSPYKDYEVKKEGS

(SEQ ID NO:1042)
>gi\|4507343\|ref\|NP_0010491\| substance-P receptor isoform long {Homosapiens}
MDNVLPVDSDLSPNISTNTSEPNQFVQPAWQIVLWAAAYTVIVVTSVVGNVVVMWIILAHK
RMRTVTNYFLVNLAFAEASMAAFNTVVNFTYAVHNEWYYGLFYCKFHNFFPIAAVFASIYS
MTAVAFDRYMAIIHPLQPRLSATATKVVICVIWVLALLLAFPQGYYSTTETMPSRVVCMIEW
PEHPNKIYEKVYHICVTVLIYFLPLLVIGYAYTVVGITLWASEIPGDSSDRYHEQVSAKRKVV
KMMIVVVCTFAICWLPFHIFFLLPYINPDLYLKKFIQQVYLAIMWLAMSSTMYNPIIYCCLND
RFRLGFKHAFRCCPFISAGDYEGLEMKSTRYLQTQGSVYKVSRLETTISTVVGAHEEEPEDGP
KATPSSLDLTSNCSSRSDSKTMTESFSFSSNVLS

(SEQ ID NO:1043)
>gi\|4507381\|ref\|NP_0010511\| thromboxane A2 receptor isoform alpha
{Homosapiens}
MWPNGSSLGPCFRPTNITLEERRLIASPWFAASFCVVGLASNLLALSVLAGARQGGSHTRSSF
LTFLCGLVLTDFLGLLVTGTIVVSQHAALFEWHAVDPGCRLCRFMGVVMIFFGLSPLLLGAA
MASERYLGITRPFSRPAVASQRRAWATVGLVWAAALALGLLPLLGVGRYTVQYPGSWCFLT
LGAESGDVAFGLLFSMLGGLSVGLSFLLNTVSVATLCHVYHGQEAAQQRPRDSEVEMMAQL
LGIMVVASVCWLPLLVFIAQTVLRNPPAMSPAGQLSRTTEKELLIYLRVATWNQILDPWVYIL
FRRAVLRRLQPRLSTRPRSLSLQPQLTQRSGLQ

(SEQ ID NO:1044)
>gi\|4507681\|ref\|NP_0032921\| thyrotropin-releasing hormone receptor
{Homosapiens}
MENETVSELNQTQLQPRAVVALEYQVVTILLVLIICGLGIVGNIMVVLVVMRTKHMRTPTNC
YLVSLAVADLMVLVAAGLPNITDSIYGSWVYGYVGCLCITYLQYLGINASSCSITAFTIERYIA
ICHPIKAQFLCTFSRAKKIIIFVWAFTSLYCMLWFFLLDLNISTYKDAIVISCGYKISRNYYSPIY
LMDFGVFYVVPMILATVLYGFIARILFLNPIPSDPKENSKTWKNDSTHQNTNLNVNTSNRCFN
STVSSRKQVTKMLAVVVILFALLWMPYRTLVVVNSFLSSPFQENWFLLFCRICIYLNSAINPVI
YNLMSQKFRAAFRKLCNCKQKPTEKPANYSVALNYSVIKESDHFSTELDDITVTDTYLSATK
VSFDDTCLASEVSFSQS

(SEQ ID NO:1045)
>gi\|4557265\|ref\|NP_0006751\| beta-1 adrenergic receptor {Homosapiens}
MGAGVLVLGASEPGNLSSAAPLPDGAATAARLLVPASPPASLLPPASESPEPLSQQWTAGMG
LLMALIVLLIVAGNVLVIVAIAKTPRLQTLTNLFIMSLASADLVMGLLVVPFGATIVVWGRW
EYGSFFCELWTSVDVLCVTASIETLCVIALDRYLAITSPFRYQSLLTRARARGLVCTVWAISAL
VSFLPILMHWWRAESDEARRCYNDPKCCDFVTNRAYAIASSVVSFYVPLCIMAFVYLRVFRE
AQKQVKKIDSCERRFLGGPARPPSPSPSPVPAPAPPPGPPRPAAAAATAPLANGRAGKRRPSR
LVALREQKALKTLGIIMGVFTLCWLPFFLANVVKAFHRELVPDRLFVFFNWLGYANSAFNPII
YCRSPDFRKAFQGLLCCARRAARRRHATHGDRPRASGCLARPGPPPSPGAASDDDDDDVVG
ATPPARLLEPWAGCNGGAAADSDSSLDEPCRPGFASESKV

(SEQ ID NO:1046)
>gi\|4557267\|ref\|NP_0000161\| adrenergic, beta-3-, receptor {Homosapiens}
MAPWPHENSSLAPWPDLPTLAPNTANTSGLPGVPWEAALAGALLALAVLATVGGNLLVIVA
IAWTPRLQTMTNVFVTSLAAADLVMGLLVVPPAATLALTGHWPLGATGCELWTSVDVLCV
TASIETLCALAVDRYLAVTNPLRYGALVTKRCARTAVVLVWVVSAAVSFAPIMSQWWRVG
ADAEAQRCHSNPRCCAFASNMPYVLLSSSVSFYLPLLVMLFVYARVFVVATRQLRLLRGEL
GRFPPEESPPAPSRSLAPAPVGTCAPPEGVPACGRRPARLLPLREHRALCTLGLIMGTFTLCWL
PFFLANVLRALGGPSLVPGPAFLALNWLGYANSAFNPLIYCRSPDFRSAFRRLLCRCGRRLPP
EPCAAARPALFPSGVPAARSSPAQPRLCQRLDGASWGV

(SEQ ID NO:1047)
>gi\|4557345\|ref\|NP_0000451\| vasopressin V2 receptor isoform 1 {Homosapiens}
MLMASTTSAVPGHPSLPSLPS NSSQERPLDTRDPLLARAELALLSIVFVAVALSNGLVLAALA
RRGRRGHWAPIHVFIGHLCLADLAVALFQVLPQLAWKATDRFRGPDALCRAVKYLQMVGM
YASSYMILAMTLDRHRAICRPMLAYRHGSGAHWNRPVLVAWAFSLLLSLPQLFIFAQRNVE
GGSGVTDCWACFAEPWGRRTYVTVVIALMVFVAPTLGIAACQVLIFREIHASLVPGPSERPGG
RRRGRRTGSPGEGAHVSAAVAKTVRMTLVIVVVYVLCWAPFFLVQLWAAWDPEAPLEGAP
FVLLMLLASLNSCTNPWIYASFSSSVSSELRSLLCCARGRTPPSLGPQDESCTTASSSLAKDTS
S

(SEQ ID NO:1048)
>gi\|4557359\|ref\|NP_0006141\| B2 bradykinin receptor {Homosapiens}
MFSPWKISMFLSVREDSVPTTASFSADMLNVTLQGPTLNGTFAQSKCPQVEWLGWLNTIQPP
FLWVLFVLATLENIFVLSVFCLHKSSCTVAEIYLGNLAAADLILACGLPFVVAITISNNFDWLFG
ETLCRVVNAIISMNLYSSICFLMLVSIDRYLALVKTMSMGRMRGVRWAKLYSLVIVVGCTLLL
SSPMLVFRTMKEYSDEGHNVTACVISYPSLIVVEVFTNMLLNVVGFLLPLSVITFCTMQIMQVL
RNNEMQKFKEIQTERRATVLVLVVLLLFIICWLPFQISTFLDTLHRLGILSSCQDERIIDVITQIA
SFMAYSNSCLNPLVYVIVGKRFRKKSWEVYQGVCQKGGCRSEPIQMENSMGTLRTSISVERQ
IHKLQDWAGSRQ

(SEQ ID NO:1049)
>gi\|4557547\|ref\|NP_0001061\| endothelin B receptor isoform 1 precursor
{Homosapiens}
MQPPPSLCGRALVALVLACGLSRIVVGEERGFPPDRATPLLQTAEIMTPPTKTLWPKGSNASLA
RSLAPAEVPKGDRTAGSPPRTISPPPCQGPIEIKETFKYINTVVSCLVFVLGIIGNSTLLRIIYKN
KCMRNGPNILIASLALGDLLHIVIDIPINVYKLLAEDWPFGAEMCKLVPFIQKASVGITVLSLC
ALSIDRYRAVASWSRIKGIGVPKWTAVEIVLIVVVVSVVLAVPEAIGFDIITMDYKGSYLRICLL
HPVQKTAFMQFYKTAKDWWLFSFYFCLPLAITAFFYTLMTCEMLRKKSGMQIALNDHLKQR
REVAKTVFCLVLVFALCWLPLHLSRILKLTLYNQNDPNRCELLSFLLVLDYIGINMASLNSCI
NPIALYLVSKRFKNCFKSCLCCWCQSFEEKQSLEEKQSCLKFKANDHGYDNFRSSNKYSSS

(SEQ ID NO:1050)
>gi\|4557857\|ref\|NP_0010401\| somatostatin receptor type 1 {Homosapiens}
MFPNGTASSPSSSPSPSPGSCGEGGGSRGPGAGAADGMEEPGRNASQNGTLSEGQGSAILISFI
YSVVCLVGLCGNSMVIYVILRYAKMKTATNIYILNLAIADELLMLSVPFLVTSTLLRHWPFGA
LLCRLVLSVDAVNMFTSIYCLTVLSVDRYVAVVHPIKAARYRRPTVAKVVNLGVWVLSLLV
ILPIVVFSRTAANSDGTVACNMLMPEPAQRWLVGFVLYTFLMGFLLPVGAICLCYVLIIAKM
RMVALKAGWQQRKRSERKITLMVMMVVMVFVICWMPFYVVQLVNVFAEQDDATVSQLSV
ILGYANSCANPILYGFLSDNFKRSFQRILCLSWMDNAAEEPVDYYATALKSRAYSVEDFQPE
NLESGGVFRNGTCTSRITTL

(SEQ ID NO:1051)
>gi\|4557859\|ref\|NP_0010411\| somatostatin receptor type 2 {Homosapiens}
MDMADEPLNGSHTWLSIPFDLNGSVVSTNTSNQTEPYYDLTSNAVLTFIYFVVCIIGLCGNTL
VIYVILRYAKMKTITNIYILNLAIADELFMLGLPFLAMQVALVHWPFGKAICRVVMTVDGINQ
FTSIFCLTVMSIDRYLAVVHPIKSAKWRRPRTAKMITMAVWGVSLLVILPIMIYAGLRSNQW
GRSSCTINWPGESGAWYTGFIIYTFILGFLVPLTIICLCYLFIIIKVKSSGIRVGSSKRKKSEKKVT
RMVSIVVAVFIFCWLPFYIFNVSSVSMAISPTPALKGMFDFVVVLTYANSCANPILYAFLSDNF
KKSFQNVLCLVKVSGTDDGERSDSKQDKSRLNETTETQRTLLNGDLQTSI

(SEQ ID NO:1052)
>gi\|4557861\|ref\|NP_0010421\| somatostatin receptor type 3 {Homosapiens}
MDMLHPSSVSTTSEPENASSAWPPDATLGNVSAGPSPAGLAVSGVLIPLVYLVVCVVGLLGN
SLVIYVVLRHTASPSVTNVYILNLALADELFMLGLPFLAAQNALSYWPFGSLMCRLVMAVD
GINQFTSIFCLTVMSVDRYLAVVHPTRSARWRTAPVARTVSAAVWVASAVVVLPVVVFSGV
PRGMSTCHMQWPEPAAAWRAGFHYTAALGFFGPLLVICLCYLLIVVKVRSAGRRVVVAPSCQ
RRRRSERRVTRMVVAVVALFVLCWMPFYVLNIVNVVCPLPEEPAFFGLYFLVVALPYANSC
ANPILYGFLSYRFKQGFRRVLLRPSRRVRSQEPTVGPPEKTEEEDEEEEDGEESREGGKGKEM
NGRVSQITQPGTSGQERPPSRVASKEQQLLPQEASTGEKSSTMRISYL

(SEQ ID NO:1053)
>gi\|4557865\|ref\|NP_0010441\| somatostatin receptor type 5 {Homosapiens}
MEPLFPASTPSWNASSPGAASGGGDNRTLVGPAPSAGARAVLVPVLYLLVCAAGLGGNTLVI
YVVLRFAKMKTVTNIYILNLAVADVLYMLGLPFLATQNAASFVVPFGPVLCRLVMTLDGVNQ
FTSVFCLTVMSVDRYLAVVHPLSSARWRRPRVAKLASAAAWVLSLCMSLPLLVFADVQEGG
TCNASWPEPVGLWGAVFIIYTAVLGFFAPLLVICLCYLLIVVKVRAAGVRVGCVRRRSERKV
TRMVLVVVLVFAGCWLPFFTVNIVNLAVALPQEPASAGLYFFVVILSYANSCANPVLYGFLS
DNFRQSFQKVLCLRKGSGAKDADATEPRPDRIRQQQEATPPAHRAAANGLMQTSKL

(SEQ ID NO:1054)
>gi\|4757888\|ref\|NP_0040451\| C3a anaphylatoxin chemotactic receptor
{Homosapiens}
MASFSAETNSTDLLSQPWNEPPVILSMVILSLTFLLGLPGNGLVLWVAGLKMQRTVNTIVVFL
HLTLADLLCCLSLPFSLAHLALQGQWPYGRFLCKLIPSIIVLNMFASVFLLTAISLDRCLVVFK
PIVVCQNHRNVGMACSICGCIVVVVAFVMCIPVFVYREIFTTDNHNRCGYKFGLSSSLDYPDFY
GDPLENRSLENIVQPPGEMNDRLDPSSFQTNDHPWTVPTVFQPQTFQRPSADSLPRGSARLTS
QNLYSNVFKPADVVSPKIPSGFPIEDHETSPLDNSDAFLSTHLKLFPSASSNSFYESELPQGFQD
YYNLGQFTDDDQVPTPLVAITITRLVVGFLLPSVIMIACYSFIVFRMQRGRFAKSQSKTFRVA
VVVVAVFLVCWTPYHIFGVLSLLTDPETPLGKTLMSWDHVCIALASANSCFNPFLYALLGKD
FRKKARQSIQGILEAAFSEELTRSTHCPSNNVISERNSTTV

(SEQ ID NO:1055)
>gi\|4758014\|ref\|NP_0040631\| chemokine receptor-like 1 isoform b {Homosapiens}
MEDEDYNTSISYGDEYPDYLDSIVVLEDLSPLEARVTRIFLVVVYSIVCFLGILGNGLVIIIATF
KMKKTVNMVWFLNLAVADFLFNVFLPIHITYAAMDYHWVFGTAMCKISNFLLIHNMFTSVF
LLTIISSDRCISVLLPVVVSQNHRSVRLAYMACMVIWVLAFFLSSPSLVFRDTANLHGKISCFNN
FSLSTPGSSSWPTHSQMDPVGYSRHMVVTVTRFLCGFLVPVLIITACYLTIVCKLQRNRLAKT
KKPFKIIVTIIITFFLCWCPYHTLNLLELHHTAMPGSVFSLGLPLATALAIANSCMNPILYVFMG
QDFKKFKVALFSRLVNALSEDTGHSSYPSHRSFTKMSSMNERTSMNERETGML

(SEQ ID NO:1056)
>gi\|4758326\|ref\|NP_0040921\| proteinase-activated receptor 3 precursor
{Homosapiens}
MKALIFAAAGLLLLLPTFCQSGMENDTNNLAKPTLPIKTFRGAPPNSFEEFPFSALEGWTGATI
TVKIKCPEESASHLHVKNATMGYLTSSLSTKLIPAIYLLVFVVGVPANAVTLWMLFFRTRSIC
TTVFYTNLAIADFLFCVTLPFKIAYHLNGNNWVFGEVLCRATTVIFYGNMYCSILLLACISINR
YLAIVHPFTYRGLPKHTYALVTCGLVWATVFLYMLPFFILKQEYYLVQPDITTCHDVHNTCE
SSSPFQLYYFISLAFFGFLIPFVLIIYCYAAHRTLNAYDHRWLWYVKASLLILVIFTICFAPSNHL
IIHHANYYYNNTDGLYFIYLIALCLGSLNSCLDPFLYFLMSKTRNHSTAYLTK

(SEQ ID NO:1057)
>gi\|4758438\|ref\|NP_0042371\| glucagon-like peptide 2 receptor precursor
{Homosapiens}
MKLGSSRAGPGRGSAGLLPGVHELPMGIPAPWGTSPLSFHRKCSLWAPGRPFLTLVLLVSIKQ
VTGSLLEETTRKWAQYKQACLRDLLKEPSGIFCNGTFDQYVCWPHSSPGNVSVPCPSYLPW
WSEESSGRAYRHCLAQGTWQTIENATDIVVQDDSECSENHSFKQNVDRYALLSTLQLMYTVG
YSFSLISLFLALTLLLFLRKLHCTRNYIHMNLFASFILRTLAVLVKDVVFYNSYSKRPDNENG
WMSYLSEMSTSCRSVQVLLHYFVGANYLWLLVEGLYLHTLLEPTVLPERRLWPRYLLLGW
AFPVLFVVPWGFARAHLENTGCWTTNGNKKIVVWIIRGPMMLCVTVNFFIFLKILKLLISKLK
AHQMCFRDYKYRLAKSTLVLIPLLGVHEILFSFITDDQVEGFAKLIRLFIQLTLSSFHGFLVAL
QYGFANGEVKAELRKYWVRFLLARHSGCRACVLGKDFRFLGKCPKKLSEGDGAEKLRKLQ
PSLNSGRLLHLAMRGLGELGAQPQQDHARWPRGSSLSECSEGDVTMANTMEEILEESEI

(SEQ ID NO:1058)
>gi\|4758474\|ref\|NP_0042391\| prolactin-releasing peptide receptor
{Homosapiens}
MASSTTRGPRVSDLFSGLPPAVTTPANQSAEASAGNGSVAGADAPAVTPFQSLQLVHQLKGL
IVLLYSVVVVVGLVGNCLLVLVIARVRRLHNVTNFLIGNLALSDVLMCTACVPLTLAYAFEP
RGWVFGGGLCHLVFFLQPVTVYVSVFTLTTIAVDRYVVLVHPLRRRISLRLSAYAVLAIWAL
SAVLALPAAVHTYHVELKPHDVRLCEEFWGSQERQRQLYAWGLLLVTYLLPLLVILLSYVR
VSVKLRNRVVPGCVTQSQADWDRARRRRTFCLLVVVVVVFAVCWLPLHVFNLLRDLDPHA
IDPYAFGLVQLLCHWLAMSSACYNPFIYAWLHDSFREELRKLLVAWPRKIAPHGQNMTVSV
VI

(SEQ ID NO:1059)
>gi\|4758864\|ref\|NP_004145 1\| pyrimidinergic receptor P2Y6 {Homosapiens}
MEWDNGTGQALGLPPTTCVYRENFKQLLLPPVYSAVLAAGLPLNICVITQICTSRRALTRTA
VYTLNLALADLLYACSLPLLIYNYAQGDHWPFGDFACRLVRFLFYANLHGSILFLTCISFQRY
LGICHPLAPWHKRGGRRAAWLVCVAVWLAVTTQCLPTAIFAATGIQRNRTVCYDLSPPALA
THYMPYGMALTVIGFLLPFAALLACYCLLACRLCRQDGPAEPVAQERRGKAARMAVVVAA
AFAISFLPFHITKTAYLAVRSTPGVPCTVLEAFAAAYKGTRPFASANSVLDPILFYFTQKKFRR
RPHELLQKLTAKWQRQGR

(SEQ ID NO:1060)
>gi\|4826706\|ref\|NP_0049421\| G-protein coupled receptor 183 {Homosapiens}
MDIQMANNFTPPSATPQGNDCDLYAHHSTARIVMPLHYSLVFIIGLVGNLLALVVIVQNRKKI
NSTTLYSTNLVISDILFTTALPTRIAYYAMGFDWRIGDALCRITALVFYINTYAGVNFMTCLSI
DRFIAVVHPLRYNKIKRIEHAKGVCIFVWILVFAQTLPLLINPMSKQEAERITCMEYPNFEETK
SLPWILLGACFIGYVLPLIIILICYSQICCKLFRTAKQNPLTEKSGVNKKALNTIILIIVVFVLCFT
PYHVAIIQHMIKKLRFSNFLECSQRHSFQISLHFTVCLMNFNCCMDPFIYFFACKGYKRKVMR
MLKRQVSVSISSAVKSAPEENSREMTETQMMIHSKSSNGK

(SEQ ID NO:1061)
>gi\|4826954\|ref\|NP_0050391\| parathyroid hormone 2 receptor precursor
{Homosapiens}
MAGLGASLHVWGWLMLGSCLLARAQLDSDGTITIEEQIVLVLKAKVQCELNITAQLQEGEG
NCFPEWDGLICWPRGTVGKISAVPCPPYIYDFNHKGVAFRHCNPNGTWDFMHSLNKTWANY
SDCLRFLQPDISIGKQEFFERLYVMYTVGYSISFGSLAVAILIIGYFRRLHCTRNYIHMHLFVSF
MLRATSIFVKDRVVHAHIGVKELESLIMQDDPQNSIEATSVDKSQYIGCKIAVVMFIYFLATN
YYWILVEGLYLHNLIFVAFFSDTKYLWGFILIGWGFPAAFVAAWAVARATLADARCWELSA
GDIKWIYQAPILAAIGLNFILFLNTVRVLATKIVVETNAVGHDTRKQYRKLAKSTLVLVLVFGV
HYIVFVCLPHSFTGLGWERMHCELFFNSFQGFFVSIIYCYCNGEVQAEVKKMWSRWNLSVD
WKRTPPCGSRRCGSVLTTVTHSTSSQSQVAASTRMVLISGKAAKIASRQPDSHITLPGYVWSN
SEQDCLPHSFHEETKEDSGRQGDDILMEKPSRPMESNPDTEGCQGETEDVL

(SEQ ID NO:1062)
>gi\|4885057\|ref\|NP_005152 1\| apelin receptor {Homosapiens}
MEEGGDFDNYYGADNQSECEYTDWKSSGALIPAIYMLVFLLGTTGNGLVLWTVFRSSREKR
RSADIFIASLAVADLTFVVTLPLWATYTYRDYDWPFGTFFCKLSSYLIFVNMYASVFCLTGLS
FDRYLAIVRPVANARLRLRVSGAVATAVLWVLAALLAMPVMVLRTTGDLENTTKVQCYMD
YSMVATVSSEWAWEVGLGVSSTTVGFVVPFTIMLTCYFFIAQTIAGHFRKERIEGLRKRRRLL
SIIVVLVVTFALCWMPYHLVKTLYMLGSLLHWPCDFDLFLMNIFPYCTCISYVNSCLNPFLYA
FFDPRFRQACTSMLCCGQSRCAGTSHSSSGEKSASYSSGHSQGPGPNMGKGGEQMHEKSIPY
SQETLVVD

(SEQ ID NO:1063)
>gi\|4885121\|ref\|NP_0051921\| C-C chemokine receptor type 8 {Homosapiens}
MDYTLDLSVTTVTDYYYPDIFSSPCDAELIQTNGKLLLAVFYCLLFVFSLLGNSLVILVLVVC
KKLRSITDVYLLNLALSDLLFVFSFPFQTYYLLDQWVFGTVMCKVVSGFYYIGFYSSMFFITL
MSVDRYLAVVHAVYALKVRTIRMGTTLCLAVWLTAIMATIPLLVFYQVASEDGVLQCYSFY
NQQTLKWKIFTNFKMNILGLLIPFTIFMFCYIKILHQLKRCQNHNKTKAIRLVLIVVIASLLFVV
VPFNVVLFLTSLHSMHILDGCSISQQLTYATHVTEIISFTHCCVNPVIYAFVGEKFKKHLSEIFQ
KSCSQIFNYLGRQMPRESCEKSSSCQQHSSRSSSVDYIL

(SEQ ID NO:1064)
>gi\|4885295\|ref\|NP_0052791\| G-protein coupled receptor 12 {Homosapiens}
MNEDLKVNLSGLPRDYLDAAAAENISAAVSSRVPAVEPEPELVVNPWDIVLCTSGTLISCEN
AIVVLIIFHNPSLRAPMFLLIGSLALADLLAGIGLITNFVFAYLLQSEATKLVTIGLIVASFSASV
CSLLAITVDRYLSLYYALTYHSERTVTFTYVMLVMLWGTSICLGLLPVMGWNCLRDESTCS
VVRPLTKNNAAILSVSFLFMFALMLQLYIQICKIVMRHAHQIALQHHFLATSHYVTTRKGVST
LAHLGTFAACWMPFTLYSLIADYTYPSIYTYATLLPATYNSIINPVIYAFRNQEIQKALCLICCG
CIPSSLAQRARSPSDV

(SEQ ID NO:1065)
>gi\|4885299\|ref\|NP_0052811\| G protein-coupled receptor 15 {Homosapiens}
MDPEETSVYLDYYYATSPNSDIRETHSHVPYTSVFLPVFYTAVFLTGVLGNLVLMGALHFKP
GSRRLIDIFIINLAASDFIFLVTLPLWVDKEASLGLWRTGSFLCKGSSYMISVNMHCSVLLLTC
MSVDRYLAIVWPVVSRKFRRTDCAYVVCASIVVFISCLLGLPTLLSRELTLIDDKPYCAEKKAT
PIKLIVVSLVALIFTFFVPLLSIVTCYCCIARKLCAHYQQSGKHNKKLKKSIKIIFIVVAAFLVSW
LPFNTFKFLAIVSGLRQEHYLPSAILQLGMEVSGPLAFANSCVNPFIYYIFDSYIRRAIVHCLCP
CLKNYDFGSSTETSDSHLTKALSTFIHAEDFARRRKRSVSL

(SEQ ID NO:1066)
>gi\|4885301\|ref\|NP_0052821\| uracil nucleotide/cysteinyl leukotriene receptor
isoform a {Homosapiens }
MSKRSWWAGSRKPPREMLKLSGSDSSQSMNGLEVAPPGLITNFSLATAEQCGQETPLENMLF
ASFYLLDFILALVGNTLALWLFIRDHKSGTPANVFLMHLAVADLSCVLVLPTRLVYHFSGNH
WPFGEIACRLTGFLFYLNMYASIYFLTCISADRFLAIVHPVKSLKLRRPLYAHLACAFLWVVV
AVAMAPLLVSPQTVQTNHTVVCLQLYREKASHHALVSLAVAFTFPFITTVTCYLLIIRSLRQG
LRVEKRLKTKAVRMIAIVLAIFLVCFVPYHVNRSVYVLHYRSHGASCATQRILALANRITSCL
TSLNGALDPIMYFFVAEKFRHALCNLLCGKRLKGPPPSFEGKTNESSLSAKSEL

(SEQ ID NO:1067)
>gi\|4885307\|ref\|NP_0052851\| G protein-coupled receptor 21 {Homosapiens}
MNSTLDGNQSSHPFCLLAFGYLETVNFCLLEVLIIVFLTVLIISGNIIVIFVFHCAPLLNHHTTSY
FIQTMAYADLFVGVSCVVPSLSLLHHPLPVEESLTCQIFGFVVSVLKSVSMASLACISIDRYIAI
TKPLTYNTLVTPWRLRLCIFLIVVLYSTLVFLPSFFHWGKPGYHGDVFQWCAESWHTDSYFTL
FIVMMLYAPAALIVCFTYFNIFRICQQHTKDISERQARFSSQSGETGEVQACPDKRYAMVLFRI
TSVFYILWLPYIIYFLLESSTGHSNRFASFLTTWLAISNSFCNCVIYSLSNSVFQRGLKRLSGAM
CTSCASQTTANDPYTVRSKGPLNGCHI

(SEQ ID NO:1068)
>gi\|4885311\|ref\|NP_0052871\| lysophosphatidic acid receptor 4 {Homosapiens}
MGDRRFIDFQFQDSNSSLRPRLGNATANNTCIVDDSFKYNLNGAVYSVVFILGLITNSVSLFV
FCFRMKMRSETAIFITNLAVSDLLFVCTLPFKIFYNFNRHWPFGDTLCKISGTAFLTNIYGSML
FLTCISVDRFLAIVYPFRSRTIRTRRNSAIVCAGVWILVLSGGISASLFSTTNVNNATTTCFEGF
SKRVVVKTYLSKITIFIEVVGFIIPLILNVSCSSVVLRTLRKPATLSQIGTNKKKVLKMITVHMAV
FVVCFVPYNSVLFLYALVRSQAITNCFLERFAKIMYPITLCLATLNCCFDPFIYYFTLESFQKSF
YINAHIRMESLFKTETPLTTKPSLPAIQEEVSDQTTNNGGELMLESTF

(SEQ ID NO:1069)
>gi\|4885319\|ref\|NP_0052911\| probable G-protein coupled receptor 34
{Homosapiens}
MRSHTITMTTTSVSSWPYSSHRMRFITNHSDQPPQNFSATPNVTTCPMDEKLLSTVLTTSYSVI
FIVGLVGNIIALYVFLGIHRKRNSIQIYLLNVAIADLLLIFCLPFRIMYHINQNKWTLGVILCKV
VGTLFYMNMYISIILLGFISLDRYIKINRSIQQRKAITTKQSIYVCCIVWMLALGGFLTMIILTLK
KGGHNSTMCFHYRDKHNAKGEAIFNFILVVMFVVLIFLLIILSYIKIGKNLLRISKRRSKFPNSG
KYATTARNSFIVLIIFTICFVPYHAFRFIYISSQLNVSSCYVVKEIVHKTNEIMLVLSSFNSCLDPV
MYFLMSSNIRKIMCQLLFRRFQGEPSRSESTSEFKPGYSLHDTSVAVKIQSSSKST

(SEQ ID NO:1070)
>gi\|4885323\|ref\|NP_0052931\| probable G-protein coupled receptor 37 precursor
{Homosapiens}
MRAPGALLARMSRLLLLLLLKVSASSALGVAPASRNETCLGESCAPTVIQRRGRDAWGPGNS
ARDVLRARAPREEQGAAFLAGPSWDLPAAPGRDPAAGRGAEASAAGPPGPPTRPPGPWRW
KGARGQEPSETLGRGNPTALQLFLQISEEEEKGPRGAGISGRSQEQSVKTVPGASDLFYWPRR
AGKLQGSHHKPLSKTANGLAGHEGWTIALPGRALAQNGSLGEGIHEPGGPRRGNSTNRRVR
LKNPFYPLTQESYGAYAVMCLSVVIFGTGIIGNLAVMCIVCHNYYMRSISNSLLANLAFVVDF
LIIFFCLPLVIFHELTKKWLLEDFSCKIVPYIEVASLGVTTFTLCALCIDRFRAATNVQMYYEMI
ENCSSTTAKLAVIWVGALLLALPEVVLRQLSKEDLGFSGRAPAERCIIKISPDLPDTIYVLALT
YDSARLWWYFGCYFCLPTLFTITCSLVTARKIRKAEKACTRGNKRQIQLESQMNCTVVALTI
LYGFCIIPENICNIVTAYMATGVSQQTMDLLNIISQFLLFFKSCVTPVLLFCLCKPFSRAFMECC
CCCCEECIQKSSTVTSDDNDNEYTTELELSPFSTIRREMSTFASVGTHC

(SEQ ID NO:1071)
>gi\|4885325\|ref\|NP_0052721\| G protein-coupled receptor 3 {Homosapiens}
MMWGAGSPLAWLSAGSGNVNVSSVGPAEGPTGPAAPLPSPKAWDVVLCISGTLVSCENALV
VAHVGTPAFRAPMFLLVGSLAVADLLAGLGLVLHFAAVFCIGSAEMSLVLVGVLAMAFTASI
GSLLAITVDRYLSLYNALTYYSETTVTRTYVMLALVWGGALGLGLLPVLAWNCLDGLTTCG
VVYPLSKNHLVVLAIAFFMVFGIMLQLYAQICRIVCRHAQQIALQRHLLPASHYVATRKGIAT
LAVVLGAFAACWLPFTVYCLLGDAHSPPLYTYLTLLPATYNSMINPIIYAFRNQDVQKVLWA
VCCCCSSSKIPFRSRSPSDV

(SEQ ID NO:1072)
>gi\|4885327\|ref\|NP_0052941\| free fatty acid receptor 1 {Homosapiens}
MDLPPQLSFGLYVAAFALGFPLNVLAIRGATAHARLRLTPSLVYALNLGCSDLLLTVSLPLKA
VEALASGAWPLPASLCPVFAVAHFFPLYAGGGFLAALSAGRYLGAAFPLGYQAFRRPCYSW
GVCAAIWALVLCHLGLVFGLEAPGGWLDHSNTSLGINTPVNGSPVCLEAWDPASAGPARFS
LSLLLFFLPLAITAFCYVGCLRALARSGLTHRRKLRAAWVAGGALLTLLLCVGPYNASNVAS
FLYPNLGGSWRKLGLITGAWSVVLNPLVTGYLGRGPGLKTVCAARTQGGKSQK

(SEQ ID NO:1073)
>gi\|4885329\|ref\|NP_0052951\| free fatty acid receptor 3 {Homosapiens}
MDTGPDQSYFSGNHWFVFSVYLLTFLVGLPLNLLALVVFVGKLQRRPVAVDVLLLNLTASD
LLLLLFLPFRMVEAANGMHWPLPFILCPLSGFIFFTTIYLTALFLAAVSIERFLSVAHPLWYKT
RPRLGQAGLVSVACWLLASAHCSVVYVIEFSGDISHSQGTNGTCYLEFRKDQLAILLPVRLE
MAVVLFVVPLIITSYCYSRLVVVILGRGGSHRRQRRVAGLLAATLLNFLVCFGPYNVSHVVGY
ICGESPAWRIYVTLLSTLNSCVDPFVYYFSSSGFQADFHELLRRLCGLWGQWQQESSMELKE
QKGGEEQRADRPAERKTSEHSQGCGTGGQVACAES

(SEQ ID NO:1074)
>gi\|4885333\|ref\|NP_0052971\| free fatty acid receptor 2 {Homosapiens}
MLPDWKSSLILMAYIIIFLTGLPANLLALRAFVGRIRQPQPAPVHILLLSLTLADLLLLLLLPFKI
IEAASNFRWYLPKVVCALTSFGFYSSIYCSTVVLLAGISIERYLGVAFPVQYKLSRRPLYGVIAA
LVAWVMSFGHCTIVIIVQYLNTTEQVRSGNEITCYENFTDNQLDVVLPVRLELCLVLFFIPMA
VTIFCYWRFVVVIMLSQPLVGAQRRRRAVGLAVVTLLNFLVCFGPYNVSHLVGYHQRKSPW
WRSIAVVFSSLNASLDPLLFYFSSSVVRRAFGRGLQVLRNQGSSLLGRRGKDTAEGTNEDRG
VGQGEGMPSSDFTTE

(SEQ ID NO:1075)
>gi\|4885335\|ref\|NP_0052731\| G-protein coupled receptor 4 {Homosapiens}
MGNHTWEGCHVDSRVDHLFPPSLYIFVIGVGLPTNCLALWAAYRQVQQRNELGVYLMNLSI
ADLLYICTLPLWVDYFLHHDNVVIHGPGSCKLFGFIFYTNIYISIAFLCCISVDRYLAVAHPLRF
ARLRRVKTAVAVSSVVWATELGANSAPLFHDELFRDRYNHTFCFEKFPMEGWVAWMNLYR
VFVGFLFPWALMLLSYRGILRAVRGSVSTERQEKAKIKRLALSLIAIVLVCFAPYHVLLLSRS
AIYLGRPWDCGFEERVFSAYHSSLAFTSLNCVADPILYCLVNEGARSDVAKALHNLLRFLAS
DKPQEMANASLTLETPLTSKRNSTAKAMTGSWAATPPSQGDQVQLKMLPPAQ

(SEQ ID NO:1076)
>gi\|4885339\|ref\|NP_0052741\| chemokine XC receptor 1 {Homosapiens}
MESSGNPESTTFFYYDLQSQPCENQAWVFATLATTVLYCLVFLLSLVGNSLVLWVLVKYESL
ESLTNIFILNLCLSDLVFACLLPVWISPYHWGWVLGDFLCKLLNMIFSISLYSSIFFLTIMTIHRY
LSVVSPLSTLRVPTLRCRVLVTMAVWVASILSSILDTIFHKVLSSGCDYSELTWYLTSVYQHN
LFFLLSLGIILFCYVEILRTLFRSRSKRRHRTVKLIFAIVVAYFLSWGPYNFTLFLQTLFRTQIIRS
CEAKQQLEYALLICRNLAFSHCCFNPVLYVFVGVKFRTHLKHVLRQFVVFCRLQAPSPASIPHS
PGAFAYEGASFY

(SEQ ID NO:1077)
>gi\|4885341\|ref\|NP_0052751\| G-protein coupled receptor 6 {Homosapiens}
MNASAASLNDSQVVVVAAEGAAAAATAAGGPDTGEWGPPAAAALGAGGGANGSLELSSQ
LSAGPPGLLLPAVNPWDVLLCVSGTVIAGENALVVALIASTPALRTPMFVLVGSLATADLLA
GCGLILHFVFQYLVPSETVSLLTVGFLVASFAASVSSLLAITVDRYLSLYNALTYYSRRTLLGV
HLLLAATWTVSLGLGLLPVLGWNCLAERAACSVVRPLARSHVALLSAAFFMVFGIMLHLYV
RICQVVWRHAHQIALQQHCLAPPHLAATRKGVGTLAVVLGTFGASWLPFAIYCVVGSHEDP
AVYTYATLLPATYNSMINPIIYAFRNQEIQRALWLLLCGCFQSKVPFRSRSPSEV

(SEQ ID NO:1078)
>gi\|488536 1 \|ref\|NP_0053051\| gastrin-releasing peptide receptor
{Homosapiens}
MALNDCFLLNLEVDHFMHCNISSHSADLPVNDDWSHPGILYVIPAVYGVIILIGLIGNITLIKIF
CTVKSMRNVPNLFISSLALGDLLLLITCAPVDASRYLADRWLFGRIGCKLIPFIQLTSVGVSVF
TLTALSADRYKAIVRPMDIQASHALMKICLKAAFIVVIISMLLAIPEAVFSDLHPFHEESTNQTFI
SCAPYPHSNELHPKIHSMASFLVFYVIPLSIISVYYYFIAKNLIQSAYNLPVEGNIHVKKQIESR
KRLAKTVLVFVGLFAFCWLPNHVIYLYRSYHYSEVDTSMLHFVTSICARLLAFTNSCVNPFA
LYLLSKSFRKQFNTQLLCCQPGLIIRSHSTGRSTTCMTSLKSTNPSVATFSLINGNICHERYV

(SEQ ID NO:1079)
>gi\|5031621\|ref\|NP_0057861\| calcitonin gene-related peptide type 1 receptor
precursor {Homosapiens}
MEKKCTLYFLVLLPFFMILVTAELEESPEDSIQLGVTRNKIMTAQYECYQKIMQDPIQQAEGV
YCNRTWDGWLCWNDVAAGTESMQLCPDYFQDFDPSEKVTKICDQDGNWFRHPASNRTWT
NYTQCNVNTHEKVKTALNLFYLTIIGHGLSIASLLISLGIFFYFKSLSCQRITLHKNLFFSFVCN
SVVTIIHLTAVANNQALVATNPVSCKVSQFIHLYLMGCNYFVVMLCEGIYLHTLIVVAVFAEK
QHLMWYYFLGWGFPLIPACIHAIARSLYYNDNCWISSDTHLLYIIHGPICAALLVNLFFLLNIV
RVLITKLKVTHQAESNLYMKAVRATLILVPLLGIEFVLIPWRPEGKIAEEVYDYIMHILMHFQ
GLLVSTIFCFFNGEVQAILRRNWNQYKIQFGNSFSNSEALRSASYTVSTISDGPGYSHDCPSEH
LNGKSIHDIENVLLKPENLYN

(SEQ ID NO:1080)
>gi\|5031627\|ref\|NP_0054991\| C-C chemokine receptor type 4 {Homosapiens}
MNPTDIADTTLDESIYSNYYLYESIPKPCTKEGIKAFGELFLPPLYSLVFVFGLLGNSVVVLVL
FKYKRLRSMTDVYLLNLAISDLLFVFSLPFVVGYYAADQWVFGLGLCKMISWMYLVGFYSGI
FFVMLMSIDRYLAIVHAVFSLRARTLTYGVITSLATWSVAVFASLPGFLFSTCYTERNHTYCK
TKYSLNSTTVVKVLSSLEINILGLVIPLGIMLFCYSMIIRTLQHCKNEKKNKAVKMIFAVVVLFL
GFVVTPYNIVLFLETLVELEVLQDCTFERYLDYAIQATETLAFVHCCLNPHYFFLGEKFRKYIL
QLFKTCRGLFVLCQYCGLLQIYSADTPSSSYTQSTMDHDLHDAL

(SEQ ID NO:1081)
>gi\|5174535\|ref\|NP_0059041\| melanocortin 5 receptor {Homosapiens}
MNSSFHLHFLDLNLNATEGNLSGPNVKNKSSPCEDMGIAVEVFLTLGVISLLENILVIGAIVKN
KNLHSPMYFFVCSLAVADMLVSMSSAWETITIYLLNNKHLVIADAFVRHIDNVFDSMICISVV
ASMCSLLAIAVDRYVTIFYALRYHHIMTARRSGAIIAGIVVAFCTGCGIVFILYSESTYVILCLIS
MFFAMLFLLVSLYIHMFLLARTHVKRIAALPGASSARQRTSMQGAVTVTMLLGVFTVCWAP
FFLHLTLMLSCPQNLYCSRFMSHFNMYLILIMCNSVMDPLIYAFRSQEMRKTFKEIICCRGFRI
ACSFPRRD

(SEQ ID NO:1082)
>gi\|5174593\|ref\|NP_0059491\| melatonin receptor 1 A {Homosapiens}
MQGNGSALPNASQPVLRGDGARPSWLASALACVLIFTIVVDILGNLLVILSVYRNKKLRNAG
NIFVVSLAVADLVVAIYPYPLVLMSIFNNGWNLGYLHCQVSGFLMGLSVIGSIFNITGIAINRY
CYICHSLKYDKLYSSKNSLCYVLLIVVLLTLAAVLPNLRAGTLQYDPRIYSCTFAQSVSSAYTI
AVVVFHFLVPMIIVIFCYLRIVVILVLQVRQRVKPDRKPKLKPQDFRNFVTMFVVFVLFAICWA
PLNFIGLAVASDPASMVPRIPEWLFVASYYMAYFNSCLNAIIYGLLNQNFRKEYRRIIVSLCTA
RVFFVDSSNDVADRVKWKPSPLMTNNNVVKVDSV

(SEQ ID NO:1083)
>gi\|5174595\|ref\|NP_0059501\| melatonin receptor 1B {Homosapiens}
MSENGSFANCCEAGGWAVRPGWSGAGSARPSRTPRPPWVAPALSAVLIVTTAVDVVGNLL
VILSVLRNRKLRNAGNLFLVSLALADLVVAFYPYPLILVAIFYDGWALGEEHCKASAFVMGL
SVIGSVFNITAIAINRYCYICHSMAYHRIYRRWHTPLHICLIWLLTVVALLPNFFVGSLEYDPRI
YSCTFIQTASTQYTAAVVVIHFLLPIAVVSFCYLRIWVLVLQARRKAKPESRLCLKPSDLRSFL
TMFVVFVIFAICWAPLNCIGLAVAINPQEMAPQIPEGLFVTSYLLAYFNSCLNAIVYGLLNQNF
RREYKRILLALWNPRHCIQDASKGSHAEGLQSPAPPIIGVQHQADAL

(SEQ ID NO:1084)
>gi\|5453666\|ref\|NP_0061341\| probable G-protein coupled receptor 19 {Homosapiens}
MVFAHRMDNSKPHLIIPTLLVPLQNRSCTETATPLPSQYLMELSEEHSWMSNQTDLHYVLKP
GEVATASIFFGILWLFSIFGNSLVCLVIHRSRRTQSTTNYFVVSMACADLLISVASTPFVLLQFT
TGRWTLGSATCKVVRYFQYLTPGVQIYVLLSICIDRFYTIVYPLSFKVSREKAKKMIAASWIF
DAGFVTPVLFFYGSNWDSHCNYFLPSSWEGTAYTVIHFLVGFVIPSVLIILFYQKVIKYIVVRIG
TDGRTVRRTMNIVPRTKVKTIKMFLILNLLFLLSWLPFHVAQLWHPHEQDYKKSSLVFTAIT
WISFSSSASKPTLYSIYNANFRRGMKETFCMSSMKCYRSNAYTITTSSRMAKKNYVGISEIPS
MAKTITKDSIYDSFDREAKEKKLAWPINSNPPNTFV

(SEQ ID NO:1085)
>gi\|5453796\|ref\|NP_0061651\| neuropeptide Y receptor Y5 {Homosapiens}
MDLELDEYYNKTLATENNTAATRNSDFPVVVDDYKSSVDDLQYFLIGLYTFVSLLGFMGNLL
ILMALMKKRNQKTTVNFLIGNLAFSDILVVLFCSPFTLTSVLLDQWMFGKVMCHIMPFLQCV
SVLVSTLILISIAIVRYHMIKHPISNNLTANHGYFLIATVWTLGFAICSPLPVFHSLVELQETFGS
ALLSSRYLCVESWPSDSYRIAFTISLLLVQYILPLVCLTVSHTSVCRSISCGLSNKENRLEENEM
INLTLHPSKKSGPQVKLSGSHKWSYSFIKKHRRRYSKKTACVLPAPERPSQENHSRILPENFGS
VRSQLSSSSKFIPGVPTCFEIKPEENSDVHELRVKRSVTRIKKRSRSVFYRLTILILVFAVSWMP
LHLFHVVTDFNDNLISNRHFKLVYCICHLLGMMSCCLNPILYGFLNNGIKADLVSLIHCLHM

(SEQ ID NO:1086)
>gi\|5729798\|ref\|NP_0066301\| cysteinyl leukotriene receptor 1 {Homosapiens}
MDETGNLTVSSATCHDTIDDFRNQVYSTLYSMISVVGFFGNGFVLYVLIKTYHKKSAFQVYM
INLAVADLLCVCTLPLRVVYYVHKGIVVLFGDFLCRLSTYALYVNLYCSIFFMTAMSFFRCIAI
VFPVQNINLVTQKKARFVCVGIVVIFVILTSSPFLMAKPQKDEKNNTKCFEPPQDNQTKNHVL
VLHYVSLFVGFIIPFVIIIVCYTMIILTLLKKSMKKNLSSHKKAIGMIMVVTAAFLVSFMPYHIQ
RTIHLHFLHNETKPCDSVLRMQKSVVITLSLAASNCCFDPLLYFFSGGNFRKRLSTFRKHSLSS
VTYVPRKKASLPEKGEEICKV

(SEQ ID NO:1087)
>gi\|5730106\|ref\|NP_0065551\| C-X-C chemokine receptor type 6 {Homosapiens}
MAEHDYHEDYGFSSFNDSSQEEHQDFLQFSKVFLPCMYLVVFVCGLVGNSLVLVISIFYHKL
QSLTDVFLVNLPLADLVFVCTLPFWAYAGIHEWVFGQVMCKSLLGIYTINFYTSMLILTCITV
DRFIVVVKATKAYNQQAKRMTWGKVTSLLIVVVISLLVSLPQIIYGNVFNLDKLICGYHDEAIS
TVVLATQMTLGFFLPLLTMIVCYSVIIKTLLHAGGFQKHRSLKIIFLVMAVFLLTQMPFNLMK
FIRSTHWEYYAMTSFHYTIMVTEAIAYLRACLNPVLYAFVSLKFRKNFWKLVKDIGCLPYLG
VSHQWKSSEDNSKTFSASHNVEATSMFQL

(SEQ ID NO:1088)
>gi\|5803025\|ref\|NP_0067851\| probable G-protein coupled receptor 75
{Homosapiens}
MNSTGHLQDAPNATSLHVPHSQEGNSTSLQEGLQDLIHTATLVTCTFLLAVIFCLGSYGNFIV
FLSFFDPAFRKFRTNFDFMILNLSFCDLFICGVTAPMFTFVLFFSSASSIPDAFCFTFHLTSSGFII
MSLKTVAVIALHRLRMVLGKQPNRTASFPCTVLLTLLLWATSFTLATLATLKTSKSHLCLPM
SSLIAGKGKAILSLYVVDFTFCVAVVSVSYIMIAQTLRKNAQVRKCPPVITVDASRPQPFMGV
PVQGGGDPIQCAMPALYRNQNYNKLQHVQTRGYTKSPNQLVTPAASRLQLVSAINLSTAKD
SKAVVTCVIIVLSVLVCCLPLGISLVQVVLSSNGSFILYQFELFGFTLIFFKSGLNPFIYSRNSAG
LRRKVLWCLQYIGLGFFCCKQKTRLRAMGKGNLEVNRNKSSHHETNSAYMLSPKPQKKFV
DQACGPSHSKESMVSPKISAGHQHCGQSSSTPINTRIEPYYSIYNSSPSQEESSPCNLQPVNSFG
FANSYIAMHYHTTNDLVQEYDSTSAKQIPVPSV

(SEQ ID NO:1089)
>gi\|5921992\|ref\|NP_0006662\| adenosine receptor A2a {Homosapiens}
MPIMGSSVYITVELAIAVLAILGNVLVCWAVWLNSNLQNVTNYFVVSLAAADIAVGVLAIPF
AITISTGFCAACHGCLFIACFVLVLTQSSIFSLLAIAIDRYIAIRIPLRYNGLVTGTRAKGIIAICW
VLSFAIGLTPMLGWNNCGQPKEGKNHSQGCGEGQVACLFEDVVPMNYMVYFNFFACVLVP
LLLMLGVYLRIFLAARRQLKQMESQPLPGERARSTLQKEVHAAKSLAHVGLFALCWLPLHII
NCFTFFCPDCSHAPLWLMYLAIVLSHTNSVVNPFIYAYRIREFRQTFRKIIRSHVLRQQEPFKA
AGTSARVLAAHGSDGEQVSLRLNGHPPGVVVANGSAPHPERRPNGYALGLVSGGSAQESQG
NTGLPDVELLSHELKGVCPEPPGLDDPLAQDGAGVS

(SEQ ID NO:1090)
>gi\|6005705\|ref\|NP_0091951\| G-protein coupled receptor 182 {Homosapiens}
MSVKPSWGPGPSEGVTAVPTSDLGEIHNWTELLDLFNHTLSECHVELSQSTKRVVLFALYLA
MFVVGLVENLLVICVNWRGSGRAGLMNLYILNMAIADLGIVLSLPVWMLEVTLDYTWLWG
SFSCRFTHYFYFVNMYSSIFFLVCLSVDRYVTLTSASPSWQRYQHRVRRAMCAGIVVVLSAIIP
LPEVVHIQLVEGPEPMCLFMAPFETYSTWALAVALSTTILGFLLPFPLITVFNVLTACRLRQPG
QPKSRRHCLLLCAYVAVFVMCWLPYHVTLLLLTLHGTHISLHCHLVHLLYFFYDVIDCFSML
HCVINPILYNFLSPHFRGRLLNAVVHYLPKDQTKAGTCASSSSCSTQHSIIITKGDSQPAAAAP
HPEPSLSFQAHHLLPNTSPISPTQPLTPS

(SEQ ID NO:1091)
>gi\|6323236\|ref\|NP_0133081\| Hrd3p {Saccharomyces cereyisiae}
MITLLLYLCVICNAIVLIRADSIADPWPEARHLLNTIAKSRDPMKEAAMEPNADEFVGFYVPM
DYSPRNEEKNYQSIVVQNEITDSQRHIYELLVQSSEQFNNSEATYTLSQIHLWSQYNFPHNMTL
AHKYLEKFNDLTHFTNHSAIFDLAVMYATGGCASGNDQTVIPQDSAKALLYYQRAAQLGNL
KAKQVLAYKYYSGFNVPRNFHKSLVLYRDIAEQLRKSYSRDEWDIVFPYVVESYNVRISDFES
GLLGKGLNSVPSSTVRKRTTRPDIGSPFIAQVNGVQMTLQIEPMGRFAFNGNDGNINGDEDD
EDASERRIIRIYYAALNDYKGTYSQSRNCERAKNLLELTYKEFQPHVDNLDPLQVFYYVRCL
QLLGHMYFTGEGSSKPNIHMAEEILTTSLEISRRAQGPIGRACIDLGLINQYITNNISQAISYYM
KAMKTQANNGIVEFQLSKLATSFPEEKIGDPFNLMETAYLNGFIPAIYEFAVMIESGMNSKSS
VENTAYLFKTFVDKNEAIMAPKLRTAFAALINDRSEVALWAYSQLAEQGYETAQVSAAYLM
YQLPYEFEDPPRTTDQRKTLAISYYTRAFKQGNIDAGVVAGDIYFQMQNYSKAMALYQGAA
LKYSIQAIVVNLGYMHEHGLGVNRDFHLAKRYYDQVSEHDHRFYLASKLSVLKLHLKSWLT
WITREKVNYWKPSSPLNPNEDTQHSKTSWYKQLTKILQRMRHKEDSDKAAEDSHKHRTVV
QNGANHRGDDQEEASEILGFQMEDLVTMGCILGIFLLSILMSTLAARRGWNVRFNGAQLNA
NGNRQQEQQQQQQAQGPPGWDFNVQIFAI

(SEQ ID NO:1092)
>gi\|6912348\|ref\|NP_0362841\| lysophosphatidic acid receptor 3 {Homosapiens}
MNECHYDKHMDFFYNRSNTDTVDDWTGTKLVIVLCVGTFFCLFIFFSNSLVIAAVIKNRKFH
FPFYYLLANLAAADFFAGIAYVFLMFNTGPVSKTLTVNRWFLRQGLLDSSLTASLTNLLVIAV
ERHMSIMRMRVHSNLTKKRVTLLILLVWAIAIFMGAVPTLGWNCLCNISACSSLAPIYSRSYL
VFVVTVSNLMAFLIMVVVYLRIYVYVKRKTNVLSPHTSGSISRRRTPMKLMKTVMTVLGAFV
VCWTPGLVVLLLDGLNCRQCGVQHVKRWFLLLALLNSVVNPIIYSYKDEDMYGTMKKMIC
CFSQENPERRPSRIPSTVLSRSDTGSQYIEDSISQGAVCNKSTS

(SEQ ID NO:1093)
>gi\|6912464 \|ref\|NP_0364341\| latrophilin-2 precursor {Homosapiens}
MVSS GCRMRSLWFIIVISFLPNTEGFSRAALPFGLVRRELSCEGYSIDLRCPGSDVIMIESANYG
RTDDKICDADPFQMENTDCYLPDAFKIMTQRCNNRTQCIVVTGSDVFPDPCPGTYKYLEVQY
ECVPYIFVCPGTLKAIVDSPCIYEAEQKAGAWCKDPLQAADKIYFMPWTPYRTDTLIEYASLE
DFQNSRQTTTYKLPNRVDGTGFVVYDGAVFFNKERTRNIVKFDLRTRIKSGEAIINYANYHD
TSPYRWGGKTDIDLAVDENGLWVIYATEQNNGMIVISQLNPYTLRFEATWETVYDKRAASN
AFMICGVLYVVRSVYQDNESETGKNSIDYIYNTRLNRGEYVDVPFPNQYQYIAAVDYNPRD
NQLYVWNNNFILRYSLEFGPPDPAQVPTTAVTITSSAELFKTIISTTSTTSQKGPMSTTVAGSQ
EGSKGTKPPPAVSTTKIPPITNIFPLPERFCEALDSKGIKWPQTQRGMMVERPCPKGTRGTASY
LCMISTGTWNPKGPDLSNCTSHWVNQLAQKIRSGENAASLANELAKHTKGPVFAGDVSSSV
RLMEQLVDILDAQLQELKPSEKDSAGRSYNKAIVDTVDNLLRPEALESWKHMNSSEQAHTA
TMLLDTLEEGAFVLADNLLEPTRVSMPTENIVLEVAVLSTEGQIQDFKFPLGIKGAGSSIQLSA
NTVKQNSRNGLAKLVFIIYRSLGQFLSTENATIKLGADFIGRNSTIAVNSHVISVSINKESSRVY
LTDPVLFTLPHIDPDNYFNANCSFWNYSERTMMGYWSTQGCKLVDTNKTRTTCACSHLTNF
AILMAHREIAYKDGVHELLLTVITWVGIVISLVCLAICIFTFCFFRGLQSDRNTIHKNLCINLFIA
EFIFLIGIDKTKYAIACPIFAGLLHFFFLAAFAWMCLEGVQLYLMLVEVFESEYSRKKYYYVA
GYLFPATVVGVSAAIDYKSYGTEKACWLHVDNYFIVVSFIGPVTFIILLNIIFLVITLCKMVKHS
NTLKPDSSRLENIKSWVLGAFALLCLLGLTWSFGLLFINEETIVMAYLFTIFNAFQGVFIFIFHC
ALQKKVRKEYGKCFRHSYCCGGLPTESPHSSVKASTTRTSARYSSGTQSRIRRMWNDTVRK
QSESSFISGDINSTSTLNQGHSLNNARDTSAMDTLPLNGNFNNSYSLHKGDYNDSVQVVDCG
LSLNDTAFEKMIISELVHNNLRGSSKTHNLELTLPVKPVIGGSSSEDDAIVADASSLMHSDNPG
LELHHKELEAPLIPQRTHSLLYQPQKKVKSEGTDSYVSQLTAEAEDHLQSPNRDSLYTSMPNL
RDSPYPESSPDMEEDLSPSRRSENEDIYYKSMPNLGAGHQLQMCYQISRGNSDGYIIPINKEGC
IPEGDVREGQMQLVTSL

(SEQ ID NO:1094)
>gi\|6912538\|ref\|NP_0364761\| neurotensin receptor type 2 {Homosapiens}
METSSPRPPRPSSNPGLSLDARLGVDTRLWAKVLFTALYALIWALGAAGNALSVHVVLKAR
AGRAGRLRHHVLSLALAGLLLLLVGVPVELYSFVWFHYPWVFGDLGCRGYYFVHELCAYA
TVLSVAGLSAERCLAVCQPLRARSLLTPRRTRWLVALSWAASLGLALPMAVIMGQKHELET
ADGEPEPASRVCTVLVSRTALQVFIQVNVLVSFVLPLALTAFLNGVTVSHLLALCSQVPSTST
PGSSTPSRLELLSEEGLLSFIVVVKKTFIQGGQVSLVRHKDVRRIRSLQRSVQVLRAIVVMYVIC
WLPYHARRLMYCYVPDDAWTDPLYNFYHYFYMVTNTLFYVSSAVTPLLYNAVSSSFRKLFL
EAVSSLCGEHHPMKRLPPKPQSPTLMDTASGFGDPPETRT

(SEQ ID NO:1095)
>gi\|7019387\|ref\|NP_0374771\| probable G-protein coupled receptor 132
{Homosapiens}
MCPMLLKNGYNGNATPVTTTAPWASLGLSAKTCNNVSFEESRIVLVVVYSAVCTLGVPANC
LTAWLALLQVLQGNVLAVYLLCLALCELLYTGTLPLWVIYIRNQHRWTLGLLACKVTAYIFF
CNIYVSILFLCCISCDRFVAVVYALESRGRRRRRTAILISACIFILVGIVHYPVFQTEDKETCFD
MLQMDSRIAGYYYARFTVGFAIPLSIIAFTNHRIFRSIKQSMGLSAAQKAKVKHSAIAVVVIFL
VCFAPYHLVLLVKAAAFSYYRGDRNAMCGLEERLYTASVVFLCLSTVNGVADPIIYVLATD
HSRQEVSRIHKGWKEWSMKTDVTRLTHSRDTEELQSPVALADHYTFSRPVHPPGSPCPAKRL
IEESC

(SEQ ID NO:1096)
>gi\|7108336\|ref\|NP_0362571\| cholinergic receptor, muscarinic 5 {Homosapiens}
MEGDSYHNATTVNGTPVNHQPLERHRLWEVITIAAVTAVVSLITIVGNVLVMISFKVNSQLK
TVNNYYLLSLACADLIIGIFSMNLYTTYILMGRWALGSLACDLWLALDYVASNASVMNLLVI
SFDRYFSITRPLTYRAKRTPKRAGIMIGLAWLISFILWAPAILCWQYLVGKRTVPLDECQIQFL
SEPTITFGTAIAAFYIPVSVMTILYCRIYRETEKRTKDLADLQGSDSVTKAEKRKPAHRALFRS
CLRCPRPTLAQRERNQASWSSSRRSTSTTGKPSQATGPSANVVAKAEQLTTCSSYPSSEDEDKP
ATDPVLQVVYKSQGKESPGEEFSAEETEETFVKAETEKSDYDTPNYLLSPAAAHRPKSQKCV
AYKFRLVVKADGNQETNNGCHKVKIMPCPFPVAKEPSTKGLNPNPSHQMTKRKRVVLVKE
RKAAQTLSAILLAFIITWTPYNIMVLVSTFCDKCVPVTLWHLGYVVLCYVNSTVNPICYALCN
RTFRKTFKMLLLCRWKKKKVEEKLYWQGNSKLP

(SEQ ID NO:1097)
>gi\|7305013\|ref\|NP_0047112\| lysophosphatidic acid receptor 2 {Homosapiens}
MVIMGQCYYNETIGFFYNNSGKELSSHWRPKDVVVVALGLTVSVLVLLTNLLVIAAIASNRR
FHQPIYYLLGNLAAADLFAGVAYLFLMFHTGPRTARLSLEGWFLRQGLLDTSLTASVATLLA
IAVERHRSVMAVQLHSRLPRGRVVMLIVGVWVAALGLGLLPAHSWHCLCALDRCSRMAPL
LSRSYLAVWALSSLLVFLLMVAVYTRIFFYVRRRVQRMAEHVSCHPRYRETTLSLVKTVVIIL
GAFVVCWTPGQVVLLLDGLGCESCNVLAVEKYFLLLAEANSLVNAAVYSCRDAEMRRTFR
RLLCCACLRQSTRESVHYTSSAQGGASTRIMLPENGHPLMDSTL

(SEQ ID NO:1098)
>gi\|7657136\|ref\|NP_0551881\| probable G-protein coupled receptor 160
{Homosapiens}
MTALSSENCSFQYQLRQTNQPLDVNYLLFLIILGKILLNILTLGMRRKNTCQNFMEYFCISLAF
VDLLLLVNISIILYFRDFVLLSIRFTKYHICLFTQIISFTYGFLHYPVFLTACIDYCLNFSKTTKLS
FKCQKLFYFFTVILIVVISVLAYVLGDPAIYQSLKAQNAYSRHCPFYVSIQSYVVLSFFMVMILFV
AFITCWEEVTTLVQAIRITSYMNETILYFPFSSHSSYTVRSKKIFLSKLIVCFLSTWLPFVLLQVI
IVLLKVQIPAYIEMNIPWLYFVNSFLIATVYWFNCHKLNLKDIGLPLDPFVNWKCCFIPLTIPN
LEQIEKPISIMIC

(SEQ ID NO:1099)
>gi\|7669548\|ref\|NP_0010501\| tachykinin receptor 3 {Homosapiens}
MATLPAAETWIDGGGGVGADAVNLTASLAAGAATGAVETGWLQLLDQAGNLSSSPSALGL
PVASPAPSQPWANLTNQFVQPSWRIALWSLAYGVVVAVAVLGNLIVIWIILAHKRMRTVTN
YFLVNLAFSDASMAAFNTLVNFIYALHSEWYFGANYCRFQNFFPITAVFASIYSMTAIAVDRY
MAIIDPLKPRLSATATKIVIGSIVVILAFLLAFPQCLYSKTKVMPGRTLCFVQWPEGPKQHFTYH
IIVIILVYCFPLLIMGITYTIVGITLWGGEIPGDTCDKYHEQLKAKRKVVKMMIIVVMTFAICW
LPYHIYFILTAIYQQLNRWKYIQQVYLASFWLAMSSTMYNPIIYCCLNKRFRAGFKRAFRWC
PFIKVSSYDELELKTTRFHPNRQSSMYTVTRMESMTVVFDPNDADTTRSSRKKRATPRDPSFN
GCSRRNSKSASATSSFISSPYTSVDEYS

(SEQ ID NO:1100)
>gi\|7706103\|ref\|NP_0576521\| relaxin/insulin-like family peptide receptor 3
{Homosapiens}
MQMADAATIATMNKAAGGDKLAELFSLVPDLLEAANTSGNASLQLPDLWWELGLELPDGA
PPGHPPGSGGAESADTEARVRILISVVYWVVCALGLAGNLLVLYLMKSMQGWRKSSINLFV
TNLALTDFQFVLTLPFVVAVENALDFKWPFGKAMCKIVSMVTSMNMYASVFFLTAMSVTRY
HSVASALKSHRTRGHGRGDCCGRSLGDSCCFSAKALCVWIVVALAALASLPSAIFSTTVKVM
GEELCLVRFPDKLLGRDRQFVVLGLYHSQKVLLGFVLPLGIIILCYLLLVRFIADRRAAGTKGG
AAVAGGRPTGASARRLSKVTKSVTIVVLSFFLCWLPNQALTTWSILIKFNAVPFSQEYFLCQV
YAFPVSVCLAHSNSCLNPVLYCLVRREFRKALKS LLWRIASPSITSMRPFTATTKPEHEDQGL
QAPAPPHAAAEPDLLYYPPGVVVYSGGRYDLLPSSSAY

(SEQ ID NO:1101)
>gi\|7706451\|ref\|NP_0573191\| G-protein coupled receptor family C group 5
member B precursor {Homosapiens}
MFVASERKMRAHQVLTFLLLFVITSVASENASTSRGCGLDLLPQYVSLCDLDAIWGIVVEAV
AGAGALITLLLMLILLVRLPFIKEKEKKSPVGLHFLFLLGTLGLFGLTFAFIIQEDETICSVRRFL
WGVLFALCFSCLLSQAWRVRRLVRHGTGPAGWQLVGLALCLMLVQVIIAVEWLVLTVLRD
TRPACAYEPMDFVMALIYDMVLLVVTLGLALFTLCGKFKRWKLNGAFLLITAFLSVLIVVVA
WMTMYLFGNVKLQQGDAWNDPTLAITLAASGWVFVIFHAIPEIHCTLLPALQENTPNYFDTS
QPRMRETAFEEDVQLPRAYMENKAFSMDEHNAALRTAGFPNGSLGKRPSGSLGKRPSAPFR
SNVYQPTEMAVVLNGGTIPTAPPSHTGRHLW

(SEQ ID NO:1102)
>gi\|8923705\|ref\|NP_0611241\| G-protein coupled receptor family C group 5
member D {Homosapiens}
MYKDCIESTGDYFLLCDAEGPWGIILESLAILGIVVTILLLLAFLFLMRKIQDCSQWNVLPTQL
LFLLSVLGLFGLAFAFIIELNQQTAPVRYFLFGVLFALCFSCLLAHASNLVKLVRGCVSFSWTT
ILCIAIGCSLLQIIIATEYVTLIMTRGMMFVNMTPCQLNVDFVVLLVYVLFLMALTFFVSKATF
CGPCENWKQHGRLIFITVLFSIIIVVVVWISMLLRGNPQFQRQPQWDDPVVCIALVTNAWVFLL
LYIVPELCILYRSCRQECPLQGNACPVTAYQHSFQVENQELSRARDSDGAEEDVALTSYGTPI
QPQTVDPTQECFIPQAKLSPQQDAGGV

(SEQ ID NO:1103)
>gi\|8923873\|ref\|NP_0609551\| G protein-coupled receptor 77 {Homosapiens}
MGNDSVSYEYGDYSDLSDRPVDCLDGACLAIDPLRVAPLPLYAAIFLVGVPGNAMVAWVA
GKVARRRVGATWLLHLAVADLLCCLSLPILAVPIARGGHWPYGAVGCRALPSIILLTMYASV
LLLAALSADLCFLALGPAWWSTVQRACGVQVACGAAWTLALLLTVPSAIYRRLHQEHFPAR
LQCVVDYGGSSSTENAVTAIRFLFGFLGPLVAVASCHSALLCWAARRCRPLGTAIVVGFFVC
WAPYHLLGLVLTVAAPNSALLARALRAEPLIVGLALAHSCLNPMLFLYFGRAQLRRSLPAAC
HWALRESQGQDESVDSKKSTSHDLVSEMEV

(SEQ ID NO:1104)
>gi\|9506745\|ref\|NP_0618221\| urotensin 2 receptor {Homosapiens}
MALTPESPSSFPGLAATGSSVPEPPGGPNATLNSSWASPTEPSSLEDLVATGTIGTLLSAMGVV
GVVGNAYTLVVTCRSLRAVASMYVYVVNLALADLLYLLSIPFIVATYVTKEWHFGDVGCRV
LFGLDFLTMHASIFTLTVMSSERYAAVLRPLDTVQRPKGYRKLLALGTWLLALLLTLPVMLA
MRLVRRGPKSLCLPAWGPRAHRAYLTLLFATSIAGPGLLIGLLYARLARAYRRSQRASFKRA
RRPGARALRLVLGIVLLFVVACFLPFWLWQLLAQYHQAPLAPRTARIVNYLTTCLTYGNSCA
NPFLYTLLTRNYRDHLRGRVRGPGSGGGRGPVPSLQPRARFQRCSGRSLSSCSPQPTDSLVLA
PAAPARPAPEGPRAPA

(SEQ ID NO:1105)
>gi\|9506747\|ref\|NP_0618441\| G protein-coupled receptor 27 {Homosapiens}
MANASEPGGSGGGEAAALGLKLATLSLLLCVSLAGNVLFALLIVRERSLHRAPYYLLLDLCL
ADGLRALACLPAVMLAARRAAAAAGAPPGALGCKLLAFLAALFCFHAAFLLLGVGVTRYL
AIAHHRFYAERLAGWPCAAMLVCAAWALALAAAFPPVLDGGGDDEDAPCALEQRPDGAPG
ALGFLLLLAVVVGATHLVYLRLLFFIHDRRKMRPARLVPAVSHDWTFHGPGATGQAAANVV
TAGFGRGPTPPALVGIRPAGPGRGARRLLVLEEFKTEKRLCKMFYAVTLLFLLLWGPYVVAS
YLRVLVRPGAVPQAYLTASVWLTFAQAGINPVVCFLFNRELRDCFRAQFPCCQSPRTTQATH
PCDLKGIGL

(SEQ ID NO:1106)
>gi\|9507143\|ref\|NP_0618421\| probable G-protein coupled receptor 173
{Homosapiens}
MANTTGEPEEVSGALSPPSASAYVKLVLLGLIMCVSLAGNAILSLLVLKERALHKAPYYFLL
DLCLADGIRSAVCFPFVLASVRHGSSWTFSALSCKIVAFMAVLFCFHAAFMLFCISVTRYMAI
AHHRFYAKRMTLWTCAAVICMAWTLSVAMAFPPVFDVGTYKFIREEDQCIFEHRYFKANDT
LGFMLMLAVLMAATHAVYGKLLLFEYRHRKMKPVQMVPAISQNWTFHGPGATGQAAAN
WIAGFGRGPMPPTLLGIRQNGHAASRRLLGMDEVKGEKQLGRMFYAITLLFLLLWSPYIVAC
YWRVFVKACAVPHRYLATAVWMSFAQAAVNPIVCFLLNKDLKKCLRTHAPCWGTGGAPA
PREPYCVM

(SEQ ID NO:1107)
>gi\|9627743\|ref\|NP_0540301\| protein tyrosine phosphatase {Autographa
californicanucleopolyhedrovirus }
MFPARWHNYLQCGQVIKDSNLICFKTPLRPELFAYVTSEEDVWTAEQIVKQNPSIGAIIDLTN
TSKYYDGVHFLRAGLLYKKIQVPGQTLPPESIVQEFIDTVKEFTEKCPGMLVGVHCTHGINRT
GYMVCRYLMHTLGIAPQEAIDRFEKARGHKIERQNYVQDLLI

(SEQ ID NO:1108)
>gi\|9951913\|ref\|NP_0628321\| probable G-protein coupled receptor 162 isoform 2
{Homosapiens}
MARGGAGAEEASLRSNALSWLACGLLALLANAWIILSISAKQQKHKPLELLLCFLAGTHILM
AAVPLTTFAVVQLRRQASSDYDWNESICKVFVSTYYTLALATCFTVASLSYHRMWMVRWP
VNYRLSNAKKQALHAVMGIVVMVSFILSTLPSIGWHNNGERYYARGCQFIVSKIGLGFGVCFS
LLLLGGIVMGLVCVAITFYQTLWARPRRARQARRVGGGGGTKAGGPGALGTRPAFEVPAIV
VEDARGKRRS SLDGSESAKTSLQVTNLVSAIVFLYDSLTGVPILVVSFFSLKSDSAPPWMVLA
VLWCSMAQTLLLPSFIVVSCERYRADVRTVWEQCVAIMSEEDGDDDGGCDDYAEGRVCKVR
FDANGATGPGSRDPAQVKLLPGRHMLFPPLERVHYLQVPLSRRLSHDETNIFSTPREPGSFLH
KWSSSDDIRVLPAQSRALGGPPEYLGQRHRLEDEEDEEEAEGGGLASLRQFLESGVLGSGGG
PPRGPGFFREEITTFIDETPLPSPTASPGHS PRRPRPLGLSPRRLSLGSPESRAVGLPLGLSAGRR
CSLTGGEESARAWGGSWGPGNPIFPQLTL

(SEQ ID NO:1109)
>gi\|9966839\|ref\|NP_0651031\| G protein-coupled receptor 84 {Homosapiens}
MWNSSDANFSCYHESVLGYRYVAVSWGVVVAVTGTVGNVLTLLALAIQPKLRTRFNLLIAN
LTLADLLYCTLLQPFSVDTYLHLHWRTGATFCRVFGLLLFASNSVSILTLCLIALGRYLLIAHP
KLFPQVFSAKGIVLALVSTWVVGVASFAPLWPIYILVPVVCTCSFDRIRGRPYTTILMGIYFVL
GLSSVGIFYCLIHRQVKRAAQALDQYKLRQASIHSNHVARTDEAMPGRFQELDSRLASGGPS
EGISSEPVSAATTQTLEGDSSEVGDQINSKRAKQMAEKSPPEASAKAQPIKGARRAPDSSSEF
GKVTRMCFAVFLCFALSYIPFLLLNILDARVQAPRVVHMLAANLTWLNGCINPVLYAAMNR
QFRQAYGSILKRGPRSFHRLH

(SEQ ID NO:1110)
>gi\|9966851\|ref\|NP_0651101\| cysteinyl leukotriene receptor 2 {Homosapiens}
MERKFMSLQPSISVSEMEPNGTFSNNNSRNCTIENFKREFFPIVYLIIFFWGVLGNGLSIYVFLQ
PYKKSTSVNVFMLNLAISDLLFISTLPFRADYYLRGSNWIFGDLACRIMSYSLYVNMYSSIYFL
TVLSVVRFLAMVHPFRLLHVTSIRSAWILCGIIVVILIMASSIMLLDSGSEQNGSVTSCLELNLY
KIAKLQTMNYIALVVGCLLPFFTLSICYLLIIRVLLKVEVPESGLRVSHRKALTTIIITLIIFFLCF
LPYHTLRTVHLTTWKVGLCKDRLHKALVITLALAAANACFNPLLYYFAGENFKDRLKSALR
KGHPQKAKTKCVFPVSVWLRKETRV

(SEQ ID NO:1111)
>gi\|9966879\|ref\|NP_0651331\| lysophosphatidic acid receptor 5 {Homosapiens}
MLANSSSTNSSVLPCPDYRPTHRLHLVVYSLVLAAGLPLNALALWVFLRALRVHSVVSVYM
CNLAASDLLFTLSLPVRLSYYALHHWPFPDLLCQTTGAIFQMNMYGSCIFLMLINVDRYAAI
VHPLRLRHLRRPRVARLLCLGVWALILVFAVPAARVHRPSRCRYRDLEVRLCFESFSDELWK
GRLLPLVLLAEALGFLLPLAAVVYSSGRVFWTLARPDATQSQRRRKTVRLLLANLVIFLLCF
VPYNSTLAVYGLLRSKLVAASVPARDRVRGVLMVMVLLAGANCVLDPLVYYFSAEGFRNT
LRGLGTPHRARTSATNGTRAALAQSERSAVTTDATRPDAASQGLLRPSDSHSLSSFTQCPQDS
AL

(SEQ ID NO:1112)
>gi\|10092633\|ref\|NP_0553141\| putative P2Y purinoceptor 10 {Homosapiens}
MANLDKYTETFKMGSNSTSTAEIYCNVTNVKFQYSLYATTYILIFIPGLLANSAALWVLCRFI
SKKNKAIIFMINLSVADLAHVLSLPLRIYYYISHHWPFQRALCLLCFYLKYLNMYASICFLTCI
SLQRCFFLLKPFRARDWKRRYDVGISAAIWIVVGTACLPFPILRSTDLNNNKSCFADLGYKQ
MNAVALVGMITVAELAGFVIPVIIIAWCTWKTTISLRQPPMAFQGISERQKALRMVFMCAAV
FFICFTPYHINFIFYTMVKETIISSCPVVRIALYFHPFCLCLASLCCLLDPILYYFMASEFRDQLS
RHGSSVTRSRLMSKESGSSMIG

(SEQ ID NO:1113)
>gi\|10835015\|ref\|NP_0014611\| gamma-aminobutyric acid (GABA) B receptor 1
isoform a precursor {Homosapiens}
MLLLLLLAPLFLRPPGAGGAQTPNATSEGCQIIHPPWEGGIRYRGLTRDQVKAINFLPVDYEIE
YVCRGEREVVGPKVRKCLANGSWTDMDTPSRCVRICSKSYLTLENGKVFLTGGDLPALDGA
RVDFRCDPDFHLVGSSRSICSQGQWSTPKPHCQVNRTPHSERRAVYIGALFPMSGGWPGGQA
CQPAVEMALEDVNSRRDILPDYELKLIHHDSKCDPGQATKYLYELLYNDPIKIILMPGCSSVS
TLVAEAARMWNLIVLSYGSSSPALSNRQRFPTFFRTHPSATLHNPTRVKLFEKWGWKKIATI
QQTTEVFTSTLDDLEERVKEAGIEITFRQSFFSDPAVPVKNLKRQDARIIVGLFYETEARKVFC
EVYKERLFGKKYVWFLIGWYADNWFKIYDPSINCTVDEMTEAVEGHITTEIVMLNPANTRSI
SNMTSQEFVEKLTKRLKRHPEETGGFQEAPLAYDAIWALALALNKTSGGGGRSGVRLEDFN
YNNQTITDQIYRAMNSSSFEGVSGHVVFDASGSRMAWTLIEQLQGGSYKKIGYYDSTKDDLS
WSKTDKWIGGSPPADQTLVIKTFRFLSQKLFISVSVLSSLGIVLAVVCLSFNIYNSHVRYIQNS
QPNLNNLTAVGCSLALAAVFPLGLDGYHIGRNQFPFVCQARLWLLGLGFSLGYGSMFTKIVV
WVHTVFTKKEEKKEWRKTLEPWKLYATVGLLVGMDVLTLAIWQIVDPLHRTIETFAKEEPK
EDIDVSILPQLEHCSSRKMNTWLGIFYGYKGLLLLLGIFLAYETKSVSTEKINDHRAVGMAIY
NVAVLCLITAPVTMILSSQQDAAFAFASLAIVFSSYITLVVLFVPKMRRLITRGEWQSEAQDT
MKTGSSTNNNEEEKSRLLEKENRELEKIIAEKEERVSELRHQLQSRQQLRSRRHPPTPPEPSGG
LPRGPPEPPDRLSCDGSRVHLLYK

(SEQ ID NO:1114)
>gi\|10835175\|ref\|NP_0006121\| 5-hydroxytryptamine receptor 2A isoform 1
{Homosapiens}
MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLS
PSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGF
LVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNS
RTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITY
FLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQ
KACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTL
FNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCS
MVALGKQHSEEASKDNSDGVNEKVSCV

(SEQ ID NO:1115)
>gi\|10835197 \|ref\|NP_0008571\| 5-hydroxytryptamine receptor 1F {Homosapiens}
MDFLNSSDQNLTSEELLNRMPSKILVSLTLSGLALMTTTINSLVIAAIIVTRKLHHPANYLICSL
AVTDFLVAVLVMPFSIVYIVRESWIMGQVVCDIWLSVDITCCTCSILHLSAIALDRYRAITDAV
EYARKRTPKHAGIMITIVWIISVFISMPPLFVVRHQGTSRDDECIIKHDHIVSTIYSTFGAFYIPLA
LILILYYKIYRAAKTLYHKRQASRIAKEEVNGQVLLESGEKSTKSVSTSYVLEKSLSDPS TDFD
KIHSTVRSLRSEFKHEKSWRRQKISGTRERKAATTLGLILGAFVICWLPFFVKELVVNVCDKC
KISEEMSNFLAWLGYLNSLINPLIYTIFNEDFKKAFQKLVRCRC

(SEQ ID NO:1116)
>gi\|11321563\|ref\|NP_0008611\| 5-hydroxytryptamine receptor 4 isoform b
{Homosapiens}
MDKLDANVSSEEGFGSVEKVVLLTFLSTVILMAILGNLLVMVAVCWDRQLRKIKTNYFIVSL
AFADLLVSVLVMPFGAIELVQDIVVIYGEVFCLVRTSLDVLLTTASIFHLCCISLDRYYAICCQP
LVYRNKMTPLRIALMLGGCWVIPTFISFLPIMQGWNNIGIIDLIEKRKFNQNSNSTYCVFMVN
KPYAITCSVVAFYIPFLLMVLAYYRIYVTAKEHAHQIQMLQRAGASSESRPQSADQHSTHRM
RTETKAAKTLCIIMGCFCLCWAPFFVTNIVDPFIDYTVPGQVWTAFLWLGYINSGLNPFLYAF
LNKSFRRAFLIILCCDDERYRRPSILGQTVPCSTTTINGSTHVLRDAVECGGQWESQCHPPATS
PLVAAQPSDT

(SEQ ID NO:1117)
>gi\|11545887 \|ref\|NP_0714291\| neuropeptide FF receptor 1 {Homosapiens}
MEGEPSQPPNSSWPLSQNGTNTEATPATNLTFSSYYQHTSPVAAMFIVAYALIFLLCMVGNTL
VCFIVLKNRHMHTVTNMFILNLAVSDLLVGIFCMPTTLVDNLITGWPFDNATCKMSGLVQG
MSVSASVFTLVAIAVERFRCIVHPFREKLTLRKALVTIAVIVVALALLIMCPSAVTLTVTREEHH
FMVDARNRSYPLYSCWEAWPEKGMRRVYTTVLFSHIYLAPLALIVVMYARIARKLCQAPGP
APGGEEAADPRASRRRARVVHMLVMVALFFTLSWLPLWALLLLIDYGQLSAPQLHLVTVYA
FPFAHWLAFFNSSANPIIYGYFNENFRRGFQAAFRARLCPRPSGSHKEAYSERPGGLLHRRVF
VVVRPSDSGLPSESGPSSGAPRPGRLPLRNGRVAHHGLPREGPGCSHLPLTIPAWDI

(SEQ ID NO:1118)
>gi\|12232483\|ref\|NP_0736251\| P2Y purinoceptor 12 {Homosapiens}
MQAVDNLTSAPGNTSLCTRDYKITQVLFPLLYTVLFFVGLITNGLAMRIFFQIRSKSNFIIFLKN
TVISDLLMILTFPFKILSDAKLGTGPLRTFVCQVTSVIFYFTMYISISFLGLITIDRYQKTTRPFKT
SNPKNLLGAKILSVVIVVAFMFLLSLPNMILTNRQPRDKNVKKCSFLKSEFGLVWHEIVNYICQ
VIFVVINFLIVIVCYTLITKELYRSYVRTRGVGKVPRKKVNVKVFIIIAVFFICFVPFHFARIPYTL
SQTRDVFDCTAENTLFYVKESTLWLTSLNACLDPFIYFFLCKSFRNSLISMLKCPNSATSLSQD
NRKKEQDGGDPNEETPM

(SEQ ID NO:1119)
>gi\|13027636\|ref\|NP_0013912\| sphingosine 1-phosphate receptor 1 {Homosapiens}
MGPTSVPLVKAHRSSVSDYVNYDIIVRHYNYTGKLNISADKENSIKLTSVVFILICCFIILENIF
VLLTIVVKTKKFHRPMYYFIGNLALSDLLAGVAYTANLLLSGATTYKLTPAQWFLREGSMFV
ALSASVFSLLAIAIERYITMLKMKLHNGSNNFRLFLLISACWVISLILGGLPIMGWNCISALSSC
STVLPLYHKHYILFCTTVFTLLLLSIVILYCRIYSLVRTRSRRLTFRKNISKASRSSEKSLALLKT
VIIVLSVFIACWAPLFILLLLDVGCKVKTCDILFRAEYFLVLAVLNSGTNPIIYTLTNKEMRRAF
IRIMSCCKCPSGDSAGKFKRPIIAGMEFSRSKSDNSSHPQKDEGDNPETIMSSGNVNSSS

(SEQ ID NO:1120)
>gi\|13236497\|ref\|NP_0769171\| 5-hydroxytryptamine receptor 5A {Homosapiens }
MDLPVNLTSFSLSTPSPLETNHSLGKDDLRPSSPLLSVFGVLILTLLGFLVAATFAWNLLVLAT
ILRVRTFHRVPHNLVASMAVSDVLVAALVMPLSLVHELSGRRWQLGRRLCQLWIACDVLCC
TASIVVNVTAIALDRYWSITRHMEYTLRTRKCVSNVMIALTWALSAVISLAPLLFGWGETYSE
GSEECQVSREPSYAVFSTVGAFYLPLCVVLFVYVVKIYKAAKFRVGSRKTNSVSPISEAVEVK
DSAKQPQMVFTVRHATVTFQPEGDTWREQKEQRAALMVGILIGVFVLCWIPFFLTELISPLCS
CDIPAIWKSIFLWLGYSNSFFNPLIYTAFNKNYNSAFKNFFSRQH

(SEQ ID NO:1121)
>gi\|13325064\|ref\|NP_0013991\| cadherin EGF LAG seven-pass G-type receptor 2
precursor {Homosapiens }
MRSPATGVPLPTPPPPLLLLLLLLLPPPLLGDQVGPCRSLGSRGRGSSGACAPMGWLCPSSAS
NLWLYTSRCRDAGTELTGHLVPHHDGLRVWCPESEAHIPLPPAPEGCPWSCRLLGIGGHLSP
QGKLTLPEEHPCLKAPRLRCQSCKLAQAPGLRAGERSPEESLGGRRKRNVNTAPQFQPPSYQ
ATVPENQPAGTPVASLRAIDPDEGEAGRLEYTMDALFDSRSNQFFSLDPVTGAVTTAEELDR
ETKSTHVFRVTAQDHGMPRRSALATLTILVTDTNDHDPVFEQQEYKESLRENLEVGYEVLTV
RATDGDAPPNANILYRLLEGSGGSPSEVFEIDPRSGVIRTRGPVDREEVESYQLTVEASDQGR
DPGPRSTTAAVFLSVEDDNDNAPQFSEKRYVVQVREDVTPGAPVLRVTASDRDKGSNAVVH
YSIMSGNARGQFYLDAQTGALDVVSPLDYETTKEYTLRVRAQDGGRPPLSNVSGLVTVQVL
DINDNAPIFVSTPFQATVLESVPLGYLVLHVQAIDADAGDNARLEYRLAGVGHDFPFTINNGT
GWISVAAELDREEVDFYSFGVEARDHGTPALTASASVSVTVLDVNDNNPTFTQPEYTVRLNE
DAAVGTSVVTVSAVDRDAHSVITYQITSGNTRNRFSITSQSGGGLVSLALPLDYKLERQYVL
AVTASDGTRQDTAQIVVNVTDANTHRPVFQSSHYTVNVNEDRPAGTTVVLISATDEDTGEN
ARITYFMEDSIPQFRIDADTGAVTTQAELDYEDQVSYTLAITARDNGIPQKSDTTYLEILVNDV
NDNAPQFLRDSYQGSVYEDVPPFTSVLQISATDRDSGLNGRVFYTFQGGDDGDGDFIVESTS
GIVRTLRRLDRENVAQYVLRAYAVDKGMPPARTPMEVTVTVLDVNDNPPVFEQDEFDVFVE
ENSPIGLAVARVTATDPDEGTNAQIMYQIVEGNIPEVFQLDIFSGELTALVDLDYEDRPEYVL
VIQATSAPLVSRATVHVRLLDRNDNPPVLGNFEILFNNYVTNRSSSFPGGAIGRVPAHDPDISD
SLTYSFERGNELSLVLLNASTGELKLSRALDNNRPLEAIMSVLVSDGVHSVTAQCALRVTIIT
DEMLTHSITLRLEDMSPERFLSPLLGLFIQAVAATLATPPDHVVVFNVQRDTDAPGGHILNVS
LSVGQPPGPGGGPPFLPSEDLQERLYLNRSLLTAISAQRVLPFDDNICLREPCENYMRCVSVLR
FDSSAPFIASSSVLFRPIHPVGGLRCRCPPGFTGDYCETEVDLCYSRPCGPHGRCRSREGGYTC
LCRDGYTGEHCEVSARSGRCTPGVCKNGGTCVNLLVGGFKCDCPSGDFEKPYCQVTTRSFP
AHSFITFRGLRQRFHFTLALSFATKERDGLLLYNGRFNEKHDFVALEVIQEQVQLTFSAGEST
TTVSPFVPGGVSDGQWHTVQLKYYNKPLLGQTGLPQGPSEQKVAVVTVDGCDTGVALRFG
SVLGNYSCAAQGTQGGSKKSLDLTGPLLLGGVPDLPESFPVRMRQFVGCMRNLQVDSRHID
MADFIANNGTVPGCPAKKNVCDSNTCHNGGTCVNQWDAFSCECPLGFGGKSCAQEMANPQ
HFLGSSLVAWHGLSLPISQPWYLSLMFRTRQADGVLLQAITRGRSTITLQLREGHVMLSVEG
TGLQASSLRLEPGRANDGDWHHAQLALGASGGPGHAILSFDYGQQRAEGNLGPRLHGLHLS
NITVGGIPGPAGGVARGFRGCLQGVRVSDTPEGVNSLDPSHGESINVEQGCSLPDPCDSNPCP
ANSYCSNDWDSYSCSCDPGYYGDNCTNVCDLNPCEHQSVCTRKPSAPHGYTCECPPNYLGP
YCETRIDQPCPRGWWGHPTCGPCNCDVSKGFDPDCNKTSGECHCKENHYRPPGSPTCLLCD
CYPTGSLSRVCDPEDGQCPCKPGVIGRQCDRCDNPFAEVTTNGCEVNYDSCPRAIEAGIVVWP
RTRFGLPAAAPCPKGSFGTAVRHCDEHRGWLPPNLFNCTSITFSELKGFAERLQRNESGLDSG
RSQQLALLLRNATQHTAGYFGSDVKVAYQLATRLLAHESTQRGFGLSATQDVHFTENLLRV
GSALLDTANKRHWELIQQTEGGTAWLLQHYEAYASALAQNMRHTYLSPFTIVTPNIVISVVR
LDKGNFAGAKLPRYEALRGEQPPDLETTVILPESVFRETPPVVRPAGPGEAQEPEELARRQRR
HPELSQGEAVASVIIYRTLAGLLPHNYDPDKRSLRVPKRPIINTPVVSISVHDDEELLPRALDK
PVTVQFRLLETEERTKPICVFVVNHSILVSGTGGWSARGCEVVFRNESHVSCQCNHMTSFAVL
MDVSRRENGEILPLKTLTYVALGVTLAALLLTFFFLTLLRILRSNQHGIRRNLTAALGLAQLV
FLLGINQADLPFACTVIAILLHFLYLCTFSWALLEALHLYRALTEVRDVNTGPMRFYYMLGW
GVPAFITGLAVGLDPEGYGNPDFCWLSIYDTLIVVSFAGPVAFAVSMSVFLYILAARASCAAQ
RQGFEKKGPVSGLQPSFAVLLLLSATWLLALLSVNSDTLLFHYLFATCNCIQGPFIFLSYVVLS
KEVRKALKLACSRKPSPDPALTTKSTLTSSYNCPSPYADGRLYQPYGDSAGSLHSSRSGKSQ
PSYIPFLLREESALNPGQGPPGLGDPGSLFLEGQDQQHDPDTDSDSDLSLEDDQSGSYASTHSS
DSEEEEEEEEEEAAFPGEQGWDSLLGPGAERLPLHSTPKDGGPGPGKAPWPGDFGTTAKESS
GNGAPEERLRENGDALSREGSLGPLPGSSAQPHKGILKKKCLPTISEKSSLLRLPLEQCTGSSR
GSSASEGSRGGPPPRPPPRQSLQEQLNGVMPIAMSIKAGTVDEDSSGSEFLFFNFLH

(SEQ ID NO:1122)
>gi\|13435405\|ref\|NP_0716401\| histamine H2 receptor isoform 2 {Homosapiens}
MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSLAITD
LLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAVMDPLRYP
VLVTPVRVAIS LVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNEVYGLVDGLVT
FYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVMGAFIICWFPYFTAF
VYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQQLFCCRLANRNSHKTS
LRSNASQLSRTQSREPRQQEEKPLKLQVVVSGTEVTAPQGATDR

(SEQ ID NO:1123)
>gi\|13540517\|ref\|NP_1103871\| endothelial differentiation, sphingolipid G-
protein-coupled receptor,8 {Homosapiens}
MESGLLRPAPVSEVIVLHYNYTGKLRGARYQPGAGLRADAVVCLAVCAFIVLENLAVLLVL
GRHPRFHAPMFLLLGSLTLSDLLAGAAYAANILLSGPLTLKLSPALWFAREGGVFVALTASV
LSLLAIALERSLTMARRGPAPVSSRGRTLAMAAAAWGVSLLLGLLPALGWNCLGRLDACST
VLPLYAKAYVLFCVLAFVGILAAICALYARIYCQVRANARRLPARPGTAGTTSTRARRKPRS
LALLRTLSVVLLAFVACWGPLFLLLLLDVACPARTCPVLLQADPFLGLAMANSLLNPIIYTLT
NRDLRHALLRLVCCGRHSCGRDPSGSQQSASAAEASGGLRRCLPPGLDGSFSGSERSSPQRD
GLDTSGSTGSPGAPTAARTLVSEPAAD

(SEQ ID NO:1124)
>gi\|13540557\|ref\|NP_1104111\| probable G-protein coupled receptor 63
{Homosapiens}
MVFSAVLTAFHTGTSNTTFVVYENTYMNITLPPPFQHPDLSPLLRYSFETMAPTGLSSLTVNS
TAVPTTPAAFKSLNLPLQITLSAIMIFILFVSFLGNLVVCLMVYQKAAMRSAINILLASLAFAD
MLLAVLNMPFALVTILTTRWIFGKFFCRVSAMFFVVLFVIEGVAILLIISIDRFLIIVQRQDKLNP
YRAKVLIAVSWATSFCVAFPLAVGNPDLQIPSRAPQCVFGYTTNPGYQAYVILISLISFFIPFLV
ILYSFMGILNTLRHNALRIHSYPEGICLSQASKLGLMSLQRPFQMSIDMGFKTRAFTTILILFAV
FIVCWAPFTTYSLVATFSKHFYYQHNFFEISTWLLWLCYLKSALNPLIYYWRIKKFHDACLD
MMPKSFKFLPQLPGHTKRRIRPSAVYVCGEHRTVV

(SEQ ID NO:1125)
>gi\|13929467\|ref\|NP_0012872\| chemokine-binding protein 2 {Homosapiens}
MAATASPQPLATEDADSENSSFYYYDYLDEVAFMLCRKDAVVSFGKVFLPVFYSLIFVLGLS
GNLLLLMVLLRYVPRRRMVEIYLLNLAISNLLFLVTLPFVVGISVAWHWVFGSFLCKMVSTLY
TINFYSGIFFISCMSLDKYLEIVHAQPYHRLRTRAKSLLLATIVWAVSLAVSIPDMVFVQTHEN
PKGVWNCHADFGGHGTIVVKLFLRFQQNLLGFLLPLLAMIFFYSRIGCVLVRLRPAGQGRALK
IAAALVVAFFVLWFPYNLTLFLHTLLDLQVFGNCEVSQHLDYALQVTESIAFLHCCFSPILYA
FSSHRFRQYLKAFLAAVLGWHLAPGTAQASLSSCSESSILTAQEEMTGMNDLGERQSENYPN
KEDVGNKSA

(SEQ ID NO:1126)
>gi\|14043044\|ref\|NP_0066322\| C-C chemokine receptor type 9 isoform B
{Homosapiens}
MADDYGSESTSSMEDYVNFNFTDFYCEKNNVRQFASHFLPPLYWLVFIVGALGNSLVILVY
WYCTRVKTMTDMFLLNLAIADLLFLVTLPFVVAIAAADQWKFQTFMCKVVNSMYKMNFYS
CVLLIMCISVDRYIAIAQAMRAHTWREKRLLYSKMVCFTIVVVLAAALCIPEILYSQIKEESGIA
ICTMVYPSDES TKLKSAVLTLKVILGFFLPFVVMACCYTIIIHTLIQAKKSSKHKALKVTITVLT
VFVLSQFPYNCILLVQTIDAYAMFISNCAVSTNIDICFQVTQTIAFFHSCLNPVLYVFVGERFRR
DLVKTLKNLGCISQAQWVSFTRREGSLKLSSMLLETTSGALSL

(SEQ ID NO:1127)
>gi\|14211849\|ref\|NP_1159421\| probable G-protein coupled receptor 174
{Homosapiens}
MPANYTCTRPDGDNTDFRYFIYAVTYTVILVPGLIGNILALWVFYGYMKETKRAVIFMINLAI
ADLLQVLSLPLRIFYYLNHDWPFGPGLCMFCFYLKYVNMYASIYFLVCISVRRFVVFLMYPFR
FHDCKQKYDLYISIAGWLIICLACVLFPLLRTSDDTSGNRTKCFVDLPTRNVNLAQSVVMMTI
GELIGFVTPLLIVLYCTWKTVLSLQDKYPMAQDLGEKQKALKMILTCAGVFLICFAPYHFSFP
LDFLVKSNEIKSCLARRVILIFHSVALCLASLNSCLDPVIYYFSTNEFRRRLSRQDLHDSIQLHA
KSFVSNHTASTMTPELC

(SEQ ID NO:1128)
>gi\|1421185 1 \|ref\|NP_1159431\| G-protein coupled receptor 81 {Homosapiens}
MYNGSCCRIEGDTISQVMPPLLIVAFVLGALGNGVALCGFCFHMKTWKPSTVYLFNLAVAD
FLLMICLPFRTDYYLRRRHWAFGDIPCRVGLFTLAMNRAGSIVFLTVVAADRYFKVVHPHHA
VNTISTRVAAGIVCTLWALVILGTVYLLLENHLCVQETAVSCESFIMESANGWHDIMFQLEFF
MPLGIILFCSFKIVWSLRRRQQLARQARMKKATRFIMVVAIVFITCYLPSVSARLYFLWTVPSS
ACDPSVHGALHITLSFTYMNSMLDPLVYYFSSPSFPKFYNKLKICSLKPKQPGHSKTQRPEEM
PISNLGRRSCISVANSFQSQSDGQWDPHIVEWH

(SEQ ID NO:1129)
>gi\|14251205\|ref\|NP_0676372\| histamine H4 receptor isoform 1 {Homosapiens}
MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAISDFFV
GVISIPLYIPHTLFEWDFGKEICVFVVLTTDYLLCTASVYNIVLISYDRYLSVSNAVSYRTQHTG
VLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSFLEFVIPVILVAY
FNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSASTEVPASFHSERQRR
KSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARRLAKSLAILLGVFAVCWA
PYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPLCHKRFQKAFLKIFCIKKQPLP
SQHSRSVSS

(SEQ ID NO:1130)
>gi\|14589869\|ref\|NP_1167431\| Burkitt lymphoma receptor 1 isoform 2
{Homosapiens}
MASFKAVFVPVAYSLIFLLGVIGNVLVLVILERHRQTRSSTETFLFHLAVADLLLVFILPFAVA
EGSVGWVLGTFLCKTVIALHKVNFYCSSLLLACIAVDRYLAIVHAVHAYRHRRLLSIHITCGT
IVVLVGFLLALPEILFAKVSQGHHNNSLPRCTFSQENQAETHAWFTSRFLYHVAGFLLPMLVM
GWCYVGVVHRLRQAQRRPQRQKAVRVAILVTSIFFLCWSPYHIVIFLDTLARLKAVDNTCKL
NGSLPVAITMCEFLGLAHCCLNPMLYTFAGVKFRSDLSRLLTKLGCTGPASLCQLFPSWRRSS
LSESENATSLTTF

(SEQ ID NO:1131)
>gi\|15029528\|ref\|NP_0052831\| N-arachidonyl glycine receptor {Homosapiens}
MITLNNQDQPVPFNSSHPDEYKIAALVFYSCIFIIGLFVNITALWVFSCTTKKRTTVTIYMMNV
ALVDLIFIMTLPFRMFYYAKDEWPFGEYFCQILGALTVFYPSIALWLLAFISADRYMAIVQPK
YAKELKNTCKAVLACVGVWIMTLTTTTPLLLLYKDPDKDSTPATCLKISDIIYLKAVNVLNL
TRLTFFFLIPLFIMIGCYLVIIHNLLHGRTSKLKPKVKEKSIRIIITLLVQVLVCFMPFHICFAFLM
LGTGENSYNPWGAFTTFLMNLSTCLDVILYYIVSKQFQARVISVMLYRNYLRSMRRKSFRSG
SLRSLSNINSEML

(SEQ ID NO:1132)
>gi\|15619006\|ref\|NP_0046152\| vasoactive intestinal polypeptide receptor 1
precursor {Homosapiens}
MRPPSPLPARWLCVLAGALAWALGPAGGQAARLQEECDYVQMIEVQHKQCLEEAQLENETI
GCSKMWDNLTCWPATPRGQVVVLACPLIFKLFSSIQGRNVS RSCTDEGWTHLEPGPYPIACG
LDDKAASLDEQQTMFYGSVKTGYTIGYGLSLATLLVATAILSLFRKLHCTRNYIHMHLFISFIL
RAAAVFIKDLALFDSGESDQCSEGSVGCKAAMVFFQYCVMANFFVVLLVEGLYLYTLLAVSF
FSERKYFVVGYILIGWGVPSTFTMVWTIARIHFEDYGCWDTINSSLWWIIKGPILTSILVNFILFI
CIIRILLQKLRPPDIRKSDSSPYSRLARSTLLLIPLFGVHYIMFAFFPDNFKPEVKMVFELVVGSF
QGFVVAILYCFLNGEVQAELRRKWRRWHLQGVLGWNPKYRHPSGGSNGATCSTQVSMLTR
VSPGARRSSSFQAEVSLV

(SEQ ID NO:1133)
>gi\|16418463\|ref\|NP_4431991\| MAS1 oncogene-like {Homosapiens}
MVWGKICWFSQRAGWTVFAESQISLSCSLCLHSGDQEAQNPNLVSQLCGVFLQNETNETIH
MQMSMAVGQQALPLNIIAPKAVLVSLCGVLLNGTVFWLLCCGATNPYMVYILHLVAADVIY
LCCSAVGFLQVTLLTYHGVVFFIPDFLAILSPFSFEVCLCLLVAISTERCVCVLFPIVVYRCHRPK
YTSNVVCTLIVVGLPFCINIVKSLFLTYWKHVKACVIFLKLSGLFHAILSLVMCVSSLTLLIRFL
CCSQQQKATRVYAVVQISAPMFLLWALPLSVAPLITDFKMFVTTSYLISLFLIINSSANPIIYFF
VGSLRKKRLKESLRVILQRALADKPEVGRNKKAAGIDPMEQPHSTQHVENLLPREHRVDVET

(SEQ ID NO:1134)
>gi\|16751917\|ref\|NP_4445081\| trace amine associated receptor 8 {Homosapiens}
MTSNFSQPVVQLCYEDVNGSCIETPYSPGSRVILYTAFSFGSLLAVFGNLLVMTSVLHFKQLH
SPTNFLIASLACADFLVGVTVMLFSMVRTVESCWYFGAKFCTLHSCCDVAFCYSSVLHLCFIC
IDRYIVVTDPLVYATKFTVSVSGICISVSWILPLTYSGAVFYTGVNDDGLEELVSALNCVGGC
QIIVSQGWVLIDFLLFFIPTLVMIILYSKIFLIAKQQAIKIETTSSKVESSSESYKIRVAKRERKAA
KTLGVTVLAFVISWLPYTVDILIDAFMGFLTPAYIYEICCWSAYYNSAMNPLIYALFYPWFRK
AIKLILSGDVLKASSSTISLFLE

(SEQ ID NO:1135)
>gi\|16876435\|ref\|NP_4733621\| probable G-protein coupled receptor 101
{Homosapiens}
MTSTCTNSTRESNSSHTCMPLSKMPISLAHGIIRSTVLVIFLAASFVGNIVLALVLQRKPQLLQ
VTNRFIFNLLVTDLLQISLVAPWVVATSVPLFVVPLNSHFCTALVSLTHLFAFASVNTIVVVSV
DRYLSIIHPLSYPSKMTQRRGYLLLYGTWIVAILQSTPPLYGWGQAAFDERNALCSMIVVGASP
SYTILSVVSFIVIPLIVMIACYSVVFCAARRQHALLYNVKRHSLEVRVKDCVENEDEEGAEKK
EEFQDESEFRRQHEGEVKAKEGRMEAKDGSLKAKEGSTGTSESSVEARGSEEVRESSTVASD
GSMEGKEGSTKVEENSMKADKGRTEVNQCSIDLGEDDMEFGEDDINFSEDDVEAVNIPESLP
PSRRNSNSNPPLPRCYQCKAAKVIFIIIFSYVLSLGPYCFLAVLAVWVDVETQVPQWVITIIIVVL
FFLQCCIHPYVYGYMHKTIKKEIQDMLKKFFCKEKPPKEDSHPDLPGTEGGTEGKIVPSYDSA
TFP

(SEQ ID NO:1136)
>gi\|16950636\|ref\|NP_0013922\| lysophosphatidic acid receptor 1 {Homosapiens}
MAAISTSIPVISQPQFTAMNEPQCFYNESIAFFYNRSGKHLATEWNTVSKLVMGLGITVCIFIM
LANLLVMVAIYVNRRFHFPIYYLMANLAAADFFAGLAYFYLMFNTGPNTRRLTVSTWLLRQ
GLIDTSLTASVANLLAIAIERHITVFRMQLHTRMSNRRVVVVIVVIVVTMAIVMGAIPSVGWNC
ICDIENCSNMAPLYS DSYLVFVVAIFNLVTFVVMVVLYAHIFGYVRQRTMRMSRHSSGPRRNR
DTMMSLLKTVVIVLGAFIICWTPGLVLLLLDVCCPQCDVLAYEKFFLLLAEFNSAMNPIIYSY
RDKEMSATFRQILCCQRSENPTGPTEGSDRSASSLNHTILAGVHSNDHSVV

(SEQ ID NO:1137)
>gi\|17978491\|ref\|NP_5109661\| CD97 antigen isoform 1 precursor {Homosapiens}
MGGRVFLAFCVWLTLPGAETQDSRGCARWCPQNSSCVNATACRCNPGFSSFSEIITTPTETCD
DINECATPSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDVDECQQNPR
LCKSYGTCVNTLGSYTCQCLPGFKFIPEDPKVCTDVNECTSGQNPCHSSTHCLNNVGSYQCR
CRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRCRPGWKPRHGIPN
NQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDSKTSSAEVTIQNVIKLVDELMEA
PGDVEALAPPVRHLIATQLLSNLEDIMRILAKSLPKGPFTYISPSNTELTLMIQERGDKNVTMG
QSSARMKLNWAVAAGAEDPGPAVAGILSIQNMTTLLANASLNLHSKKQAELEEIYESSIRGV
QLRRLSAVNSIFLSHNNTKELNSPILFAFSHLESSDGEAGRDPPAKDVMPGPRQELLCAFWKS
DSDRGGHWATEGCQVLGSKNGSTTCQCSHLSSFAILMAHYDVEDWKLTLITRVGLALSLFC
LLLCILTFLLVRPIQGSRTTIHLHLCICLFVGSTIFLAGIENEGGQVGLRCRLVAGLLHYCFLAA
FCWMSLEGLELYFLVVRVFQGQGLSTRWLCLIGYGVPLLIVGVSAAIYSKGYGRPRYCWLDF
EQGFLWSFLGPVTFIILCNAVIFVTTVWKLTQKFSEINPDMKKLKKARALTITAIAQLFLLGCT
WVFGLFIFDDRSLVLTYVFTILNCLQGAFLYLLHCLLNKKVREEYRKWACLVAGGSKYSEFT
STTSGTGHNQTRALRASESGI

(SEQ ID NO:1138)
>gi\|18201870\|ref\|NP_5430071\| probable G-protein coupled receptor 82
{Homosapiens}
MNNNTTCIQPSMISSMALPIIYILLCIVGVFGNTLSQWIFLTKIGKKTSTHIYLSHLVTANLLVC
SAMPFMSIYFLKGFQWEYQSAQCRVVNFLGTLSMHASMFVSLLILSWIAISRYATLMQKDSS
QETTSCYEKIFYGHLLKKFRQPNFARKLCIYIWGVVLGIIIPVTVYYSVIEATEGEESLCYNRQ
MELGAMISQIAGLIGTTFIGFSFLVVLTSYYSFVSHLRKIRTCTSIMEKDLTYSSVKRHLLVIQIL
LIVCFLPYSIFKPIFYVLHQRDNCQQLNYLIETKNILTCLASARSSTDPIIFLLLDKTFKKTLYNL
FTKSNSAHMQSYG

(SEQ ID NO:1139)
>gi\|18677729\|ref\|NP_5707181\| relaxin receptor 2 isoform 1 {Homosapiens}
MIVFLVFKHLFSLRLITMFFLLHFIVLINVKDFALTQGSMITPSCQKGYFPCGNLTKCLPRAFH
CDGKDDCGNGADEENCGDTSGWATIFGTVHGNANSVALTQECFLKQYPQCCDCKETELEC
VNGDLKSVPMISNNVTLLSLKKNKIHSLPDKVFIKYTKLKKIFLQHNCIRHISRKAFFGLCNLQ
ILYLNHNCITTLRPGIFKDLHQLTWLILDDNPITRISQRLFTGLNSLFFLSMVNNYLEALPKQM
CAQMPQLNWVDLEGNRIKYLTNSTFLSCDSLTVLFLPRNQIGFVPEKTFSSLKNLGELDLSSN
TITELSPHLFKDLKLLQKLNLSSNPLMYLHKNQFESLKQLQSLDLERIEIPNINTRMFQPMKNL
SHIYFKNFRYCSYAPHVRICMPLTDGISSFEDLLANNILRIFVWVIAFITCFGNLFVIGMRSFIKA
ENTTHAMSIKILCCADCLMGVYLFFVGIFDIKYRGQYQKYALLWMESVQCRLMGFLAMLST
EVSVLLLTYLTLEKFLVIVFPFSNIRPGKRQTSVILICIWMAGFLIAVIPFWNKDYFGNFYGKN
GVCFPLYYDQTEDIGSKGYSLGIFLGVNLLAFLIIVFSYITMFCSIQKTALQTTEVRNCFGREV
AVANRFFFIVFSDAICWIPVFVVKILSLFRVEIPDTMTSWIVIFFLPVNSALNPILYTLTTNFFKD
KLKQLLHKHQRKSIFKIKKKSLSTSIVVVIEDSSSLKLGVLNKITLGDSIMKPVS

(SEQ ID NO:1140)
>gi\|19923245\|ref\|NP_0043732\| corticotropin-releasing factor receptor 1
isoform 2 {Homosapiens}
MGGHPQLRLVKALLLLGLNPVSASLQDQHCESLSLASNISGLQCNASVDLIGTCWPRSPAGQ
LVVRPCPAFFYGVRYNTTNNGYRECLANGSWAARVNYSECQEILNEEKKSKVHYHVAVIIN
YLGHCISLVALLVAFVLFLRLRSIRCLRNIIHWNLISAFILRNATWFVVQLTMSPEVHQSNVG
WCRLVTAAYNYFHVTNFFVVMFGEGCYLHTAIVLTYSTDRLRKWMFICIGWGVPFPIIVAWAI
GKLYYDNEKCWFGKRPGVYTDYIYQGPMILVLLINFIFLFNIVRILMTKLRASTTSETIQYRKA
VKATLVLLPLLGITYMLFFVNPGEDEVSRVVFIYFNSFLESFQGFFVSVFYCFLNSEVRSAIRK
RWHRWQDKHSIRARVARAMSIPTSPTRVSFHSIKQSTAV

(SEQ ID NO:1141)
>gi\|19923975 \|ref\|NP_612454 1\| G protein-coupled receptor 146 {Homosapiens}
MWSCSWFNGTGLVEELPACQDLQLGLSLLSLLGLVVGVPVGLCYNALLVLANLHSKASMT
MPDVYFVNMAVAGLVLSALAPVHLLGPPSSRWALWSVGGEVHVALQIPFNVSSLVAMYST
ALLSLDHYIERALPRTYMASVYNTRHVCGFVWGGALLTSFSSLLFYICSHVSTRALECAKMQ
NAEAADATLVFIGYVVPALATLYALVLLSRVRREDTPLDRDTGRLEPSAHRLLVATVCTQFG
LWTPHYLILLGHTVIISRGKPVDAHYLGLLHFVKDFSKLLAFSSSFVTPLLYRYMNQSFPSKL
QRLMKKLPCGDRHCSPDHMGVQQVLA

(SEQ ID NO:1142)
>gi\|20373179\|ref\|NP_6204141\| G protein-coupled receptor 73 {Homosapiens}
METTMGFMDDNATNTSTSFLSVLNPHGAHATSFPFNFSYSDYDMPLDEDEDVTNSRTFFAA
KIVIGMALVGIMLVCGIGNFIFIAALVRYKKLRNLTNLLIANLAISDFLVAIVCCPFEMDYYVV
RQLSWEHGHVLCTSVNYLRTVSLYVSTNALLAIAIDRYLAIVHPLRPRMKCQTATGLIALVW
TVSILIAIPSAYFTTETVLVIVKSQEKIFCGQIVVPVDQQLYYKSYFLFIFGIEFVGPVVTMTLCY
ARISRELWFKAVPGFQTEQIRKRLRCRRKTVLVLMCILTAYVLCWAPFYGFTIVRDFFPTVFV
KEKHYLTAFYIVECIAMSNSMINTLCFVTVKNDTVKYFKKIMLLHWKASYNGGKSSADLDL
KTIGMPATEEVDCIRLK

(SEQ ID NO:1143)
>gi\|20544172 \|ref\|NP_000701 2\| B1 bradykinin receptor {Homosapiens}
MASSWPPLELQSSNQSQLFPQNATACDNAPEAWDLLHRVLPTFIISICFFGLLGNLFVLLVFLL
PRRQLNVAEIYLANLAASDLVFVLGLPFWAENIWNQFNWPFGALLCRVINGVIKANLFISIFL
VVAISQDRYRVLVHPMASRRQQRRRQARVTCVLIVVVVGGLLSIPTFLLRSIQAVPDLNITACI
LLLPHEAWHFARIVELNILGFLLPLAAIVFFNYHILASLRTREEVSRTRCGGRKDSKTTALILTL
VVAFLVCWAPYHFFAFLEFLFQVQAVRGCFVVEDFIDLGLQLANFFAFTNSSLNPVIYVFVGR
LFRTKVVVELYKQCTPKSLAPISSSHRKEIFQLFVVRN

(SEQ ID NO:1144)
>gi\|21264324\|ref\|NP_6122001\| trace amine associated receptor 1 {Homosapiens}
MMPFCHNIINISCVKNNWSNDVRASLYSLMVLIILTTLVGNLIVIVSISHFKQLHTPTNWLIHS
MATVDFLLGCLVMPYSMVRSAEHCWYFGEVFCKIHTSTDIMLSSASIFHLSFISIDRYYAVCD
PLRYKAKMNILVICVMIFISWSVPAVFAFGMIFLELNFKGAEEIYYKHVHCRGGCSVFFSKISG
VLTFMTSFYIPGSIMLCVYYRIYLIAKEQARLISDANQKLQIGLEMKNGISQSKERKAVKTLGI
VMGVFLICWCPFFICTVMDPFLHYIIPPTLNDVLIVVFGYLNSTFNPMVYAFFYPWFRKALKM
MLFGKIFQKDSSRCKLFLELSS

(SEQ ID NO:1145)
>gi\|21361557 \|ref\|NP_0033732\| vasoactive intestinal polypeptide receptor 2
{Homosapiens}
MRTLLPPALLTCWLLAPVNSIHPECRFHLEIQEEETKCAELLRSQTEKHKACSGVWDNITCW
RPANVGETVTVPCPKVFSNFYSKAGNISKNCTSDGWSETFPDFVDACGYSDPEDESKITFYIL
VKAIYTLGYSVSLMSLATGSIILCLFRKLHCTRNYIHLNLFLSFILRAISVLVKDDVLYSSSGTL
HCPDQPSSWVGCKLSLVFLQYCIMANFFVVLLVEGLYLHTLLVAMLPPRRCFLAYLLIGWGLP
TVCIGAWTAARLYLEDTGCWDTNDHSVPWWVIRIPILISIIVNFVLFISIIRILLQKLTSPDVGG
NDQSQYKRLAKSTLLLIPLFGVHYMVFAVFPISISSKYQILFELCLGSFQGLVVAVLYCFLNSE
VQCELKRKWRSRCPTPSASRDYRVCGSSFSRNGSEGALQFHRGSRAQSFLQTETSVI

(SEQ ID NO:1146)
>gi\|21426829\|ref\|NP_6589861\| prokineticin receptor 2 {Homosapiens}
MAAQNGNTSFTPNFNPPQDHASSLSFNFSYGDYDLPMDEDEDMTKTRTFFAAKIVIGIALAGI
MLVCGIGNFVFIAALTRYKKLRNLTNLLIANLAISDFLVAIICCPFEMDYYVVRQLSWEHGHV
LCASVNYLRTVSLYVSTNALLAIAIDRYLAIVHPLKPRMNYQTASFLIALVWMVSILIAIPSAY
FATETVLFIVKSQEKIFCGQIVVPVDQQLYYKSYFLFIFGVEFVGPVVTMTLCYARISRELWFK
AVPGFQTEQIRKRLRCRRKTVLVLMCILTAYVLCWAPFYGFTIVRDFFPTVFVKEKHYLTAF
YVVECIAMSNSMINTVCFVTVKNNTMKYFKKMMLLHWRPSQRGSKSSADLDLRTNGVPTT
EEVDCIRLK

(SEQ ID NO:1147)
>gi\|22507376 \|ref\|NP_6837651\| oxoeicosanoid receptor 1 {Homosapiens}
MLCHRGGQLIVPIIPLCPEHSCRGRRLQNLLSGPWPKQPMELHNLSSPSPSLSSSVLPPSFSPSP
SSAPSAFTTVGGSSGGPCHPTSSSLVSAFLAPILALEFVLGLVGNSLALFIFCIHTRPWTSNTVF
LVSLVAADFLLISNLPLRVDYYLLHETWRFGAAACKVNLFMLSTNRTASVVFLTAIALNRYL
KVVQPHHVLSRASVGAAARVAGGLWVGILLLNGHLLLSTFSGPSCLSYRVGTKPSASLRWH
QALYLLEFFLPLALILFAIVSIGLTIRNRGLGGQAGPQRAMRVLAMVVAVYTICFLPSIIFGMA
SMVAFWLSACRSLDLCTQLFHGSLAFTYLNSVLDPVLYCFSSPNFLHQSRALLGLTRGRQGP
VSDESSYQPSRQWRYREASRKAEAIGKLKVQGEVSLEKEGSSQG

(SEQ ID NO:1148)
>gi\|23238240\|ref\|NP_0006772\| type-2 angiotensin II receptor {Homosapiens}
MKGNSTLATTSKNITSGLHFGLVNISGNNESTLNCSQKPSDKHLDAIPILYYIIFVIGFLVNIVV
VTLFCCQKGPKKVSSIYIFNLAVADLLLLATLPLWATYYSYRYDWLFGPVMCKVFGSFLTLN
MFASIFFITCMSVDRYQSVIYPFLSQRRNPWQASYIVPLVWCMACLSSLPTFYFRDVRTIEYLG
VNACIMAFPPEKYAQWSAGIALMKNILGFIIPLIFIATCYFGIRKHLLKTNSYGKNRITRDQVL
KMAAAVVLAFIICWLPFHVLTFLDALAWMGVINSCEVIAVIDLALPFAILLGFTNSCVNPFLY
CFVGNRFQQKLRSVFRVPITWLQGKRESMSCRKSSSLREMETFVS

(SEQ ID NO:1149)
>gi\|2339768 1 \|ref\|NP_0384752\| EGF-like module-containing mucin-like hormone
receptor-like 2 isoform a {Homosapiens}
MGGRVFLVFLAFCVWLTLPGAETQDSRGCARWCPQDSSCVNATACRCNPGFSSFSEIITTPM
ETCDDINECATLSKVSCGKFSDCWNTEGSYDCVCSPGYEPVSGAKTFKNESENTCQDVDECQ
QNPRLCKSYGTCVNTLGSYTCQCLPGFKLKPEDPKLCTDVNECTSGQNPCHSSTHCLNNVGS
YQCRCRPGWQPIPGSPNGPNNTVCEDVDECSSGQHQCDSSTVCFNTVGSYSCRCRPGWKPR
HGIPNNQKDTVCEDMTFSTWTPPPGVHSQTLSRFFDKVQDLGRDYKPGLANNTIQSILQALD
ELLEAPGDLETLPRLQQHCVASHLLDGLEDVLRGLSKNLSNGLLNFSYPAGTELSLEVQKQV
DRSVTLRQNQAVMQLDWNQAQKSGDPGPSVVGLVSIPGMGKLLAEAPLVLEPEKQMLLHE
THQGLLQDGSPILLSDVISAFLSNNDTQNLSSPVTFTFSHRSVIPRQKVLCVFWEHGQNGCGH
WATTGCSTIGTRDTSTICRCTHLSSFAVLMAHYDVQEEDPVLTVITYMGLSVSLLCLLLAALT
FLLCKAIQNTSTSLHLQLSLCLFLAHLLFLVAIDQTGHKVLCSIIAGTLHYLYLATLTWMLLEA
LYLFLTARNLTVVNYSSINRFMKKLMFPVGYGVPAVTVAISAASRPHLYGTPSRCWLQPEKG
FIVVGFLGPVCAIFSVNLVLFLVTLWILKNRLSSLNSEVSTLRNTRMLAFKATAQLFILGCTWC
LGILQVGPAARVMAYLFTIINSLQGVFIFLVYCLLSQQVREQYGKWSKGIRKLKTESEMHTLS
SSAKADTSKPSTVN

(SEQ ID NO:1150)
>gi\|23463303\|ref\|NP_0025572\| purinergic receptor P2Y11 {Homosapiens}
MAANVSGAKSCPANFLAAADDKLSGFQGDFLWPILVVEFLVAVASNGLALYRFSIRKQRPW
HPAVVFSVQLAVSDLLCALTLPPLAAYLYPPKHWRYGEAACRLERFLFTCNLLGSVIFITCISL
NRYLGIVHPFFARSHLRPKHAWAVSAAGWVLAALLAMPTLSFSHLKRPQQGAGNCSVARPE
ACIKCLGTADHGLAAYRAYSLVLAGLGCGLPLLLTLAAYGALGRAVLRSPGMTVAEKLRVA
ALVASGVALYASSYVPYHIMRVLNVDARRRWSTRCPSFADIAQATAALELGPYVGYQVMR
GLMPLAFCVHPLLYMAAVPSLGCCCRHCPGYRDSWNPEDAKSTGQALPLNATAAPKPSEPQ
SRELSQ

(SEQ ID NO:1151)
>gi\|23592220\|ref\|NP_7031431\| G-protein coupled receptor 26 {Homosapiens}
MNSWDAGLAGLLVGTMGVSLLSNALVLLCLLHSADIRRQAPALFTLNLTCGNLLCTVVNMP
LTLAGVVAQRQPAGDRLCRLAAFLDTFLAANSMLSMAALSIDRWVAVVFPLSYRAKMRLR
DAALMVAYTWLHALTFPAAALALSWLGFHQLYASCTLCSRRPDERLRFAVFTGAFHALSFL
LSFVVLCCTYLKVLKVARFHCKRIDVITMQTLVLLVDLHPSVRERCLEEQKRRRQRATKKIST
FIGTFLVCFAPYVITRLVELFSTVPIGSHWGVLSKCLAYSKAASDPFVYSLLRHQYRKSCKEIL
NRLLHRRSIHSSGLTGDSHSQNILPVSE

(SEQ ID NO:1152)
>gi\|24475871\|ref\|NP_7225791\| G protein-coupled receptor 114 precursor
{Homosapiens}
MDHCGALFLCLCLLTLQNATTETWEELLSYMENMQVSRGRSSVFSSRQLHQLEQMLLNTSF
PGYNLTLQTPTIQSLAFKLSCDFSGLSLTSATLKRVPQAGGQHARGQHAMQFPAELTRDACK
TRPRELRLICIYFSNTHFFKDENNSSLLNNYVLGAQLSHGHVNNLRDPVNISFVVHNQSLEGYT
LTCVFVVKEGARKQPWGGWSPEGCRTEQPSHSQVLCRCNHLTYFAVLMQLSPALVPAELLAP
LTYISLVGCSISIVASLITVLLHFHFRKQSDSLTRIHMNLHASVLLLNIAFLLSPAFAMSPVPGS
ACTALAAALHYALLSCLTWMAIEGFNLYLLLGRVYNIYIRRYVFKLGVLGWGAPALLVLLS
LSVKSSVYGPCTIPVFDSWENGTGFQNMSICWVRSPVVHSVLVMGYGGLTSLFNLVVLAWA
LWTLRRLRERADAPSVRACHDTVTVLGLTVLLGTTWALAFFSFGVFLLPQLFLFTILNSLYGF
FLFLWFCSQRCRSEAEAKAQIEAFSSSQTTQ

(SEQ ID NO:1153)
>gi\|24476016\|ref\|NP_7225611\| G protein-coupled receptor 161 isoform 2
{Homosapiens}
MSLNSSLSCRKELSNLTEEEGGEGGVIITQFIAIIVITIFVCLGNLVIVVTLYKKSYLLTLSNKFV
FSLTLSNFLLSVLVLPFVVTSSIRREWIFGVVWCNFSALLYLLISSASMLTLGVIAIDRYYAVL
YPMVYPMKITGNRAVMALVYIVVLHSLIGCLPPLFGWSSVEFDEFKWMCVAAWHREPGYTA
FVVQIVVCALFPFLVMLVCYGFIFRVARVKARKVHCGTVVIVEEDAQRTGRKNSSTSTSSSGSR
RNAFQGVVYSANQCKALITILVVLGAFMVTWGPYMVVIASEALWGKSSVSPSLETWATWLS
FASAVCHPLIYGLWNKTVRKELLGMCFGDRYYREPFVQRQRTSRLFSISNRITDLGLSPHLTA
LMAGGQPLGHSSSTGDTGFSCSQDSGTDMMLLEDYTSDDNPPSHCTCPPKRRSSVTFEDEVE
QIKEAAKNSILHVKAEVHKSLDSYAASLAKAIEAEAKINLFGEEALPGVLVTARTVPGGGFG
GRRGSRTLVSQRLQLQSIEEGDVLAAEQR

(SEQ ID NO:1154)
>gi\|28173558\|ref\|NP_7782371\| trace amine-associated receptor 6 {Homosapiens}
MSSNSSLLVAVQLCYANVNGSCVKIPFSPGSRVILYIVFGFGAVLAVFGNLLVMISILHFKQLH
SPTNFLVASLACADFLVGVTVMPFSMVRTVESCWYFGRSFCTFHTCCDVAFCYSSLFHLCFIS
IDRYIAVTDPLVYPTKFTVSVSGICISVSWILPLMYSGAVFYTGVYDDGLEELSDALNCIGGCQ
TVVNQNVVVLTDFLSFFIPTFIMIILYGNIFLVARRQAKKIENTGSKTESSSESYKARVARRERK
AAKTLGVTVVAFMISWLPYSIDSLIDAFMGFITPACIYEICCWCAYYNSAMNPLIYALFYPWF
RKAIKVIVTGQVLKNSSATMNLFSEHI

(SEQ ID NO:1155)
>gi\|28466969\|ref\|NP_0009441\| prostaglandin D2 receptor {Homosapiens}
MKSPFYRCQNTTSVEKGNSAVMGGVLFSTGLLGNLLALGLLARSGLGWCSRRPLRPLPSVFY
MLVCGLTVTDLLGKCLLSPVVLAAYAQNRSLRVLAPALDNSLCQAFAFFMSFFGLSSTLQLL
AMALECWLSLGHPFFYRRHITLRLGALVAPVVSAFSLAFCALPFMGFGKFVQYCPGTWCFIQ
MVHEEGSLSVLGYSVLYSSLMALLVLATVLCNLGAMRNLYAMHRRLQRHPRSCTRDCAEP
RADGREASPQPLEELDHLLLLALMTVLFTMCSLPVIYRAYYGAFKDVKEKNRTSEEAEDLRA
LRFLSVISIVDPWIFIIFRSPVFRIFFHKIFIRPLRYRSRCSNSTNMESSL

(SEQ ID NO:1156)
>gi\|28872720\|ref\|NP_0025552\| P2Y purinoceptor 2 {Homosapiens}
MAADLGPWNDTINGTWDGDELGYRCRFNEDFKYVLLPVSYGVVCVPGLCLNAVALYIFLC
RLKTWNASTTYMFHLAVSDALYAASLPLLVYYYARGDHWPFSTVLCKLVRFLFYTNLYCSI
LFLTCISVHRCLGVLRPLRSLRWGRARYARRVAGAVWVLVLACQAPVLYFVTTSARGGRVT
CHDTSAPELFSRFVAYSSVMLGLLFAVPFAVILVCYVLMARRLLKPAYGTSGGLPRAKRKSV
RTIAVVLAVFALCFLPFHVTRTLYYSFRSLDLSCHTLNAINMAYKVTRPLASANSCLDPVLYF
LAGQRLVRFARDAKPPTGPSPATPARRRLGLRRSDRTDMQRIEDVLGSSEDSRRTESTPAGSE
NTKDIRL

(SEQ ID NO:1157)
>gi\|28875799\|ref\|NP_7953441\| gastrinicholecystokinin type B receptor
{Homosapiens}
MELLKLNRSVQGTGPGPGASLCRPGAPLLNSSSVGNLSCEPPRIRGAGTRELELAIRITLYAVI
FLMSVGGNMLIIVVLGLSRRLRTVTNAFLLSLAVSDLLLAVACMPFTLLPNLMGTFIFGTVIC
KAVSYLMGVSVSVSTLSLVAIALERYSAICRPLQARVWQTRSHAARVIVATWLLSGLLMVPY
PVYTVVQPVGPRVLQCVHRWPSARVRQTWSVLLLLLLFFIPGVVMAVAYGLISRELYLGLRF
DGDSDSDSQSRVRNQGGLPGAVHQNGRCRPETGAVGEDSDGCYVQLPRSRPALELTALTAP
GPGSGSRPTQAKLLAKKRVVRMLLVIVVLFFLCWLPVYSANTWRAFDGPGAHRALSGAPISF
IHLLSYASACVNPLVYCFMHRRFRQACLETCARCCPRPPRARPRALPDEDPPTPSIASLSRLSY
TTISTLGPG

(SEQ ID NO:1158)
>gi\|2917131 1 \|ref\|NP_8082191\| G-protein coupled receptor 109A {Homosapiens}
MNRHHLQDHFLEIDKKNCCVFRDDFIVKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWKSSR
IFLFNLAVADFLLIICLPFLMDNYVRRWDWKFGDIPCRLMLFMLAMNRQGSIIFLTVVAVDR
YFRVVHPHHALNKISNRTAAIISCLLWGITIGLTVHLLKKKMPIQNGGANLCSSFSICHTFQWH
EAMFLLEFFLPLGIILFCSARIIVVSLRQRQMDRHAKIKRAITFIMVVAIVFVICFLPSVVVRIRIF
WLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPSFPNFFSTLINRCLQRKMT
GEPDNNRSTSVELTGDPNKTRGAPEALMANSGEPWSPSYLGPTSP

(SEQ ID NO:1159)
>gi\|29171759\|ref\|NP_0011092\| pituitary adenylate cyclase-activating
polypeptide type I receptor precursor {Homosapiens}
MAGVVHVSLAALLLLPMAPAMHSDCIFKKEQAMCLEKIQRANELMGFNDSSPGCPGMWDN
ITCWKPAHVGEMVLVSCPELFRIFNPDQVVVETETIGESDFGDSNSLDLSDMGVVSRNCTEDG
WSEPFPHYFDACGFDEYESETGDQDYYYLSVKALYTVGYSTSLVTLTTAMVILCRFRKLHCT
RNFIHMNLFVSFMLRAISVFIKDWILYAEQDSNHCFISTVECKAVMVFFHYCVVSNYFVVLFIE
GLYLFTLLVETFFPERRYFYVVYTIIGWGTPTVCVTVWATLRLYFDDTGCWDMNDSTALWW
VIKGPVVGSIMVNFVLFIGIIVILVQKLQSPDMGGNESSIYLRLARSTLLLIPLFGIHYTVFAFSP
ENVSKRERLVFELGLGSFQGFVVAVLYCFLNGEVQAEIKRKWRSWKVNRYFAVDFKHRHPS
LASSGVNGGTQLSILSKSSSQIRMSGLPADNLAT

(SEQ ID NO:1160)
>gi\|30023826\|ref\|NP_8352301\| P2Y purinoceptor 8 {Homosapiens}
MQVPNSTGPDNATLQMLRNPAIAVALPVVYSLVAAVSIPGNLFSLWVLCRRMGPRSPSVIFM
INLSVTDLMLASVLPFQIYYHCNRHHWVFGVLLCNVVTVAFYANMYSSILTMTCISVERFLG
VLYPLSSKRWRRRRYAVAACAGTWLLLLTALSPLARTDLTYPVHALGIITCFDVLKWTMLPS
VAMWAVFLFTIFILLFLIPFVITVACYTATILKLLRTEEAHGREQRRRAVGLAAVVLLAFVTCF
APNNFVLLAHIVSRLFYGKSYYHVYKLTLCLSCLNNCLDPFVYYFASREFQLRLREYLGCRR
VPRDTLDTRRESLFSARTTSVRSEAGAHPEGMEGATRPGLQRQESVF

(SEQ ID NO:1161)
>gi\|30425400\|ref\|NP_8485661\| glucose-dependent insulinotropic receptor
{Homosapiens }
MESSFSFGVILAVLA LIIATNTLVAVAVLLLIHKNDGVSLCFTLNLAVADTLIGVAISGLLTD
QLSSPSRPTQKTLCSLRMAFVTSSAAASVLTVMLITFDRYLAIKQPFRYLKIMSGFVAGACIA
GLWLVSYLIGFLPLGIPMFQQTAYKGQCSFFAVFHPHFVLTLSCVGFFPAMLLFVFFYCDMLK
IASMHSQQIRKMEHAGAMAGGYRSPRTPSDFKALRTVSVLIGSFALSWTPFLITGIVQVACQE
CHLYLVLERYLWLLGVGNSLLNPLIYAYWQKEVRLQLYHMALGVKKVLTSFLLFLSARNCG
PERPRESSCHIVTISSSEFDG

(SEQ ID NO:1162)
>gi\|30581164\|ref\|NP_0052772\| neuropeptides B/W receptor type 2 {Homosapiens}
MQAAGHPEPLDSRGSFSLPTMGANVSQDNGTGHNATFSEPLPFLYVLLPAVYSGICAVGLTG
NTAVILVILRAPKMKTVTNVFILNLAVADGLFTLVLPVNIAEHLLQYWPFGELLCKLVLAVD
HYNIFSSIYFLAVMSVDRYLVVLATVRSRHMPWRTYRGAKVASLCVWLGVTVLVLPFFSFA
GVYSNELQVPSCGLSFPWPEQVVVFKASRVYTLVLGFVLPVCTICVLYTDLLRRLRAVRLRSG
AKALGKARRKVTVLVLVVLAVCLLCWTPFHLASVVALTTDLPQTPLVISMSYVITSLSYANS
CLNPFLYAFLDDNFRKNFRSILRC

(SEQ ID NO:1163)
>gi\|30795217\|ref\|NP_8485401\| chemokine (C-C motif) receptor-like 1
{Homosapiens}
MALEQNQSTDYYYEENEMNGTYDYSQYELICIKEDVREFAKVFLPVFLTIVFVIGLAGNSMV
VAIYAYYKKQRTKTDVYILNLAVADLLLLFTLPFWAVNAVHGWVLGKIMCKITSALYTLNF
VSGMQFLACISIDRYVAVTKVPSQSGVGKPCWIICFCVVVMAAILLSIPQLVFYTVNDNARCIPI
FPRYLGTSMKALIQMLEICIGFVVPFLIMGVCYFITARTLMKMPNIKISRPLKVLLTVVIVFIVT
QLPYNIVKFCRAIDIIYSLITSCNMSKRMDIAIQVTESIALFHSCLNPILYVFMGASFKNYVMKV
AKKYGSWRRQRQSVEEFPFDSEGPTEPTSTFSI

(SEQ ID NO:1164)
>gi\|31083315 \|ref\|NP_0091583\| probable G-protein coupled receptor 45
{Homosapiens }
MACNSTSLEAYTYLLLNTS NASDSGSTQLPAPLRISLAIVMLLMTVVGFLGNTVVCIIVYQRP
AMRSAINLLLATLAFSDIMLSLCCMPFTAVTLITVRWHFGDHFCRLSATLYWFFVLEGVAILL
IISVDRFLIIVQRQDKLNPRRAKVIIAVSWVLSFCIAGPSLTGWTLVEVPARAPQCVLGYTELP
ADRAYVVTLVVAVFFAPFGVMLCAYMCILNTVRKNAVRVHNQSDSLDLRQLTRAGLRRLQ
RQQQVSVDLSFKTKAFTTILILFVGFSLCWLPHSVYSLLSVFSQRFYCGSSFYATSTCVLWLSY
LKSVFNPIVYCWRIKKFREACIELLPQTFQILPKVPERIRRRIQPSTVYVCNENQSAV

(SEQ ID NO:1165)
>gi\|31083344\|ref\|NP_0647071\| C-X-C chemokine receptor type 7 {Homosapiens}
MDLHLFDYSEPGNFSDISWPCNSSDCIVVDTVMCPNMPNKSVLLYTLSFIYIFIFVIGMIANSV
VVWVNIQAKTTGYDTHCYILNLAIADLWVVLTIPVWVVSLVQHNQWPMGELTCKVTHLIFS
INLFGSIFFLTCMSVDRYLSITYFTNTPSSRKKMVRRVVCILVVVLLAFCVSLPDTYYLKTVTSA
SNNETYCRSFYPEHSIKEWLIGMELVSVVLGFAVPFSIIAVFYFLLARAISASSDQEKHSSRKIIF
SYVVVFLVCWLPYHVAVLLDIFSILHYIPFTCRLEHALFTALHVTQCLSLVHCCVNPVLYSFIN
RNYRYELMKAFIFKYSAKTGLTKLIDASRVSETEYSALEQSTK

(SEQ ID NO:1166)
>gi\|31657138\|ref\|NP_0001362\| follicle-stimulating hormone receptor isoform 1
precursor {Homosapiens }
MALLLVSLLAFLSLGSGCHHRICHCSNRVFLCQESKVTEIPSDLPRNAIELRFVLTKLRVIQKG
AFSGFGDLEKIEISQNDVLEVIEADVFSNLPKLHEIRIEKANNLLYINPEAFQNLPNLQYLLISN
TGIKHLPDVHKIHSLQKVLLDIQDNINIHTIERNSFVGLSFESVILWLNKNGIQEIHNCAFNGTQ
LDELNLSDNNNLEELPNDVFHGASGPVILDISRTRIHSLPSYGLENLKKLRARSTYNLKKLPTL
EKLVALMEASLTYPSHCCAFANVVRRQISELHPICNKS ILRQEVDYMTQARGQRSSLAEDNES
SYSRGFDMTYTEFDYDLCNEVVDVTCSPKPDAFNPCEDIMGYNILRVLIWFISILAITGNIIVLV
ILTTSQYKLTVPRFLMCNLAFADLCIGIYLLLIASVDIHTKSQYHNYAIDWQTGAGCDAAGFF
TVFASELSVYTLTAITLERWHTITHAMQLDCKVQLRHAASVMVMGWIFAFAAALFPIFGISSY
MKVSICLPMDIDSPLSQLYVMSLLVLNVLAFVVICGCYIHIYLTVRNPNIVSSSSDTRIAKRMA
MLIFTDFLCMAPISFFAISASLKVPLITVSKAKILLVLFHPINSCANPFLYAIFTKNFRRDFFILLS
KCGCYEMQAQIYRTETSSTVHNTHPRNGHCSSAPRVTSGSTYILVPLSHLAQN

(SEQ ID NO:1167)
>gi\|31881630\|ref\|NP_0009472\| prostaglandin E2 receptor EP2 subtype
{Homosapiens}
MGNASNDSQSEDCETRQWLPPGESPAISSVMFSAGVLGNLIALALLARRWRGDVGCSAGRR
SSLSLFHVLVTELVFTDLLGTCLISPVVLASYARNQTLVALAPESRACTYFAFAMTFFSLATM
LMLFAMALERYLSIGHPYFYQRRVSRSGGLAVLPVIYAVSLLFCSLPLLDYGQYVQYCPGTW
CFIRHGRTAYLQLYATLLLLLIVSVLACNFSVILNLIRMHRRSRRSRCGPSLGSGRGGPGARRR
GERVSMAEETDHLILLAIMTITFAVCSLPFTIFAYMNETSSRKEKWDLQALRFLSINSIIDPWVF
AILRPPVLRLMRSVLCCRISLRTQDATQTSCSTQSDASKQADL

(SEQ ID NO:1168)
>gi\|31881792\|ref\|NP_8580431\| leukotriene B4 receptor 1 {Homosapiens}
MNTTSSAAPPSLGVEFISLLAIILLSVALAVGLPGNSFVVWSILKRMQKRSVTALMVLNLALA
DLAVLLTAPFFLHFLAQGTWSFGLAGCRLCHYVCGVSMYASVLLITAMSLDRSLAVARPFVS
QKLRTKAMARRVLAGIVVVLSFLLATPVLAYRTVVPWKTNMSLCFPRYPSEGHRAFHLIFEA
VTGFLLPFLAVVASYSDIGRRLQARRFRRSRRTGRLVVLIILTFAAFWLPYHVVNLAEAGRAL
AGQAAGLGLVGKRLSLARNVLIALAFLSSSVNPVLYACAGGGLLRSAGVGFVAKLLEGTGS
EASSTRRGGSLGQTARSGPAALEPGPSESLTASSPLKLNELN

(SEQ ID NO:1169)
>gi\|32261309\|ref\|NP_0720932\| probable G-protein coupled receptor 135
{Homosapiens}
MEEPQPPRPPASMALLGSQHSGAPSAAGPPGGTSSAATAAVLSFSTVATAALGNLSDASGGG
TAAAPGGGGLGGSGAAREAGAAVRRPLGPEAAPLLSHGAAVAAQALVLLLIFLLSSLGNCA
VMGVIVKHRQLRTVTNAFILSLSLSDLLTALLCLPAAFLDLFTPPGGSAPAAAAGPWRGFCA
ASRFFSSCFGIVSTLSVALISLDRYCAIVRPPREKIGRRRALQLLAGAWLTALGFSLPWELLGA
PRELAAAQSFHGCLYRTSPDPAQLGAAFSVGLVVACYLLPFLLMCFCHYHICKTVRLSDVRV
RPVNTYARVLRFFSEVRTATTVLIMIVFVICCWGPYCFLVLLAAARQAQTMQAPSLLSVVAV
WLTVVANGAINPVIYAIRNPNISMLLGRNREEGYRTRNVDAFLPSQGPGLQARSRSRLRNRYA
NRLGACNRMSSSNPASGVAGDVAMWARKNPVVLFCREGPPEPVTAVTKQPKSEAGDTSL

(SEQ ID NO:1170)
>gi\|32307152\|ref\|NP_0009072\| oxytocin receptor {Homosapiens}
MEGALAANVVSAEAANASAAPPGAEGNRTAGPPRRNEALARVEVAVLCLILLLALSGNACVL
LALRTTRQKHSRLFFFMKHLSIADLVVAVFQVLPQLLWDITFRFYGPDLLCRLVKYLQVVGM
FASTYLLLLMSLDRCLAICQPLRSLRRRTDRLAVLATWLGCLVASAPQVHIFSLREVADGVF
DCWAVFIQPWGPKAYITWITLAVYIVPVIVLAACYGLISFKIVVQNLRLKTAAAAAAEAPEGA
AAGDGGRVALARVSSVKLISKAKIRTVKMTFIIVLAFIVCWTPFFFVQMWSVWDANAPKEAS
AFIIVMLLASLNSCCNPWIYMLFTGHLFHELVQRFLCCSASYLKGRRLGETSASKKSNSSSFV
LSHRSSSQRSCSQPSTA

(SEQ ID NO:1171)
>gi\|32307159\|ref\|NP_0018742\| corticotropin-releasing factor receptor 2
precursor {Homosapiens}
MDAALLHSLLEANCSLALAEELLLDGWGPPLDPEGPYSYCNTTLDQIGTCWPRSAAGALVE
RPCPEYFNGVKYNTTRNAYRECLENGTWASKINYSQCEPILDDKQRKYDLHYRIALVVNYL
GHCVSVAALVAAFLLFLALRSIRCLRNVIHWNLITTFILRNVMWFLLQLVDHEVHESNEVVVC
RCITTIFNYFVVTNFFWMFVEGCYLHTAIVMTYSTERLRKCLFLFIGWCIPFPIIVAWAIGKLY
YENEQCWFGKEPGDLVDYIYQGPIILVLLINFVFLFNIVRILMTKLRASTTSETIQYRKAVKAT
LVLLPLLGITYMLFFVNPGEDDLSQIMFIYFNSFLQSFQGFFVSVFYCFFNGEVRSAVRKRWH
RWQDHHSLRVPMARAMSIPTSPTRISFHSIKQTAAV

(SEQ ID NO:1172)
>gi\|32401433\|ref\|NP_8614551\| G protein-coupled receptor 142 {Homosapiens}
MSIMMLPMEQKIQWVPTSLQDITAVLGTEAYTEEDKSMVSHAQKSQHSCLSHSRWLRSPQV
TGGSWDLR1RPSKDSSSFRQAQCLRKDPGANNHLESQGVRGTAGDADRELRGPSEKATAGQ
PRVTLLPTPHVSGLSQEFESHWPEIAERSPCVAGVIPVIYYSVLLGLGLPVSLLTAVALARLAT
RTRRPSYYYLLALTASDIIIQVVIVFAGFLLQGAVLARQVPQAVVRTANILEFAANHASVWIAI
LLTVDRYTALCHPLHHRAASSPGRTRRAIAAVLSAALLTGIPFYWWLDMWRDTDSPRTLDE
VLKWAHCLTVYFIPCGVFLVTNSAIIHRLRRRGRSGLQPRVGKSTAILLGITTLFTLLWAPRVF
VMLYHMYVAPVHRDWRVHLALDVANMVAMLHTAANFGLYCFVSKTFRATVRQVIHDAY
LPCTLASQPEGMAAKPVMEPPGLPTGAEV

(SEQ ID NO:1173)
>gi\|32401435\|ref\|NP_8614561\| G protein-coupled receptor 141 {Homosapiens}
MPGHNTSRNSSCDPIVTPHLISLYFIVLIGGLVGVISILFLLVKMNTRSVTTMAVINLVVVHSVF
LLTVPFRLTYLIKKTVVMFGLPFCKFVSAMLHIHMYLTFLFYVVILVTRYLIFFKCKDKVEFYR
KLHAVAASAGMWTLVIVIVVPLVVSRYGIHEEYNEEHCFKFHKELAYTYVKIINYMIVIFVIA
VAVILLVFQVFIIMLMVQKLRHSLLSHQEFVVAQLKNLFFIGVILVCFLPYQFFRIYYLNVVTHS
NACNSKVAFYNEIFLSVTAISCYDLLLFVFGGSHWFKQKIIGLWNCVLCR

(SEQ ID NO:1174)
>gi\|32483397 \|ref\|NP_000788 2\| d(4) dopamine receptor {Homosapiens}
MGNRSTADADGLLAGRGPAAGASAGASAGLAGQGAAALVGGVLLIGAVLAGNSLVCVSVA
TERALQTPTNSFIVSLAAADLLLALLVLPLFVYS EVQGGAWLLSPRLCDALMAMDVMLCTA
SIFNLCAISVDRFVAVAVPLRYNRQGGSRRQLLLIGATWLLSAAVAAPVLCGLNDVRGRDPA
VCRLEDRDYVVYSSVCS FFLPCPLMLLLYWATFRGLQRWEVARRAKLHGRAPRRPSGPGPP
SPTPPAPRLPQDPCGPDCAPPAPGLPRGPCGPDCAPAAPSLPQDPCGPDCAPPAPGLPPDPCGS
NCAPPDAVRAAALPPQTPPQTRRRRRAKITGRERKAMRVLPVVVGAFLLCWTPFFVVHITQA
LCPACSVPPRLVSAVTWLGYVNSALNPVIYTVFNAEFRNVFRKALRACC

(SEQ ID NO:1175)
>gi\|32490567\|ref\|NP_8710011\| relaxin-3 receptor 2 {Homosapiens}
MPTLNTSASPPTFFVVANASGGSVLSADDAPMPVKFLALRLMVALAYGLVGAIGLLGNLAVL
WVLSNCARRAPGPPSDTFVFNLALADLGLALTLPFVVAAESALDFHWPFGGALCKMVLTATV
LNVYASIFLITALSVARYWVVAMAAGPGTHLSLFVVARIATLAVWAAAALVTVPTAVFGVEG
EVCGVRLCLLRFPSRYVVLGAYQLQRVVLAFMVPLGVITTSYLLLLAFLQRRQRRRQDSRVV
ARSVRILVASFFLCWFPNHVVTLWGVLVKFDLVPWNSTFYTIQTYVFPVTTCLAHSNSCLNP
VLYCLLRREPRQALAGTFRDLRLRLWPQGGGWVQQVALKQVGRRWVASNPRESRPSTLLT
NLDRGTPG

(SEQ ID NO:1176)
>gi\|33598960\|ref\|NP_0006732\| alpha-2B adrenergic receptor {Homosapiens}
MDHQDPYSVQATAAIAAAITFLILFTIFGNALVILAVLTSRSLRAPQNLFLVSLAAADILVATLI
IPFSLANELLGYWYFRRTVVCEVYLALDVLFCTSSIVHLCAISLDRYWAVSRALEYNSKRTPRR
IKCIILTVWLIAAVISLPPLIYKGDQGPQPRGRPQCKLNQEAWYILASSIGSFFAPCLIMILVYLR
IYLIAKRSNRRGPRAKGGPGQGESKQPRPDHGGALASAKLPALASVASAREVNGHSKSTGEK
EEGETPEDTGTRALPPSWAALPNSGQGQKEGVCGASPEDEAEEEEEEEEEEEECEPQAVPVSP
ASACSPPLQQPQGSRVLATLRGQVLLGRGVGAIGGQWWRRRAQLTREKRFTFVLAVVIGVF
VLCWFPFFFSYSLGAICPKHCKVPHGLFQFFFWIGYCNSSLNPVIYTIFNQDFRRAFRRILCRP
WTQTAW

(SEQ ID NO:1177)
>gi\|33695097\|ref\|NP_0052922\| G protein-coupled receptor 35 {Homosapiens}
MNGTYNTCGSSDLTWPPAIKLGFYAYLGVLLVLGLLLNSLALWVFCCRMQQWTETRIYMT
NLAVADLCLLCTLPFVLHSLRDTSDTPLCQLSQGIYLTNRYMSISLVTAIAVDRYVAVRHPLR
ARGLRSPRQAAAVCAVLWVLVIGSLVARWLLGIQEGGFCFRSTRHNFNSMAFPLLGFYLPLA
VVVFCSLKVVTALAQRPPTDVGQAEATRKAARMVWANLLVFVVCFLPLHVGLTVRLAVG
WNACALLETIRRALYITSKLSDANCCLDAICYYYMAKEFQEASALAVAPSAKAHKSQDSLCV
TLA

(SEQ ID NO:1178)
>gi\|33695104\|ref\|NP_0035992\| G protein-coupled receptor 65 {Homosapiens}
MNSTCIEEQHDLDHYLFPIVYIFVIIVSIPANIGSLCVSFLQAKKESELGIYLFSLSLSDLLYALT
LPLWIDYTWNKDNWTFSPALCKGSAFLMYMNFYSSTAFLTCIAVDRYLAVVYPLKFFFLRTR
RFALMVSLSIVVILETIFNAVMLWEDETVVEYCDAEKSNFTLCYDKYPLEKWQINLNLFRTCT
GYAIPLVTILICNRKVYQAVRHNKATENKEKKRIIKLLVSITVTFVLCFTPFHVMLLIRCILEHA
VNFEDHSNSGKRTYTMYRITVALTSLNCVADPILYCFVTETGRYDMWNILKFCTGRCNTSQR
QRKRILSVSTKDTMELEVLE

(SEQ ID NO:1179)
>gi\|33695107\|ref\|NP_0056742\| G-protein coupled receptor 55 {Homosapiens}
MSQQNTSGDCLFDGVNELMKTLQFAVHIPTFVLGLLLNLLAIHGFSTFLKNRWPDYAATSIY
MINLAVFDLLLVLSLPFKMVLSQVQSPFPSLCTLVECLYFVSMYGSVFTICFISMDRFLAIRYP
LLVSHLRSPRKIFGICCTIVVVLVVVTGSIPIYSFHGKVEKYMCFHNMSDDTWSAKVFFPLEVFG
FLLPMGIMGFCCSRSIHILLGRRDHTQDWVQQKACIYSIAASLAVFVVSFLPVHLGFFLQFLV
RNSFIVECRAKQSISFFLQLSMCFSNVNCCLDVFCYYFVIKEFRMNIRAHRPSRVQLVLQDTTI
SRG

(SEQ ID NO:1180)
>gi\|33695113\|ref\|NP_0057582\| G-protein coupled purinergic receptor P2Y5
{Homosapiens}
MVSVNSSHCFYNDSFKYTLYGCMFSMVFVLGLISNCVAIYIFICVLKVRNETTTYMINLAMS
DLLFVFTLPFRIFYFTTRNWPFGDLLCKISVMLFYTNMYGSILFLTCISVDRFLAIVYPFKSKTL
RTKRNAKIVCTGVWLTVIGGSAPAVFVQSTHSQGNNASEACFENFPEATWKTYLSRIVIFIEIV
GFFIPLILNVTCSSMVLKTLTKPVTLSRSKINKTKVLKMIFVHLIIFCFCFVPYNINLILYSLVRT
QTFVNCSVVAAVRTMYPITLCIAVSNCCFDPIVYYFTSDTIQNSIKMKNWSVRRSDFRFSEVH
GAENFIQHNLQTLKSKIFDNESAA

(SEQ ID NO:1181)
>gi\|34577052\|ref\|NP_0052333\| proteinase-activated receptor 2 precursor
{Homosapiens}
MRSPSAAWLLGAAILLAASLSCSGTIQGTNRSSKGRSLIGKVDGTSHVTGKGVTVETVFSVDE
FSASVLTGKLTTVFLPIVYTIVFVVGLPSNGMALWVFLFRTKKKHPAVIYMANLALADLLSVI
WFPLKIAYHIHGNNWIYGEALCNVLIGFFYGNMYCSILFMTCLSVQRYWVIVNPMGHSRKK
ANIAIGISLAIWLLILLVTIPLYVVKQTIFIPALNITTCHDVLPEQLLVGDMFNYFLSLAIGVFLF
PAFLTASAYVLMIRMLRSSAMDENSEKKRKRAIKLIVTVLAMYLICFTPSNLLLVVHYFLIKS
QGQSHVYALYIVALCLSTLNSCIDPFVYYFVSHDFRDHAKNALLCRSVRTVKQMQVSLTSKK
HSRKSSSYSSSSTTVKTSY

(SEQ ID NO:1182)
>gi\|36951012\|ref\|NP_0052702\| probable G-protein coupled receptor 1
{Homosapiens}
MEDLEETLFEEFENYSYDLDYYSLESDLEEKVQLGVVHWVSLVLYCLAFVLGIPGNAIVIVVF
TGFKWKKTVTTLWFLNLAIADFIFLLFLPLYISYVAMNFHWPFGIVVLCKANSFTAQLNMFAS
VFFLTVISLDHYIHLIHPVLSHRHRTLKNSLIVIIFIVVLLASLIGGPALYFRDTVEFNNHTLCYNN
FQKHDPDLTLIRHHVLTWVKFIIGYLFPLLTMSICYLCLIFKVKKRSILISSRHFWTILVVVVAF
VVCWTPYHLFSIVVELTIHHNSYSHHVMQAGIPLSTGLAFLNSCLNPILYVLISKKFQARFRSSV
AEILKYTLWEVSCSGTVSEQLRNSETKNLCLLETAQ

(SEQ ID NO:1183)
>gi\|36951034\|ref\|NP_5430092\| G-protein coupled receptor 78 {Homosapiens}
MGPGEALLAGLLVMVLAVALLSNALVLLCCAYSAELRTRASGVLLVNLSLGHLLLAALDMP
FTLLGVMRGRTPSAPGACQVIGFLDTFLASNAALSVAALSADQWLAVGFPLRYAGRLRPRY
AGLLLGCAWGQSLAFSGAALGCSWLGYSSAFASCSLRLPPEPERPRFAAFTATLHAVGFVLP
LAVLCLTSLQVHRVARRHCQRMDTVTMKALALLADLHPSVRQRCLIQQKRRRHRATRKIGI
AIATFLICFAPYVMTRLAELVPFVTVNAQWGILSKCLTYSKAVADPFTYSLLRRPFRQVLAG
MVHRLLKRTPRPASTHDSSLDVAGMVHQLLKRTPRPASTHNGSVDTENDSCLQQTH

(SEQ ID NO:1184)
>gi\|37187860\|ref\|NP_0043582\| C-C chemokine receptor type 6 {Homosapiens}
MSGESMNFSDVFDSSEDYFVSVNTSYYSVDSEMLLCSLQEVRQFSRLFVPIAYSLICVFGLLG
NILVVITFAFYKKARSMTDVYLLNMAIADILFVLTLPFVVAVSHATGAWVFSNATCKLLKGIY
AINFNCGMLLLTCISMDRYIAIVQATKSFRLRSRTLPRSKIICLVVVVGLSVHSSSTFVFNQKYN
TQGSDVCEPKYQTVSEPIRWKLLMLGLELLFGFFIPLMFMIFCYTFIVKTLVQAQNSKRHKAI
RVIIAVVLVFLACQIPHNMVLLVTAANLGKMNRSCQSEKLIGYTKTVTEVLAFLHCCLNPVL
YAFIGQKFRNYFLKILKDLWCVRRKYKSSGFSCAGRYSENISRQTSETADNDNASSFTM

(SEQ ID NO:1185)
>gi\|37577159\|ref\|NP_0003792\| calcium-sensing receptor precursor {Homosapiens}
MAFYSCCWVLLALTWHTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQDLKSRPESVECIR
YNFRGFRWLQAMIFAIEEINSSPALLPNLTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLD
EFCNCSEHIPSTIAVVGATGSGVSTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDE
HQATAMADHEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQHV
VEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIVVLASEAWASSSLIAMPQYFHVVGGTIGF
ALKAGQIPGFREFLKKVHPRKSVHNGFAKEFVVEETFNCHLQEGAKGPLPVDTFLRGHEESGD
RFSNSSTAFRPLCTGDENISSVETPYIDYTHLRISYNVYLAVYSIAHALQDIYTCLPGRGLFTNG
SCADIKKVEAWQVLKHLRHLNFTNNMGEQVTFDECGDLVGNYSIINWHLSPEDGSIVFKEV
GYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGE
YSDETDASACNKCPDDFWSNENHTSCIAKEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIK
FRNTPIVKATNRELSYLLLFSLLCCFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRV
LLVFEAKIPTSFHRKWWGLNLQFLLVFLCTFMQIVICVIVVLYTAPPSSYRNQELEDEIIFITCHE
GSLMALGFLIGYTCLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFV
SAVEVIAILAASFGLLACIFFNKIYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRKR
SSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKQQQPLALTQQEQQQQPLTLPQQQRSQQQPRC
KQKVIFGSGTVTFSLSFDEPQKNAMAHRNSTHQNSLEAQKSSDTLTRHQPLLPLQCGETDLD
LTVQETGLQGPVGGDQRPEVEDPEELSPALVVSSSQSFVISGGGSTVTENVVNS

(SEQ ID NO:1186)
>gi\|37622910\|ref\|NP_0007292\| cholinergic receptor, muscarinic 1 {Homosapiens}
MNTSAPPAVSPNITVLAPGKGPWQVAFIGITTGLLSLATVTGNLLVLISFKVNTELKTVNNYF
LLSLACADLIIGTFSMNLYTTYLLMGHWALGTLACDLWLALDYVASNASVMNLLLISFDRYF
SVTRPLSYRAKRTPRRAALMIGLAWLVSFVLWAPAILFWQYLVGERTVLAGQCYIQFLSQPII
TFGTAMAAFYLPVTVMCTLYWRIYRETENRARELAALQGSETPGKGGGSSSSSERSQPGAEG
SPETPPGRCCRCCRAPRLLQAYSWKEEEEEDEGSMESLTSSEGEEPGSEVVIKMPMVDPEAQ
APTKQPPRSSPNTVKRPTKKGRDRAGKGQKPRGKEQLAKRKTFSLVKEKKAARTLSAILLAF
ILTWTPYNIMVLVSTFCKDCVPETLWELGYWLCYVNSTINPMCYALCNKAFRDTFRLLLLCR
WDKRRWRKIPKRPGSVHRTPSRQC

(SEQ ID NO:1187)
>gi\|38194224\|ref\|NP_0052892\| G protein-coupled receptor 25 {Homosapiens}
MAPTEPWSPSPGSAPWDYSGLDGLEELELCPAGDLPYGYVYIPALYLAAFAVGLLGNAFVV
WLLAGRRGPRRLVDTFVLHLAAADLGFVLTLPLWAAAAALGGRWPFGDGLCKLSSFALAG
TRCAGALLLAGMSVDRYLAVVKLLEARPLRTPRCALASCCGVWAVALLAGLPSLVYRGLQP
LPGGQDSQCGEEPSHAFQGLSLLLLLLTFVLPLVVTLFCYCRISRRLRRPPHVGRARRNSLRIIF
AIESTFVGSWLPFSALRAVFHLARLGALPLPCPLLLALRWGLTIATCLAFVNSCANPLIYLLLD
RSFRARALDGACGRTGRLARRISSASSLSRDDSSVFRCRAQAANTASASW

(SEQ ID NO:1188)
>gi\|38455410\|ref\|NP_9407991\| growth hormone secretagogue receptor type 1
isoform 1a {Homosapiens}
MWNATPSEEPGFNLTLADLDWDASPGNDSLGDELLQLFPAPLLAGVTATCVALFVVGIAGN
LLTMLVVSRFRELRTTTNLYLSSMAFSDLLIFLCMPLDLVRLWQYRPWNFGDLLCKLFQFVS
ESCTYATVLTITALSVERYFAICFPLRAKVVVTKGRVKLVIFVIVVAVAFCSAGPIFVLVGVEHE
NGTDPWDTNECRPTEFAVRSGLLTVMVWVSSIFFFLPVFCLTVLYSLIGRKLWRRRRGDAVV
GASLRDQNHKQTVKMLAVVVFAFILCWLPFHVGRYLFSKSFEPGSLEIAQISQYCNLVSFVLF
YLSAAINPILYNIMSKKYRVAVFRLLGFEPFSQRKLSTLKDESSRAWTESSINT

(SEQ ID NO:1189)
>gi\|38455413\|ref\|NP_0020213\| N-formyl peptide receptor 3 {Homosapiens}
METNFSIPLNETEEVLPEPAGHTVLWIFSLLVHGVTFVFGVLGNGLVIVVVAGFRMTRTVNTIC
YLNLALADFSFSAILPFRMVSVAMREKWPFGSFLCKLVHVMIDINLFVSVYLITIIALDRCICV
LHPAWAQNHRTMSLAKRVMTGLWIFTIVLTLPNFIFVVTTISTTNGDTYCIFNFAFWGDTAVE
RLNVFITMAKVFLILHFIIGFSVPMSIITVCYGIIAAKIHRNHMIKSSRPLRVFAAVVASFFICWF
PYELIGILMAVWLKEMLLNGKYKIILVLINPTSSLAFFNSCLNPILYVFMGRNFQERLIRSLPTS
LERALTEVPDSAQTSNTDTTSASPPEETELQAM

(SEQ ID NO:1190)
>gi\|38505172\|ref\|NP_0009482\| prostaglandin E receptor 3, subtype EP3 isoform

1 {Homosapiens}
MKETRGYGGDAPFCTRLNHSYTGMWAPERSAEARGNLTRPPGSGEDCGSVSVAFPITMLLT
GFVGNALAMLLVSRSYRRRESKRKKSFLLCIGWLALTDLVGQLLTTPVVIVVYLSKQRWEHI
DPSGRLCTFFGLTMTVFGLSSLFIASAMAVERALAIRAPHWYASHMKTRATRAVLLGVWLA
VLAFALLPVLGVGQYTVQWPGTWCFISTGRGGNGTSSSHNVVGNLFFASAFAFLGLLALTVTF
SCNLATIKALVSRCRAKATASQSSAQWGRITTETAIQLMGIMCVLSVCWSPLLIMMLKMIFN
QTSVEHCKTHTEKQKECNFFLIAVRLASLNQILDPWVYLLLRKILLRKFCQMRKRRLREQAP
LLPTSTVIDPSRFCAQPFRWFLDLSFPAMSSSHPQLPLTLASFKLLREPCSVQLS

(SEQ ID NO:1191)
>gi\|38505194\|ref\|NP_0009462\| prostaglandin E2 receptor EP1 subtype
{Homosapiens}
MSPCGPLNLSLAGEATTCAAPWVPNTSAVPPSGASPALPIFSMTLGAVSNLLALALLAQAAG
RLRRRRSAATFLLFVASLLATDLAGHVIPGALVLRLYTAGRAPAGGACHFLGGCMVFFGLCP
LLLGCGMAVERCVGVTRPLLHAARVSVARARLALAAVAAVALAVALLPLARVGRYELQYP
GTWCFIGLGPPGGWRQALLAGLFASLGLVALLAALVCNTLSGLALLRARWRRRSRRPPPAS
GPDSRRRWGAHGPRSASASSASSIASASTFFGGSRSSGSARRARAHDVEMVGQLVGIMVVSC
ICWSPMLVLVALAVGGWSSTSLQRPLFLAVRLASWNQILDPWVYILLRQAVLRQLLRLLPPR
AGAKGGPAGLGLTPSAWEASSLRSSRHSGLSHF

(SEQ ID NO:1192)
>gi\|38678524\|ref\|NP_8595281\| opsin 5 isoform 1 {Homosapiens}
MALNHTALPQDERLPHYLRDGDPFASKLSWEADLVAGFYLTIIGILSTFGNGYVLYMSSRRK
KKLRPAEIMTINLAVCDLGISVVGKPFTIISCFCHRWVFGWIGCRWYGWAGFFFGCGSLITMT
AVSLDRYLKICYLSYGVWLKRKHAYICLAAIVVAYASFVVTTMPLVGLGDYVPEPFGTSCTLD
WWLAQASVGGQVFILNILFFCLLLPTAVIVFSYVKIIAKVKSSSKEVAHFDSRIHSSHVLEMKL
TKVAMLICAGFLIAWIPYAVVSVWSAFGRPDSIPIQLSVVPTLLAKSAAMYNPIIYQVIDYKFA
CCQTGGLKATKKKSLEGFRLHTVTTVRKSSAVLEIHEEWE

(SEQ ID NO:1193)
>gi\|38683844\|ref\|NP_0571672\| cannabinoid receptor 1 isoform a {Homosapiens}
MKSILDGLADTTFRTITTDLLYVGSNDIQYEDIKGDMASKLGYFPQKFPLTSFRGSPFQEKMT
AGDNPQLVPADQVNITEFYNKSLSSFKENEENIQCGENFMDIECFMVLNPSQQLAIAVLSLTL
GTFTVLENLLVLCVILHSRSLRCRPSYHFIGSLAVADLLGSVIFVYSFIDFHVFHRKDSRNVFLF
KLGGVTASFTASVGSLFLTAIDRYISIHRPLAYKRIVTRPKAVVAFCLMWTIAIVIAVLPLLGW
NCEKLQSVCSDIFPHIDETYLMFVVIGVTSVLLLFIVYAYMYILWKAHSHAVRMIQRGTQKSIII
HTSEDGKVQVTRPDQARMDIRLAKTLVLILVVLIICWGPLLAIMVYDVFGKMNKLIKTVFAF
CSMLCLLNSTVNPIIYALRSKDLRHAFRSMFPSCEGTAQPLDNSMGDSDCLHKHANNAASVH
RAAESCIKSTVKIAKVTMSVSTDTSAEAL

(SEQ ID NO:1194)
>gi\|38788193\|ref\|NP_0052172\| sphingosine-1-phosphate receptor 3 {Homosapiens}
MATALPPRLQPVRGNETLREHYQYVGKLAGRLKEASEGSTLTTVLFLVICSFIVLENLMVLIA
IVVKNNKFHNRMYFFIGNLALCDLLAGIAYKVNILMSGKKTFSLSPTVWFLREGSMFVALGAS
TCSLLAIAIERHLTMIKMRPYDANKRHRVFLLIGMCWLIAFTLGALPILGWNCLHNLPDCSTIL
PLYSKKYIAFCISIFTAILVTIVILYARIYFLVKSSSRKVANHNNSERSMALLRTVVIVVSVFIAC
WSPLFILFLIDVACRVQACPILFKAQWFIVLAVLNSAMNPVIYTLASKEMRRAFFRLVCNCLV
RGRGARASPIQPALDPSRSKSSSSNNSSHSPKVKEDLPHTAPSSCIMDKNAALQNGIFCN

(SEQ ID NO:1195)
>gi\|39725940\|ref\|NP_0009032\| kappa-type opioid receptor {Homosapiens}
MDSPIQIFRGEPGPTCAPSACLPPNSSAWFPGWAEPDSNGSAGSEDAQLEPAHISPAIPVIITAV
YSVVFVVGLVGNSLVMFVIIRYTKMKTATNIYIFNLALADALVTTTMPFQSTVYLMNSWPFG
DVLCKIVISIDYYNMFTSIFTLTMMSVDRYIAVCHPVKALDFRTPLKAKIINICIVVLLSSSVGIS
AIVLGGTKVREDVDVIECSLQFPDDDYSWWDLFMKICVFIFAFVIPVLIIIVCYTLMILRLKSV
RLLSGSREKDRNLRRITRLVLVVVAVFVVCWTPIHIFILVEALGSTSHSTAALSSYYFCIALGY
TNSSLNPILYAFLDENFKRCFRDFCFPLKMRMERQSTSRVRNTVQDPAYLRDIDGMNKPV

(SEQ ID NO:1196)
>gi\|40217829\|ref\|NP_0034762\| ovarian cancer G-protein coupled receptor 1 {Homosapiens}
MRSVAPSGPKMGNITADNSSMSCTIDHTIHQTLAPVVYVTVLVVGFPANCLSLYFGYLQIKA
RNELGVYLCNLTVADLFYICSLPFVVLQYVLQHDNWSHGDLSCQVCGILLYENIYISVGFLCCI
SVDRYLAVAHPFRFHQFRTLKAAVGVSVVIWAKELLTSIYFLMHEEVIEDENQHRVCFEHYPI
QAWQRAINYYRFLVGFLFPICLLLASYQGILRAVRRSHGTQKSRKDQIQRLVLSTVVIFLACF
LPYHVLLLVRSVVVEASCDFAKGVFNAYHFSLLLTSFNCVADPVLYCFVSETTHRDLARLRGA
CLAFLTCSRTGRAREAYPLGAPEASGKSGAQGEEPELLTKLHPAFQTPNSPGSGGFPTGRLA

(SEQ ID NO:1197)
>gi\|40217833\|ref\|NP_0611233\| G-protein coupled receptor family C group 5
member C isoform b {Homosapiens}
MGTQPEPGLGARMAIHKALVMCLGLPLFLFPGAWAQGHVPPGCSQGLNPLYYNLCDRSGA
WGIVLEAVAGAGIVTTFVLTIILVASLPFVQDTKKRSLLGTQVFFLLGTLGLFCLVFACVVKP
DFSTCASRRFLFGVLFAICFSCLAAHVFALNFLARKNHGPRGWVIFTVALLLTLVEVIINTEWL
IITLVRGSGEGGPQGNSSAGWAVASPCAIANMDFVMALIYVMLLLLGAFLGAWPALCGRYK
RWRKHGVFVLLTTATSVAIWVVWIVMYTYGNKQHNSPTWDDPTLAIALAANAWAFVLFYV
IPEVSQVTKSSPEQSYQGDMYPTRGVGYETILKEQKGQSMFVENKAFSMDEPVAAKRPVSPY
SGYNGQLLTSVYQPTEMALMHKVPSEGAYDIILPRATANSQVMGSANSTLRAEDMYSAQSH
QAATPPKDGKNSQVFRNPYVVVD

(SEQ ID NO:1198)
>gi\|40255245\|ref\|NP_0054495\| gamma-aminobutyric acid type B receptor subunit
2 precursor {Homosapiens}
MASPRSSGQPGPPPPPPPPPARLLLLLLLPLLLPLAPGAWGWARGAPRPPPSSPPLSIMGLMPL
TKEVAKGSIGRGVLPAVELAIEQIRNESLLRPYFLDLRLYDTECDNAKGLKAFYDAIKYGPNH
LMVFGGVCPSVTSHAESLQGWNLVQLSFAATTPVLADKKKYPYFFRTVPSDNAVNPAILKLL
KHYQWKRVGTLTQDVQRFSEVRNDLTGVLYGEDIEISDTESFSNDPCTSVKKLKGNDVRIIL
GQFDQNMAAKVFCCAYEENMYGSKYQWIIPGWYEPSWWEQVHTEANSSRCLRKNLLAAM
EGYIGVDFEPLSSKQIKTISGKTPQQYEREYNNKRSGVGPSKFHGYAYDGIVVVIAKTLQRAM
ETLHASSRHQRIQDFNYTDHTLGRIILNAMNETNFFGVTGQVVFRNGERMGTIKFTQFQDSRE
VKVGEYNAVADTLEIINDTIRFQGSEPPKDKTIILEQLRKISLPLYSILSALTILGMIMASAFLFF
NIKNRNQKLIKMSSPYMNNLIILGGMLSYASIFLFGLDGSFVSEKTFETLCTVRTVVILTVGYTT
AFGAMFAKTWRVHAIFKNVKMKKKIIKDQKLLVIVGGMLLIDLCILICWQAVDPLRRTVEKY
SMEPDPAGRDISIRPLLEHCENTHMTIVVLGIVYAYKGLLMLFGCFLAWETRNVSIPALNDSKY
IGMSVYNVGIMCIIGAAVSFLTRDQPNVQFCIVALVIIFCSTITLCLVFVPKLITLRTNPDAATQ
NRRFQFTQNQKKEDSKTSTSVTSVNQASTSRLEGLQSENHRLRMKITELDKDLEEVTMQLQD
TPEKTTYIKQNHYQELNDILNLGNFTESTDGGKAILKNHLDQNPQLQWNTTEPSRTCKDPIED
INSPEHIQRRLSLQLPILHHAYLPSIGGVDASCVSPCVSPTASPRHRHVPPSFRVMVSGL

(SEQ ID NO:1199)
>gi\|40385873\|ref\|NP_9547131\| G protein-coupled receptor 150 {Homosapiens}
MEDLFSPSILPPAPNISVPILLGWGLNLTLGQGAPASGPPSRRVRLVFLGVILVVAVAGNTTVL
CRLCGGGGPWAGPKRRKMDFLLVQLALADLYACGGTALSQLAWELLGEPRAATGDLACRF
LQLLQASGRGASAHLVVLIALERRRAVRLPHGRPLPARALAALGWLLALLLALPPAFVVRGD
SPSPLPPPPPPTSLQPGAPPAARAWPGERRCHGIFAPLPRWHLQVYAFYEAVAGFVAPVTVLG
VACGHLLSVWWRHRPQAPAAAAPWSASPGRAPAPSALPRAKVQSLKMSLLLALLFVGCELP
YFAARLAAAWSSGPAGDWEGEGLSAALRVVAMANSALNPFVYLFFQAGDCRLRRQLRKRL
GSLCCAPQGGAEDEEGPRGHQALYRQRWPHPHYHHARREPLDEGGLRPPPPRPRPLPCSCES
AF

(SEQ ID NO:1200)
>gi\|40807489\|ref\|NP_0019653\| EGF-like module-containing mucin-like hormone
receptor-like 1 precursor {Homosapiens}
MRGFNLLLFWGCCVMHSWEGHIRPTRKPNTKGNNCRDSTLCPAYATCTNTVDSYYCACKQ
GFLSSNGQNHFKDPGVRCKDIDECSQSPQPCGPNSSCKNLSGRYKCSCLDGFSSPTGNDWVP
GKPGNFSCTDINECLTSSVCPEHSDCVNSMGSYSCSCQVGFISRNSTCEDVDECADPRACPEH
ATCNNTVGNYSCFCNPGFESSSGHLSFQGLKASCEDIDECTEMCPINSTCTNTPGSYFCTCHP
GFAPSNGQLNFTDQGVECRDIDECRQDPSTCGPNSICTNALGSYSCGCIAGFHPNPEGSQKDG
NFSCQRVLFKCKEDVIPDNKQIQQCQEGTAVKPAYVSFCAQINNIFSVLDKVCENKTTVVSLK
NTTESFVPVLKQISTWTKFTKEETSSLATVFLESVESMTLASFVVKPSANITPAVRTEYLDIESK
VINKECSEENVTLDLVAKGDKMKIGCSTIEESESTETTGVAFVSFVGMESVLNERFFKDHQAP
LTTSEIKLKMNSRVVGGIMTGEKKDGFSDPIIYTLENIQPKQKFERPICVSWSTDVKGGRWTS
FGCVILEASETYTICSCNQMANLAVIMASGELTMDFSLYIISHVGIIISLVCLVLAIATFLLCRSI
RNHNTYLHLHLCVCLLLAKTLFLAGIHKTDNKMGCAIIAGFLHYLFLACFFVVMLVEAVILFL
MVRNLKVVNYFSSRNIKMLHICAFGYGLPMLVVVISASVQPQGYGMHNRCWLNTETGFIVVS
FLGPVCTVIVINSLLLTWTLWILRQRLSSVNAEVSTLKDTRLLTFKAFAQLFILGCSWVLGIFQI
GPVAGVMAYLFTIINSLQGAFIFLIHCLLNGQVREEYKRWITGKTKPSSQSQTSRILLSSMPSA
SKT

(SEQ ID NO:1201)
>gi\|41281557\|ref\|NP_05573621\| atrophilin-1 isoform 2 precursor {Homosapiens}
MARLAAVLWNLCVTAVLVTSATQGLSRAGLPFGLMRRELACEGYPIELRCPGSDVIMVENA
NYGRTDDKICDADPFQMENVQCYLPDAFKIMSQRCNNRTQCVVVAGSDAFPDPCPGTYKYL
EVQYDCVPYIFVCPGTLQKVLEPTSTHESEHQSGAWCKDPLQAGDRIYVMPWIPYRTDTLTE
YASWEDYVAARHTTTYRLPNRVDGTGFVVYDGAVFYNKERTRNIVKYDLRTRIKSGETVIN
TANYHDTSPYRWGGKTDIDLAVDENGLWVIYATEGNNGRLVVSQLNPYTLRFEGTWETGY
DKRSASNAFMVCGVLYVLRSVYVDDDSEAAGNRVDYAFNTNANREEPVSLTFPNPYQFISS
VDYNPRDNQLYVWNNYFVVRYSLEFGPPDPSAGPATSPPLSTTTTARPTPLTSTASPAATTPL
RRAPLTTHPVGAINQLGPDLPPATAPVPSTRRPPAPNLHVSPELFCEPREVRRVQWPATQQGM
LVERPCPKGTRGIASFQCLPALGLWNPRGPDLSNCTSPWVNQVAQKIKSGENAANIASELAR
HTRGSIYAGDVSSSVKLMEQLLDILDAQLQALRPIERESAGKNYNKMHKRERTCKDYIKAVV
ETVDNLLRPEALESWKDMNATEQVHTATMLLDVLEEGAFLLADNVREPARFLAAKENVVL
EVTVLNTEGQVQELVFPQEEYPRKNSIQLSAKTIKQNSRNGVVKVVFILYNNLGLFLSTENAT
VKLAGEAGPGGPGGASLVVNSQVIAASINKESSRVFLMDPVIFTVAHLEDKNHFNANCSFVVN
YSERSMLGYWSTQGCRLVESNKTHTTCACSHLTNFAVLMAHREIYQGRINELLLSVITWVGI
VISLVCLAICISTFCFLRGLQTDRNTIHKNLCINLFLAELLFLVGIDKTQYEIACPIFAGLLHYFF
LAAFSWLCLEGVHLYLLLVEVFESEYSRTKYYYLGGYCFPALVVGIAAAIDYRSYGTEKAC
WLRVDNYFIVVSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSWALGAIALLF
LLGLTWAFGLLFINKESVVMAYLFTTFNAFQGVFIFVFHCALQKKVHKEYSKCLRHSYCCIRS
PPGGTHGSLKTSAMRSNTRYYTGTQSRIRRMWNDTVRKQTESSFMAGDINSTPTLNRGTMG
NHLLTNPVLQPRGGTSPYNTLIAESVGFNPSSPPVFNSPGSYREPKHPLGGREACGMDTLPLN
GNFNNSYSLRSGDFPPGDGGPEPPRGRNLADAAAFEKMIISELVHNNLRGSSSAAKGPPPPEP
PVPPVPGGGGEEEAGGPGGADRAEIELLYKALEEPLLLPRAQSVLYQSDLDESESCTAEDGAT
SRPLSSPPGRDSLYASGANLRDSPSYPDSSPEGPSEALPPPPPAPPGPPEIYYTSRPPALVARNPL
QGYYQVRRPSHEGYLAAPGLEGPGPDGDGQMQLVTSL

(SEQ ID NO:1202)
>gi\|41584200\|ref\|NP_0056733\| G-protein coupled receptor 56 isoform a precursor {Homosapiens }
MTPQSLLQTTLFLLSLLFLVQGAHGRGHREDFRFCSQRNQTHRSSLHYKPTPDLRISIENSEEA
LTVHAPFPAAHPASRSFPDPRGLYHFCLYWNRHAGRLHLLYGKRDFLLSDKASSLLCFQHQE
ESLAQGPPLLATSVTSWWSPQNISLPSAASFTFSFHSPPHTAAHNASVDMCELKRDLQLLSQF
LKHPQKASRRPSAAPASQQLQSLESKLTSVRFMGDMVSFEEDRINATVWKLQPTAGLQDLHI
HSRQEEEQSEIMEYSVLLPRTLFQRTKGRSGEAEKRLLLVDFSSQALFQDKNSSQVLGEKVLG
IVVQNTKVANLTEPVVLTFQHQLQPKNVTLQCVFVVVEDPTLSSPGHWSSAGCETVRRETQTS
CFCNHLTYFAVLMVSSVEVDAVHKHYLSLLSYVGCVVSALACLVTIAAYLCSRVPLPCRRKP
RDYTIKVHMNLLLAVFLLDTSFLLSEPVALTGSEAGCRASAIFLHFSLLTCLSWMGLEGYNLY
RLVVEVFGTYVPGYLLKLSAMGWGFPIFLVTLVALVDVDNYGPIILAVHRTPEGVIYPSMCW
IRDSLVSYITNLGLFSLVFLFNMAMLATMVVQILRLRPHTQKWSHVLTLLGLSLVLGLPWALI
FFSFASGTFQLVVLYLFSIITSFQGFLIFIVVYVVSMRLQARGGPSPLKSNSDSARLPISSGSTSSSR
I

(SEQ ID NO:1203)
>gi\|42794265\|ref\|NP_9446052\| mas-related G-protein coupled receptor member D
{Homosapiens}
MNQTLNSSGTVESALNYSRGSTVHTAYLVLSSLAMFTCLCGMAGNSMVIVVLLGFRMHRNPF
CIYILNLAAADLLFLFSMASTLSLETQPLVNTTDKVHELMKRLMYFAYTVGLSLLTAISTQRC
LSVLFPIVVFKCHRPRHLSAWVCGLLWTLCLLMNGLTSSFCSKFLKFNEDRCFRVDMVQAALI
MGVLTPVMTLSSLTLFVWVRRSSQQWRRQPTRLFVVVLASVLVFLICSLPLSIYWFVLYWLS
LPPEMQVLCFSLSRLSSSVSSSANPVIYFLVGSRRSHRLPTRSLGTVLQQALREEPELEGGETPT
VGTNEMGA

(SEQ ID NO:1204)
>gi\|42822887\|ref\|NP_0020272\| Duffy blood group antigen isoform b
{Homosapiens}
MGNCLHRAELSPSTENSSQLDFEDVWNSSYGVNDSFPDGDYGANLEAAAPCHSCNLLDDSA
LPFFILTSVLGILASSTVLFMLFRPLFRWQLCPGWPVLAQLAVGSALFSIVVPVLAPGLGSTRS
SALCSLGYCVWYGSAFAQALLLGCHASLGHRLGAGQVPGLTLGLTVGIVVGVAALLTLPVTL
ASGASGGLCTLIYSTELKALQATHTVACLAIFVLLPLGLFGAKGLKKALGMGPGPWMNILW
AWFIFVVWPHGVVLGLDFLVRSKLLLLSTCLAQQALDLLLNLAEALAILHCVATPLLLALFCH
QATRTLLPSLPLPEGWSSHLDTLGSKS

(SEQ ID NO:1205)
>gi\|45433552\|ref\|NP_9421222\| probable G-protein coupled receptor 133
precursor {Homosapiens}
MEKLLRLCCWYSWLLLFYYNFQVRGVYSRSQDHPGFQVLASASHYWPLENVDGIHELQDT
TGDIVEGKVNKGIYLKEEKGVTLLYYGRYNSSCISKPEQCGPEGVTFSFFWKTQGEQSRPIPS
AYGGQVISNGFKVCSSGGRGSVELYTRDNSMTWEASFSPPGPYVVTHVLFTVVKSKEGLKVYV
NGTLSTSDPSGKVSRDYGESNVNLVIGSEQDQAKCYENGAFDEFIIVVERALTPDEIAMYFTAA
IGKHALLSSTLPSLFMTSTASPVMPTDAYHPIITNLTEERKTFQSPGVILSYLQNVSLSLPSKSLS
EQTALNLTKTFLKAVGEILLLPGWIALSEDSAVVLSLIDTIDTVMGHVSSNLHGSTPQVTVEG
SSAMAEFSVAKILPKTVNSSHYRFPAHGQSFIQIPHEAFHRHAWSTVVGLLYHSMHYYLNNI
WPAHTKIAEAMHHQDCLLFATSHLISLEVSPPPTLSQNLSGSPLITVHLKHRLTRKQHSEATNS
SNRVFVYCAFLDFSSGEGVVVSNHGCALTRGNLTYSVCRCTHLTNFAILMQVVPLELARGHQ
VALSSISYVGCSLSVLCLVATLVTFAVLSSVSTIRNQRYHIHANLSFAVLVAQVLLLISFRLEP
GTTPCQVMAVLLHYFFLSAFAWMLVEGLHLYSMVIKVFGS EDSKHRYYYGMGWGFPLLICI
ISLSFAMDSYGTSNNCWLSLASGAIWAFVAPALFVIVVNIGILIAVTRVISQISADNYKIHGDPS
AFKLTAKAVAVLLPILGTSWVFGVLAVNGCAVVFQYMFATLNSLQGLFIFLFHCLLNSEVRA
AFKHKTKVWSLTSSSARTSNAKPFHSDLMNGTRPGMASTKLSPWDKSSHSAHRVDLSAV

(SEQ ID NO:1206)
>gi\|4624367 1 \|ref\|NP_9968801\| G protein-coupled receptor 152 {Homosapiens }
MDTTMEADLGATGHRPRTELDDEDSYPQGGWDTVFLVALLLLGLPANGLMAWLAGSQAR
HGAGTRLALLLLSLALSDFLFLAAAAFQILEIRHGGHWPLGTAACRFYYFLWGVSYSSGLFLL
AALSLDRCLLALCPHWYPGHRPVRLPLWVCAGVWVLATLFSVPWLVFPEAAVWWYDLVIC
LDFWDSEELSLRMLEVLGGFLPFLLLLVCHVLTQATACRTCHRQQQPAACRGFARVARTILS
AYVVLRLPYQLAQLLYLAFLWDVYSGYLLWEALVYSDYLILLNSCLSPFLCLMASADLRTLL
RSVLSSFAAALCEERPGSFTPTEPQTQLDSEGPTLPEPMAEAQSQMDPVAQPQVNPTLQPRSD
PTAQPQLNPTAQPQSDPTAQPQLNLMAQPQSDSVAQPQADTNVQTPAPAASSVPSPCDEASP
TPSSHPTPGALEDPATPPASEGESPSSTPPEAAPGAGPT

(SEQ ID NO:1207)
>gi\|46358417\|ref\|NP_0008312\| metabotropic glutamate receptor 3 precursor
{Homosapiens}
MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRINED
RGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKVDEAEY
MCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDYFART
VPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNICIATAEKVGRSNIR
KSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVASDGWGAQESIIKGSEH
VAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQCSLQNKRNHRRVCDK
HLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCDAMKILDGKKLYKDYL
LKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSYLKVGHWAETLSLDVNS
IHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYLADEFTCMDCGSGQWPTA
DLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIKHNNTPLVKASGRELCYILL
FGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALLTKTNCIARIFDGVKNGAQRPKFIS
PSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLAEKRETVILKCNVKDSSMLISLTYDVILVI
LCTVYAFKTRKCPENFNEAKFIGFTMYTTCIIVVLAFLPIFYVTSSDYRVQTTTMCISVSLSGFV
VLGCLFAPKVHIILFQPQKNVVTHRLHLNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTT
SSL

(SEQ ID NO:1208)
>gi\|46395496\|ref\|NP_9970551\| neuropeptide S receptor isoform A {Homosapiens}
MPANFTEGSFDSSGTGQTLDSSPVACTETVTFTEVVEGKEWGSFYYSFKTEQLITLWVLFVFT
IVGNSVVLFSTVVRRKKKSRMTFFVTQLAITDSFTGLVNILTDINWRFTGDFTAPDLVCRVVRY
LQVVLLYASTYVLVSLSIDRYHAIVYPMKFLQGEKQARVLIVIAWSLSFLFSIPTLIIFGKRTLS
NGEVQCWALWPDDSYWTPYMTIVAFLVYFIPLTIISIMYGIVIRTIVVIKSKTYETVISNCSDGK
LCSSYNRGLISKAKIKAIKYSIIIILAFICCWSPYFLFDILDNFNLLPDTQERFYASVIIQNLPALN
SAINPLIYCVFSSSISFPCREQRSQDSRMTFRERTERHEMQILSKPEFI

(SEQ ID NO:1209)
>gi\|47271392\|ref\|NP_1490392\| succinate receptor 1 {Homosapiens}
MLGIMAWNATCKNWLAAEAALEKYYLSIFYGIEFVVGVLGNTIVVYGYIFSLKNWNSSNIYL
FNLSVSDLAFLCTLPMLIRSYANGNWIYGDVLCISNRYVLHANLYTSILFLTFISIDRYLIIKYPF
REHLLQKKEFAILISLAIWVLVTLELLPILPLINPVITDNGTTCNDFASSGDPNYNLIYSMCLTL
LGFLIPLFVMCFFYYKIALFLKQRNRQVATALPLEKPLNLVIMAVVIFSVLFTPYHVMRNVRI
ASRLGSWKQYQCTQVVINSFYIVTRPLAFLNSVINPVFYFLLGDHFRDMLMNQLRHNFKSLT
SFSRWAHELLLSFREK

(SEQ ID NO:1210)
>gi\|50897278\|ref\|NP_0010029111\| probable G-protein coupled receptor 139
{Homosapiens}
MEHTHAHLAANSSLSWWSPGSACGLGFVPVVYYSLLLCLGLPANILTVIILSQLVARRQKSS
YNYLLALAAADILVLFFIVFVDFLLEDFILNMQMPQVPDKIIEVLEFSSIHTSIVVITVPLTIDRYI
AVCHPLKYHTVSYPARTRKVIVSVYITCFLTSIPYYWWPNIVVTEDYISTSVHHVLIWIHCFTV
YLVPCSIFFILNSIIVYKLRRKSNFRLRGYSTGKTTAILFTITSIFATLWAPRIIMILYHLYGAPIQ
NRWLVHIMSDIANMLALLNTAINFFLYCFISKRFRTMAAATLKAFFKCQKQPVQFYTNHNFSI
TSSPWISPANSHCIKMLVYQYDKNGKPIKVSP

(SEQ ID NO:1211)
>gi\|52426748\|ref\|NP_0007322\| cholinergic receptor, muscarinic 4 {Homosapiens}
MANFTPVNGSSGNQSVRLVTSSSHNRYETVEMVFIATVTGSLSLVTVVGNILVMLSIKVNRQ
LQTVNNYFLFSLACADLIIGAFSMNLYTVYIIKGYWPLGAVVCDLWLALDYVVSNASVMNL
LIISFDRYFCVTKPLTYPARRTTKMAGLMIAAAWVLSFVLWAPAILFWQFVVGKRTVPDNQC
FIQFLSNPAVTFGTAIAAFYLPVVIMTVLYIHISLASRSRVHKHRPEGPKEKKAKTLAFLKSPL
MKQSVKKPPPGEAAREELRNGKLEEAPPPALPPPPRPVADKDTSNESSSGSATQNTKERPATE
LSTTEATTPAMPAPPLQPRALNPASRWSKIQIVTKQTGNECVTAIEIVPATPAGMRPAANVAR
KFASIARNQVRKKRQMAARERKVTRTIFAILLAFILTWTPYNVMVLVNTFCQSCIPDTVWSIG
YWLCYVNSTINPACYALCNATFKKTFRHLLLCQYRNIGTAR

(SEQ ID NO:1212)
>gi\|52426789\|ref\|NP_5430083\| 2-oxoglutarate receptor 1 {Homosapiens}
MNEPLDYLANASDFPDYAAAFGNCTDENIPLKMHYLPVIYGIIFLVGFPGNAVVISTYIFKMR
PWKSSTIIMLNLACTDLLYLTSLPFLIHYYASGENWIFGDFMCKFIRFSFHFNLYSSILFLTCFSI
FRYCVIIHPMSCFSIHKTRCAVVACAVVWIISLVAVIPMTFLITSTNRTNRSACLDLTSSDELNT
IKWYNLILTATTFCLPLVIVTLCYTTIIHTLTHGLQTDSCLKQKARRLTILLLLAFYVCFLPFHIL
RVIRIESRLLSISCSIENQIHEAYIVSRPLAALNTFGNLLLYVVVSDNFQQAVCSTVRCKVSGNL
EQAKKISYSNNP

(SEQ ID NO:1213)
>gi\|53828924\|ref\|NP_0052762\| neuropeptides B/W receptor type 1 {Homosapiens}
MDNASFSEPWPANASGPDPALSCSNASTLAPLPAPLAVAVPVVYAVICAVGLAGNSAVLYV
LLRAPRMKTVTNLFILNLAIADELFTLVLPINIADFLLRQWPFGELMCKLIVAIDQYNTFSSLY
FLTVMSADRYLVVLATAESRRVAGRTYSAARAVSLAVWGIVTLVVLPFAVFARLDDEQGRR
QCVLVFPQPEAFWWRASRLYTLVLGFAIPVSTICVLYTTLLCRLHAMRLDSHAKALERAKKR
VTFLVVAILAVCLLCWTPYHLSTVVALTTDLPQTPLVIAISYFITSLSYANSCLNPFLYAFLDA
SFRRNLRQLITCRAAA

(SEQ ID NO:1214)
>gi\|55953085\|ref\|NP_8595292\| G-protein coupled receptor 120 {Homosapiens}
MSPECARAAGDAPLRSLEQANRTRFPFFSDVKGDHRLVLAAVETTVLVLIFAVSLLGNVCAL
VLVARRRRRGATACLVLNLFCADLLFISAIPLVLAVRWTEAWLLGPVACHLLFYVMTLSGSV
TILTLAAVSLERMVCIVHLQRGVRGPGRRARAVLLALIVVGYSAVAALPLCVFFRVVPQRLPG
ADQEISICTLIVVPTIPGEISWDVSFVTLNFLVPGLVIVISYSKILQTSEHLLDARAVVTHSEITKA
SRKRLTVSLAYSESHQIRVSQQDFRLFRTLFLLMVSFFIMWSPIIITILLILIQNFKQDLVIVVPSLF
FVVVVAFTFANSALNPILYNMTLCRNEWKKIFCCFVVFPEKGAILTDTSVKRNDLSIISG

(SEQ ID NO:1215)
>gi\|55956923\|ref\|NP_0005152\| 5-hydroxytryptamine receptor 1A {Homosapiens}
MDVLSPGQGNNTTSPPAPFETGGNTTGISDVTVSYQVITSLLLGTLIFCAVLGNACVVAAIAL
ERSLQNVANYLIGSLAVTDLMVSVLVLPMAALYQVLNKWTLGQVTCDLFIALDVLCCTSSIL
HLCAIALDRYWAITDPIDYVNKRTPRRAAALISLTWLIGFLISIPPMLGWRTPEDRSDPDACTIS
KDHGYTIYSTFGAFYIPLLLMLVLYGRIFRAARFRIRKTVKKVEKTGADTRHGASPAPQPKKS
VNGESGSRNWRLGVESKAGGALCANGAVRQGDDGAALEVIEVHRVGNSKEHLPLPSEAGPT
PCAPASFERKNERNAEAKRKMALARERKTVKTLGIIMGTFILCWLPFFIVALVLPFCESSCHM
PTLLGAIINWLGYSNSLLNPVIYAYFNKDFQNAFKKIIKCKFCRQ

(SEQ ID NO:1216)
>gi\|57165355\|ref\|NP_0010087011\| latrophilin-1 is oform 1 precursor
{Homosapiens}
MARLAAVLWNLCVTAVLVTSATQGLSRAGLPFGLMRRELACEGYPIELRCPGSDVIMVENA
NYGRTDDKICDADPFQMENVQCYLPDAFKIMSQRCNNRTQCVVVAGSDAFPDPCPGTYKYL
EVQYDCVPYKVEQKVFVCPGTLQKVLEPTSTHESEHQSGAWCKDPLQAGDRIYVMPWIPYR
TDTLTEYASWEDYVAARHTTTYRLPNRVDGTGFVVYDGAVFYNKERTRNIVKYDLRTRIKS
GETVINTANYHDTSPYRWGGKTDIDLAVDENGLWVIYATEGNNGRLVVSQLNPYTLRFEGT
WETGYDKRSASNAFMVCGVLYVLRSVYVDDDSEAAGNRVDYAFNTNANREEPVSLTFPNP
YQFISSVDYNPRDNQLYVWNNYFVVRYSLEFGPPDPSAGPATSPPLSTTTTARPTPLTSTASPA
ATTPLRRAPLTTHPVGAINQLGPDLPPATAPVPSTRRPPAPNLHVSPELFCEPREVRRVQWPA
TQQGMLVERPCPKGTRGIASFQCLPALGLWNPRGPDLSNCTSPWVNQVAQKIKSGENAANIA
SELARHTRGSIYAGDVSSSVKLMEQLLDILDAQLQALRPIERESAGKNYNKMHKRERTCKDY
IKAVVETVDNLLRPEALESWKDMNATEQVHTATMLLDVLEEGAFLLADNVREPARFLAAKE
NVVLEVTVLNTEGQVQELVFPQEEYPRKNSIQLSAKTIKQNSRNGVVKVVFILYNNLGLFLST
ENATVKLAGEAGPGGPGGASLVVNSQVIAASINKESSRVFLMDPVIFTVAHLEDKNHFNANC
SFVVNYSERSMLGYWSTQGCRLVESNKTHTTCACSHLTNFAVLMAHREIYQGRINELLLSVIT
WVGIVISLVCLAICISTFCFLRGLQTDRNTIHKNLCINLFLAELLFLVGIDKTQYEIACPIFAGLL
HYFFLAAFSWLCLEGVHLYLLLVEVFESEYSRTKYYYLGGYCFPALVVGIAAAIDYRSYGTE
KACWLRVDNYFIWSFIGPVSFVIVVNLVFLMVTLHKMIRSSSVLKPDSSRLDNIKSWALGAIA
LLFLLGLTWAFGLLFINKESVVMAYLFTTFNAFQGVFIFVFHCALQKKVHKEYSKCLRHSYC
CIRSPPGGTHGSLKTSAMRSNTRYYTGTQSRIRRMWNDTVRKQTESSFMAGDINSTPTLNRG
TMGNHLLTNPVLQPRGGTSPYNTLIAESVGFNPSSPPVFNSPGSYREPKHPLGGREACGMDTL
PLNGNFNNSYSLRSGDFPPGDGGPEPPRGRNLADAAAFEKMIISELVHNNLRGSSSAAKGPPP
PEPPVPPVPGGGGEEEAGGPGGADRAEIELLYKALEEPLLLPRAQSVLYQSDLDESESCTAED
GATSRPLSSPPGRDSLYASGANLRDSPSYPDSSPEGPSEALPPPPPAPPGPPEIYYTSRPPALVA
RNPLQGYYQVRRPSHEGYLAAPGLEGPGPDGDGQMQLVTSL

(SEQ ID NO:1217)
>gi\|57165371\|ref\|NP_1141423\| probable G-protein coupled receptor 61
{Homosapiens}
MESSPIPQSSGNSSTLGRVPQTPGPSTASGVPEVGLRDVASESVALFFMLLLDLTAVAGNAAV
MAVIAKTPALRKFVFVFHLCLVDLLAALTLMPLAMLSSSALFDHALFGEVACRLYLFLSVCF
VSLAILSVSAINVERYYYVVHPMRYEVRMTLGLVASVLVGVWVKALAMASVPVLGRVSWE
EGAPSVPPGCSLQWSHSAYCQLFVVVFAVLYFLLPLLLILVVYCSMFRVARVAAMQHGPLPT
WMETPRQRSESLSSRSTMVTSSGAPQTTPHRTFGGGKAAVVLLAVGGQFLLCWLPYFSFHLY
VALSAQPISTGQVESVVTWIGYFCFTSNPFFYGCLNRQIRGELSKQFVCFFKPAPEEELRLPSR
EGSIEENFLQFLQGTGCPSESWVSRPLPSPKQEPPAVDFRIPGQIAEETSEFLEQQLTSDIIMSDS
YLRPAASPRLES

(SEQ ID NO:1218)
>gi\|57977305\|ref\|NP_9192272\| G protein-coupled receptor 151 {Homosapiens}
MLAAAFADSNSSSMNVSFAHLHFAGGYLPSDSQDWRTIIPALLVAVCLVGFVGNLCVIGILL
HNAWKGKPSMIHSLILNLSLADLSLLLFSAPIRATAYSKSVWDLGWFVCKSSDWFIHTCMAA
KSLTIVVVAKVCFMYASDPAKQVSIHNYTIWSVLVAIWTVASLLPLPEWFFSTIRHHEGVEM
CLVDVPAVAEEFMSMFGKLYPLLAFGLPLFFASFYFWRAYDQCKKRGTKTQNLRNQIRSKQ
VTVMLLSIAIISALLWLPEWVAWLWVVVHLKAAGPAPPQGFIALSQVLMFSISSANPLIFLVMS
EEFREGLKGVWKWMITKKPPTVSESQETPAGNSEGLPDKVPSPESPASIPEKEKPSSPSSGKGK
TEKAEIPILPDVEQFVVHERDTVPSVQDNDPIPWEHEDQETGEGVK

(SEQ ID NO:1219)
>gi\|58530851\|ref\|NP_0008142\| growth hormone-releasing hormone receptor
isoform a precursor {Homosapiens}
MDRRMWGAHVFCVLSPLPTVLGHMHPECDFITQLREDESACLQAAEEMPNTTLGCPATWD
GLLCWPTAGSGEWVTLPCPDFFSHFSSESGAVKRDCTITGWSEPFPP YPVACPVPLELLAEEE
SYFSTVKIIYTVGHSISIVALFVAITILVALRRLHCPRNYVHTQLFTTFILKAGAVFLKDAALFH
SDDTDHCSFSTVLCKVSVAASHFATMTNFSWLLAEAVYLNCLLASTSPSSRRAFWWLVLAG
WGLPVLFTGTWVSCKLAFEDIACWDLDDTSPYVVWIIKGPIVLSVGVNFGLFLNIIRILVRKLE
PAQGSLHTQSQYWRLSKSTLFLIPLFGIHYIIFNFLPDNAGLGIRLPLELGLGSFQGFIVAILYCF
LNQEVRTEISRKWHGHDPELLPAWRTRAKWTTPSRSAAKVLTSMC

(SEQ ID NO:1220)
>gi\|59710093\|ref\|NP_7225763\| probable G-protein coupled receptor 112
{Homosapiens}
MKEHIIYQKLYGLILMSSFIFLSDTLSLKGKKLDFFGRGDTYVSLIDTIPELSRFTACIDLVFMD
DNSRYWMAFSYITNNALLGREDIDLGLAGDHQQLILYRLGKTFSIRHHLASFQWHTICLIVVD
GVKGKLELFLNKERILEVTDQPHNLTPHGTLFLGHFLKNESSEVKSMMRSFPGSLYYFQLWD
HILENEEFMKCLDGNIVSWEEDVWLVNKIIPTVDRTLRCFVPENMTIQEKSTTVSQQIDMTTP
SQITGVKPQNTAHSSTLLSQSIPIFATDYTTISYSNTTSPPLETMTAQKILKTLVDETATFAVDV
LSTSSAISLPTQSISIDNTTNSMKKTKSPSSESTKTTKMVEAMATEIFQPPTPSNFLSTSRFTKNS
VVSTTSAIKSQSAVTKTTSLFSTIESTSMSTTPCLKQKSTNTGALPISTAGQEFIESTAAGTVPW
FTVEKTSPASTHVGTASSFPPEPVLISTAAPVDSVFPRNQTAFPLATTDMKIAFTVHSLTLPTRL
IETTPAPRTAETELTSTNFQDVSLPRVEDAMSTSMSKETSSKTFSFLTSFSFTGTESVQTVIDAE
ATRTALTPEITLASTVAETMLSSTITGRVYTQNTPTADGHLLTLMSTRSASTSKAPESGPTSTT
DEAAHLFSSNETIVVTSRPDQALLASMNTTTILTFVPNENFTSAFHENTTYTEYLSATTNITPLK
ASPEGKGTTANDATTARYTTAVSKLTSPWFANFSIVSGTTSITNMPEFKLTTLLLKTIPMSTKP
ANELPLTPRETVVPSVDIISTLACIQPNFSTEESASETTQTEINGAIVFGGTTTPVPKSATTQRLN
ATVTRKEATSHYLMRKSTIAAVAEVSPFSTMLEVTDESAQRVTASVTVSSFPDIEKLSTPLDN
KTATTEVRESWLLTKLVKTTPRSSYNEMTEMFNFNHTYVAHWTSETSEGISAGSPTSGSTHIF
GEPLGASTTRIS TSFSTTPTDRTATSLSDGILPPQPTAAHSSATPVPVTHMFSLPVNGSSVVAE
ETEVTMSEPSTLARAFSTSVLSDVSNLSSTTMTTALVPPLDQTASTTIVIVPTHGDLIRTTSEAT
VISVRKTSMAVPSLTETPFHSLRLSTPVTAKAETTLFSTSVDTVTPSTHTLVCSKPPPDNIPPAS
STHVISTTSTPEATQPISQVEETSTYALSFPYTFSGGGVVASLATGTTETSVVDETTPSHISANK
LTTSVNSHISSSATYRVHTPVSIQLVTSTSVLSSDKDQMTISLGKTPRTMEVTEMSPSKNSFISY
SRGTPSLEMTDTGFPETTKISSHQTHSPSEIPLGTPSDGNLASSPTSGSTQITPTLTSSNTVGVHI
PEMSTSLGKTALPSQALTITTFLCPEKESTSALPAYTPRTVEMIVNSTYVTHSVSYGQDTSFVD
TTTSSSTRISNPMDINTTFSHLHSLRTQPEVTSVASFISESTQTFPESLSLSTAGLYNDGFTVLSD
RITTAFSVPNVPTMLPRESSMATSTPIYQMSSLPVNVTAFTSKKVSDTPPIVITKSSKTMHPGC
LKSPCTATSGPMSEMSSIPVNNSAFTPATVSSDTSTRVGLFSTLLSSVTPRTTMTMQTSTLDVT
PVIYAGATSKNKMVSSAFTTEMIEAPSRITPTTFLSPTEPTLPFVKTVPTTIMAGIVTPFVGTTA
FSPLSSKSTGAISSIPKTTFSPFLSATQQSSQADEATTLGILSGITNRSLSTVNSGTGVALTDTYS
RITVPENMLSPTHADSLHTSFNIQVSPSLTSFKSASGPTKNVKTTTNCFSSNTRKMTSLLEKTS
LTNYATSLNTPVSYPPWTPSSATLPSLTSFVYSPHSTEAEISTPKTSPPPTSQMVEFPVLGTRMT
SSNTQPLLMTSWNIPTAEGSQFPISTTINVPTSNEMETETLHLVPGPLSTFTASQTGLVSKDVM
AMSSIPMSGILPNHGLSENPSLSTSLRAITSTLADVKHTFEKMTTSVTPGTTLPSILSGATSGSVI
SKSPILTVVLLSSLPSGSPPATVSNAPHVMTSSTVEVSKSTFLTSDMISAHPFTNLTTLPSATMST
ILTRTIPTPTLGGITTGFPTSLPMSINVTDDIVYISTHPEASSRTTITANPRTVSHPSSFSRKTMSP
STTDHTLSVGAMPLPSSTITSSWNRIPTASSPSTLIIPKPTLDSLLNIMTTTSTVPGASFPLISTGV
TYPFTATVSSPISSFFETTVVLDSTPSFLSTEASTSPTATKSTVSFYNVEMSFSVFVEEPRIPITSVI
NEFTENSLNSIFQNSEFSLATLETQIKSRDISEEEMVMDRAILEQREGQEMATISYVPYSCVCQ
VIIKASSSLASSELMRKIKSKIHGNFTHGNFTQDQLTLLVNCEHVAVKKLEPGNCKADETASK
YKGTYKWLLTNPTETAQTRCIKNEDGNATRFCSISINTGKSQWEKPKFKQCKLLQELPDKIV
DLANITISDENAEDVAEHILNLINESPALGKEETKIIVSKISDISQCDEISMNLTHVMLQIINVVL
EKQNNSASDLHEISNEILRIIERTGHKMEFSGQIANLTVAGLALAVLRGDHTFDGMAFSIHSYE
EGTDPEIFLGNVPVGGILASIYLPKSLTERIPLSNLQTILFNFFGQTSLFKTKNVTKALTTYVVS
ASISDDMFIQNLADPVVITLQHIGGNQNYGQVHCAFWDFENNNGLGGWNSSGCKVKETNVN
YTICQCDHLTHFGVLMDLSRSTVDSVNEQILALITYTGCGISSIFLGVAVVTYIAFHKLRKDYP
AKILINLCTALLMLNLVFLINSWLSSFQKVGVCITAAVALHYFLLVSFTVVMGLEAVHMYLAL
VKVFNIYIPNYILKFCLVGWGIPAIMVAITVSVKKDLYGTLSPTTPFCWIKDDSIFYISVVAYFC
LIFLMNLSMFCTVLVQLNSVKSQIQKTRRKMILHDLKGTMSLTFLLGLTWGFAFFAWGPMR
NFFLYLFAIFNTLQGFFIFVFHCVMKESVREQWWILCCGWLRLDNSSDGSSRCQIKVGYKQE
GLKKIFEHKLLTPSLKSTATSSTFKSLGSAQGTPSEISFPNDDFDKDPYCSSP

(SEQ ID NO:1221)
>gi\|59823631\|ref\|NP_6603332\| probable G-protein coupled receptor 125
precursor {Homosapiens}
MEPPGRRRGRAQPPLLLPLSLLALLALLGGGGGGGAAALPAGCKHDGRPRGAGRAAGAAE
GKVVCSSLELAQVLPPDTLPNRTVTLILSNNKISELKNGSFSGLSLLERLDLRNNLISSIDPGAF
WGLSSLKRLDLTNNRIGCLNADIFRGLTNLVRLNLSGNLFSSLSQGTFDYLASLRSLEFQTEY
LLCDCNILWMHRWVKEKNITVRDTRCVYPKSLQAQPVTGVKQELLTCDPPLELPSFYMTPSH
RQVVFEGDSLPFQCMASYIDQDMQVLWYQDGRIVETDESQGIFVEKNMIHNCSLIASALTISN
IQAGSTGNWGCHVQTKRGNNTRTVDIVVLESSAQYCPPERVVNNKGDFRWPRTLAGITAYL
QCTRNTHGSGIYPGNPQDERKAWRRCDRGGFVVADDDYSRCQYANDVTRVLYMFNQMPLN
LTNAVATARQLLAYTVEAANFSDKMDVIFVAEMIEKFGRFTKEEKSKELGDVMVDIASNIML
ADERVLWLAQREAKACSRIVQCLQRIATYRLAGGAHVYSTYSPNIALEAYVIKSTGFTGMTC
TVFQKVAASDRTGLSDYGRRDPEGNLDKQLSFKCNVSNTFSSLALKNTIVEASIQLPPSLFSPK
QKRELRPTDDSLYKLQLIAFRNGKLFPATGNSTNLADDGKRRTVVTPVILTKIDGVNVDTHHI
PVNVTLRRIAHGADAVAARWDFDLLNGQGGWKSDGCHILYSDENITTIQCYSLSNYAVLMD
LTGSELYTQAASLLHPVVYTTAIILLLCLLAVIVSYIYHHSLIRISLKSWHMLVNLCFHIFLTCV
VFVGGITQTRNASICQAVGIILHYSTLATVLWVGVTARNIYKQVTKKAKRCQDPDEPPPPPRP
MLRFYLIGGGIPIIVCGITAAANIKNYGSRPNAPYCWMAWEPSLGAFYGPASFITFVNCMYFL
SIFIQLKRHPERKYELKEPTEEQQRLAANENGEINHQDSMSLSLISTSALENEHTFHSQLLGAS
LTLLLYVALWMFGALAVSLYYPLDLVFSFVFGATSLSFSAFFVVHHCVNREDVRLAWIMTC
CPGRSSYSVQVNVQPPNSNGTNGEAPKCPNSSAESSCTNKSASSFKNSSQGCKLTNLQAAAA
QCHANSLPLNSTPQLDNSLTEHSMDNDIKMHVAPLEVQFRTNVHSSRHHKNRSKGHRASRL
TVLREYAYDVPTSVEGSVQNGLPKSRLGNNEGHSRSRRAYLAYRERQYNPPQQDSSDACST
LPKSSRNFEKPVSTTSKKDALRKPAVVELENQQKSYGLNLAIQNGPIKSNGQEGPLLGTDSTG
NVRTGLWKHETTV

(SEQ ID NO:1222)
>gi\|61743940\|ref\|NP_7225822\| probable G-protein coupled receptor 110 isoform
1 {Homosapiens}
MKVGVLWLISFFTFTDGHGGFLGKNDGIKTKKELIVNKKKHLGPVEEYQLLLQVTYRDSKE
KRDLRNFLKLLKPPLLWSHGLIRIIRAKATTDCNSLNGVLQCTCEDSYTVVFPPSCLDPQNCYL
HTAGALPSCECHLNNLSQSVNFCERTKIVVGTFKINERFTNDLLNSSSAIYSKYANGIEIQLKKA
YERIQGFESVQVTQFRNGSIVAGYEVVGSSSASELLSAIEHVAEKAKTALHKLFPLEDGSFRV
FGKAQCNDIVFGFGSKDDEYTLPCSSGYRGNITAKCESSGWQVIRETCVLSLLEELNKNFSMI
VGNATEAAVSSFVQNLSVIIRQNPSTTVGNLASVVSILSNISSLSLASHFRVSNSTMEDVISIAD
NILNSASVTNWTVLLREEKYASSRLLETLENISTLVPPTALPLNFSRKFIDWKGIPVNKSQLKR
GYSYQIKMCPQNTSIPIRGRVLIGSDQFQRSLPETHSMASLTLGNILPVSKNGNAQVNGPVIST
VIQNYSINEVFLFFSKIESNLSQPHCVFVVDFSHLQWNDAGCHLVNETQDIVTCQCTHLTSFSIL
MSPFVPSTIFPVVKWITYVGLGISIGSLILCLIIEALFVVKQIKKSQTSHTRRICMVNIALSLLIAD
VWFIVGATVDTTVNPSGVCTAAVFFTHFFYLSLFFWMLMLGILLAYRIILVFHHMAQHLMM
AVGFCLGYGCPLIISVITIAVTQPSNTYKRKDVCWLNWSNGSKPLLAFVVPALAIVAVNFVVV
LLVLTKLWRPTVGERLSRDDKATIIRVGKSLLILTPLLGLTWGFGIGTIVDSQNLAWHVIFALL
NAFQGFFILCFGILLDSKLRQLLFNKLSALSSWKQTEKQNSSDLSAKPKFSKPFNPLQNKGHY
AFSHTGDSSDNIMLTQFVSNE

(SEQ ID NO:1223)
>gi\|62865887\|ref\|NP_1159402\| kiSS-1 receptor {Homosapiens}
MHTVATSGPNASWGAPANASGCPGCGANASDGPVPSPRAVDAWLVPLFFAALMLLGLVGN
SLVIYVICRHKPMRTVTNFYIANLAATDVTFLLCCVPFTALLYPLPGWVLGDFMCKFVNYIQ
QVSVQATCATLTAMSVDRWYVTVFPLRALHRRTPRLALAVSLSIVVVGSAAVSAPVLALHRL
SPGPRAYCSEAFPSRALERAFALYNLLALYLLPLLATCACYAAMLRHLGRVAVRPAPADSAL
QGQVLAERAGAVRAKVSRLVAAVVLLFAACWGPIQLFLVLQALGPAGSWHPRSYAAYALK
TWAHCMSYSNSALNPLLYAFLGSHFRQAFRRVCPCAPRRPRRPRRPGPSDPAAPHAELLRLG
SHPAPARAQKPGSSGLAARGLCVLGEDNAPL

(SEQ ID NO:1224)
>gi\|62912472\|ref\|NP_06764921\| eucine-rich repeat-containing G protein-coupled
receptor 6 isoform 2 {Homosapiens}
MGRPRLTLVCQVSIIISARDLSMNNLTELQPGLFHHLRFLEELRLSGNHLSHIPGQAFSGLYSL
KILMLQNNQLGGIPAEALWELPSLQSLRLDANLISLVPERSFEGLSSLRHLWLDDNALTEIPVR
ALNNLPALQAMTLALNRISHIPDYAFQNLTSLVVLHLHNNRIQHLGTHSFEGLHNLETLDLN
YNKLQEFPVAIRTLGRLQELGFHNNNIKAIPEKAFMGNPLLQTIHFYDNPIQFVGRSAFQYLPK
LHTLSLNGAMDIQEFPDLKGTTSLEILTLTRAGIRLLPSGMCQQLPRLRVLELSHNQIEELPSL
HRCQKLEEIGLQHNRIVVEIGADTFSQLSSLQALDLSWNAIRSIHPEAFSTLHSLVKLDLTDNQL
TTLPLAGLGGLMHLKLKGNLALSQAFSKDSFPKLRILEVPYAYQCCPYGMCASFFKASGQW
EAEDLHLDDEESSKRPLGLLARQAENHYDQDLDELQLEMEDSKPHPSVQCSPTPGPFKPCEY
LFESWGIRLAVWAIVLLSVLCNGLVLLTVFAGGPVPLPPVKFVVGAIAGANTLTGISCGLLAS
VDALTFGQFSEYGARWETGLGCRATGFLAVLGSEASVLLLTLAAVQCSVSVSCVRAYGKSP
SLGSVRAGVLGCLALAGLAAALPLASVGEYGASPLCLPYAPPEGQPAALGFTVALVMMNSF
CFLVVAGAYIKLYCDLPRGDFEAVWDCAMVRHVAWLIFADGLLYCPVAFLSFASMLGLFPV
TPEAVKSVLLVVLPLPACLNPLLYLLFNPHFRDDLRRLRPRAGDSGPLAYAAAGELEKSSCDS
TQALVAFSDVDLILEASEAGRPPGLETYGFPSVTLISCQQPGAPRLEGSHCVEPEGNHFGNPQP
SMDGELLLRAEGSTPAGGGLSGGGGFQPSGLAFASHV

(SEQ ID NO:1225)
>gi\|63477962\|ref\|NP_0009023\| delta-type opioid receptor {Homosapiens}
MEPAPSAGAELQPPLFANASDAYPSACPSAGANASGPPGARSASSLALAIAITALYSAVCAVG
LLGNVLVMFGIVRYTKMKTATNIYIFNLALADALATSTLPFQSAKYLMETWPFGELLCKAVL
SIDYYNMFTSIFTLTMMSVDRYIAVCHPVKALDFRTPAKAKLINICIVVVLASGVGVPIMVMA
VTRPRDGAVVCMLQFPSPSWYWDTVTKICVFLFAFVVPILIITVCYGLMLLRLRSVRLLSGSK
EKDRSLRRITRMVLVVVGAFVVCWAPIHIFVIVWTLVDIDRRDPLVVAALHLCIALGYANSSL
NPVLYAFLDENFKRCFRQLCRKPCGRPDPSSFSRAREATARERVTACTPSDGPGGGAAA

(SEQ ID NO:1226)
>gi\|64085121\|ref\|NP_0003602\| thyroid stimulating hormone receptor isoform 1
precursor {Homosapiens}
MRPADLLQLVLLLDLPRDLGGMGCSSPPCECHQEEDFRVTCKDIQRIPSLPPSTQTLKLIETHL
RTIPSHAFSNLPNISRIYVSIDVTLQQLESHSFYNLSKVTHIEIRNTRNLTYIDPDALKELPLLKF
LGIFNTGLKMFPDLTKVYSTDIFFILEITDNPYMTSIPVNAFQGLCNETLTLKLYNNGFTSVQG
YAFNGTKLDAVYLNKNKYLTVIDKDAFGGVYSGPSLLDVSQTSVTALPSKGLEHLKELIARN
TWTLKKLPLSLSFLHLTRADLSYPSHCCAFKNQKKIRGILESLMCNESSMQSLRQRKSVNALN
SPLHQEYEENLGDSIVGYKEKSKFQDTHNNAHYYVFFEEQEDEIIGFGQELKNPQEETLQAFD
SHYDYTICGDSEDMVCTPKSDEFNPCEDIMGYKFLRIVVWFVSLLALLGNVFVLLILLTSHYK
LNVPRFLMCNLAFADFCMGMYLLLIASVDLYTHSEYYNHAIDWQTGPGCNTAGFFTVFASE
LSVYTLTVITLERWYAITFAMRLDRKIRLRHACAIMVGGWVCCFLLALLPLVGISSYAKVSIC
LPMDTETPLALAYIVFVLTLNIVAFVIVCCCYVKIYITVRNPQYNPGDKDTKIAKRMAVLIFTD
FICMAPISFYALSAILNKPLITVSNSKILLVLFYPLNSCANPFLYAIFTKAFQRDVFILLSKFGICK
RQAQAYRGQRVPPKNSTDIQVQKVTHEMRQGLHNMEDVYELIENSHLTPKKQGQISEEYMQ
TVL

(SEQ ID NO:1227
>gi\|66529100\|ref\|NP_0008302\| metabotropic glutamate receptor 2 isoform a
precursor {Homosapiens}
MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQR
LEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHICPDG
SYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDYFARTVPPD
FFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEKVGRAMSRAAF
EGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGALESVVAGSEGA
AEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQRDCAAHSLRAVPFE
QESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYKDFVLNVKFDAPFR
PADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTLDTSLIPWASPSAGPL
PASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADCGLGYWPNASLTGCFELP
QEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKASGRELCYILLGGVFLCYC
MTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARIFGGAREGAQRPRFISPASQVAIC
LALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLRCNHRDASMLGSLAYNVLLIALCTLY
AFKTRKCPENFNEAKFIGFTMYTTCHVVLAFLPIFYVTSSDYRVQTTTMCVSVSLSGSVVLGCL
FAPKLHIILFQPQKNVVSHRAPTSRFGSAAARASSSLGQGSGSQFVPTVCNGREVVDSTTSSL

(SEQ ID NO:1228)
>gi\|68215224\|ref\|NP_0039562\| C-C chemokine receptor-like 2 isoform 1
{Homosapiens}
MANYTLAPEDEYDVLIEGELESDEAEQCDKYDAQALSAQLVPS LCSAVFVIGVLDNLLVVLI
LVKYKGLKRVENIYLLNLAVSNLCFLLTLPFWAHAGGDPMCKILIGLYFVGLYSETFFNCLLT
VQRYLVFLHKGNFFSARRRVPCGIITSVLAWVTAILATLPEFVVYKPQMEDQKYKCAFSRTPF
LPADETFWKHFLTLKMNISVLVLPLFIFTFLYVQMRKTLRFREQRYSLFKLVFAIMVVFLLM
WAPYNIAFFLSTFKEHFSLSDCKSSYNLDKSVHITKLIATTHCCINPLLYAFLDGTFSKYLCRC
FHLRSNTPLQPRGQSAQGTSREEPDHSTEV

(SEQ ID NO:1229)
>gi\|71773208 \|ref\|NP_000674 2\| alpha-2C adrenergic receptor {Homosapiens}
MASPALAAALAVAAAAGPNASGAGERGSGGVANASGASWGPPRGQYSAGAVAGLAAVVG
FLIVFTVVGNVLVVIAVLTSRALRAPQNLFLVSLASADILVATLVMPFSLANELMAYWYFGQ
VWCGVYLALDVLFCTSSIVHLCAISLDRYWSVTQAVEYNLKRTPRRVKATIVAVWLISAVIS
FPPLVSLYRQPDGAAYPQCGLNDETWYILSSCIGSFFAPCLIMGLVYARIYRVAKLRTRTLSE
KRAPVGPDGASPTTENGLGAAAGAGENGHCAPPPADVEPDESSAAAERRRRRGALRRGGRR
RAGAEGGAGGADGQGAGPGAAESGALTASRSPGPGGRLSRASSRSVEFFLSRRRRARSSVCR
RKVAQAREKRFTFVLAVVMGVFVLCWFPFFFSYSLYGICREACQVPGPLFKFFFVVIGYCNSS
LNPVIYTVFNQDFRRSFKHILFRRRRRGFRQ

(SEQ ID NO:1230)
+22gi 17199913 1 \|ref\|NP_0551372\| opsin-3 {Homosapiens}
MYSGNRSGGHGYWDGGGAAGAEGPAPAGTLSPAPLFSPGTYERLALLLGSIGLLGVGNNLL
VLVLYYKFQRLRTPTHLLLVNISLSDLLVSLFGVTFTFVSCLRNGWVVVDTVGCVWDGFSGSL
FGIVSIATLTVLAYERYIRVVHARVINFSWAWRAITYIVVLYSLAWAGAPLLGWNRYILDVHG
LGCTVDWKSKDANDSSFVLFLFLGCLVVPLGVIAHCYGHILYSIRMLRCVEDLQTIQVIKILK
YEKKLAKMCFLMIFTFLVCWMPYIVICFLVVNGHGHLVTPTISIVSYLFAKSNTVYNPVIYVF
MIRKFRRSLLQLLCLRLLRCQRPAKDLPAAGSEMQIRPIVMSQKDGDRPKKKVTFNSSSIIFIIT
SDESLSVDDSDKTNGSKVDVIQVRPL

(SEQ ID NO:1231)
>gi\|74048357\|ref\|NP_0651884\| G-protein coupled receptor 126 alpha 1 precursor
{Homosapiens}
MMFRSDRMWSCHWKWKPSPLLFLFALYIMCVPHSVWGCANCRVVLSNPSGTFTSPCYPND
YPNSQACMWTLRAPTGYIIQITFNDFDIEEAPNCIYDSLSLDNGESQTKFCGATAKGLSFNSSA
NEMHVSFSSDFSIQKKGFNASYIRVAVSLRNQKVILPQTSDAYQVSVAKSISIPELSAFTLCFE
ATKVGHEDSDWTAFSYSNASFTQLLSFGKAKSGYFLSISDSKCLLNNALPVKEKEDIFAESFE
QLCLVWNNSLGSIGVNFKRNYETVPCDSTISKVIPGNGKLLLGSNQNEIVSLKGDIYNFRLWN
FTMNAKILSNLSCNVKGNVVDWQNDFVVNIPNLALKAESNLSCGSYLIPLPAAELASCADLGT
LCQATVNSPSTTPPTVTTNMPVTNRIDKQRNDGIIYRISVVIQNILRHPEVKVQSKVAEWLNST
FQNWNYTVYVVNISFHLSAGEDKIKVKRSLEDEPRLVLWALLVYNATNNTNLEGKIIQQKLL
KNNESLDEGLRLHTVNVRQLGHCLAMEEPKGYYWPSIQPSEYVLPCPDKPGFSASRICFYNA
TNPLVTYWGPVDISNCLKEANEVANQILNLTADGQNLTSANITNIVEQVKRIVNKEENIDITL
GSTLMNIFSNILSSSDSDLLESSSEALKTIDELAFKIDLNSTSHVNITTRNLALSVSSLLPGTNAIS
NFSIGLPSNNESYFQMDFESGQVDPLASVILPPNLLENLSPEDSVLVRRAQFTFFNKTGLFQDV
GPQRKTLVSYVMACSIGNITIQNLKDPVQIKIKHTRTQEVHHPICAFVVDLNKNKSFGGWNTS
GCVAHRDSDASETVCLCNHFTHFGVLMDLPRSASQLDARNTKVLTFISYIGCGISAIFSAATL
LTYVAFEKLRRDYPSKILMNLSTALLFLNLLFLLDGWITSFNVDGLCIAVAVLLHFFLLATFT
WMGLEAIHMYIALVKVFNTYIRRYILKFCIIGWGLPALVVSVVLASRNNNEVYGKESYGKEK
GDEFCWIQDPVIFYVTCAGYFGVMFFLNIAMFIVVMVQICGRNGKRSNRTLREEVLRNLRSV
VSLTFLLGMTWGFAFFAWGPLNIPFMYLFSIFNSLQGLFIFIFHCAMKENVQKQWRRHLCCG
RFRLADNSDWSKTATNIIKKSSDNLGKSLSSSSIGSNSTYLTSKSKSSSTTYFKRNSHTDNVSY
EHSFNKSGSLRQCFHGQVLVKTGPC)

(SEQ ID NO:1232)
>gi\|74275344\|ref\|NP_0010282521\| trace amine-associated receptor 2 isoform 1
{Homosapiens}
MAVSSEQHELSHFKRTQTKKEKFNCSEYGNRSCPENERSLGVRVAMYSFMAGSIFITIFGNLA
MIISISYFKQLHTPTNFLILSMAITDFLLGFTIMPYSMIRSVENCWYFGLTFCKIYYSFDLMLSIT
SIFHLCSVAIDRFYAICYPLLYSTKITIPVIKRLLLLCWSVPGAFAFGVVFSEAYADGIEGYDIL
VACSSSCPVMFNKLWGTTLFMAGFFTPGSMMVGIYGKIFAVSRKHAHAINNLRENQNNQVK
KDKKAAKTLGIVIGVFLLCWFPCFFTILLDPFLNFSTPVVLFDALTWFGYFNSTCNPLIYGFFY
PWFRRALKYILLGKIFSSCFHNTILCMQKESE

(SEQ ID NO:1233)
>gi\|84662753\|ref\|NP_0010337941\| G protein-coupled receptor 149 {Homosapiens}
MSLFLSNLSTNDSSLWKENHNSTDLLNPPGTLNIYLFCLTCLMTFAALVGSIYSLISLLKMQN
RTVVSMLVASWSVDDLMSVLSVTIFMFLQWPNEVPGYFQFLCTTSALMYLCQGLSSNLKAT
LLVSYNFYTMHRGVGSQTASRRSGQVLGVVLTVVVAASLLLSALPLCGWGAFVRTPWGCLV
DCSSSYVLFLSIVYALAFGLLVGLSVPLTHRLLCSEEPPRLHSNYQEISRGASIPGTPPTAGRVV
SLSPEDAPGPSLRRSGGCSPSSDTVFGPGAPAAAGAEACRRENRGTLYGTRSFTVSVAQKRFA
LILALTKVVLWLPMMMHMVVQNVVGFQSLPLETFSFLLTLLATTVTPVFVLSKRWTHLPCG
CIINCRQNAYAVASDGKKIKRKGFEFNLSFQKSYGIYKIAHEDYYDDDENSIFYHNLMNSECE
TTKDPQRDNRNIFNAIKVEISTTPSLDSSTQRGINKCTNTDITEAKQDSNNKKDAFSDKTGGDI
NYEETTFSEGPERRLSHEESQKPDLSDWEWCRSKSERTPRQRSGYALAIPLCAFQGTVSLHAP
TGKTLSLSTYEVSAEGQKITPASKKIEVYRSKSVGHEPNSEDSSSTFVDTSVKIHLEVLEICDNE
EALDTVSIISNISQSSTQVRSPSLRYSRKENRFVSCDLGETASYSLFLPTSNPDGDINISIPDTVE
AHRQNSKRQHQERDGYQEEIQLLNKAYRKREEESKGS

(SEQ ID NO:1234)
>gi\|85986587\|ref\|NP_0010342541\| mas-related G-protein coupled receptor member
E {Homosapiens}
MEPREAGQHVGAANGAQEDVAFNLIILSLTEGLGLGGLLGNGAVLWLLSS NVYRNPFAIYLL
DVACADLIFLGCHMVAIVPDLLQGRLDFPGFVQTSLATLRFFCYIVGLSLLAAVSVEQCLAAL
FPAWYSCRRPRHLTTCVCALTWALCLLLHLLLSGACTQFFGEPSRHLCRTLWLVAAVLLALL
CCTMCGASLMLLLRVERGPQRPPPRGFPGLILLTVLLFLFCGLPFGIYVVLSRNLLWYIPHYFY
HFSFLMAAVHCAAKPVVYFCLGSAQGRRLPLRLVLQRALGDEAELGAVRETSRRGLVDIAA

(SEQ ID NO:1235)
>gi\|85986601\|ref\|NP_0676472\| relaxin/insulin-like family peptide receptor 1
{Homosapiens}
MTSGSVFFYILIFGKYFSHGGGQDVKCSLGYFPCGNITKCLPQLLHCNGVDDCGNQADEDNC
GDNNGWSLQFDKYFASYYKMTSQYPFEAETPECLVGSVPVQCLCQGLELDCDETNLRAVPS
VSSNVTAMSLQWNLIRKLPPDCFKNYHDLQKLYLQNNKITSISIYAFRGLNSLTKLYLSHNRI
TFLKPGVFEDLHRLEWLIIEDNHLSRISPPTFYGLNSLILLVLMNNVLTRLPDKPLCQHMPRLH
WLDLEGNHIHNLRNLTFISCSNLTVLVMRKNKINHLNENTFAPLQKLDELDLGSNKIENLPPLI
FKDLKELSQLNLSYNPIQKIQANQFDYLVKLKSLSLEGIEISNIQQRMFRPLMNLSHIYFKKFQ
YCGYAPHVRSCKPNTDGISSLENLLASIIQRVFVWVVSAVTCFGNIFVICMRPYIRSENKLYA
MSIISLCCADCLMGIYLFVIGGFDLKFRGEYNKHAQLWMESTHCQLVGSLAILSTEVSVLLLT
FLTLEKYICIVYPFRCVRPGKCRTITVLILIVVITGFIVAFIPLSNKEFFKNYYGTNGVCFPLHSED
TESIGAQIYSVAIFLGINLAAFIIIVFSYGSMFYSVHQSAITATEIRNQVKKEMILAKRFFFIVFTD
ALCWIPIFVVKFLSLLQVEIPGTITSWVVIFILPINSALNPILYTLTTRPFKEMIHRFWYNYRQRK
SMDSKGQKTYAPSFIVVVEMWPLQEMPPELMKPDLFTYPCEMSLISQSTRLNSY

(SEQ ID NO:1236)
>gi\|88758590\|ref\|NP_0052883\| melanin-concentrating hormone receptor 1
{Homosapiens}
MSVGAMKKGVGRAVGLGGGSGCQATEEDPLPNCGACAPGQGGRRWRLPQPAWVEGSSAR
LWEQATGTGWMDLEASLLPTGPNASNTSDGPDNLTSAGSPPRTGSISYINIIMPSVFGTICLLG
IIGNSTVIFAVVKKSKLHWCNNVPDIFIINLSVVDLLFLLGMPFMIHQLMGNGVWHFGETMCT
LITAMDANSQFTSTYILTAMAIDRYLATVHPISSTKFRKPSVATLVICLLWALSFISITPVVVLYA
RLIPFPGGAVGCGIRLPNPDTDLYWFTLYQFFLAFALPFVVITAAYVRILQRMTSSVAPASQRS
IRLRTKRVTRTAIAICLVFFVCWAPYYVLQLTQLSISRPTLTFVYLYNAAISLGYANSCLNPFV
YIVLCETFRKRLVLSVKPAAQGQLRAVSNAQTADEERTESKGT

(SEQ ID NO:1237)
>gi\|89191861\|ref\|NP_0007872\| d(3) dopamine receptor isoform a {Homosapiens}
MASLSQLSGHLNYTCGAENS TGASQARPHAYYALSYCAULAIVFGNGLVCMAVLKERALQ
TTTNYLVVSLAVADLLVATLVMPWVVYLEVTGGVWNFSRICCDVFVTLDVMMCTASILNL
CAISIDRYTAVVMPVHYQHGTGQSSCRRVALMITAVWVLAFAVSCPLLFGFNTTGDPTVCSI
SNPDFVIYSSVVSFYLPFGVTVLVYARIYVVLKQRRRKRILTRQNSQCNSVRPGFPQQTLSPDP
AHLELKRYYSICQDTALGGPGFQERGGELKREEKTRNSLSPTIAPKLSLEVRKLSNGRLSTSL
KLGPLQPRGVPLREKKATQMVAIVLGAFIVCWLPFFLTHVLNTHCQTCHVSPELYSATTWLG
YVNSALNPVIYTTFNIEFRKAFLKILSC

(SEQ ID NO:1238)
>gi\|89257346\|ref\|NP_0052842\| G-protein coupled receptor 20 {Homosapiens}
MPSVSPAGPSAGAVPNATAVTTVRTNASGLEVPLFHLFARLDEELHGTFPGLWLALMAVHG
AIFLAGLVLNGLALYVFCCRTRAKTPSVIYTINLVVTDLLVGLSLPTRFAVYYGARGCLRCAF
PHVLGYFLNMHCSILFLTCICVDRYLAIVRPEGSRRCRQPACARAVCAFVWLAAGAVTLSVL
GVTGSRPCCRVFALTVLEFLLPLLVISVFTGRIMCALSRPGLLHQGRQRRVRAMQLLLTVLIIF
LVCFTPFHARQVAVALWPDMPHHTSLVVYHVAVTLSSLNSCMDPIVYCFVTSGFQATVRGL
FGQHGEREPSSGDVVSMHRSSKGSGRHHILSAGPHALTQALANGPEA

(SEQ ID NO:1239)
>gi\|89353783\|ref\|NP_0039412\| proteinase-activated receptor 4 precursor
{Homosapiens}
MWGRLLLWPLVLGFSLSGGTQTPSVYDESGSTGGGDDSTPSILPAPRGYPGQVCANDSDTLE
LPDSSRALLLGWVPTRLVPALYGLVLVVGLPANGLALWVLATQAPRLPSTMLLMNLAAADL
LLALALPPRIAYHLRGQRWPFGEAACRLATAALYGHMYGSVLLLAAVSLDRYLALVHPLRA
RALRGRRLALGLCMAAWLMAAALALPLTLQRQTFRLARSDRVLCHDALPLDAQASHWQPA
FTCLALLGCFLPLLAMLLCYGATLHTLAASGRRYGHALRLTAVVLASAVAFFVPSNLLLLLH
YSDPSPSAWGNLYGAYVPSLALSTLNSCVDPFIYYYVSAEFRDKVRAGLFQRSPGDTVASKA
SAEGGSRGMGTHSSLLQ

(SEQ ID NO:1240)
>gi\|91106202\|ref\|NP_0052862\| probable G-protein coupled receptor 22
{Homosapiens}
MCFSPILEINMQSESNITVRDDIDDINTNMYQPLSYPLSFQVSLTGFLMLEIVLGLGSNLTVLV
LYCMKSNLINSVSNIITMNLHVLDVIICVGCIPLTIVILLLSLESNTALICCFHEACVSFASVSTAI
NVFAITLDRYDISVKPANRILTMGRAVMLMISIVVIFSFFSFLIPFIEVNFFSLQSGNTWENKTLL
CVSTNEYYTELGMYYHLLVQIPIFFFTVVVMLITYTKILQALNIRIGTRFSTGQKKKARKKKTI
SLTTQHEATDMSQSSGGRNVVFGVRTSVSVIIALRRAVKRHRERRERQKRVFRMSLLIISTFL
LCWTPISVLNTTILCLGPSDLLVKLRLCFLVMAYGTTIFHPLLYAFTRQKFQKVLKSKMKKRV
VSIVEADPLPNNAVIHNSWIDPKRNKKITFEDSEIREKCLVPQVVTD

(SEQ ID NO:1241)
>gi\|93204867\|ref\|NP_0658032\| probable G-protein coupled receptor 158
precursor {Homosapiens}
MGAMAYPLLLCLLLAQLGLGAVGASRDPQGRPDSPRERTPKGKPHAQQPGRASASDSSAPW
SRSTDGTILAQKLAEEVPMDVASYLYTGDSHQLKRANCSGRYELAGLPGKWPALASAHPSL
HRALDTLTHATNFLNVMLQSNKSREQNLQDDLDWYQALVWSLLEGEPSISRAAITFSTDSLS
APAPQVFLQATREESRILLQDLSSSAPHLANATLETEWFHGLRRKWRPHLHRRGPNQGPRGL
GHSWRRKDGLGGDKSHFKWSPPYLECENGSYKPGWLVTLSSAIYGLQPNLVPEFRGVMKV
DINLQKVDIDQCSSDGWFSGTHKCHLNNSECMPIKGLGFVLGAYECICKAGFYHPGVLPVNN
FRRRGPDQHISGSTKDVSEEAYVCLPCREGCPFCADDSPCFVQEDKYLRLAIISFQALCMLLD
FVSMLVVYHFRKAKSIRASGLILLETILFGSLLLYFPVVILYFEPSTFRCILLRWARLLGFATVY
GTVTLKLHRVLKVFLSRTAQRIPYMTGGRVMRMLAVILLVVFVVFLIGWTSSVCQNLEKQISL
IGQGKTSDHLIFNMCLIDRWDYMTAVAEFLFLLWGVYLCYAVRTVPSAFHEPRYMAVAVH
NELIISAIFHTIRFVLASRLQSDWMLMLYFAHTHLTVTVTIGLLLIPKFSHSSNNPRDDIATEAY
EDELDMGRSGSYLNSSINSAWSEHSLDPEDIRDELKKLYAQLEIYKRKKMITNNPHLQKKRC
SKKGLGRSIMRRITEIPETVSRQCSKEDKEGADHGTAKGTALIRKNPPESSGNTGKSKEETLK
NRVFSLKKSHSTYDHVRDQTEESSSLPTESQEEETTENSTLESLSGKKLTQKLKEDSEAESTES
VPLVCKSASAHNLSSEKKTGHPRTSMLQKSLSVIASAKEKTLGLAGKTQTAGVEERTKSQKP
LPKDKETNRNHSNSDNTETKDPAPQNSNPAEEPRKPQKSGIMKQQRVNPTTANSDLNPGTTQ
MKDNFDIGEVCPWEVYDLTPGPVPSESKVQKHVSIVASEMEKNPTFSLKEKSHHKPKAAEVC
QQSNQKRIDKAEVCLWESQGQSILEDEKLLISKTPVLPERAKEENGGQPRAANVCAGQSEEL
PPKAVASKTENENLNQIGHQEKKTSSSEENVRGSYNSSNNFQQPLTSRAEVCPWEFETPAQPN
AGRSVALPASSALSANKIAGPRKEEIVVDSFKV

(SEQ ID NO:1242)
>gi\|93204873\|ref\|NP_0792564\| probable G-protein coupled receptor 157
{Homosapiens}
MQPSPPPTELVPSERAVVLLSCALSALGSGLLVATHALWPDLRSRARRLLLFLSLADLLSAAS
YFYGVLQNFAGPSWDCVLQGALSTFANTSSFFWTVAIALYLYLSIVRAARGPRTDRLLWAFH
VVSWGVPLVITVAAVALKKIGYDASDVSVGWCWIDLEAKDHVLWMLLTGKLWEMLAYVL
LPLLYLLVRKHINRAHTALSEYRPILSQEHRLLRHSSMADKKLVLIPLIFIGLRVWSTVRFVLT
LCGSPAVQTPVLVVLHGIGNTFQGGANCIMFVLCTRAVRTRLFSLCCCCCSSQPPTKSPAGTP
KAPAPSKPGESQESQGTPGELPST

(SEQ ID NO:1243)
>gi\|93277083\|ref\|NP_0010352691\| melanin-concentrating hormone receptor 2
{Homosapiens}
MNPFHASCWNTSAELLNKSWNKEFAYQTASVVDTVILPSMIGIICSTGLVGNILIVFTIIRSRK
KTVPDIYICNLAVADLVHIVGMPFLIHQWARGGEWVFGGPLCTIITSLDTCNQFACSAIMTVM
SVDRYFALVQPFRLTRWRTRYKTIRINLGLWAASFILALPVWVYSKVIKFKDGVESCAFDLTS
PDDVLWYTLYLTITTFFFPLPLILVCYILILCYTVVEMYQQNKDARCCNPSVPKQRVMKLTKM
VLVLVVVFILSAAPYHVIQLVNLQMEQPTLAFYVGYYLSICLSYASSSINPFLYILLSGNFQKR
LPQIQRRATEKEINNMGNTLKSHF

(SEQ ID NO:1244)
>gi\|93352554\|ref\|NP_0010043342\| probable G-protein coupled receptor 179
precursor {Homosapiens}
MGTRGAVMPPPMWGLLGCCFVCAWALGGPRPIRSLPPLSSQVKPGSVPMQVPLEGAEAALA
YLYSGDAQQLSQVNCSERYEARGAGAMPGLPPSLQGAAGTLAQAANFLNMLLQANDIRESS
VEEDVEWYQALVRSVAEGDPRVYRALLTFNPPPGASHLQLALQATRTGEETILQDLSGNWV
QEENPPGDLDTPALKKRVLTNDLGSLGSPKWPQADGYVGDTQQVRLSPPFLECQEGRLRPG
WLITLSATFYGLKPDLSPEVRGQVQMDVDLQSVDINQCASGPGWYSNTHLCDLNSTQCVPL
ESQGFVLGRYLCRCRPGFYGASPSGGLEESDFQTTGQFGFPEGRSGRLLQCLPCPEGCTSCMD
ATPCLVEEAAVLRAAVLACQACCMLAIFLSMLVSYRCRRNKRIVVASGVVLLETVLFGFLLLY
FPVFILYFKPSVFRCIALRWVRLLGFAIVYGTIILKLYRVLQLFLSRTAQRSALLSSGRLLRRLG
LLLLPVLGFLAVWTVGALERGIQHAPLVIRGHTPSGRHFYLCHHDRWDYIMVVAELLLLCW
GSFLCYATRAVLSAFHEPRYMGIALHNELLLSAAFHTARFVLVPSLHPDWTLLLFFFHTHSTV
TTTLALIFIPKFVVKLGAPPREEMVDEVCEDELDLQHSGSYLGSSIASAWSEHSLDPGDIRDELK
KLYAQLEVHKTKEMAANNPHLPKKRGSSCQGLGRSFMRYLAEFPEALARQHSRDSGSPGHG
SLPGSSRRRLLSSSLQEPEGTPALHKSRSTYDQRREQDPPLLDSLLRRKLAKKASRTESRESVE
GPPALGFRSASAHNLTVGERLPRARPASLQKSLSVASSREKALLMASQAYLEETYRQAKERE
ERKKAKAAMASLVRRPSARRLERPRGAPLSAPPSPAKSSSVDSSHTSGRLHEEARRRLPHPPI
RHQVSTPILALSGGLGEPRMLSPTSTLAPALLPALAPTPAPALAPVPVSPQSPNLLTYICPWEN
AELPAKQENVPQEGPSGPERGHHSPAPARARLWRALSVAVEKSRAGENEMDAEDAHHQRE
ANDVDEDRPKIFPKSHSLKAPVQQGSMRSLGLAIKALTRSRSTYREKESVEESPEGQNSGTAG
ESMGAPSRSPRLGRPKAVSKQAALIPSDDKESLQNQQNAHTSRMLQVCQREGSREQEDRGR
RMTQGLGERKAERAGKTGLAMLRQVSRDKNIKQSKETPVGWQELPKAGLQSLGSADHRVA
EVCPWEVTESETRQPDSGNKAEICPWETSEGAPESRALRQDPGDSQKKRGEARGKSEPIDVV
PMMRKKPERLVREQEAVCPWESADRGGLSPGSAPQDPGRIRDKSEAGDSVEARKVEKPGWE
AAGPEAHTPDITKAEPCPWEASEGGEDGKPAQEAVKDLPQEKQKTRKATFWKEQKPGGDLE
SLCPWESTDFRGPSAVSIQAPGSSECSGSLGSGIAEVCLWEAGDAPAIQKAEICPWELDDNVM
GQEMLSLGTGRESLQEKEKASRKGSFGEMGEQTVKAVQKLSQQQESVCPRESTVPGHSSPCL
DNSSSKAGSQFLCNGGSRATQVCPQEDLRPEAQEATPAKTEICPWEVNERTREEWTSAQVPR
GGESQKDKEKMPGKSEIEDVTAWEKPEGQIQKQEAVGPWESVDPGSFSPQPRPQDTERPQTL
LQMSGSVGSKAADICPLDVEENLTAGKAEICPWEVGAGAGEERALGAEAIRKSPNDTGKVS
ADLGPRERAVTAPEKPQKPTPEWEVACPWGSVGPGACSQHPGTLDADGPKAGFQELDHMG
CRPGEVCPWEAQEAATSEKAKICPWEVSEGTTGKGLDQKAGSESAEQREKALEKGRLTSLG
EDVSKGMAKLCQQQETICIVVENKDLRESPAQAPKISDLPSSMSSEVAEGHSLEATEKGDLRQ
DPKTGSFPEHITQEKAPAADTEEFTTEDGEKTSHELQSVCPWETTAPADSVSHLDRQRPDQPK
ASSQRLVSTGGRAADVCPWDVPDAGVYKSDSSAKAETCPWEVTERIPVKGVSRQDGKGDS
QEEKGRAPEKSEPKGVPVQKKPEMADFRQQEAVCPWESQDGKGLSPQPAPDASDRSRGSSE
AAGSVETRVAEVCLWEVVEAPSAKKAEICPWEAGGGAAEEGEQERESQGQGEMFLQKAGP
GGTEEHFSKAAAKPREQEAVCPGEGTGSGGLLPQSGALDPELKVSPKEAGSMGSRMAELCQ
WEITDPEGNKIKGTMADICPGEETGVPSEESGLLALTATRREFFPTAPEKPLCLLVHGPLDHFF
PESKIPCPKVSRPASTFTLEGVRELQGPSGLEPRTSLAPEPSLQEAESQSSSLTEDSGQVAFEAQ
YEEFTPPTVYPWDWE

(SEQ ID NO:1245)
>gi\|106067657\|ref\|NP_0002242\| luteinizing hormone/choriogonadotropin receptor
precursor {Homosapiens}
MKQRFSALQLLKLLLLLQPPLPRALREALCPEPCNCVPDGALRCPGPTAGLTRLSLAYLPVKV
IPSQAFRGLNEVIKIEISQIDSLERIEANAFDNLLNLSEILIQNTKNLRYIEPGAFINLPRLKYLSIC
NTGIRKFPDVTKVFSSESNFILEICDNLHITTIPGNAFQGMNNESVTLKLYGNGFEEVQSHAFN
GTTLTSLELKENVHLEKMHNGAFRGATGPKTLDISSTKLQALPSYGLESIQRLIATSSYSLKKL
PSRETFVNLLEATLTYPSHCCAFRNLPTKEQNFSHSISENFSKQCESTVRKVNNKTLYSSMLA
ESELSGWDYEYGFCLPKTPRCAPEPDAFNPCEDIMGYDFLRVLIVVLINILAIMGNMTVLFVLL
TSRYKLTVPRFLMCNLSFADFCMGLYLLLIASVDSQTKGQYYNHAIDWQTGSGCSTAGFFTV
FASELSVYTLTVITLERWHTITYAIHLDQKLRLRHAILIMLGGWLFSSLIAMLPLVGVSNYMK
VSICFPMDVETTLSQVYILTILILNVVAFFIICACYIKIYFAVRNPELMATNKDTKIAKKMAILIF
TDFTCMAPISFFAISAAFKVPLITVTNSKVLLVLFYPINSCANPFLYAIFTKTFQRDFFLLLSKFG
CCKRRAELYRRKDFSAYTSNCKNGFTGSNKPSQSTLKLSTLHCQGTALLDKTRYTEC

(SEQ ID NO:1246)
>gi\|110611176\|ref\|NP_0008342\| metabotropic glutamate receptor 6 precursor
{Homosapiens}
MARPRRAREPLLVALLPLAWLAQAGLARAAGSVRLAGGLTLGGLFPVHARGAAGRACGQL
KKEQGVHRLEAMLYALDRVNADPELLPGVRLGARLLDTCSRDTYALEQALSFVQALIRGRG
DGDEVGVRCPGGVPPLRPAPPERVVAVVGASASSVSIMVANVLRLFAIPQISYASTAPELSDS
TRYDFFSRVVPPDSYQAQAMVDIVRALGWNYVSTLASEGNYGESGVEAFVQISREAGGVCI
AQSIKIPREPKPGEFSKVIRRLMETPNARGIIIFANEDDIRRVLEAARQANLTGHFLWVGSDSW
GAKTSPILSLEDVAVGAITILPKRASIDGFDQYFMTRSLENNRRNIVVFAEFVVEENFNCKLTSSG
TQSDDSTRKCTGEERIGRDSTYEQEGKVQFVIDAVYAIAHALHSMHQALCPGHTGLCPAMEP
TDGRMLLQYIRAVRFNGSAGTPVMFNENGDAPGRYDIFQYQATNGSASSGGYQAVGQWAE
TLRLDVEALQWSGDPHEVPSSLCSLPCGPGERKKMVKGVPCCWHCEACDGYRFQVDEFTCE
ACPGDMRPTPNHTGCRPTPVVRLSWSSPWAAPPLLLAVLGIVATTTVVATFVRYNNTPIVRA
SGRELSYVLLTGIFLIYAITFLMVAEPGAAVCAARRLFLGLGTTLSYSALLTKTNRIYRIFEQG
KRSVTPPPFISPTSQLVITFSLTSLQVVGMIAWLGARPPHSVIDYEEQRTVDPEQARGVLKCD
MSDLSLIGCLGYSLLLMVTCTVYAIKARGVPETFNEAKPIGFTMYTTCHVVLAFVPIFFGTAQS
AEKIYIQTTTLTVSLSLSASVSLGMLYVPKTYVILFHPEQNVQKRKRSLKATSTVAAPPKGED
AEAHK

(SEQ ID NO:1247)
>gi\|110611243\|ref\|NP_0025222\| neurotensin receptor type 1 {Homosapiens}
MRLNSSAPGTPGTPAADPFQRAQAGLEEALLAPGFGNASGNASERVLAAPSSELDVNTDIYS
KVLVTAVYLALFVVGTVGNTVTAFTLARKKSLQSLQSTVHYHLGSLALSDLLTLLLAMPVE
LYNFIVVVHHPWAFGDAGCRGYYFLRDACTYATALNVASLSVERYLAICHPFKAKTLMSRSR
TKKFISAIWLASALLAVPMLFTMGEQNRSADGQHAGGLVCTPTIHTATVKVVIQVNTFMSFIF
PMVVISVLNTHANKLTVMVRQAAEQGQVCTVGGEHSTFSMAIEPGRVQALRHGVRVLRAV
VIAFVVCWLPYHVRRLMFCYISDEQWTPFLYDFYHYFYMVTNALFYVSSTINPILYNLVSAN
FRHIFLATLACLCPVWRRRRKRPAFSRKADSVSSNHTLSSNATRETLY

(SEQ ID NO:1248)
>gi\|110618256\|ref\|NP_7782273\| trace amine-associated receptor 9 {Homosapiens}
MVNNFSQAEAVELCYKNVNESCIKTPYSPGPRSILYAVLGFGAVLAAFGNLLVMIAILHFKQL
HTPTNFLIASLACADFLVGVTVMPFSTVRSVESCWYFGDSYCKFHTCFDTSFCFASLFHLCCIS
VDRYIAVTDPLTYPTKFTVSVSGICIVLSWFFSVTYSFSIFYTGANEEGIEELVVALTCVGGCQ
APLNQNVVVLLCFLLFFIPNVAMVFIYSKIFLVAKHQARKIESTASQAQSSSESYKERVAKRER
KAAKTLGIAMAAFLVSWLPYLVDAVIDAYMNFITPPYVYEILVWCVYYNSAMNPLIYAFFY
QWFGKAIKLIVSGKVLRTDSSTTNLFSEEVETD

(SEQ ID NO:1249)
>gi\|111118992\|ref\|NP_0006712\| alpha-1A adrenergic receptor isoform 1
{Homosapiens}
MVFLSGNASDSSNCTQPPAPVNISKAILLGVILGGLILFGVLGNILVILSVACHRHLHSVTHYYI
VNLAVADLLLTSTVLPFSAIFEVLGYWAFGRVFCNIVVAAVDVLCCTASIMGLCIISIDRYIGVS
YPLRYPTIVTQRRGLMALLCVWALSLVISIGPLFGWRQPAPEDETICQINEEPGYVLFSALGSF
YLPLAIILVMYCRVYVVAKRESRGLKSGLKTDKSDSEQVTLRIHRKNAPAGGSGMASAKTKT
HFSVRLLKFSREKKAAKTLGIVVGCFVLCWLPFFLVMPIGSFFPDFKPSETVFKIVFVVLGYLNS
CINPIIYPCSSQEFKKAFQNVLRIQCLCRKQSSKHALGYTLHPPSQAVEGQHKDMVRIPVGSRE
TFYRISKTDGVCEWKFFSSMPRGSARITVSKDQSSCTTARVRSKSFLQVCCCVGPSTPSLDKN
HQVPTIKVHTISLSENGEEV

(SEQ ID NO:1250)
>gi\|111118994\|ref\|NP_0016932\| brain-specific angiogenesis inhibitor 1
precursor {Homosapiens }
MRGQAAAPGPVWILAPLLLLLLLLGRRARAAAGADAGPGPEPCATLVQGKFFGYFSAAAVF
PANASRCSWTLRNPDPRRYTLYMKVAKAPVPCSGPGRVRTYQFDSFLESTRTYLGVESFDEV
LRLCDPSAPLAFLQASKQFLQMRRQQPPQHDGLRPRAGPPGPTDDFSVEYLVVGNRNPSRAA
CQMLCRWLDACLAGSRSSHPCGIMQTPCACLGGEAGGPAAGPLAPRGDVCLRDAVAGGPE
NCLTSLTQDRGGHGATGGWKLWSLWGECTRDCGGGLQTRTRTCLPAPGVEGGGCEGVLEE
GRQCNREACGPAGRTSSRSQSLRSTDARRREELGDELQQFGFPAPQTGDPAAEEWSPWSVCS
STCGEGWQTRTRFCVSSSYSTQCSGPLREQRLCNNSAVCPVHGAWDEWSPWSLCSSTCGRG
FRDRTRTCRPPQFGGNPCEGPEKQTKFCNIALCPGRAVDGNWNEWSSWSACSASCSQGRQQ
RTRECNGPSYGGAECQGHWVETRDCFLQQCPVDGKWQAWASWGSCSVTCGAGSQRRERV
CSGPFFGGAACQGPQDEYRQCGTQRCPEPHEICDEDNFGAVIVVKETPAGEVAAVRCPRNAT
GLILRRCELDEEGIAYWEPPTYIRCVSIDYRNIQMMTREHLAKAQRGLPGEGVSEVIQTLVEIS
QDGTSYSGDLLSTIDVLRNMTEIFRRAYYSPTPGDVQNFVQILSNLLAEENRDKWEEAQLAG
PNAKELFRLVEDFVDVIGFRMKDLRDAYQVTDNLVLSIHKLPASGATDISFPMKGWRATGD
WAKVPEDRVTVSKSVFSTGLTEADEASVFVVGTVLYRNLGSFLALQRNTTVLNSKVISVTVK
PPPRSLRTPLEIEFAHMYNGTTNQTCILWDETDVPSSSAPPQLGPWSWRGCRTVPLDALRTRC
LCDRLSTFAILAQLSADANMEKATLPSVTLIVGCGVSSLTLLMLVIIYVSVWRYIRSERSVILIN
FCLSIISSNALILIGQTQTRNKVVCTLVAAFLHFFFLSSFCWVLTEAWQSYMAVTGHLRNRLIR
KRFLCLGWGLPALVVAISVGFTKAKGYSTMNYCWLSLEGGLLYAFVGPAAAVVLVNMVIGI
LVFNKLVSKDGITDKKLKERAGASLWSSCVVLPLLALTWMSAVLAVTDRRSALFQILFAVFD
SLEGFVIVMVHCILRREVQDAVKCRVVDRQEEGNGDSGGSFQNGHAQLMTDFEKDVDLAC
RSVLNKDIAACRTATITGTLKRPSLPEEEKLKLAHAKGPPTNFNSLPANVSKLHLHGSPRYPG
GPLPDFPNHSLTLKRDKAPKSSFVGDGDIFKKLDSELSRAQEKALDTSYVILPTATATLRPKPK
EEPKYSIHIDQMPQTRLIHLSTAPEASLPARSPPSRQPPSGGPPEAPPAQPPPPPPPPPPPPQQPLP
PPPNLEPAPPSLGDPGEPAAHPGPSTGPSTKNENVATLSVSSLERRKSRYAELDFEKIMHTRKR
HQDMFQDLNRKLQHAAEKDKEVLGPDSKPEKQQTPNKRPWESLRKAHGTPTWVKKELEPL
QPSPLELRSVEWERSGATIPLVGQDIIDLQTEV

(SEQ ID NO:1251)
>gi\|112807234\|ref\|NP_6837662\| G-protein coupled receptor family C group 6
member A precursor {Homosapiens}
MAFLIILITCFVIILATSQPCQTPDDFVAATSPGHIIIGGLFAIHEKMLSSEDSPRRPQIQECVGFEI
SVFLQTLAMIHSIEMINNSTLLPGVKLGYEIYDTCTEVTVAMAATLRFLSKFNCSRETVEFKC
DYSSYMPRVKAVIGSGYSEITMAVSRMLNLQLMPQVGYESTAEILSDKIRFPSFLRTVPSDFH
QIKAMAHLIQKSGWNWIGHTTDDDYGRLALNTFIIQAEANNVCIAFKEVLPAFLSDNTIEVRI
NRTLKKIILEAQVNVIVVFLRQFHVFDLFNKAIEMNINKMWIASDNWSTATKITTIPNVKKIG
KVVGFAFRRGNISSFHSFLQNLHLLPSDSHKLLHEYAMHLSACAYVKDTDLSQCIFNHSQRTL
AYKANKAIERNFVMRNDFLWDYAEPGLIHSIQLAVFALGYAIRDLCQARDCQNPNAFQPWE
LLGVLKNVTFTDGWNSFHFDAHGDLNTGYDVVLWKEINGHMTVTKMAEYDLQNDVFIIPD
QETKNEFRNLKQIQSKCSKECSPGQMKKTTRSQHICCYECQNCPENHYTNQTDMPHCLLCN
NKTHWAPVRSTMCFEKEVEYLNWNDSLAILLLILSLLGIIFVLVVGIIFTRNLNTPVVKSSGGL
RVCYVILLCHFLNFASTSFFIGEPQDFTCKTRQTMFGVSFTLCISCILTKSLKILLAFSFDPKLQK
FLKCLYRPILIIFTCTGIQVVICTLWLIFAAPTVEVNVSLPRVIILECEEGSILAFGTMLGYIAILA
FICFIFAFKGKYENYNEAKFITFGMLIYFIAWITFIPIYATTFGKYVPAVEIIVILISNYGILYCTFI
PKCYVIICKQEINTKSAFLKMIYSYSSHSVSSIALSPASLDSMSGNVTMTNPSSSGKSATWQKS
KDLQAQAFAHICRENATSVSKTLPRKRMSSI

(SEQ ID NO:1252)
>gi\|113722120\|ref\|NP_1154953\| G-protein coupled receptor 98 precursor
{Homosapiens }
MSVFLGPGMPSASLLVNLLSALLILFVFGETEIRFTGQTEFVVNETSTTVIRLIIERIGEPANVTA
IVSLYGEDAGDFFDTYAAAFIPAGETNRTVYIAVCDDDLPEPDETFIFHLTLQKPSANVKLGW
PRTVTVTILSNDNAFGIISFNMLPSIAVSEPKGRNESMPLTLIREKGTYGMVMVTFEVEGGPNP
PDEDLSPVKGNITFPPGRATVIYNLTVLDDEVPENDEIFLIQLKSVEGGAEINTSRNSIEIIIKKN
DSPVRFLQSIYLVPEEDHILIIPVVRGKDNNGNLIGSDEYEVSISYAVTTGNSTAHAQQNLDFID
LQPNTTVVFPPFIHESHLKFQIVDDTIPEIAESFHIMLLKDTLQGDAVLISPSVVQVTIKPNDKP
YGVLSFNSVLFERTVIIDEDRISRYEEITVVRNGGTHGNVSANWVLTRNSTDPSPVTADIRPSS
GVLHFAQGQMLATIPLTVVDDDLPEEAEAYLLQILPHTIRGGAEVSEPAELLFYIQDSDDVYG
LITFFPMENQKIESSPGERYLSLSFTRLGGTKGDVRLLYSVLYIPAGAVDPLQAKEGILNISRRN
DLIFPEQKTQVTTKLPIRNDAFLQNGAHFLVQLETVELLNIIPLIPPISPRFGEICNISLLVTPAIA
NGEIGFLSNLPIILHEPEDFAAEVVYIPLHRDGTDGQATVYWSLKPSGFNSKAVTPDDIGPFNG
SVLFLSGQSDTTINITIKGDDIPEMNETVTLSLDRVNVENQVLKSGYTSRDLIILENDDPGGVF
EFSPASRGPYVIKEGESVELHIIRSRGSLVKQFLHYRVEPRDSNEFYGNTGVLEFKPGEREIVIT
LLARLDGIPELDEHYWVVLSSHGERESKLGSATIVNITILKNDDPHGIIEFVSDGLIVMINESKG
DAIYSAVYDVVRNRGNFGDVSVSWVVSPDFTQDVFPVQGTVVFGDQEFSKNITIYSLPDEIPE
EMEEFTVILLNGTGGAKVGNRTTATLRIRRNDDPIYFAEPRVVRVQEGETANFTVLRNGSVD
VTCMVQYATKDGKATARERDFIPVEKGETLIFEVGSRQQSISIFVNEDGIPETDEPFYIILLNST
GDTVVYQYGVATVIIEANDDPNGIFSLEPIDKAVEEGKTNAFWILRHRGYFGSVSVSWQLFQ
NDSALQPGQEFYETSGTVNFMDGEEAKPIILHAFPDKIPEFNEFYFLKLVNISGGSPGPGGQLA
ETNLQVTVMVPFNDDPFGVFILDPECLEREVAEDVLSEDDMSYITNFTILRQQGVFGDVQLG
WEILSSEFPAGLPPMIDFLLVGIFPTTVHLQQHMRRHHSGTDALYFTGLEGAFGTVNPKYHPS
RNNTIANFTFSAWVMPNANTNGFIIAKDDGNGSIYYGVKIQTNESHVTLSLHYKTLGSNATYI
AKTTVMKYLEESVWLHLLIILEDGIIEFYLDGNAMPRGIKSLKGEAITDGPGILRIGAGINGND
RFTGLMQDVRSYERKLTLEEIYELHAMPAKSDLHPISGYLEFRQGETNKSFIISARDDNDEEG
EELFILKLVSVYGGARISEENTTARLTIQKSDNANGLFGFTGACIPEIAEEGSTISCVVERTRGA
LDYVHVFYTISQIETDGINYLVDDFANASGTITFLPWQRSEVLNIYVLDDDIPELNEYFRVTLV
SAIPGDGKLGSTPTSGASIDPEKETTDITIKASDHPYGLLQFSTGLPPQPKDAMTLPASSVPHIT
VEEEDGEIRLLVIRAQGLLGRVTAEFRTVSLTAFSPEDYQNVAGTLEFQPGERYKYIFINITDN
SIPELEKSFKVELLNLEGGVAELFRVDGSGSGDGDMEFFLPTIHKRASLGVASQILVTIAASDH
AHGVFEFSPESLFVSGTEPEDGYSTVTLNVIRHHGTLSPVTLHWNIDSDPDGDLAFTSGNITFE
IGQTSANITVEILPDEDPELDKAFSVSVLSVSSGSLGAHINATLTVLASDDPYGIFIFSEKNRPV
KVEEATQNITLSIIRLKGLMGKVLVSYATLDDMEKPPYFPPNLARATQGRDYIPASGFALFGA
NQSEATIAISILDDDEPERSESVFIELLNSTLVAKVQSRSIPNSPRLGPKVETIAQLIIIANDDAFG
TLQLSAPIVRVAENHVGPIINVTRTGGAFADVSVKFKAVPITAIAGEDYSIASSDVVLLEGETS
KAVPIYVINDIYPELEESFLVQLMNETTGGARLGALTEAVIIIEASDDPYGLFGFQITKLIVEEPE
FNSVKVNLPIIRNSGTLGNVTVQWVATINGQLATGDLRVVSGNVTFAPGETIQTLLLEVLAD
DVPEIEEVIQVQLTDASGGGTIGLDRIANIIIPANDDPYGTVAFAQMVYRVQEPLERSSCANIT
VRRSGGHFGRLLLFYSTSDIDVVALAMEEGQDLLSYYESPIQGVPDPLWRTWMNVSAVGEP
LYTCATLCLKEQACSAFSFFSASEGPQCFWMTSWISPAVNNSDFWTYRKNMTRVASLFSGQ
AVAGSDYEPVTRQWAIMQEGDEFANLTVSILPDDFPEMDESFLISLLEVHLMNISASLKNQPT
IGQPNISTVVIALNGDAFGVFVIYNISPNTSEDGLFVEVQEQPQTLVELMIHRTGGSLGQVAVE
WRVVGGTATEGLDFIGAGEILTFAEGETKKTVILTILDDSEPEDDESIIVSLVYTEGGSRILPSS
DTVRVNILANDNVAGIVSFQTASRSVIGHEGEILQFHVIRTFPGRGNVTVNWKIIGQNLELNFA
NFSGQLFFPEGSLNTTLFVHLLDDNIPEEKEVYQVILYDVRTQGVPPAGIALLDAQGYAAVLT
VEASDEPHGVLNFALSSRFVLLQEANITIQLFINREFGSLGAINVTYTTVPGMLSLKNQTVGNL
AEPEVDFVPIIGFLILEEGETAAAINITILEDDVPELEEYFLVNLTYVGLTMAASTSFPPRLDSEG
LTAQVIIDANDGARGVIEWQQSRFEVNETHGSLTLVAQRSREPLGHVSLFVYAQNLEAQVGL
DYIFTPMILHFADGERYKNVNIMILDDDIPEGDEKFQLILTNPSPGLELGKNTIALIIVLANDDG
PGVLSFNNSEHFFLREPTALYVQESVAVLYIVREPAQGLFGTVTVQFIVTEVNSSNESKDLTPS
KGYIVLEEGVRFKALQISAILDTEPEMDEYFVCTLFNPTGGARLGVHVQTLITVLQNQAPLGL
FSISAVENRATSIDIEEANRTVYLNVSRTNGIDLAVSVQWETVSETAFGMRGMDVVFSVFQSF
LDESASGWCFFTLENLIYGIMLRKSSVTVYRWQGIFIPVEDLNIENPKTCEAFNIGFSPYFVITH
EERNEEKPSLNSVFTFTSGFKLFLVQTIIILESSQVRYFTSDSQDYLIIASQRDDSELTQVFRWN
GGSFVLHQKLPVRGVLTVALFNKGGSVFLAISQANARLNSLLFRWSGSGFINFQEVPVSGTTE
VEALSSANDIYLIFAENVFLGDQNSIDIFIVVEMGQSSFRYFQSVDFAAVNRIHSFTPASGIAHIL
LIGQDMSALYCWNSERNQFSFVLEVPSAYDVASVTVKSLNSSKNLIALVGAHSHIYELAYISS
HSDFIPSSGELIFEPGEREATIAVNILDDTVPEKEESFKVQLKNPKGGAEIGINDSVTITILSNDD
AYGIVAFAQNSLYKQVEEMEQDSLVTLNVERLKGTYGRITIAWEADGSISDIFPTSGVILFTEG
QVLSTITLTILADNIPELSEVVIVTLTRITTEGVEDSYKGATIDQDRSKSVITTLPNDSPFGLVG
WRAASVFIRVAEPKENTTTLQLQIARDKGLLGDIAIHLRAQPNFLLHVDNQATENEDYVLQE
TIIIMKENIKEAHAEVSILPDDLPELEEGFIVTITEVNLVNSDFSTGQPSVRRPGMEIAEIMIEEN
DDPRGIFMFHVTRGAGEVITAYEVPPPLNVLQVPVVRLAGSFGAVNVYWKASPDSAGLEDF
KPSHGILEFADKQVTAMIEITIIDDAEFELTETFNISLISVAGGGRLGDDVVVTVVIPQNDSPFG
VFGFEEKTVMIDESLSSDDPDSYVTLTVVRSPGGKGTVRLEWTIDEKAKHNLSPLNGTLHFD
ETESQKTIVLHTLQDTVLEEDRRFTIQLISIDEVEISPVKGSASIIIRGDKRASGEVGIAPSSRHILI
GEPSAKYNGTAIISLVRGPGILGEVTVFWRIFPPSVGEFAETSGKLTMRDEQSAVIVVIQALND
DIPEEKSFYEFQLTAVSEGGVLSESSSTANITVVASDSPYGRFAFSHEQLRVSEAQRVNITIIRSS
GDFGHVRLWYKTMSGTAEAGLDFVPAAGELLFEAGEMRKSLHVEILDDDYPEGPEEFSLTIT
KVELQGRGYDFTIQENGLQIDQPPEIGNISIVRIIIMKNDNAEGIIEFDPKYTAFEVEEDVGLIMI
PVVRLHGTYGYVTADFISQSSSASPGGVDYILHGSTVTFQHGQNLSFINISIIDDNESEFEEPIEI
LLTGATGGAVLGRHLVSRIIIAKSDSPFGVIRFLNQSKISIANPNSTMILSLVLERTGGLLGEIQV
NWETVGPNSQEALLPQNRDIADPVSGLFYFGEGEGGVRTIILTIYPHEEIEVEETFIIKLHLVKG
EAKLDSRAKDVTLTIQEFGDPNGVVQFAPETLSKKTYSEPLALEGPLLITFFVRRVKGTFGEIM
VYWELSSEFDITEDFLSTSGFFTIADGESEASFDVHLLPDEVPEIEEDYVIQLVSVEGGAELDLE
KSITWFSVYANDDPHGVFALYSDRQSILIGQNLIRSIQINITRLAGTFGDVAVGLRISSDHKEQP
IVTENAERQLVVKDGATYKVDVVPIKNQVFLSLGSNFTLQLVTVMLVGGRFYGMPTILQEA
KSAVLPVSEKAANSQVGFESTAFQLMNITAGTSHVMISRRGTYGALSVAWTTGYAPGLEIPE
FIVVGNMTPTLGSLSFSHGEQRKGVFLWTFPSPGWPEAFVLHLSGVQSSAPGGAQLRSGFIVA
EIEPMGVFQFSTSSRNIIVSEDTQMIRLHVQRLFGFHSDLIKVSYQTTAGSAKPLEDFEPVQNG
ELFFQKFQTEVDFEITIINDQLSEIEEFFYINLTSVEIRGLQKFDVNWSPRLNLDFSVAVITILDN
DDLAGMDISFPETTVAVAVDTTLIPVETESTTYLSTSKTTTILQPTNVVAIVTEATGVSAIPEKL
VTLHGTPAVSEKPDVATVTANVSIHGTFSLGPSIVYIEEEMKNGTFNTAEVLIRRTGGFTGNV
SITVKTFGERCAQMEPNALPFRGIYGISNLTWAVEEEDFEEQTLTLIFLDGERERKVSVQILDD
DEPEGQEFFYVFLTNPQGGAQIVEEKDDTGFAAFAMVIITGSDLHNGIIGFSEESQSGLELREG
AVMRRLHLIVTRQPNRAFEDVKVFVVRVTLNKTVVVLQKDGVNLVEELQSVSGTTTCTMGQ
TKCFISIELKPEKVPQVEVYFFVELYEATAGAAINNSARFAQIKILESDESQSLVYFSVGSRLAV
AHKKATLISLQVARDSGTGLMMSVNFSTQELRSAETIGRTIISPAISGKDFVITEGTLVFEPGQR
STVLDVILTPETGSLNSFPKRFQIVLFDPKGGARIDKVYGTANITLVSDADSQAIVVGLADQLH
QPVNDDILNRVLHTISMKVATENTDEQLSAMMHLIEKITTEGKIQAFSVASRTLFYEILCSLIN
PKRKDTRGFSHFAEVTENFAFSLLTNVTCGSPGEKSKTILDSCPYLSILALHWYPQQINGHKFE
GKEGDYIRIPERLLDVQDAEIMAGKSTCKLVQFTEYSSQQWFISGNNLPTLKNKVLSLSVKGQ
SSQLLTNDNEVLYRIYAAEPRIIPQTSLCLLWNQAAASWLSDSQFCKVVEETADYVECACSH
MSVYAVYARTDNLSSYNEAFFTSGFICISGLCLAVLSHIFCARYSMFAAKLLTHMMAASLGT
QILFLASAYASPQLAEESCSAMAAVTHYLYLCQFSWMLIQSVNFVVYVLVMNDEHTERRYLL
FFLLSWGLPAFVVILLIVILKGIYHQSMSQIYGLIHGDLCFIPNVYAALFTAALVPLTCLVVVFV
VFIHAYQVKPQWKAYDDVFRGRTNAAEIPLILYLFALISVTWLWGGLHMAYRHFVVMLVLF
VIFNSLQGLYVFMVYFILHNQMCCPMKASYTVEMNGHPGPSTAFFTPGSGMPPAGGEISKST
QNLIGAMEEVPPDWERASFQQGSQASPDLKPSPQNGATFPSSGGYGQGSLIADEESQEFDDLI
FALKTGAGLSVSDNESGQGSQEGGTLTDSQIVELRRIPIADTHL

(SEQ ID NO:1253)
>gi\|114205383\|ref\|NP_0029712\| secretin receptor precursor {Homosapiens}
MRPHLSPPLQQLLLPVLLACAAHSTGALPRLCDVLQVLWEEQDQCLQELSREQTGDLGTEQP
VPGCEGMWDNISCWPSSVPGRMVEVECPRFLRMLTSRNGSLFRNCTQDGWSETFPRPNLAC
GVNVNDSSNEKRHSYLLKLKVMYTVGYSSSLVMLLVALGILCAFRRLHCTRNYIHMHLFVS
FILRALSNFIKDAVLFSSDDVTYCDAHRAGCKLVMVLFQYCIMANYSWLLVEGLYLHTLLAI
SFFSERKYLQGFVAFGWGSPAIFVALWAIARHFLEDVGCWDINANASIVVWIIRGPVILSILINFI
LFINILRILMRKLRTQETRGNEVSHYKRLARSTLLLIPLFGIHYIVFAFSPEDAMEIQLFFELALG
SFQGLVVAVLYCFLNGEVQLEVQKKWQQWHLREFPLHPVASFSNSTKASHLEQSQGTCRTSI
I

(SEQ ID NO:1254)
>gi\|115387099\|ref\|NP_0016942\| brain-specific angiogenesis inhibitor 2 precursor {Homosapiens}
MENTGWMGKGHRMTPACPLLLSVILSLRLATAFDPAPSACSALASGVLYGAFSLQDLFPTIA
SGCSWTLENPDPTKYSLYLRFNRQEQVCAHFAPRLLPLDHYLVNFTCLRPSPEEAVAQAESE
VGRPEEEEAEAAAGLELCSGSGPFTFLHFDKNFVQLCLSAEPSEAPRLLAPAALAFRFVEVLLI
NNNNSSQFTCGVLCRWSEECGRAAGRACGFAQPGCSCPGEAGAGSTTTTSPGPPAAHTLSNA
LVPGGPAPPAEADLHSGSSNDLFTTEMRYGEEPEEEPKVKTQWPRSADEPGLYMAQTGDPA
AEEWSPWSVCSLTCGQGLQVRTRSCVSSPYGTLCSGPLRETRPCNNSATCPVHGVWEEWGS
WSLCSRSCGRGSRSRMRTCVPPQHGGKACEGPELQTKLCSMAACPVEGQWLEWGPWGPCS
TSCANGTQQRSRKCSVAGPAWATCTGALTDTRECSNLECPATDSKWGPWNAWSLCSKTCD
TGWQRRFRMCQATGTQGYPCEGTGEEVKPCSEKRCPAFHEMCRDEYVMLMTWKKAAAGE
IIYNKCPPNASGSASRRCLLSAQGVAYWGLPSFARCISHEYRYLYLSLREHLAKGQRMLAGE
GMSQVVRSLQELLARRTYYSGDLLFSVDILRNVTDTFKRATYVPSADDVQRFFQVVSFMVD
AENKEKWDDAQQVSPGSVHLLRVVEDFIHLVGDALKAFQSSLIVTDNLVISIQREPVSAVSSD
ITFPMRGRRGMKDWVRHSEDRLFLPKEVLSLSSPGKPATSGAAGSPGRGRGPGTVPPGPGHS
HQRLLPADPDESSYFVIGAVLYRTLGLILPPPRPPLAVTSRVMTVTVRPPTQPPAEPLITVELSY
IINGTTDPHCASWDYSRADASSGDWDTENCQTLETQAAHTRCQCQHLSTFAVLAQPPKDLTL
ELAGSPSVPLVIGCAVSCMALLTLLAIYAAFWRFIKSERSIILLNFCLSILASNILILVGQSRVLS
KGVCTMTAAFLHFFFLSSFCWVLTEAWQSYLAVIGRMRTRLVRKRFLCLGWGLPALVVAVS
VGFTRTKGYGTSSYCWLSLEGGLLYAFVGPAAVIVLVNMLIGIIVFNKLMARDGISDKSKKQ
RAGSERCPWASLLLPCSACGAVPSPLLSSASARNAMASLWSSCVVLPLLALTWMSAVLAMT
DRRSVLFQALFAVFNSAQGFVITAVHCFLRREVQDVVKCQMGVCRADESEDSPDSCKNGQL
QILSDFEKDVDLACQTVLFKEVNTCNPSTITGTLSRLSLDEDEEPKSCLVGPEGSLSFSPLPGNI
LVPMAASPGLGEPPPPQEANPVYMCGEGGLRQLDLTWLRPTEPGSEGDYMVLPRRTLSLQP
GGGGGGGEDAPRARPEGTPRRAAKTVAHTEGYPSFLSVDHSGLGLGPAYGSLQNPYGMTFQ
PPPPTPSARQVPEPGERSRTMPRTVPGSTMKMGSLERKKLRYSDLDFEKVMHTRKRHSELYH
ELNQKFHTFDRYRSQSTAKREKRWSVSSGGAAERSVCTDKPSPGERPSLSQHRRHQSWSTFK
SMTLGSLPPKPRERLTLHRAAAWEPTEPPDGDFQTEV

(SEQ ID NO:1255)
>gi\|116063556\|ref\|NP_0713322\| probable G-protein coupled receptor 88 {Homosapiens}
MTNSSSTSTSSTTGGSLLLLCEEEESWAGRRIPVSLLYSGLAIGGTLANGMVIYLVSSFRKLQT
TSNAFIVNGCAADLSVCALWMPQEAVLGLLPTGSAEPPADWDGAGGSYRLLRGGLLGLGLT
VSLLSHCLVALNRYLLITRAPATYQALYQRRHTAGMLALSWALALGLVLLLPPWAPRPGAA
PPRVHYPALLAAAALLAQTALLLHCYLGIVRRVRVSVKRVSVLNFHLLHQLPGCAAAAAAF
PGAQHAPGPGGAAHPAQAQPLPPALHPRRAQRRLSGLSVLLLCCVFLLATQPLVWVSLASGF
SLPVPWGVQAASWLLCCALSALNPLLYTWRNEEFRRSVRSVLPGVGDAAAAAVAATAVPA
VSQAQLGTRAAGQHW

(SEQ ID NO:1256)
>gi\|116284382\|ref\|NP_0010706621\| G-protein coupled bile acid receptor 1
{Homosapiens}
MTPNSTGEVPSPIPKGALGLSLALASLIITANLLLALGIAWDRRLRSPPAGCFFLSLLLAGLLTG
LALPTLPGLWNQSRRGYWSCLLVYLAPNFSFLSLLANLLLVHGERYMAVLRPLQPPGSIRLA
LLLTWAGPLLFASLPALGWNHWTPGANCSSQAIFPAPYLYLEVYGLLLPAVGAAAFLSVRVL
ATAHRQLQDICRLERAVCRDEPSALARALTWRQARAQAGAMLLFGLCWGPYVATLLLSVL
AYEQRPPLGPGTLLSLLSLGSASAAAVPVAMGLGDQRYTAPWRAAAQRCLQGLWGRASRD
SPGPSIAYHPSSQSSVDLDLN

(SEQ ID NO:1257)
>gi\|116517328\|ref\|NP_7225803\| probable G-protein coupled receptor 115
precursor {Homosapiens}
MKMKSQATMICCLVFFLSTECSHYRSKIHLKAGDKLQSPEGKPKTGRIQEKCEGPCISSSNCS
QPCAKDFHGEIGFTCNQKKWQKSAETCTSLSVEKLFKDSTGASRLSVAAPSIPLHILDFRAPET
IESVAQGIRKNCPFDYACITDMVKSSETTSGNIAFIVELLKNISTDLSDNVTREKMKSYSEVAN
HILDTAAISNWAFIPNKNASSDLLQSVNLFARQLHIHNNSENIVNELFIQTKGFHINHNTSEKSL
NFSMSMNNTTEDILGMVQIPRQELRKLWPNASQAISIAFPTLGAILREAHLQNVSLPRQVNGL
VLSVVLPERLQEIILTFEKINKTRNARAQCVGWHSKKRRWDEKACQMMLDIRNEVKCRCNY
TSVVMSFSILMSSKSMTDKVLDYITCIGLSVSILSLVLCLIIEATVWSRVVVTEISYMRHVCIVN
IAVSLLTANVWFIIGSHFNIKAQDYNMCVAVTFFSHFFYLSLFFWMLFKALLIIYGILVIFRRM
MKSRMMVIGFAIGYGCPLHAVTTVAITEPEKGYMRPEACWLNWDNTKALLAFAIPAFVIVA
VNLIVVLVVAVNTQRPSIGSSKSQDVVIIMRISKNVAILTPLLGLTWGFGIATLIEGTSLTFHIIF
ALLNAFQGFFILLFGTIMDHKIRDALRMRMSSLKGKSRAAENASLGPTNGSKLMNRQG

(SEQ ID NO:1258)
>gi\|117940060\|ref\|NP_0009053\| opioid receptor, mu 1 isoform MOR-1
{Homosapiens}
MDSSAAPTNASNCTDALAYSSCSPAPSPGSWVNLSHLDGNLSDPCGPNRTDLGGRDSLCPPT
GSPSMITAITIMALYSIVCVVGLFGNFLVMYVIVRYTKMKTATNIYIFNLALADALATSTLPFQ
SVNYLMGTWPFGTILCKIVISIDYYNMFTSIFTLCTMSVDRYIAVCHPVKALDFRTPRNAKIIN
VCNWILSSAIGLPVMFMATTKYRQGSIDCTLTFSHPTWYVVENLLKICVFIFAFIMPVLIITVCY
GLMILRLKSVRMLSGSKEKDRNLRRITRMVLVVVAVFIVCWTPIHIYVIIKALVTIPETTFQTV
SWHFCIALGYTNSCLNPVLYAFLDENFKRCFREFCIPTSSNIEQQNSTRIRQNTRDHPSTANTV
DRTNHQLENLEAETAPLP

>gi\|119220588\|ref\|NP_1158922\| melanin-concentrating hormone receptor 2
{Homosapiens}
MNPFHASCWNTSAELLNKSWNKEFAYQTASVVDTVILPSMIGIICSTGLVGNILIVFTIIRSRK
KTVPDIYICNLAVADLVHIVGMPFLIHQWARGGEWVFGGPLCTIITSLDTCNQFACSAIMTVM
SVDRYFALVQPFRLTRWRTRYKTIRINLGLWAASFILALPVWVYSKVIKFKDGVESCAFDLTS
PDDVLWYTLYLTITTFFFPLPLILVCYILILCYTVVEMYQQNKDARCCNPSVPKQRVMKLTKM
VLVLVVVFILSAAPYHVIQLVNLQMEQPTLAFYVGYYLSICLSYASSSINPFLYILLSGNFQKR
LPQIQRRATEKEINNMGNTLKSHF

(SEQ ID NO:1259)
>gi\|119508433\|ref\|NP_0059032\| melanocortin receptor 4 {Homosapiens }
MVNSTHRGMHTSLHLWNRSSYRLHSNASESLGKGYSDGGCYEQLFVSPEVFVTLGVISLLEN
ILVIVAIAKNKNLHSPMYFFICSLAVADMLVSVSNGSETIVITLLNSTDTDAQSFTVNIDNVIDS
VICSSLLASICSLLSIAVDRYFTIFYALQYHNIMTVKRVGIIISCIVVAACTVSGILFIIYSDSSAVII
CLITMFFTMLALMASLYVHMFLMARLHIKRIAVLPGTGAIRQGANMKGAITLTILIGVFVVC
WAPFFLHLIFYISCPQNPYCVCFMSHFNLYLILIMCNSIIDPLIYALRSQELRKTFKEIICCYPLG
GLCDLSSRY

(SEQ ID NO:1260)
>gi\|119943116\|ref\|NP_0010733281\| G-protein coupled receptor 64 isoform 2 {Homosapiens}
MVFSVRQCGHVGRTEEVLLTFKIFLVIICLHVVLVTSLEEDTDNSSLSPPPAKLSVVSFAPSSN
GTPEVETTSLNDVTLSLLPSNETGVKPQRNICNLSSICNDSAFFRGEIMFQYDKESTVPQNQHI
TNGTLTGVLSLSELKRSELNKTLQTLSETYFIMCATAEAQSTLNCTFTIKLNNTMNACAVIAA
LERVKIRPMEHCCCSVRIPCPSSPEELEKLQCDLQDPIVCLADHPRGPPFSSSQSIPVVPRATVL
SQVPKATSFAEPPDYSPVTHNVPSPIGEIQPLSPQPSAPIASSPAIDMPPQSETISSPMPQTHVSG
TPPPVKASFSSPTVSAPANVNTTSAPPVQTDIVNTSSISDLENQVLQMEKALSLGSLEPNLAGE
MINQVSRLLHSPPDMLAPLAQRLLKVVDDIGLQLNFSNTTISLTSPSLALAVIRVNASSFNTTT
FVAQDPANLQVSLETQAPENSIGTITLPSSLMNNLPAHDMELASRVQFNFFETPALFQDPSLE
NLSLISYVISSSVANLTVRNLTRNVTVTLKHINPSQDELTVRCVFVVDLGRNGGRGGWSDNGC
SVKDRRLNETICTCSHLTSFGVLLDLSRTSVLPAQMMALTFITYIGCGLSSIFLSVTLVTYIAFE
KIRRDYPSKILIQLCAALLLLNLVFLLDSWIALYKMQGLCISVAVFLHYFLLVSFTVVMGLEAF
HMYLALVKVFNTYIRKYILKFCIVGWGVPAVVVTIILTISPDNYGLGSYGKFPNGSPDDFCWI
NNNAVFYITVVGYFCVIFLLNVSMFIVVLVQLCRIKKKKQLGAQRKTSIQDLRSIAGLTFLLGI
TWGFAFFAWGPVNVTFMYLFAIFNTLQGFFIFIFYCVAKENVRKQWRRYLCCGKLRLAENSD
WSKTATNGLKKQTVNQGVSSSSNSLQSSSNSTNSTTLLVNNDCSVHASGNGNASTERNGVSF
SVQNGDVCLHDFTGKQHMFNEKEDSCNGKGRMALRRTSKRGSLHFIEQM

(SEQ ID NO:1261)
>gi\|125625352\|ref\|NP_0556943\| P2Y14 receptor {Homosapiens }
MINSTSTQPPDESCSQNLLITQQIIPVLYCMVFIAGILLNGVSGWIFFYVPSSKSFIIYLKNIVIAD
FVMSLTFPFKILGDSGLGPWQLNVFVCRVSAVLFYVNMYVSIVFFGLISFDRYYKIVKPLWTS
FIQSVSYSKLLSVIVWMLMLLLAVPNIILTNQSVREVTQIKCIELKSELGRKWHKASNYIFVAI
FVVIVFLLLIVFYTAITKKIFKSHLKSSRNSTSVKKKSSRNIFSIVFVFFVCFVPYHIARIPYTKSQT
EAHYSCQSKEILRYMKEFTLLLSAANVCLDPIIYFFLCQPFREILCKKLHIPLKAQNDLDISRIK
RGNTTLESTDTL

(SEQ ID NO:1262)
>gi\|125660451\|ref\|NP_6717323\| MAS-related GPR, member X1 {Homosapiens}
MDPTISTLDTELTPINGTEETLCYKQTLSLTVLTCIVSLVGLTGNAVVLWLLGCRMRRNAFSI
YILNLAAADFLFLSGRLIYSLLSFISIPHTISKILYPVMMFSYFAGLSFLSAVSTERCLSVLWPIVV
YRCHRPTHLSAVVCVLLWALSLLRSILEWMLCGFLFSGADSAWCQTSDFITVAWLIFLCVVL
CGSSLVLLIRILCGSRKIPLTRLYVTILLTVLVFLLCGLPFGIQFFLFLWIHVDREVLFCHVHLVS
IFLSALNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDASEVDEGGGQLPEEILELSGSRLE
Q

(SEQ ID NO:1263)
>gi\|133930786\|ref\|NP_1159602\| EGF-like module-containing mucin-like hormone
receptor-like 3 {Homosapiens}
MQGPLLLPGLCFLLSLFGAVTQKTKTSCAKCPPNASCVNNTHCTCNHGYTSGSGQKLFTFPL
ETCNDINECTPPYSVYCGFNAVCYNVEGSFYCQCVPGYRLHSGNEQFSNSNENTCQDTTSSK
TTEGRKELQKIVDKFESLLTNQTLWRTEGRQEISSTATTILRDVESKVLETALKDPEQKVLKIQ
NDSVAIETQAITDNCSEERKTFNLNVQMNSMDIRCSDIIQGDTQGPSAIAFISYSSLGNIINATF
FEEMDKKDQVYLNSQVVSAAIGPKRNVSLSKSVTLTFQHVKMTPSTKKVFCVYVVKSTGQGS
QWSRDGCFLIHVNKSHTMCNCSHLSSFAVLMALTSQEEDPVLTVITYVGLSVSLLCLLLAAL
TFLLCKAIRNTSTSLHLQLSLCLFLAHLLFLVGIDRTEPKVLCSIIAGALHYLYLAAFTWMLLE
GVHLFLTARNLTVVNYSSINRLMKWIMFPVGYGVPAVTVAISAASWPHLYGTADRCWLHLD
QGFMWSFLGPVCAIFSANLVLFILVFVVILKRKLSSLNSEVSTIQNTRMLAFKATAQLFILGCT
WCLGLLQVGPAAQVMAYLFTIINSLQGFFIFLVYCLLSQQVQKQYQKWFREIVKSKSESETY
TLSSKMGPDSKPSEGDVFPGQVKRKY

(SEQ ID NO:1264)
>gi\|134244291\|ref\|NP_0047583\| endothelin B receptor-like protein 2 precursor
{Homosapiens}
MRWLWPLAVSLAVILAVGLSRVSGGAPLHLGRHRAETQEQQSRSKRGTEDEEAKGVQQYV
PEEWAEYPRPIHPAGLQPTKPLVATSPNPGKDGGTPDSGQELRGNLTGAPGQRLQIQNPLYPV
TESSYSAYAIMLLALVVFAVGIVGNLSVMCIVWHSYYLKSAWNSILASLALWDFLVLFFCLPI
VIFNEITKQRLLGDVSCRAVPFMEVSSLGVTTFSLCALGIDRFHVATSTLPKVRPIERCQSILAK
LAVIVVVGSMTLAVPELLLWQLAQEPAPTMGTLDSCIMKPSASLPESLYSLVMTYQNARMW
WYFGCYFCLPILFTVTCQLVTWRVRGPPGRKSECRASKHEQCESQLNSTVVGLTVVYAFCTL
PENVCNIVVAYLSTELTRQTLDLLGLINQFSTFFKGAITPVLLLCICRPLGQAFLDCCCCCCCE
ECGGASEASAANGSDNKLKTEVSSSIYFHKPRESPPLLPLGTPC

(SEQ ID NO:1265)
>gi\|134244587\|ref\|NP_0042213\| endothelial differentiation, sphingolipid G-
protein-coupled receptor, 5 {Homosapiens}
MGSLYSEYLNPNKVQEHYNYTKETLETQETTSRQVASAFIVILCCAIVVENLLVLIAVARNSK
FHSAMYLFLGNLAASDLLAGVAFVANTLLSGSVTLRLTPVQWFAREGSAFITLSASVFSLLAI
AIERHVAIAKVKLYGSDKSCRMLLLIGASWLISLVLGGLPILGWNCLGHLEACSTVLPLYAKH
YVLCVVTIFSIILLAIVALYVRIYCVVRSSHADMAAPQTLALLKTVTIVLGVFIVCWLPAFSILL
LDYACPVHSCPILYKAHYFFAVSTLNSLLNPVIYTWRSRDLRREVLRPLQCWRPGVGVQGRR
RGGTPGHHLLPLRSSSSLERGMHMPTSPTFLEGNTVV

(SEQ ID NO:1266)
>gi\|134288847\|ref\|NP_7225814\| probable G-protein coupled receptor 111
{Homosapiens}
MTHILLLYYLVFLLPTESCRTLYQAASKSKEKVPARPHGVCDGVCTDYSQCTQPCPPDTQGN
MGFSCRQKTVVHKITDTCQTLNALNIFEEDSRLVQPFEDNIKISVYTGKSETITDMLLQKCPTD
LSCVIRNIQQSPWIPGNIAVIVQLLHNISTAIWTGVDEAKMQSYSTIANHILNSKSISNWTFIPD
RNSSYILLHSVNSFARRLFIDKHPVDISDVFIHTMGTTISGDNIGKNFTFSMRINDTSNEVTGRV
LISRDELRKVPSPSQVISIAFPTIGAILEASLLENVTVNGLVLSAILPKELKRISLIFEKISKSEERR
TQCVGWHSVENRWDQQACKMIQENSQQAVCKCRPSKLFTSFSILMSPHILESLILTYITYVGL
GISICSLILCLSIEVLVWSQVTKTEITYLRHVCIVNIAATLLMADVWFIVASFLSGPITHHKGCV
AATFFVHFFYLSVFFVVMLAKALLILYGIMIVFHTLPKSVLVASLFSVGYGCPLAIAAITVAATE
PGKGYLRPEICWLNWDMTKALLAFVIPALAIVVVNLITVTLVIVKTQRAAIGNSMFQEVRAIV
RISKNIAILTPLLGLTWGFGVATVIDDRSLAFHIIFSLLNAFQGFFILVFGTILDPKIREALKG

(SEQ ID NO:1267)
>gi\|141802362\|ref\|NP_7225772\| probable G-protein coupled receptor 113 isoform
3 {Homosapiens}
MTTRKLSAHSAATPGYKAVTHKHHTGWARMAKTGLPEKGQSQAGGESGSGQLLDQENGA
GESALVSVYVHLDFPDKTWPPELSRTLTLPAASASSSPRPLLTGLRLTTGEYMSCFEAQGFKW
NLYEVVRVPLKATDVARLPYQLSISCATSPGFQLSCCIPSTNLAYTAAWSPGEGSKASSFNES
GSQCFVLAVQRCPMADTTYACDLQSLGLAPLRVPISITIIQDGDITCPEDASVLTWNVTKAGH
VAQAPCPESKRGIVRRLCGADGVWGPVHSSCTDARLLALFTRTKLLQAGQGSPAEEVPQILA
QLPGQAAEASSPSDLLTLLSTMKYVAKVVAEARIQLDRRALKNLLIATDKVLDMDTRSLWT
LAQARKPWAGSTLLLAVETLACSLCPQDHPFAFSLPNVLLQSQLFGPTFPADYSISFPTRPPLQ
AQIPRHSLAPLVRNGTEISITSLVLRKLDHLLPSNYGQGLGDSLYATPGLVLVISIMAGDRAFS
QGEVIMDFGNTDGSPHCVFVVDHSLFQGRGGWSKEGCQAQVASASPTAQCLCQHLTAFSVL
MSPHTVPEEPALALLTQVGLGASILALLVCLGVYWLVWRVVVRNKISYFRHAALLNMVFCL
LAADTCFLGAPFLSPGPRSPLCLAAAFLCHFLYLATFFWMLAQALVLAHQLLFVFHQLAKHR
VLPLMVLLGYLCPLGLAGVTLGLYLPQGQYLREGECWLDGKGGALYTFVGPVLAIIGVNGL
VLAMAMLKLLRPSLSEGPPAEKRQALLGVIKALLILTPIFGLTWGLGLATLLEEVSTVPHYIFT
ILNTLQGVFILLFGCLMDRKIQEALRKRFCRAQAPSSTISLATNEGCILEHSKGGSDTARKTDA
SE

(SEQ ID NO:1268)
>gi\|144922665\|ref\|NP_0010773781\| probable G-protein coupled receptor 123
{Homosapiens}
MDLKTVLSLPRYPGEFLHPVVYACTAVMLLCLLASFVTYIVHQSAIRISRKGRHTLLNFCFHA
ALTFTVFAGGINRTKYPILCQAVGIVLHYSTLSTMLWIGVTARNIYKQVTKKAPLCLDTDQPP
YPRQPLLRFYLVSGGVPFIICGVTAATNIRNYGTEDEDTAYCWMAWEPSLGAFYGPAAIITLV
TCVYFLGTYVQLRRHPGRRYELRTQPEEQRRLATPEGGRGIRPGTPPAHDAPGASVLQNEHS
FQAQLRAAAFTLFLFTATWAFGALAVSQGHFLDMVFSCLYGAFCVTLGLFVLIHHCAKRED
VWQCWWACCPPRKDAHPALDANGAALGRAACLHSPGLGQPRGFAHPPGPCKMTNLQAAQ
GHASCLSPATPCCAKMHCEPLTADEAHVHLQEEGAFGHDPHLHGCLQGRTKPPYFSRHPAE
EPEYAYHIPSSLDGSPRSSRTDSPPSSLDGPAGTHTLACCTQGDPFPMVTQPEGSDGSPALYSC
PTQPGREAALGPGHLEMLRRTQSLPFGGPSQNGLPKGKLLEGLPFGTDGTGNIRTGPWKNET
TV

(SEQ ID NO:1269)
>gi\|145309304\|ref\|NP_0013982\| cadherin EGF LAG seven-pass G-type receptor 3
precursor {Homosapiens }
MMARRPPWRGLGGRSTPILLLLLLSLFPLSQEELGGGGHQGWDPGLAATTGPRAHIGGGALA
LCPESSGVREDGGPGLGVREPIFVGLRGRRQSARNSRGPPEQPNEELGIEHGVQPLGSRERET
GQGPGSVLYWRPEVSSCGRTGPLQRGSLSPGALSSGVPGSGNSSPLPSDFLIRHHGPKPVSSQ
RNAGTGSRKRVGTARCCGELWATGSKGQGERATTSGAERTAPRRNCLPGASGSGPELDSAP
RTARTAPASGSAPRESRTAPEPAPKRMRSRGLFRCRFLPQRPGPRPPGLPARPEARKVTSANR
ARFRRAANRHPQFPQYNYQTLVPENEAAGTAVLRVVAQDPDAGEAGRLVYSLAALMNSRS
LELFSIDPQSGLIRTAAALDRESMERHYLRVTAQDHGSPRLSATTMVAVTVADRNDHSPVFE
QAQYRETLRENVEEGYPILQLRATDGDAPPNANLRYRFVGPPAARAAAAAAFEIDPRSGLIST
SGRVDREHMESYELVVEASDQGQEPGPRSATVRVHITVLDENDNAPQFSEKRYVAQVREDV
RPHTVVLRVTATDRDKDANGLVHYNIISGNSRGHFAIDSLTGEIQVVAPLDFEAEREYALRIR
AQDAGRPPLSNNTGLASIQVVDINDHIPIFVSTPFQVSVLENAPLGHSVIHIQAVDADHGENAR
LEYSLTGVAPDTPFVINSATGWVSVSGPLDRESVEHYFFGVEARDHGSPPLSASASVTVTVLD
VNDNRPEFTMKEYHLRLNEDAAVGTSVVS VTAVDRDANSAISYQITGGNTRNRFAISTQGGV
GLVTLALPLDYKQERYFKLVLTASDRALHDHCYVHINITDANTHRPVFQSAHYSVSVNEDRP
MGSTIVVISASDDDVGENARITYLLEDNLPQFRIDADSGAITLQAPLDYEDQVTYTLAITARD
NGIPQKADTTYVEVMVNDVNDNAPQFVASHYTGLVSEDAPPFTSVLQISATDRDAHANGRV
QYTFQNGEDGDGDFTIEPTSGIVRTVRRLDREAVSVYELTAYAVDRGVPPLRTPVSIQVMVQ
DVNDNAPVFPAEEFEVRVKENSIVGSVVAQITAVDPDEGPNAHIMYQIVEGNIPELFQMDIFS
GELTALIDLDYEARQEYVIVVQATSAPLVSRATVHVRLVDQNDNSPVLNNFQILFNNYVSNR
SDTFPSGIIGRIPAYDPDVSDHLFYSFERGNELQLLVVNQTSGELRLSRKLDNNRPLVASMLVT
VTDGLHSVTAQCVLRVVIITEELLANSLTVRLENMWQERFLSPLLGRFLEGVAAVLATPAED
VFIFNIQNDTDVGGTVLNVSFSALAPRGAGAGAAGPWFSSEELQEQLYVRRAALAARSLLDV
LPFDDNVCLREPCENYMKCVSVLRFDSSAPFLASASTLFRPIQPIAGLRCRCPPGFTGDFCETE
LDLCYSNPCRNGGACARREGGYTCVCRPRFTGEDCELDTEAGRCVPGVCRNGGTCTDAPNG
GFRCQCPAGGAFEGPRCEVAARSFPPSSFVMFRGLRQRFHLTLSLSFATVQQSGLLFYNGRLN
EKHDFLALELVAGQVRLTYSTGESNTVVSPTVPGGLSDGQWHTVHLRYYNKPRTDALGGA
QGPSKDKVAVLSVDDCDVAVALQFGAEIGNYSCAAAGVQTSSKKSLDLTGPLLLGGVPNLP
ENFPVSHKDFIGCMRDLHIDGRRVDMAAFVANNGTMAGCQAKLHFCDSGPCKNSGFCSER
WGSFSCDCPVGFGGKDCQLTMAHPHHFRGNGTLSWNFGSDMAVSVPWYLGLAFRTRATQG
VLMQVQAGPHSTLLCQLDRGLLSVTVTRGSGRASHLLLDQVTVSDGRWHDLRLELQEEPGG
RRGHHVLMVSLDFSLFQDTMAVGSELQGLKVKQLHVGGLPPGSAEEAPQGLVGCIQGVWL
GSTPSGSPALLPPSHRVNAEPGCVVTNACASGPCPPHADCRDLWQTFSCTCQPGYYGPGCVD
ACLLNPCQNQGSCRHLPGAPHGYTCDCVGGYFGHHCEHRMDQQCPRGWWGSPTCGPCNC
DVHKGFDPNCNKTNGQCHCKEFHYRPRGSDSCLPCDCYPVGSTSRSCAPHSGQCPCRPGAL
GRQCNSCDSPFAEVTASGCRVLYDACPKSLRSGVWWPQTKFGVLATVPCPRGALGAAVRLC
DEAQGWLEPDLFNCTSPAFRELSLLLDGLELNKTALDTMEAKKLAQRLREVTGHTDHYFSQ
DVRVTARLLAHLLAFESHQQGFGLTATQDAHFNENLLWAGSALLAPETGDLWAALGQRAP
GGSPGSAGLVRHLEEYAATLARNMELTYLNPMGLVTPNIMLSIDRMEHPSSPRGARRYPRYH
SNLFRGQDAWDPHTHVLLPSQSPRPSPSEVLPTSSSIENSTTSSVVPPPAPPEPEPGISIIILLVYR
TLGGLLPAQFQAERRGARLPQNPVMNSPVVSVAVFHGRNFLRGILESPISLEFRLLQTANRSK
AICVQWDPPGLAEQHGVWTARDCELVHRNGSHARCRCSRTGTFGVLMDASPRERLEGDLEL
LAVFTHVVVAVSVAALVLTAAILLSLRSLKSNVRGIHANVAAALGVAELLFLLGIHRTHNQL
VCTAVAILLHYFFLSTFAWLFVQGLHLYRMQVEPRNVDRGAMRFYHALGWGVPAVLLGLA
VGLDPEGYGNPDFCWISVHEPLIVVSFAGPVVLVIVMNGTMFLLAARTSCSTGQREAKKTSAL
TLRSSFLLLLLVSASWLFGLLAVNHSILAFHYLHAGLCGLQGLAVLLLFCVLNADARAAWM
PACLGRKAAPEEARPAPGLGPGAYNNTALFEESGLIRITLGASTVSSVSSARSGRTQDQDSQR
GRSYLRDNVLVRHGSAADHTDHSLQAHAGPTDLDVAMFHRDAGADSDSDSDLSLEEERSLS
IPSSESEDNGRTRGRFQRPLCRAAQSERLLTHPKDVDGNDLLSYWPALGECEAAPCALQTWG
SERRLGLDTSKDAANNNQPDPALTSGDETSLGRAQRQRKGILKNRLQYPLVPQTRGAPELSW
CRAATLGHRAVPAASYGRIYAGGGTGSLSQPASRYSSREQLDLLLRRQLSRERLEEAPAPVL
RPLSRPGSQECMDAAPGRLEPKDRGSTLPRRQPPRDYPGAMAGRFGSRDALDLGAPREWLS
TLPPPRRTRDLDPQPPPLPLSPQRQLSRDPLLPSRPLDSLSRSSNSREQLDQVPSRHPSREALGP
LPQLLRAREDSVSGPSHGPSTEQLDILSSILASFNSSALSSVQSSSTPLGPHTTATPSATASVLGP
STPRSATSHSISELSPDSEVPRSEGHS

(SEQ ID NO:1270)
>gi\|145309315\|ref\|NP_5431413\| probable G-protein coupled receptor 62
{Homosapiens}
MANSTGLNASEVAGSLGLILAAVVEVGALLGNGALLVVVLRTPGLRDALYLAHLCVVDLLA
AASIMPLGLLAAPPPGLGRVRLGPAPCRAARFLSAALLPACTLGVAALGLARYRLIVHPLRPG
SRPPPVLVLTAVWAAAGLLGALSLLGTPPAPPPAPARCSVLAGGLGPFRPLWALLAFALPAL
LLLGAYGGIFVVARRAALRPPRPARGSRLHSDSLDSRLSILPPLRPRLPGGKAALAPALAVGQ
FAACWLPYGCACLAPAARAAEAEAAVTWVAYSAFAAHPFLYGLLQRPVRLALGRLSRRAL
PGPVRACTPQAWHPRALLQCLQRPPEGPAVGPSEAPEQTPELAGGRSPAYQGPPESSLS

(SEQ ID NO:1271)
>gi\|148664220\|ref\|NP_6594523\| mas-related G-protein coupled receptor member F
{Homosapiens}
MAGNCSWEAHPGNRNKMCPGLSEAPELYSRGFLTIEQIAMLPPPAVMNYIFLLLCLCGLVGN
GLVLWFFGFSIKRNPFSIYFLHLASADVGYLFSKAVFSILNTGGFLGTFADYIRSVCRVLGLCM
FLTGVSLLPAVSAERCASVIFPAWYWRRRPKRLSAVVCALLWVLSLLVTCLHNYFCVFLGRG
APGAACRHMDIFLGILLFLLCCPLMVLPCLALILHVECRARRRQRSAKLNHVILAMVSVFLVS
SIYLGIDWFLFVVVFQIPAPFPEYVTDLCICINSSAKPIVYFLAGRDKSQRLWEPLRVVFQRALR
DGAELGEAGGSTPNTVTMEMQCPPGNAS

(SEQ ID NO:1272)
>gi\|148719673\|ref\|NP_0560494\| probable G-protein coupled receptor 116
precursor {Homosapiens}
MKSPRRTTLCLMFIVIYSSKAALNWNYESTIHPLSLHEHEPAGEEALRQKRAVATKSPTAEEY
TVNIEISFENASFLDPIKAYLNSLSFPIHGNNTDQITDILSINVTTVCRPAGNEIVVCSCETGYGW
PRERCLHNLICQERDVFLPGHHCSCLKELPPNGPFCLLQEDVTLNMRVRLNVGFQEDLMNTS
SALYRSYKTDLETAFRKGYGILPGFKGVTVTGFKSGSVVVTYEVKTTPPSLELIHKANEQVV
QSLNQTYKMDYNSFQAVTINESNFFVTPEIIFEGDTVSLVCEKEVLSSNVSWRYEEQQLEIQN
SSRFSIYTALFNNMTSVSKLTIHNITPGDAGEYVCKLILDIFEYECKKKIDVMPIQILANEEMKV
MCDNNPVSLNCCSQGNVNWSKVEWKQEGKINIPGTPETDIDSSCSRYTLKADGTQCPSGSSG
TTVIYTCEFISAYGARGSANIKVTFISVANLTITPDPISVSEGQNFSIKCISDVSNYDEVYWNTS
AGIKIYQRFYTTRRYLDGAESVLTVKTSTREWNGTYHCIFRYKNSYSIATKDVIVHPLPLKLNI
MVDPLEATVSCSGSHHIKCCIEEDGDYKVTFHTGSSSLPAAKEVNKKQVCYKHNFNASSVS
WCSKTVDVCCHFTNAANNSVWSPSMKLNLVPGENITCQDPVIGVGEPGKVIQKLCRFSNVPS
SPESPIGGTITYKCVGSQWEEKRNDCISAPINSLLQMAKALIKSPSQDEMLPTYLKDLSISIDKA
EHEISSSPGSLGAIINILDLLSTVPTQVNSEMMTHVLSTVNVILGKPVLNTWKVLQQQWTNQS
SQLLHSVERFSQALQSGDSPPLSFSQTNVQMSSMVIKSSHPETYQQRFVFPYFDLWGNVVIDK
SYLENLQSDSSIVTMAFPTLQAILAQDIQENNFAESLVMTTTVSHNTTMPFRISMTFKNNSPSG
GETKCVFVVNFRLANNTGGWDSSGCYVEEGDGDNVTCICDHLTSFSILMSPDSPDPSSLLGILL
DIISYVGVGFSILSLAACLVVEAVVWKSVTKNRTSYMRHTCIVNIAASLLVANTWFIVVAAIQ
DNRYILCKTACVAATFFIHFFYLSVFFVVMLTLGLMLFYRLVFILHETSRSTQKAIAFCLGYGC
PLAISVITLGATQPREVYTRKNVCWLNWEDTKALLAFAIPALIIVVVNITITIVVITKILRPSIGD
KPCKQEKSSLFQISKSIGVLTPLLGLTWGFGLTTVFPGTNLVFHIIFAILNVFQGLFILLFGCLW
DLKVQEALLNKFSLSRWSSQHSKSTSLGSSTPVFSMSSPISRRFNNLFGKTGTYNVSTPEATSS
SLENSSSASSLLN

(SEQ ID NO:1273)
>gi\|148806925\|ref\|NP_0714422\| EGF, latrophilin and seven transmembrane domain
containing 1precursor {Homosapiens}
MKRLPLLVVFSTLLNCSYTQNCTKTPCLPNAKCEIRNGIEACYCNMGFSGNGVTICEDDNEC
GNLTQSCGENANCTNTEGSYYCMCVPGFRSSSNQDRFITNDGTVCIENVNANCHLDNVCIAA
NINKTLTKIRSIKEPVALLQEVYRNSVTDLSPTDIITYIEILAESSSLLGYKNNTISAKDTLSNST
LTEFVKTVNNFVQRDTFVVVVDKLSVNHRRTHLTKLMHTVEQATLRISQSFQKTTEFDTNSTD
IALKVFFFDSYNMKHIHPHMNMDGDYINIFPKRKAAYDSNGNVAVAFVYYKSIGPLLSSSDN
FLLKPQNYDNSEEEERVISSVISVSMSSNPPTLYELEKITFTLSHRKVTDRYRSLCAFVVNYSPD
TMNGSWSSEGCELTYSNETHTSCRCNHLTHFAILMSSGPSIGIKDYNILTRITQLGIIISLICLAIC
IFTFWFFSEIQSTRTTIHKNLCCSLFLAELVFLVGINTNTNKLFCSIIAGLLHYFFLAAFAWMCIE
GIHLYLIVVGVIYNKGFLHKNFYIFGYLSPAVVVGFSAALGYRYYGTTKVCWLSTENNFIVVSF
IGPACLIILVNLLAFGVIIYKVFRHTAGLKPEVSCFENIRSCARGALALLFLLGTTWIFGVLHVV
HASVVTAYLFTVSNAFQGMFIFLFLCVLSRKIQEEYYRLFKNVPCCFGCLR

(SEQ ID NO:1274)
>gi\|149944554\|ref\|NP_0010432\| somatostatin receptor type 4 {Homosapiens}
MSAPSTLPPGGEEGLGTAWPSAANASSAPAEAEEAVAGPGDARAAGMVAIQCIYALVCLVG
LVGNALVIFVILRYAKMKTATNIYLLNLAVADELFMLSVPFVASSAALRHWPFGSVLCRAVL
SVDGLNMFTSVFCLTVLSVDRYVAVVHPLRAATYRRPSVAKLINLGVWLASLLVTLPIAIFA
DTRPARGGQAVACNLQWPHPAWSAVFVVYTFLLGFLLPVLAIGLCYLLIVGKMRAVALRAG
WQQRRRSEKKITRLVLMVVVVFVLCWMPFYVVQLLNLFVTSLDATVNHVSLILSYANSCAN
PILYGFLSDNFRRFFQRVLCLRCCLLEGAGGAEEEPLDYYATALKSKGGAGCMCPPLPCQQE
ALQPEPGRKRIPLTRTTTF

(SEQ ID NO:1275)
>gi\|150170722\|ref\|NP_0042152\| G protein-coupled receptor 50 {Homosapiens}
MGPTLAVPTPYGCIGCKLPQPEYPPALIIFMFCAMVITIVVDLIGNSMVILAVTKNKKLRNSGN
IFVVSLSVADMLVAIYPYPLMLHAMSIGGWDLSQLQCQMVGFITGLSVVGSIFNIVAIAINRY
CYICHSLQYERIFSVRNTCIYLVITWIMTVLAVLPNMYIGTIEYDPRTYTCIFNYLNNPVFTVTI
VCIHFVLPLLIVGFCYVRIVVTKVLAARDPAGQNPDNQLAEVRNFLTMFVIFLLFAVCWCPINV
LTVLVAVSPKEMAGKIPNWLYLAAYFIAYFNSCLNAVIYGLLNENFRREYWTIFHAMRHPIIF
FSGLISDIREMQEARTLARARAHARDQAREQDRAHACPAVEETPMNVRNVPLPGDAAAGHP
DRASGHPKPHSRSSSAYRKSASTHHKSVFSHSKAASGHLKPVSGHSKPASGHPKSATVYPKP
ASVHFKADSVHFKGDSVHFKPDSVHFKPASSNPKPITGHHVSAGSHSKSAFSAATSHPKPTTG
HIKPATSHAEPTTADYPKPATTSHPKPTAADNPELSASHCPEIPAIAHPVSDDSDLPESASSPAA
GPTKPAASQLESDTIADLPDPTVVTTSTNDYHDVVVIDVEDDPDEMAV

(SEQ ID NO:1276)
>gi\|153791424\|ref\|NP_0047692\| putative G-protein coupled receptor 44
{Homosapiens}
MSANATLKPLCPILEQMSRLQSHSNTSIRYIDHAAVLLHGLASLLGLVENGVILFVVGCRMRQ
TVVTTWVLHLALSDLLASASLPFFTYFLAVGHSWELGTTFCKLHSSIFFLNMFASGFLLSAISL
DRCLQVVRPVVVAQNHRTVAAAHKVCLVLWALAVLNTVPYFVFRDTISRLDGRIMCYYNVL
LLNPGPDRDATCNSRQVALAVSKFLLAFLVPLAIIASSHAAVSLRLQHRGRRRPGRFVRLVAA
VVAAFALCWGPYHVFSLLEARAHANPGLRPLVVVRGLPFVTSLAFFNSVANPVLYVLTCPDM
LRKLRRSLRTVLESVLVDDSELGGAGSSRRRRTSSTARSASPLALCSRPEEPRGPARLLGWLL
GSCAASPQTGPLNRALSSTSS

(SEQ ID NO:1277)
>gi\|153792268\|ref\|NP_0052902\| probable G-protein coupled receptor 31
{Homosapiens}
MPFPNCSAPSTVVATAVGVLLGLECGLGLLGNAVALWTFLFRVRVVVKPYAVYLLNLALAD
LLLAACLPFLAAFYLSLQAWHLGRVGCWALHFLLDLSRSVGMAFLAAVALDRYLRVVHPR
LKVNLLSPQAALGVSGLVWLLMVALTCPGLLISEAAQNSTRCHSFYSRADGSFSIIVVQEALSC
LQFVLPFGLIVFCNAGIIRALQKRLREPEKQPKLQRAQALVTLVVVLFALCFLPCFLARVLMHI
FQNLGSCRALCAVAHTSDVTGSLTYLHSVLNPVVYCFSSPTFRSSYRRVFHTLRGKGQAAEP
PDFNPRDSYS

(SEQ ID NO:1278)
>gi\|156104886\|ref\|NP_0576862\| C-C chemokine receptor type 10 {Homosapiens}
MGTEATEQVSWGHYSGDEEDAYSAEPLPELCYKADVQAFSRAFQPSVSLTVAALGLAGNGL
VLATHLAARRAARSPTSAHLLQLALADLLLALTLPFAAAGALQGWSLGSATCRTISGLYSAS
FHAGFLFLACISADRYVAIARALPAGPRPSTPGRAHLVSVIVWLLSLLLALPALLFSQDGQRE
GQRRCRLIFPEGLTQTVKGASAVAQVALGFALPLGVMVACYALLGRTLLAARGPERRRALR
VVVALVAAFVVLQLPYSLALLLDTADLLAARERSCPASKRKDVALLVTSGLALARCGLNPV
LYAFLGLRFRQDLRRLLRGGSCPSGPQPRRGCPRRPRLSSCSAPTETHSLSWDN

(SEQ ID NO:1279)
>gi\|157364957\|ref\|NP_0059633\| neuropeptide Y receptor type 4 {Homosapiens}
MNTSHLLALLLPKSPQGENRSKPLGTPYNFSEHCQDSVDVMVFIVTSYSIETVVGVLGNLCL
MCVTVRQKEKANVTNLLIANLAFSDFLMCLLCQPLTAVYTIMDYWIFGETLCKMSAFIQCMS
VTVSILSLVLVALERHQUINPTGWKPSISQAYLGIVLIVVVIACVLSLPFLANSILENVFHKNHS
KALEFLADKVVCTESWPLAHHRTIYTTFLLLFQYCLPLGFILVCYARIYRRLQRQGRVFHKGT
YSLRAGHMKQVNVVLVVMVVAFAVLWLPLHVFNSLEDWHHEAIPICHGNLIFLVCHLLAM
ASTCVNPFIYGFLNTNFKKEIKALVLTCQQSAPLEESEHLPLSTVHTEVSKGSLRLSGRSNPI

(SEQ ID NO:1280)
>gi\|157426873\|ref\|NP_0010482\| substance-K receptor {Homosapiens}
MGTCDIVTEANISSGPESNTTGITAFSMPSWQLALWATAYLALVLVAVTGNAIVIVVIILAHRR
MRTVTNYFIVNLALADLCMAAFNAAFNFVYASHNIVVYFGRAFCYFQNLFPITAMFVSIYSMT
AIAADRYMAIVHPFQPRLSAPSTKAVIAGIVVLVALALASPQCFYSTVTMDQGATKCVVAWPE
DSGGKTLLLYHLVVIALIYFLPLAVMFVAYSVIGLTLWRRAVPGHQAHGANLRHLQAMKKF
VKTMVLVVLTFAICWLPYHLYFILGSFQEDIYCHKFIQQVYLALFVVLAMSSTMYNPIIYCCLN
HRFRSGFRLAFRCCPWVTPTKEDKLELTPTTSLSTRVNRCHTKETLFMAGDTAPSEATSGEA
GRPQDGSGLWFGYGLLAPTKTHVEI

(SEQ ID NO:1281)
>gi\|157671951\|ref\|NP_0050612\| anion exchange protein 3 isoform 1
{Homosapiens}
MANGVIPPPGGASPLPQVRVPLEEPPLSPDVEEEDDDLGKTLAVSRFGDLISKPPAWDPEKPS
RSYSERDFEFHRHTSHHTHHPLSARLPPPHKLRRLPPTSARHTRRKRKKEKTSAPPSEGTPPIQ
EEGGAGVDEEEEEEEEEEGESEAEPVEPPPSGTPQKAKFSIGSDEDDSPGLPGRAAVTKPLPSV
GPHTDKSPQHSSSSPSPRARASRLAGEKSRPWSPSASYDLRERLCPGSALGNPGGPEQQVPTD
EAEAQMLGSADLDDMKSHRLEDNPGVRRHLVKKPSRTQGGRGSPSGLAPILRRKKKKKKLD
RRPHEVFVELNELMLDRSQEPHWRETARWIKFEEDVEEETERWGKPHVASLSFRSLLELRRTI
AHGAALLDLEQTTLPGIAHLVVETMIVSDQIRPEDRASVLRTLLLKHSHPNDDKDSGFFPRNP
SSSSMNSVLGNHHPTPSHGPDGAVPTMADDLGEPAPLWPHDPDAKEKPLHMPGGDGHRGK
SLKLLEKIPEDAEATVVLVGCVPFLEQPAAAFVRLNEAVLLESVLEVPVPVRFLFVMLGPSHT
STDYHELGRSIATLMSDKLFHEAAYQADDRQDLLSAISEFLDGSIVIPPSEVEGRDLLRSVAAF
QRELLRKRREREQTKVEMTTRGGYTAPGKELSLELGGSEATPEDDPLLRTGSVFGGLVRDVR
RRYPHYPSDLRDALHSQCVAAVLFIYFAALSPAITFGGLLGEKTEGLMGVSELIVSTAVLGVL
FSLLGAQPLLVVGFSGPLLVFEEAFFKFCRAQDLEYLTGRVWVGLWLVVFVLALVAAEGSFL
VRYISPFTQEIFAFLISLIFIYETFYKLYKVFTEHPLLPFYPPEGALEGSLDAGLEPNGSALPPTE
GPPSPRNQPNTALLSLILMLGTFFIAFFLRKFRNSRFLGGKARRIIGDFGIPISILVMVLVDYSIT
DTYTQKLTVPTGLSVTSPDKRSWFIPPLGSARPFPPWMMVAAAVPALLVLILIFMETQITALIV
SQKARRLLKGSGFHLDLLLIGSLGGLCGLFGLPWLTAATVRSVTHVNALTVMRTAIAPGDKP
QIQEVREQRVTGVLIASLVGLSIVMGAVLRRIPLAVLFGIFLYMGVTSLSGIQLSQRLLLILMP
AKHHPEQPYVTKVKTWRMHLFTCIQLGCIALLWVVKSTAASLAFPFLLLLTVPLRHCLLPRL
FQDRELQALDSEDAEPNFDEDGQDEYNELHMPV

(SEQ ID NO:1282)
>gi\|157694513\|ref\|NP_0609602\| leucine-rich repeat-containing G-protein
coupled receptor 4 precursor {Homosapiens }
MPGPLGLLCFLALGLLGSAGPSGAAPPLCAAPCSCDGDRRVDCSGKGLTAVPEGLSAFTQAL
DISMNNITQLPEDAFKNFPFLEELQLAGNDLSFIHPKALSGLKELKVLTLQNNQLKTVPSEAIR
GLSALQSLRLDANHITSVPEDSFEGLVQLRHLWLDDNSLTEVPVHPLSNLPTLQALTLALNKI
SSIPDFAFTNLSSLVVLHLHNNKIRSLSQHCFDGLDNLETLDLNYNNLGEFPQAIKALPSLKEL
GFHSNSISVIPDGAFDGNPLLRTIHLYDNPLSFVGNSAFHNLSDLHSLVIRGASMVQQFPNLTG
TVHLESLTLTGTKISSIPNNLCQEQKMLRTLDLSYNNIRDLPSFNGCHALEEISLQRNQIYQIKE
GTFQGLISLRILDLSRNLIHEIHSRAFATLGPITNLDVSFNELTSFPTEGLNGLNQLKLVGNFKL
KEALAAKDFVNLRSLSVPYAYQCCAFWGCDSYANLNTEDNSLQDHSVAQEKGTADAANVT
STLENEEHSQIIIHCTPSTGAFKPCEYLLGSWMIRLTVWFIFLVALFFNLLVILTTFASCTSLPSS
KLFIGLISVSNLFMGIYTGILTFLDAVSWGRFAEFGIVVWETGSGCKVAGFLAVFSSESAIFLLM
LATVERSLSAKDIMKNGKSNHLKQFRVAALLAFLGATVAGCFPLFHRGEYSASPLCLPFPTG
ETPSLGFTVTLVLLNSLAFLLMAVIYTKLYCNLEKEDLSENSQSSMIKHVAWLIFTNCIFFCPV
AFFSFAPLITAISISPEIMKSVTLIFFPLPACLNPVLYVFFNPKFKEDWKLLKRRVTKKSGSVSVS
ISSQGGCLEQDFYYDCGMYSHLQGNLTVCDCCESFLLTKPVSCKHLIKSHSCPALAVASCQR
PEGYWSDCGTQSAHSDYADEEDSFVSDSSDQVQACGRACFYQSRGFPLVRYAYNLPRVKD

(SEQ ID NO:1283)
>gi\|157738685\|ref\|NP_9378222\| G protein-coupled receptor 103 {Homosapiens }
MQALNITPEQFSRLLRDHNLTREQFIALYRLRPLVYTPELPGRAKLALVLTGVLIFALALFGN
ALVFYVVTRSKAMRTVTNIFICSLALSDLLITFFCIPVTMLQNISDNWLGGAFICKMVPFVQST
AVVTEILTMTCIAVERHQGLVHPFKMKWQYTNRRAFTMLGVVWLVAVIVGSPMWHVQQL
EIKYDFLYEKEHICCLEEWTSPVHQKIYTTFILVILFLLPLMVMLILYSKIGYELWIKKRVGDG
SVLRTIHGKEMSKIARKKKRAVIMMVTVVALFAVCWAPFHVVHMMIEYSNFEKEYDDVTIK
MIFAIVQIIGFSNSICNPIVYAFMNENFKKNVLSAVCYCIVNKTFSPAQRHGNSGITMMRKKA
KFSLRENPVEETKGEAFSDGNIEVKLCEQTEEKKKLKRHLALFRSELAENSPLDSGH

(SEQ ID NO:1284)
>gi\|157738694\|ref\|NP_0060092\| G-protein coupled receptor 109B {Homosapiens}
MNRHHLQDHFLEIDKKNCCVFRDDFIAKVLPPVLGLEFIFGLLGNGLALWIFCFHLKSWKSSR
IFLFNLAVADFLLIICLPFVMDYYVRRSDWKFGDIPCRLVLFMFAMNRQGSIIFLTVVAVDRY
FRVVHPHHALNKISNWTAAIISCLLWGITVGLTVHLLKKKLLIQNGTANVCISFSICHTFRWH
EAMFLLEFFLPLGIILFCSARIIVVSLRQRQMDRHAKIKRAITFIMVVAIVFVICFLPSVVVRIHIF
WLLHTSGTQNCEVYRSVDLAFFITLSFTYMNSMLDPVVYYFSSPSFPNFFSTLINRCLQRKITG
EPDNNRSTSVELTGDPNKTRGAPEALIANSGEPWSPSYLGPTSNNHSKKGHCHQEPASLEKQ
LGCCIE

(SEQ ID NO:1285)
>gi\|161484640\|ref\|NP_0025022\| neuromedin-B receptor {Homosapiens}
MPSKSLSNLSVTTGANESGSVPEGWERDFLPASDGTTTELVIRCVIPSLYLLIITVGLLGNIML
VKIFITNSAMRSVPNIFISNLAAGDLLLLLTCVPVDASRYFFDEWMFGKVGCKLIPVIQLTSVG
VSVFTLTALSADRYRAIVNPMDMQTSGALLRTCVKAMGIVVVVSVLLAVPEAVFSEVARISSL
DNSSFTACIPYPQTDELHPKIHSVLIFLVYFLIPLAIISIYYYHIAKTLIKSAHNLPGEYNEHTKK
QMETRKRLAKIVLVFVGCFIFCWFPNHILYMYRSFNYNEIDPSLGHMIVTLVARVLSFGNSCV
NPFALYLLSESFRRHFNSQLCCGRKSYQERGTSYLLSSSAVRMTSLKSNAKNMVTNSVLLNG
HSMKQEMAL

(SEQ ID NO:1286)
>gi\|163792198\|ref\|NP_05605121\| atrophilin-3 precursor {Homosapiens}
MWPSQLLIFMMLLAPIIHAFSRAPIPMAVVRRELSCESYPIELRCPGTDVIMIESANYGRTDDK
ICDSDPAQMENIRCYLPDAYKIMSQRCNNRTQCAVVAGPDVFPDPCPGTYKYLEVQYECVP
YKVEQKVFLCPGLLKGVYQSEHLFESDHQSGAWCKDPLQASDKIYYMPWTPYRTDTLTEYS
SKDDFIAGRPTTTYKLPHRVDGTGFVVYDGALFFNKERTRNIVKFDLRTRIKSGEMIANANY
HDTSPYRWGGKSDIDLAVDENGLWVIYATEQNNGKIVISQLNPYTLRIEGTWDTAYDKRSAS
NAFMICGILYVVKSVYEDDDNEATGNKIDYIYNTDQSKDSLVDVPFPNSYQYIAAVDYNPRD
NLLYVWNNYHVVKYSLDFGPLDSRSGQAHHGQVSYISPPIHLDSELERPSVKDISTTGPLGM
GSTTTSTTLRTTTLSPGRSTTPSVSGRRNRSTSTPSPAVEVLDDMTTHLPSASSQIPALEESCEA
VEAREIMWFKTRQGQIAKQPCPAGTIGVSTYLCLAPDGIVVDPQGPDLSNCSSPWVNHITQKL
KSGETAANIARELAEQTRNHLNAGDITYSVRAMDQLVGLLDVQLRNLTPGGKDSAARSLNK
LQKRERSCRAYVQAMVETVNNLLQPQALNAWRDLTTSDQLRAATMLLHTVEESAFVLADN
LLKTDIVRENTDNIKLEVARLSTEGNLEDLKFPENMGHGSTIQLSANTLKQNGRNGEIRVAFV
LYNNLGPYLSTENASMKLGTEALSTNHSVIVNSPVITAAINKEFSNKVYLADPVVFTVKHIKQ
SEENFNPNCSFVVSYSKRTMTGYWSTQGCRLLTTNKTHTTCSCNHLTNFAVLMAHVEVKHSD
AVHDLLLDVITWVGILLSLVCLLICIFTFCFFRGLQSDRNTIHKNLCISLFVAELLFLIGINRTDQ
PIACAVFAALLHFFFLAAFTWMFLEGVQLYIMLVEVFESEHSRRKYFYLVGYGMPALIVAVS
AAVDYRSYGTDKVCWLRLDTYFIVVSFIGPATLIIMLNVIFLGIALYKMFHHTAILKPESGCLD
NINYEDNRPFIKSWVIGAIALLCLLGLTWAFGLMYINESTVIMAYLFTIFNSLQGMFIFIFHCVL
QKKVRKEYGKCLRTHCCSGKSTESSIGSGKTSGSRTPGRYSTGSQSRIRRMWNDTVRKQSES
SFITGDINSSASLNREGLLNNARDTSVMDTLPLNGNHGNSYSIASGEYLSNCVQIIDRGYNHN
ETALEKKILKELTSNYIPSYLNNHERSSEQNRNLMNKLVNNLGSGREDDAIVLDDATSFNHEE
SLGLELIHEESDAPLLPPRVYSTENHQPHHYTRRRIPQDHSESFFPLLTNEHTEDLQSPHRDSL
YTSMPTLAGVAATESVTTSTQTEPPPAKCGDAEDVYYKSMPNLGSRNHVHQLHTYYQLGRG
SSDGFIVPPNKDGTPPEGSSKGPAHLVTSL

(SEQ ID NO:1287)
>gi\|166362740\|ref\|NP_0019832\| proteinase-activated receptor 1 precursor
{Homosapiens}
MGPRRLLLVAACFSLCGPLLSARTRARRPESKATNATLDPRSFLLRNPNDKYEPFVVEDEEKN
ESGLTEYRLVSINKSSPLQKQLPAFISEDASGYLTSSWLTLFVPSVYTGVFVVSLPLNIMAIVVF
ILKMKVKKPAVVYMLHLATADVLFVSVLPFKISYYFSGSDWQFGSELCRFVTAAFYCNMYA
SILLMTVISIDRFLAVVYPMQSLSWRTLGRASFTCLAIWALAIAGVVPLLLKEQTIQVPGLNIT
TCHDVLNETLLEGYYAYYFSAFSAVFFFVPLIISTVCYVSIIRCLSSSAVANRSKKSRALFLSAA
VFCIFIICFGPTNVLLIAHYSFLSHTSTTEAAYF AYLLCVCVSSISCCIDPLIYYYASSECQRYVY
SILCCKESSDPSSYNSSGQLMASKMDTCSSNLNNSIYKKLLT

(SEQ ID NO:1288)
>gi\|166795283\|ref\|NP_0020533\| glucagon-like peptide 1 receptor precursor
{Homosapiens}
MAGAPGPLRLALLLLGMVGRAGPRPQGATVSLWETVQKWREYRRQCQRSLTEDPPPATDLF
CNRTFDEYACWPDGEPGSFVNVSCPWYLPWASSVPQGHVYRFCTAEGLWLQKDNSSLPWR
DLSECEESKRGERSSPEEQLLFLYHYTVGYALSFSALVIASAILLGFRHLHCTRNYIHLNLFASF
ILRALSVFIKDAALKWMYSTAAQQHQWDGLLSYQDSLSCRLVFLLMQYCVAANYYWLLVE
GVYLYTLLAFSVLSEQWIFRLYVSIGWGVPLLFVVPWGIVKYLYEDEGCWTRNSNMNYWLII
RLPILFAIGVNFLIFVRVICIVVSKLKANLMCKTDIKCRLAKSTLTLIPLLGTHEVIFAFVMDEH
ARGTLRFIKLFTELSFTSFQGLMVAILYCFVNNEVQLEFRKSWERWRLEHLHIQRDSSMKPLK
CPTSSLSSGATAGSSMYTATCQASCS

(SEQ ID NO:1289)
>gi\|166999098\|ref\|NP_0008292\| metabotropic glutamate receptor 1 isoform alpha
precursor {Homosapiens }
MVGLLLFFFPAIFLEVSLLPRSPGRKVLLAGASSQRSVARMDGDVIIGALFSVHHQPPAEKVP
ERKCGEIREQYGIQRVEAMFHTLDKINADPVLLPNITLGSEIRDSCWHSSVALEQSIEFIRDSLI
SIRDEKDGINRCLPDGQSLPPGRTKKPIAGVIGPGSSSVAIQVQNLLQLFDIPQIAYSATSIDLSD
KTLYKYFLRVVPSDTLQARAMLDIVKRYNWTYVSAVHTEGNYGESGMDAFKELAAQEGLC
IAHSDKIYSNAGEKSFDRLLRKLRERLPKARVVVCFCEGMTVRGLLSAMRRLGVVGEFSLIG
SDGWADRDEVIEGYEVEANGGITIKLQSPEVRSFDDYFLKLRLDTNTRNPWFPEFWQHRFQC
RLPGHLLENPNFKRICTGNESLEENYVQDSKMGFVINAIYAMAHGLQNMHHALCPGHVGLC
DAMKPIDGSKLLDFLIKSSFIGVSGEEVVVFDEKGDAPGRYDIMNLQYTEANRYDYVHVGTW
HEGVLNIDDYKIQMNKSGVVRSVCSEPCLKGQIKVIRKGEVSCCWICTACKENEYVQDEFTC
KACDLGWWPNADLTGCEPIPVRYLEWSNIESHAIAFSCLGILVTLFVTLIFVLYRDTPVVKSSS
RELCYIILAGIFLGYVCPFTLIAKPTTTSCYLQRLLVGLSSAMCYSALVTKTNRIARILAGSKKK
ICTRKPRFMSAWAQVIIASILISVQLTLVVTLIIMEPPMPILSYPSIKEVYLICNTSNLGVVAPLG
YNGLLIMSCTYYAFKTRNVPANFNEAKYIAFTMYTTCHVVLAFVPIYFGSNYKIITTCFAVSLS
VTVALGCMFTPKMYHIAKPERNVRSAFTTSDVVRMHVGDGKLPCRSNTFLNIFRRKKAGAG
NANSNGKSVSWSEPGGGQVPKGQHMWHRLSVHVKTNETACNQTAVIKPLTKSYQGSGKSL
TFSDTSTKTLYNVEEEEDAQPIRFSPPGSPSMVVHRRVPSAATTPPLPSHLTAEETPLFLAEPAL
PKGLPPPLQQQQQPPPQQKSLMDQLQGVVSNFSTAIPDFHAVLAGPGGPGNGLRSLYPPPPPP
QHLQMLPLQLSTFGEELVSPPADDDDDSERFKLLQEYVYEHEREGNTEEDELEEEEEDLQAA
SKLTPDDSPALTPPSPFRDSVASGSSVPSSPVSESVLCTPPNVSYASVILRDYKQSSSTL

(SEQ ID NO:1290)
>gi\|167000885\|ref\|NP_0014712\| galanin receptor type 1 {Homosapiens}
MELAVGNLSEGNASWPEPPAPEPGPLFGIGVENFVTLVVFGLIFALGVLGNSLVITVLARSKP
GKPRSTTNLFILNLSIADLAYLLFCIPFQATVYALPTWVLGAFICKFIHYFFTVSMLVSIFTLAA
MSVDRYVAIVHSRRSSSLRVSRNALLGVGCIVVALSIAMASPVAYHQGLFHPRASNQTFCWE
QWPDPRHKKAYVVCTFVFGYLLPLLLICFCYAKVLNHLHKKLKNMSKKSEASKKKTAQTVL
VVVVVFGISWLPHHIIHLWAEFGVFPLTPASFLFRITAHCLAYSNSSVNPIIYAFLSENFRKAYK
QVFKCHIRKDSHLSDTKESKSRIDTPPSTNCTHV

(SEQ ID NO:1291)
>gi\|170671732\|ref\|NP_063941 3\| melanocortin receptor 3 {Homosapiens }
MNASCCLPSVQPTLPNGSEHLQAPFFSNQSSSAFCEQVFIKPEVFLSLGIVSLLENILVILAVVR
NGNLHSPMYFFLCSLAVADMLVSVSNALETIMIAIVHSDYLTFEDQFIQHMDNIFDSMICISLV
ASICNLLAIAVDRYVTIFYALRYHSIMTVRKALTLIVAIVVVCCGVCGVVFIVYSESKMVIVCLI
TMFFAMMLLMGTLYVHMFLFARLHVKRIAALPPADGVAPQQHSCMKGAVTITILLGVFIFC
WAPFFLHLVLIITCPTNPYCICYTAHFNTYLVLIMCNSVIDPLIYAFRSLELRNTFREILCGCNG
MNLG

(SEQ ID NO:1292)
>gi\|170932505\|ref\|NP_0645523\| neuromedin-U receptor 2 {Homosapiens}
MSGMEKLQNASWIYQQKLEDPFQKHLNSTEEYLAFLCGPRRSHFFLPVSVVYVPIFVVGVIG
NVLVCLVILQHQAMKTPTNYYLFSLAVSDLLVLLLGMPLEVYEMWRNYPFLFGPVGCYFKT
ALFETVCFASILSITTVSVERYVAILHPFRAKLQSTRRRALRILGIVWGFSVLFSLPNTSIHGIKF
HYFPNGSLVPGSATCTVIKPMWIYNFIIQVTSFLFYLLPMTVISVLYYLMALRLKKDKSLEAD
EGNANIQRPCRKS VNKMLFVLVLVFAICWAPFHIDRLFFSFVEEWSESLAAVFNLVHVVSGV
FFYLSSAVNPIIYNLLSRRFQAAFQNVISSFHKQWHSQHDPQLPPAQRNIFLTECHFVELTEDIG
PQFPCQSSMHNSHLPAALSSEQMSRTNYQSFHFNKT

(SEQ ID NO:1293)
>gi\|183979980\|ref\|NP_0011165132\| C-C chemokine receptor type 2 isoform A
{Homosapiens}
MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGNMLV
VLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLYHIGYFG
GIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTKCQKEDSVYVCG
PYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHRAVRVIFTIMIVYFLF
WTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCINPIIYAFVGEKFRSLFHIAL
GCRIAPLQKPVCGGPGVRPGKNVKVTTQGLLDGRGKGKSIGRAPEASLQDKEGA

(SEQ ID NO:1294)
>gi\|183979982\|ref\|NP_0011168681\| C-C chemokine receptor type 2 isoform B
{Homosapiens}
MLSTSRSRFIRNTNESGEEVTTFFDYDYGAPCHKFDVKQIGAQLLPPLYSLVFIFGFVGNMLV
VLILINCKKLKCLTDIYLLNLAISDLLFLITLPLWAHSAANEWVFGNAMCKLFTGLYHIGYFG
GIFFIILLTIDRYLAIVHAVFALKARTVTFGVVTSVITWLVAVFASVPGIIFTKCQKEDSVYVCG
PYFPRGWNNFHTIMRNILGLVLPLLIMVICYSGILKTLLRCRNEKKRHRAVRVIFTIMIVYFLF
WTPYNIVILLNTFQEFFGLSNCESTSQLDQATQVTETLGMTHCCINPIIYAFVGEKFRRYLSVF
FRKHITKRFCKQCPVFYRETVDGVTSTNTPSTGEQEVSAGL

(SEQ ID NO:1295)
>gi\|187960055\|ref\|NP_0056753\| probable G-protein coupled receptor 52
{Homosapiens}
MNESRWTEWRILNMSSGIVNVS ERHSCPLGFGHYSVVDVCIFETVVIVLLTFLIIAGNLTVIFV
FHCAPLLHHYTTSYFIQTMAYADLFVGVSCLVPTLSLLHYSTGVHESLTCQVFGYIISVLKSVS
MACLACISVDRYLAITKPLSYNQLVTPCRLRICIILIVVIYSCLIFLPSFFGWGKPGYHGDIFEWC
ATSWLTSAYFTGFIVCLLYAPAAFVVCFTYFHIFKICRQHTKEINDRRARFPSHEVDSSRETGH
SPDRRYAMVLFRITSVFYMLWLPYIIYFLLESSRVLDNPTLSFLTTVVLAISNSFCNCVIYSLSNS
VFRLGLRRLSETMCTSCMCVKDQEAQEPKPRKRANSCSI

(SEQ ID NO:1296)
>gi\|187960067\|ref\|NP_0008362\| metabotropic glutamate receptor 8 isoform a
precursor {Homosapiens}
MVCEGKRSASCPCFFLLTAKFYWILTMMQRTHSQEYAHSIRVDGDIILGGLFPVHAKGERGV
PCGELKKEKGIHRLEAMLYAIDQINKDPDLLSNITLGVRILDTCSRDTYALEQSLTFVQALIEK
DASDVKCANGDPPIFTKPDKISGVIGAAASSVSIMVANILRLFKIPQISYASTAPELSDNTRYDF
FSRVVPPDSYQAQAMVDIVTALGWNYVSTLASEGNYGESGVEAFTQISREIGGVCIAQSQKIP
REPRPGEFEKIIKRLLETPNARAVIMFANEDDIRRILEAAKKLNQSGHFLWIGSDSWGSKIAPV
YQQEEIAEGAVTILPKRASIDGFDRYFRSRTLANNRRNVWFAEFWEENFGCKLGSHGKRNSH
IKKCTGLERIARDSSYEQEGKVQFVIDAVYSMAYALHNMHKDLCPGYIGLCPRMSTIDGKEL
LGYIRAVNFNGSAGTPVTFNENGDAPGRYDIFQYQITNKSTEYKVIGHWTNQLHLKVEDMQ
WAHREHTHPASVCSLPCKPGERKKTVKGVPCCWHCERCEGYNYQVDELSCELCPLDQRPN
MNRTGCQLIPIIKLEWHSPWAVVPVFVAILGIIATTFVIVTFVRYNDTPIVRASGRELSYVLLTG
IFLCYSITFLMIAAPDTIICSFRRVFLGLGMCFSYAALLTKTNRIHRIFEQGKKSVTAPKFISPAS
QLVITFSLISVQLLGVFVVVFVVDPPHIIIDYGEQRTLDPEKARGVLKCDISDLSLICSLGYSILL
MVTCTVYAIKTRGVPETFNEAKPIGFTMYTTCHWLAFIPIFFGTAQSAEKMYIQTTTLTVSMS
LSASVSLGMLYMPKVYIIIFHPEQNVQKRKRSFKAVVTAATMQSKLIQKGNDRPNGEVKSEL
CESLETNTSSTKTTYISYSNHSI

(SEQ ID NO:1297)
>gi\|188497623\|ref\|NP_0060473\| neuromedin-U receptor 1 {Homosapiens}
MTPLCLNCSVLPGDLYPGGARNPMACNGSAARGHFDPEDLNLTDEALRLKYWYQQTELFM
PICATYLLIFVVGAVGNGLTCLVILRHKAMRTPTNYYLFSLAVSDLLVLLVGLPLELYEMWH
NYPFLLGVGGCYFRTLLFEMVCLASVLNVTALSVERYVAVVHPLQARSMVTRAHVRRVLG
AVWGLAMLCSLPNTSLHGIRQLHVPCRGPVPDSAVCMLVRPRALYNMVVQTTALLFFCLPM
AIMSVLYLLIGLRLRRERLLLMQEAKGRGSAAARSRYTCRLQQHDRGRRQVTKMLFVLVVV
FGICWAPFHADRVMWSVVSQWTDGLHLAFQHVHVISGIFFYLGSAANPVLYSLMSSRFRETF
QEALCLGACCHRLRPRHSSHSLSRMTTGSTLCDVGSLGSWVHPLAGNDGPEAQQETDPS

(SEQ ID NO:1298)
>gi\|193083134\|ref\|NP_0023774\| melanocyte-stimulating hormone receptor
{Homosapiens }
MAVQGSQRRLLGSLNSTPTAIPQLGLAANQTGARCLEVSISDGLFLSLGLVSLVENALVVATI
AKNRNLHSPMYCFICCLALSDLLVSGSNVLETAVILLLEAGALVARAAVLQQLDNVIDVITCS
SMLSSLCFLGAIAVDRYISIFYALRYHSIVTLPRARRAVAAIVVVASVVFSTLFIAYYDHVAVLL
CLVVFFLAMLVLMAVLYVHMLARACQHAQGIARLHKRQRPVHQGFGLKGAVTLTILLGIFF
LCWGPFFLHLTLIVLCPEHPTCGCIFKNFNLFLALIICNAHDPLIYAFHSQELRRTLKEVLTCSW

(SEQ ID NO:1299)
>gi\|194018562\|ref\|NP_0091632\| histamine receptor H3 {Homosapiens}
MERAPPDGPLNAS GALAGEAAAAGGARGFSAAWTAVLAALMALLIVATVLGNALVMLAFV
ADSSLRTQNNFFLLNLAISDFLVGAFCIPLYVPYVLTGRWTFGRGLCKLWLVVDYLLCTSSAF
NIVLISYDRFLSVTRAVSYRAQQGDTRRAVRKMLLVWVLAFLLYGPAILSWEYLSGGSSIPEG
HCYAEFFYNWYFLITASTLEFFTPFLSVTFFNLSIYLNIQRRTRLRLDGAREAAGPEPPPEAQPS
PPPPPGCWGCWQKGHGEAMPLHRYGVGEAAVGAEAGEATLGGGGGGGSVASPTSSSGSSS
RGTERPRSLKRGSKPSASSASLEKRMKMVSQSFTQRFRLSRDRKVAKSLAVIVSIFGLCWAPY
TLLMIIRAACHGHCVPDYWYETSFWLLWANSAVNPVLYPLCHHSFRRAFTKLLCPQKLKIQP
HSSLEHCWK

(SEQ ID NO:1300)
>gi\|194272183\|ref\|NP_1161667\| probable G-protein coupled receptor 124
precursor {Homosapiens}
MGAGGRRMRGAPARLLLPLLPWLLLLLAPEARGAPGCPLSIRSCKCSGERPKGLSGGVPGPA
RRRVVCSGGDLPEPPEPGLLPNGTVTLLLSNNKITGLRNGSFLGLSLLEKLDLRNNIISTVQPG
AFLGLGELKRLDLSNNRIGCLTSETFQGLPRLLRLNISGNIFSSLQPGVFDELPALKVVDLGTE
FLTCDCHLRWLLPWAQNRSLQLSEHTLCAYPSALHAQALGSLQEAQLCCEGALELHTHHLIP
SLRQVVFQGDRLPFQCSASYLGNDTRIRWYHNRAPVEGDEQAGILLAESLIHDCTFITSELTLS
HIGVWASGEWECTVSMAQGNASKKVEIVVLETSASYCPAERVANNRGDFRWPRTLAGITAY
QSCLQYPFTSVPLGGGAPGTRASRRCDRAGRWEPGDYSHCLYTNDITRVLYTFVLMPINASN
ALTLAHQLRVYTAEAASFSDMMDVVYVAQMIQKFLGYVDQIKELVEVMVDMASNLMLVD
EHLLWLAQREDKACSRIVGALERIGGAALSPHAQHISVNARNVALEAYLIKPHSYVGLTCTA
FQRREGGVPGTRPGSPGQNPPPEPEPPADQQLRFRCTTGRPNVSLSSFHIKNSVALASIQLPPSL
FSSLPAALAPPVPPDCTLQLLVFRNGRLFHSHSNTSRPGAAGPGKRRGVATPVIFAGTSGCGV
GNLTEPVAVSLRHWAEGAEPVAAWWSQEGPGEAGGWTSEGCQLRSSQPNVSALHCQHLGN
VAVLMELSAFPREVGGAGAGLHPVVYPCTALLLLCLFATIITYILNHSSIRVSRKGWHMLLNL
CFHIAMTSAVFAGGITLTNYQMVCQAVGITLHYSSLSTLLWMGVKARVLHKELTWRAPPPQ
EGDPALPTPSPMLRFYLIAGGIPLIICGITAAVNIHNYRDHSPYCWLVVVRPSLGAFYIPVALILL
ITWIYFLCAGLRLRGPLAQNPKAGNSRASLEAGEELRGSTRLRGSGPLLSDSGSLLATGSARV
GTPGPPEDGDSLYSPGVQLGALVTTHFLYLAMWACGALAVSQRWLPRVVCSCLYGVAASA
LGLFVFTHHCARRRDVRASWRACCPPASPAAPHAPPRALPAAAEDGSPVFGEGPPSLKSSPSG
SSGHPLALGPCKLTNLQLAQSQVCEAGAAAGGEGEPEPAGTRGNLAHRHPNNVHHGRRAH
KSRAKGHRAGEACGKNRLKALRGGAAGALELLSSESGSLHNSPTDSYLGSSRNSPGAGLQLE
GEPMLTPSEGSDTSAAPLSEAGRAGQRRSASRDSLKGGGALEKESHRRSYPLNAASLNGAPK
GGKYDDVTLMGAEVASGGCMKTGLWKSETTV

(SEQ ID NO:1301)
>gi\|194294562\|ref\|NP_7957132\| P2Y purinoceptor 13 {Homosapiens }
MTAAIRRQRELSILPKVTLEAMNTTVMQGFNRSERCPRDTRIVQLVFPALYTVVFLTGILLNT
LALWVFVHIPSSSTFIIYLKNTLVADLIMTLMLPFKILSDSHLAPWQLRAFVCRFSSVIFYETM
YVGIVLLGLIAFDRFLKIIRPLRNIFLKKPVFAKTVSIFIVVFFLFFISLPNTILSNKEATPSSVKKC
ASLKGPLGLKWHQMVNNICQFIFVVTVFILMLVFYVVIAKKVYDSYRKSKSKDRKNNKKLEG
KVFVVVAVFFVCFAPFHFARVPYTHSQTNNKTDCRLQNQLFIAKETTLFLAATNICMDPLIYI
FLCKKFTEKLPCMQGRKTTASSQENHSSQTDN

ITLG
(SEQ ID NO:1302)
>gi\|194353970\|ref\|NP_0006723\| alpha-2A adrenergic receptor {Homosapiens}
MFRQEQPLAEGSFAPMGSLQPDAGNASWNGTEAPGGGARATPYSLQVTLTLVCLAGLLMLL
TVFGNVLVIIAVFTSRALKAPQNLFLVSLASADILVATLVIPFSLANEVMGYWYFGKAWCEIY
LALDVLFCTSSIVHLCAISLDRYWSITQAIEYNLKRTPRRIKAIIITVWVISAVISFPPLISIEKKG
GGGGPQPAEPRCEINDQKWYVISSCIGSFFAPCLIMILVYVRIYQIAKRRTRVPPSRRGPDAVA
APPGGTERRPNGLGPERSAGPGGAEAEPLPTQLNGAPGEPAPAGPRDTDALDLEESSSSDHAE
RPPGPRRPERGPRGKGKARASQVKPGDSLPRRGPGATGIGTPAAGPGEERVGAAKASRWRG
RQNREKRFTFVLAVVIGVFVVCWFPFFFTYTLTAVGCSVPRTLFKFFFVVFGYCNSSLNPVIYTI
FNHDFRRAFKKILCRGDRKRIV

(SEQ ID NO:1303)
>gi\|222080049\|ref\|NP_0008583\| 5-hydroxytryptamine receptor 2B {Homosapiens}
MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALLILMV
IIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAMWPLPLVL
CPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVWLISIGIAIPVPIK
GIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLTIHALQKKAYLVKNKPP
QRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDETLMRRTSTIGKKSVQTISN
EQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQMLLEIFVWIGYVSSGVNPLVYTL
FNKTFRDAFGRYITCNYRATKSVKTLRKRS SKIYFRNPMAENSKFFKKHGIRNGINPAMYQSP
MRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSYV

(SEQ ID NO:1304)
>gi\|222080095\|ref\|NP_0015162\| orexin receptor type 1 {Homosapiens}
MEPSATPGAQMGVPPGSREPSPVPPDYEDEFLRYLWRDYLYPKQYEWVLIAAYVAVFVVAL
VGNTLVCLAVWRNHHMRTVTNYFIVNLSLADVLVTAICLPASLLVDITESWLFGHALCKVIP
YLQAVSVSVAVLTLSFIALDRWYAICHPLLFKSTARRARGSILGIVVAVSLAIMVPQAAVMECS
SVLPELANRTRLFSVCDERWADDLYPKIYHSCFFIVTYLAPLGLMAMAYFQIFRKLWGRQIP
GTTSALVRNWKRPSDQLGDLEQGLSGEPQPRARAFLAEVKQMRARRKTAKMLMVVLLVFA
LCYLPISVLNVLKRVFGMFRQASDREAVYACFTFSHWLVYANSAANPIIYNFLSGKFREQFK
AAFSCCLPGLGPCGSLKAPSPRSSASHKSLSLQSRCSISKISEHVVLTSVTTVLP

(SEQ ID NO:1305)
>gi\|222080109\|ref\|NP_0015172\| orexin receptor type 2 {Homosapiens}
MSGTKLEDSPPCRNWSSASELNETQEPFLNPTDYDDEEFLRYLWREYLHPKEYEWVLIAGYII
VFVVALIGNVLVCVAVWKNHHMRTVTNYFIVNLSLADVLVTITCLPATLVVDITETWFFGQS
LCKVIPYLQTVSVSVSVLTLSCIALDRWYAICHPLMFKSTAKRARNSIVIIVVIVSCIIMIPQAIV
MECSTVFPGLANKTTLFTVCDERWGGEIYPKMYHICFFLVTYMAPLCLMVLAYLQIFRKLW
CRQIPGTSSVVQRKWKPLQPVSQPRGPGQPTKSRMSAVAAEIKQIRARRKTARMLMIVLLVF
AICYLPISILNVLKRVFGMFAHTEDRETVYAWFTFSHWLVYANSAANPIIYNFLSGKFREEFK
AAFSCCCLGVHHRQEDRLTRGRTSTESRKSLTTQISNFDNISKLSEQVVLTSISTLPAANGAGP
LQNW

(SEQ ID NO:1306)
>gi\|223633971\|ref\|NP_0576243\| probable G-protein coupled receptor 83
precursor {Homosapiens}
MVPHLLLLCLLPLVRATEPHEGRADEQSAEAALAVPNASHFFSWNNYTFSDWQNFVGRRRY
GAESQNPTVKALLIVAYSFIIVFSLFGNVLVCHVIFKNQRMHSATSLFIVNLAVADIMITLLNT
PFTLVRFVNSTVVIFGKGMCHVSRFAQYCSLHVSALTLTAIAVDRHQVIMHPLKPRISITKGVI
YIAVIVVTMATFFSLPHAICQKLFTFKYSEDIVRSLCLPDFPEPADLFVVKYLDLATFILLYILPLLI
ISVAYARVAKKLWLCNMIGDVTTEQYFALRRKKKKTIKMLMLVVVLFALCWFPLNCYVLL
LSSKVIRTNNALYFAFHWFAMSSTCYNPFIYCWLNENFRIELKALLSMCQRPPKPQEDRPPSP
VPSFRVAWTEKNDGQRAPLANNLLPTSQLQSGKTDLSSVEPIVTMS

(SEQ ID NO:1307)
>gi\|223633986\|ref\|NP_0039582\| trace amine-associated receptor 5 {Homosapiens}
MRAVFIQGAEEHPAAFCYQVNGSCPRTVHTLGIQLVIYLACAAGMLIIVLGNVFVAFAVSYF
KALHTPTNFLLLSLALADMFLGLLVLPLSTIRSVESCWFFGDFLCRLHTYLDTLFCLTSIFHLC
FISIDRHCAICDPLLYPSKFTVRVALRYILAGWGVPAAYTSLFLYTDVVETRLSQWLEEMPCV
GSCQLLLNKFVVGWLNFPLFFVPCLIMISLYVKIFVVATRQAQQITTLSKSLAGAAKHERKAA
KTLGIAVGIYLLCWLPFTIDTMVDSLLHFITPPLVFDIFIVVFAYFNSACNPIIYVFSYQWFRKAL
KLTLSQKVFSPQTRTVDLYQE

(SEQ ID NO:1308)
>gi\|224586796\|ref\|NP_0764043\| G-protein coupled receptor 87 {Homosapiens}
MGFNLTLAKLPNNELHGQESHNSGNRSDGPGKNTTLHNEFDTIVLPVLYLIIFVASILLNGLA
VWIFFHIRNKTSFIFYLKNIVVADLIMTLTFPFRIVHDAGFGPWYFKFILCRYTSVLFYANMYT
SIVFLGLISIDRYLKVVKPFGDSRMYSITFTKVLSVCVWVIMAVLSLPNIILTNGQPTEDNIHDC
SKLKSPLGVKWHTAVTYVNSCLFVAVLVILIGCYIAISRYIHKSSRQFISQSSRKRKHNQSIRV
VVAVFFTCFLPYHLCRIPFTFSHLDRLLDESAQKILYYCKEITLFLSACNVCLDPIIYFFMCRSF
SRRLFKKSNIRTRSESIRSLQSVRRSEVRIYYDYTDV

(SEQ ID NO:1309)
>gi\|229093087\|ref\|NP_7407464\| probable G-protein coupled receptor 97
precursor {Homosapiens}
MATPRGLGALLLLLLLPTSGQEKPTEGPRNTCLGSNNMYDIFNLNDKALCFTKCRQSGSDSC
NVENLQRYWLNYEAHLMKEGLTQKVNTPFLKALVQNLSTNTAEDFYFSLEPSQVPRQVMK
DEDKPPDRVRLPKSLFRSLPGNRSVVRLAVTILDIGPGTLFKGPRLGLGDGSGVLNNRLVGLS
VGQMHVTKLAEPLEIVFSHQRPPPNMTLTCVFVVDVTKGTTGDWSSEGCSTEVRPEGTVCCC
DHLTFFALLLRPTLDQSTVHILTRISQAGCGVSMIFLAFTIILYAFLRLSRERFKSEDAPKIHVA
LGGSLFLLNLAFLVNVGSGSKGSDAACWARGAVFHYFLLCAFTWMGLEAFHLYLLAVRVF
NTYFGHYFLKLSLVGWGLPALMVIGTGSANSYGLYTIRDRENRTSLELCWFREGTTMYALYI
TVHGYFLITFLFGMVVLALVVWKIFTLSRATAVKERGKNRKKVLTLLGLSSLVGVTWGLAIF
TPLGLS TVYIFALFNS LQGVFICCWFTILYLPSQSTTVSSSTARLDQAHSASQE

(SEQ ID NO:1310)
>gi\|238859647\|ref\|NP_1161762\| probable G-protein coupled receptor 128
precursor {Homosapiens}
MASCRAWNLRVLVAVVCGLLTGIILGLGIVVRIVIRIQRGKSTSSSSTPTEFCRNGGTWENGRCI
CTEEWKGLRCTIANFCENSTYMGFTFARIPVGRYGPSLQTCGKDTPNAGNPMAVRLCSLSLY
GEIELQKVTIGNCNENLETLEKQVKDVTAPLNNISSEVQILTSDANKLTAENITSATRVVGQIF
NTSRNASPEAKKVAIVTVSQLLDASEDAFQRVAATANDDALTTLIEQMETYSLSLGNQSVVE
PNIAIQSANFSSENAVGPSNVRFSVQKGASSSLVSSSTFIHTNVDGLNPDAQTELQVLLNMTK
NYTKTCGFVVYQNDKLFQSKTFTAKSDFSQKIISSKTDENEQDQSASVDMVFSPKYNQKEFQ
LYSYACVYWNLSAKDWDTYGCQKDKGTDGFLRCRCNHTTNFAVLMTFKKDYQYPKSLDIL
SNVGCALSVTGLALTVIFQIVTRKVRKTSVTWVLVNLCISMLIFNLLFVFGIENSNKNLQTSD
GDINNIDFDNNDIPRTDTINIPNPMCTAIAALLHYFLLVTFTWNALSAAQLYYLLIRTMKPLPR
HFILFISLIGWGVPAIVVAITVGVIYSQNGNNPQWELDYRQEKICWLAIPEPNGVIKSPLLWSFI
VPVTIILISNVVMFITISIKVLWKNNQNLTSTKKVSSMKKIVSTLSVAVVFGITWILAYLMLVN
DDSIRIVFSYIFCLFNTTQGLQIFILYTVRTKVFQSEASKVLMLLSSIGRRKSLPSVTRPRLRVK
MYNFLRSLPTLHERFRLLETSPSTEEITLSESDNAKESI

(SEQ ID NO:1311)
>gi\|239582753\|ref\|NP_4733732\| mas-related G-protein coupled receptor member
X4 {Homosapiens }
MDPTVPVFGTKLTPINGREETPCYNQTLSFTVLTCIISLVGLTGNAVVLWLLGYRMRRNAVSI
YILNLAAADFLFLSFQIIRLPLRLINISHLIRKILVSVMTFPYFTGLSMLSAISTERCLSVLWPIVV
YRCRRPTHLSAVVCVLLWGLSLLFSMLEWRFCDFLFS GADSSWCETSDFIPVAWLIFLCVVL
CVSSLVLLVRILCGSRKMPLTRLYVTILLTVLVFLLCGLPFGILGALIYRMHLNLEVLYCHVYL
VCMSLSSLNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDKPEVDKGEGQLPEESLELSGS
RLGP

(SEQ ID NO:1312)
>gi\|256418985\|ref\|NP_0011578491\| MAS-related GPR, member G {Homosapiens}
MFGLFGLWRTFDSVVFYLTLIVGLGGPVGNGLVLWNLGFRIKKGPFSIYLLHLAAADFLFLSC
RVGFSVAQAALGAQDTLYFVLTFLWFAVGLWLLAAFSVERCLSDLFPACYQGCRPRHASAV
LCALVWTPTLPAVPLPANACGLLRNSACPLVCPRYHVASVTWFLVLARVAWTAGVVLFVW
VTCCSTRPRPRLYGIVLGALLLLFFCGLPSVFYWSLQPLLNFLLPVFSPLATLLACVNSSSKPLI
YSGLGRQPGKREPLRSVLRRALGEGAELGARGQSLPMGLL

(SEQ ID NO:1313)
>gi\|260763892\|ref\|NP_4733723\| mas-related G-protein coupled receptor member
X3 {Homosapiens}
MDSTIPVLGTELTPINGREETPCYKQTLSFTGLTCIVSLVALTGNAVVLWLLGCRMRRNAVSI
YILNLVAADFLFLSGHIICSPLRLINIRHPISKILSPVMTFPYFIGLSMLSAISTERCLSILWPIVVYH
CRRPRYLSSVMCVLLWALSLLRSILEWMFCDFLFSGANSVWCETSDFITIAWLVFLCVVLCG
SSLVLLVRILCGSRKMPLTRLYVTILLTVLVFLLCGLPFGIQWALFSRIHLDWKVLFCHVHLVS
IFLSALNSSANPIIYFFVGSFRQRQNRQNLKLVLQRALQDTPEVDEGGGWLPQETLELSGSRLE
Q

(SEQ ID NO:1314)
>gi\|269973880\|ref\|NP_6945472\| probable G-protein coupled receptor 156 isoform
1 {Homosapiens}
MEPEINCSELCDSFPGQELDRRPLHDLCKTTITSSHHSSKTISSLSPVLLGIVWTFLSCGLLLILF
FLAFTIHCRKNRIVKMSSPNLNIVTLLGSCLTYSSAYLFGIQDVLVGSSMETLIQTRLSMLCIGT
SLVFGPILGKSWRLYKVFTQRVPDKRVIIKDLQLLGLVAALLMADVILLMTWVLTDPIQCLQI
LSVSMTVTGKDVSCTSTSTHFCASRYSDVWIALIVVGCKGLLLLYGAYLAGLTGHVSSPPVNQ
SLTIMVGVNLLVLAAGLLFVVTRYLHSWPNLVFGLTSGGIFVCTTTINCFIFIPQLKQWKAFEE
ENQTIRRMAKYFSTPNKSFHTQYGEEENCHPRGEKSS MERLLTEKNAVIESLQEQVNNAKEK
IVRLMSAECTYDLPEGAAPPASSPNKDVQAVASVHTLAAAQGPSGHLSDFQNDPGMAARDS
QCTSGPSSYAQSLEGPGKDSSFSPGKEEKISDSKDFSDHLDSGCSQKPWTEQSLGPERGDQVP
MNPSQSLLPERGGSDPQRQRHLENSEEPPERRSRVSSVIREKLQEVLQDLGLGPEASLSTAPSC
HQQTWKNSAAFSPQKMPLSKELGFSPYMVRRRRAAQRARSHFPGSAPSSVGHRANRTVPGA
HSRLHVQNGDSPSLAPQTTDSRVRRPSSRKPSLPSDPQDRPGTLEGSKQSQTEPEGARGSKAA
FLRQPSGSGRAPSPAAPCLSKASPDLPEQWQLWPPVPSGCASLSSQHSYFDTESSSSDEFFCRC
HRPYCEICFQSSSDSSDSGTSDTDPEPTGGLASWEKLWARSKPIVNFKDDLKPTLV

(SEQ ID NO:1315)
>gi\|270265839\|ref\|NP_0002642\| G-protein coupled receptor 143 {Homosapiens}
MASPRLGTFCCPTRDAATQLVLSFQPRAFHALCLGSGGLRLALGLLQLLPGRRPAGPGSPATS
PPASVRILRAAAACDLLGCLGMVIRSTVWLGFPNFVDSVSDMNHTEIVVPAAFCVGSAMWIQ
LLYSACFWWLFCYAVDAYLVIRRSAGLSTILLYHIMAWGLATLLCVEGAAMLYYPSVSRCE
RGLDHAIPHYVTMYLPLLLVLVANPILFQKTVTAVASLLKGRQGIYTENERRMGAVIKIRFFK
IMLVLIICWLSNIINESLLFYLEMQTDINGGSLKPVRTAAKTTWFIMGILNPAQGFLLSLAFYG
WTGCSLGFQSPRKEIQWESLTTSAAEGAHPSPLMPHENPASGKVSQVGGQTSDEALSMLSEG
SDASTIEIHTASESCNKNEGDPALPTHGDL

(SEQ ID NO:1316)
>gi\|282403488\|ref\|NP_9972532\| probable G-protein coupled receptor 153 {Homosapiens}
MS DERRLPGSAVGWLVCGGLSLLANAWGILSVGAKQKKWKPLEFLLCTLAATHMLNVAVP
IATYSVVQLRRQRPDFEWNEGLCKVFVSTFYTLTLATCFSVTSLSYHRMWMVCWPVNYRLS
NAKKQAVHTVMGIVVMVSFILSALPAVGWHDTSERFYTHGCRFIVAEIGLGFGVCFLLLVGGS
VAMGVICTAIALFQTLAVQVGRQADRRAFTVPTIVVEDAQGKRRSSIDGSEPAKTSLQTTGL
VTTIVFIYDCLMGFPVLVVSFSSLRADASAPWMALCVLWCSVAQALLLPVFLWACDRYRAD
LKAVREKCMALMANDEESDDETSLEGGISPDLVLERSLDYGYGGDFVALDRMAKYEISALE
GGLPQLYPLRPLQEDKMQYLQVPPTRRFSHDDADVWAAVPLPAFLPRWGSGEDLAALAHL
VLPAGPERRRASLLAFAEDAPPSRARRRSAESLLSLRPSALDSGPRGARDSPPGSPRRRPGPGP
RSASASLLPDAFALTAFECEPQALRRPPGPFPAAPAAPDGADPGEAPTPPSSAQRSPGPRPSAH
SHAGSLRPGLSASWGEPGGLRAAGGGGSTSSFLSSPSESSGYATLHSDSLGSAS

(SEQ ID NO:1317)
>gi\|284447291\|ref\|NP_9972472\| probable G-protein coupled receptor 148 {Homosapiens}
MGDELAPCPVGTTAWPALIQLISKTPCMPQAASNTSLGLGDLRVPSSMLYWLFLPSSLLAAA
TLAVSPLLLVTILRNQRLRQEPHYLLPANILLSDLAYILLHMLISSSSLGGWELGRMACGILTD
AVFAACTSTILSFTAIVLHTYLAVIHPLRYLSFMSHGAAWKAVALIVVLVACCFPTFLIVVLSKW
QDAQLEEQGASYILPPSMGTQPGCGLLVIVTYTSILCVLFLCTALIANCFVVRIYAEAKTSGIVVG
QGYSRARGTLLIHSVLITLYVSTGVVFSLDMVLTRYHHIDSGTHTWLLAANSEVLMMLPRA
MLTYLYLLRYRQLLGMVRGHLPSRRQAIFTIS

(SEQ ID NO:1318)
>gi\|291042665\|ref\|NP_0628132\| leukotriene B4 receptor 2 {Homosapiens}
MSVCYRPPGNETLLSWKTSRATGTAFLLLAALLGLPGNGFVVWSLAGWRPARGRPLAATLV
LHLALADGAVLLLTPLFVAFLTRQAWPLGQAGCKAVYYVCALSMYASVLLTGLLSLQRCLA
VTRPFLAPRLRSPALARRLLLAVWLAALLLAVPAAVYRHLWRDRVCQLCHPSPVHAAAHLS
LETLTAFVLPFGLMLGCYSVTLARLRGARWGSGRHGARVGRLVSAIVLAFGLLWAPYHAVN
LLQAVAALAPPEGALAKLGGAGQAARAGTTALAFFSSSVNPVLYVFTAGDLLPRAGPRFLTR
LFEGSGEARGGGRSREGTMELRTTPQLKVVGQGRGNGDPGGGMEKDGPEWDL

(SEQ ID NO:1319)
>gi\|4503825 \|ref\|NP_0034961\| frizzled-1 precursor {Homosapiens }
MAEEEAPKKSRAAGGGASWELCAGALSARLAEEGSGDAGGRRRPPVDPRRLARQLLLLLW
LLEAPLLLGVRAQAAGQGPGQGPGPGQQPPPPPQQQQSGQQYNGERGISVPDHGYCQPISIPL
CTDIAYNQTIMPNLLGHTNQEDAGLEVHQFYPLVKVQCSAELKFFLCSMYAPVCTVLEQALP
PCRSLCERARQGCEALMNKFGFQWPDTLKCEKFPVHGAGELCVGQNTSDKGTPTPSLLPEF
WTSNPQHGGGGHRGGFPGGAGASERGKFSCPRALKVPSYLNYHFLGEKDCGAPCEPTKVYG
LMYFGPEELRFSRTVVIGIVVSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSGCYTAVAVAYIA
GFLLEDRVVCNDKFAEDGARTVAQGTKKEGCTILFMMLYFFSMASSIVVWVILSLTVVFLAAG
MKWGHEAIEANSQYFHLAAWAVPAIKTITILALGQVDGDVLSGVCFVGLNNVDALRGFVLA
PLFVYLFIGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVFSVLYTVPATIVIACYFYE
QAFRDQWERSWVAQSCKSYAIPCPHLQAGGGAPPHPPMSPDFTVFMIKYLMTLIVGITSGFW
IVVSGKTLNSWRKFYTRLTNSKQGETTV

(SEQ ID NO:1320)
>gi\|4503827 \|ref\|NP_0014571\| frizzled-2 precursor {Homosapiens }
MRPRSALPRLLLPLLLLPAAGPAQFHGEKGISIPDHGFCQPISIPLCTDIAYNQTIMPNLLGHTN
QEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLEQAIPPCRSICERARQGCEALMNK
FGFQWPERLRCEHFPRHGAEQICVGQNHSEDGAPALLTTAPPPGLQPGAGGTPGGPGGGGAP
PRYATLEHPFHCPRVLKVPSYLSYKFLGERDCAAPCEPARPDGSMFFSQEETRFARLWILTWS
VLCCASTFFTVTTYLVDMQRFRYPERPIIFLSGCYTMVSVAYIAGFVLQERVVCNERFSEDGY
RTVVQGTKKEGCTILFMMLYFFSMASSIVVWVILSLTWFLAAGMKWGHEAIEANSQYFHLAA
WAVPAVKTITILAMGQIDGDLLSGVCFVGLNSLDPLRGFVLAPLFVYLFIGTSFLLAGFVSLFR
IRTIMKHDGTKTEKLERLMVRIGVFSVLYTVPATIVIACYFYEQAFREHWERSWVSQHCKSL
AIPCPAHYTPRMSPDFTVYMIKYLMTLIVGITSGFVVIWSGKTLHSWRKFYTRLTNSRHGETTV

(SEQ ID NO:1321)
>gi\|4503833 \|ref\|NP_0034981\| frizzled-7 precursor {Homosapiens }
MRDPGAAAPLSSLGLCALVLALLGALSAGAGAQPYHGEKGISVPDHGFCQPISIPLCTDIAYN
QTILPNLLGHTNQEDAGLEVHQFYPLVKVQCSPELRFFLCSMYAPVCTVLDQAIPPCRSLCER
ARQGCEALMNKFGFQWPERLRCENFPVHGAGEICVGQNTSDGSGGPGGGPTAYPTAPYLPD
LPFTALPPGASDGRGRPAFPFSCPRQLKVPPYLGYRFLGERDCGAPCEPGRANGLMYFKEEER
RFARLWVGVWSVLCCASTLFTVLTYLVDMRRFSYPERPIIFLSGCYFMVAVAHVAGFLLEDR
AVCVERFSDDGYRTVAQGTKKEGCTILFMVLYFFGMASSIVVWVILSLTVVFLAAGMKWGHE
AIEANSQYFHLAAWAVPAVKTITILAMGQVDGDLLSGVCYVGLSSVDALRGFVLAPLFVYLF
IGTSFLLAGFVSLFRIRTIMKHDGTKTEKLEKLMVRIGVFSVLYTVPATIVLACYFYEQAFREH
WERTVVLLQTCKSYAVPCPPGHFPPMSPDFTVFMIKYLMTMIVGITTGFWIVVSGKTLQSWRRF
YHRLSHSSKGETAV

(SEQ ID NO:1322)
>gi\|4503835\|ref\|NP_0034991\| frizzled-9 precursor {Homosapiens }
MAVAPLRGALLLWQLLAAGGAALEIGRFDPERGRGAAPCQAVEIPMCRGIGYNLTRMPNLL
GHTSQGEAAAELAEFAPLVQYGCHSHLRFFLCSLYAPMCTDQVSTPIPACRPMCEQARLRCA
PIMEQFNFGWPDSLDCARLPTRNDPHALCMEAPENATAGPAEPHKGLGMLPVAPRPARPPG
DLGPGAGGSGTCENPEKFQYVEKSRSCAPRCGPGVEVFVVSRRDKDFALVWMAVWSALCFF
STAFTVLTFLLEPHRFQYPERPIIFLSMCYNVYSLAFLIRAVAGAQSVACDQEAGALYVIQEGL
ENTGCTLVFLLLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEAHGSYFHMAAWGLPA
LKTIVILTLRKVAGDELTGLCYVASTDAAALTGFVLVPLSGYLVLGSSFLLTGFVALFHIRKIM
KTGGTNTEKLEKLMVKIGVFSILYTVPATCVIVCYVYERLNMDFWRLRATEQPCAAAAGPG
GRRDCSLPGGSVPTVAVFMLKIFMSLVVGITSGVWVWSSKTFQTVVQSLCYRKIAAGRARAK
ACRAPGSYGRGTHCHYKAPTVVLHMTKTDPSLENPTHL

(SEQ ID NO:1323)
>gi\|5032099\|ref\|NP_0056221\| smoothened homolog precursor {Homosapiens }
MAAARPARGPELPLLGLLLLLLLGDPGRGAASSGNATGPGPRSAGGSARRSAAVTGPPPPLS
HCGRAAPCEPLRYNVCLGSVLPYGATSTLLAGDSDSQEEAHGKLVLWSGLRNAPRCWAVIQ
PLLCAVYMPKCENDRVELPSRTLCQATRGPCAIVERERGWPDFLRCTPDRFPEGCTNEVQNI
KFNSSGQCEVPLVRTDNPKSWYEDVEGCGIQCQNPLFTEAEHQDMHSYIAAFGAVTGLCTLF
TLATFVADWRNSNRYPAVILFYVNACFFVGSIGWLAQFMDGARREIVCRADGTMRLGEPTS
NETLSCVIIFVIVYYALMAGVVWFVVLTYAWHTSFKALGTTYQPLSGKTSYFHLLTVVSLPFV
LTVAILAVAQVDGDSVSGICFVGYKNYRYRAGFVLAPIGLVLIVGGYFLIRGVMTLFSIKSNH
PGLLSEKAASKINETMLRLGIFGFLAFGFVLITFSCHFYDFFNQAEWERSFRDYVLCQANVTIG
LPTKQPIPDCEIKNRPSLLVEKINLFAMFGTGIAMSTWVVVTKATLLIVVRRTWCRLTGQSDDEP
KRIKKSKMIAKAFSKRHELLQNPGQELSFSMHTVSHDGPVAGLAFDLNEPSADVSSAWAQH
VTKMVARRGAILPQDISVTPVATPVPPEEQANLWLVEAEISPELQKRLGRKKKRRKRKKEVC
PLAPPPELHPPAPAPSTIPRLPQLPRQKCLVAAGAWGAGDSCRQGAWTLVSNPFCPEPSPPQD
PFLPSAPAPVAWAHGRRQGLGPIHSRTNLMDTELMDADSDF

(SEQ ID NO:1324)
>gi\|6005762\|ref\|NP_0091281\| frizzled-10 precursor {Homosapiens }
MQRPGPRLWLVLQVMGSCAAISSMDMERPGDGKCQPIEIPMCKDIGYNMTRMPNLMGHEN
QREAAIQLHEFAPLVEYGCHGHLRFFLCSLYAPMCTEQVSTPIPACRVMCEQARLKCSPIMEQ
FNFKWPDSLDCRKLPNKNDPNYLCMEAPNNGSDEPTRGSGLFPPLFRPQRPHSAQEHPLKDG
GPGRGGCDNPGKFHHVEKSASCAPLCTPGVDVYVVSREDKRFAVVWLAIWAVLCFFSSAFTV
LTFLIDPARFRYPERPIIFLSMCYCVYS VGYLIRLFAGAESIACDRDSGQLYVIQEGLESTGCTL
VFLVLYYFGMASSLWWVVLTLTWFLAAGKKWGHEAIEANSSYFHLAAWAIPAVKTILILVM
RRVAGDELTGVCYVGSMDVNALTGFVLIPLACYLVIGTSFILSGFVALFHIRRVMKTGGENT
DKLEKLMVRIGLFSVLYTVPATCVIACYFYERLNMDYWKILAAQHKCKMNNQTKTLDCLM
AASIPAVEIFMVKIFMLLVVGITSGMWIVVTSKTLQSWQQVCSRRLKKKSRRKPASVITSGGIY
KKAQHPQKTHHGKYEIPAQSPTCV

(SEQ ID NO:1325)
>gi\|8393378\|ref\|NP_0591081\| frizzled-3 precursor {Homosapiens}
MAMTWIVFSLWPLTVFMGHIGGHSLFSCEPITLRMCQDLPYNTTFMPNLLNHYDQQTAALA
MEPFHPMVNLDCSRDFRPFLCALYAPICMEYGRVTLPCRRLCQRAYSECSKLMEMFGVPWP
EDMECSRFPDCDEPYPRLVDLNLAGEPTEGAPVAVQRDYGFVVCPRELKIDPDLGYSFLHVRD
CSPPCPNMYFRREELSFARYFIGLISIICLSATLFTFLTFLIDVTRFRYPERPIIFYAVCYMMVSLI
FFIGFLLEDRVACNASIPAQYKASTVTQGSHNKACTMLFMILYFFTMAGSVWWVILTITWFL
AAVPKWGSEAIEKKALLFHASAWGIPGTLTIILLAMNKIEGDNISGVCFVGLYDVDALRYFVL
APLCLYVVVGVSLLLAGIISLNRVRIEIPLEKENQDKLVKFMIRIGVFSILYLVPLLVVIGCYFY
EQAYRGIVVETTWIQERCREYHIPCPYQVTQMSRPDLILFLMKYLMALIVGIPSVFWVGSKKT
CFEWASFFHGRRKKEIVNESRQVLQEPDFAQSLLRDPNTPIIRKSRGTSTQGTSTHASSTQLA
MVDDQRSKAGSIHSKVSSYHGSLHRSRDGRYTPCSYRGMEERLPHGSMSRLTDHSRHSSSHR
LNEQSRHSSIRDLSNNPMTHITHGTSMNRVIEEDGTSA

(SEQ ID NO:1326)
>gi\|13994190\|ref\|NP_1140721\| frizzled-8 precursor {Homosapiens}
MEWGYLLEVTSLLAALALLQRSSGAAAASAKELACQEITVPLCKGIGYNYTYMPNQFNHDT
QDEAGLEVHQFVVPLVEIQCSPDLKFFLCSMYTPICLEDYKKPLPPCRSVCERAKAGCAPLMR
QYGFAWPDRMRCDRLPEQGNPDTLCMDYNRTDLTTAAPSPPRRLPPPPPGEQPPSGSGHGRP
PGARPPHRGGGRGGGGGDAAAPPARGGGGGGKARPPGGGAAPCEPGCQCRAPMVSVSSER
HPLYNRVKTGQIANCALPCHNPFFSQDERAFTVFVVIGLWSVLCFVSTFATVSTFLIDMERFKY
PERPIIFLSACYLFVSVGYLVRLVAGHEKVACSGGAPGAGGAGGAGGAAAGAGAAGAGAG
GPGGRGEYEELGAVEQHVRYETTGPALCTVVFLLVYFFGMASSIVVWVILSLTWFLAAGMK
WGNEAIAGYSQYFHLAAWLVPSVKSIAVLALSSVDGDPVAGICYVGNQSLDNLRGFVLAPL
VIYLFIGTMFLLAGFVSLFRIRSVIKQQDGPTKTHKLEKLMIRLGLFTVLYTVPAAVVVACLFY
EQHNRPRWEATHNCPCLRDLQPDQARRPDYAVFMLKYFMCLVVGITSGVWVWSGKTLES
WRSLCTRCCWASKGAAVGGGAGATAAGGGGGPGGGGGGGPGGGGGPGGGGGSLYSDVST
GLTWRSGTASSVSYPKQMPLSQV

(SEQ ID NO:1327)
>gi\|22547161\|ref\|NP_0363252\| frizzled-4 precursor {Homosapiens}
MAWRGAGPSVPGAPGGVGLSLGLLLQLLLLLGPARGFGDEEERRCDPIRISMCQNLGYNVT
KMPNLVGHELQTDAELQLTTFTPLIQYGCSSQLQFFLCSVYVPMCTEKINIPIGPCGGMCLSV
KRRCEPVLKEFGFAWPESLNCSKFPPQNDHNHMCMEGPGDEEVPLPHKTPIQPGEECHSVGT
NSDQYIWVKRSLNCVLKCGYDAGLYSRSAKEFTDIVVMAVWASLCFISTAFTVLTFLIDSSRFS
YPERPIIFLSMCYNIYSIAYIVRLTVGRERISCDFEEAAEPVLIQEGLKNTGCAIIFLLMYFFGMA
SSIVVWVILTLTVVFLAAGLKWGHEAIEMHSSYFHIAAWAIPAVKTIVILIMRLVDADELTGLCY
VGNQNLDALTGFVVAPLFTYLVIGTLFIAAGLVALFKIRSNLQKDGTKTDKLERLMVKIGVFS
VLYTVPATCVIACYFYEISNWALFRYSADDSNMAVEMLKIFMSLLVGITSGMWIWSAKTLHT
WQKCSNRLVNSGKVKREKRGNGWVKPGKGSETVV

(SEQ ID NO:1328)
>gi\|27894385\|ref\|NP_0034592\| frizzled-5 precursor {Homosapiens}
MARPDPSAPPSLLLLLLAQLVGRAAAASKAPVCQEITVPMCRGIGYNLTHMPNQFNHDTQDE
AGLEVHQFVVPLVEIQCSPDLRFFLCSMYTPICLPDYHKPLPPCRSVCERAKAGCSPLMRQYGF
AWPERMSCDRLPVLGRDAEVLCMDYNRSEATTAPPRPFPAKPTLPGPPGAPASGGECPAGGP
FVCKCREPFVPILKESHPLYNKVRTGQVPNCAVPCYQPSFSADERTFATFWIGLWSVLCFISTS
TTVATFLIDMERFRYPERPIIFLS CYLCVSLGFLVRLVVGHASVACSREHNHIHYETTGPALC
TIVFLLVYFFGMASSIVVWVILSLTWFLAAGMKWGNEAIAGYAQYFHLAAWLIPSVKSITALA
LSSVDGDPVAGICYVGNQNLNSLRGFVLGPLVLYLLVGTLFLLAGFVSLFRIRSVIKQGGTKT
DKLEKLMIRIGIFTLLYTVPASIVVACYLYEQHYRESWEAALTCACPGHDTGQPRAKPEYWV
LMLKYFMCLVVGITSGVWIVVSGKTVESWRRFTSRCCCRPRRGHKSGGAMAAGDYPEASAA
LTGRTGPPGPAATYHKQVSLSHV

(SEQ ID NO:1329)
>gi\|34734079\|ref\|NP_0034972\| frizzled-6 isoform a precursor {Homosapiens}
MEMFTFLLTCIFLPLLRGHSLFTCEPITVPRCMKMAYNMTFFPNLMGHYDQSIAAVEMEHFL
PLANLECSPNIETFLCKAFVPTCIEQIHVVPPCRKLCEKVYSDCKKLIDTFGIRWPEELECDRLQ
YCDETVPVTFDPHTEFLGPQKKTEQVQRDIGFVVCPRHLKTSGGQGYKFLGIDQCAPPCPNMY
FKSDELEFAKSFIGTVSIFCLCATLFTFLTFLIDVRRFRYPERPIIYYSVCYSIVSLMYFIGFLLGD
STACNKADEKLELGDTVVLGSQNKACTVLFMLLYFFTMAGTVWWVILTITWFLAAGRKWS
CEAIEQKAVWFHAVAWGTPGFLTVMLLAMNKVEGDNISGVCFVGLYDLDASRYFVLLPLCL
CVFVGLSLLLAGIISLNHVRQVIQHDGRNQEKLKKFMIRIGVFSGLYLVPLVTLLGCYVYEQV
NRITWEITWVSDHCRQYHIPCPYQAKAKARPELALFMIKYLMTLIVGISAVFWVGSKKTCTE
WAGFFKRNRKRDPISESRRVLQESCEFFLKHNSKVKHKKKHYKPSSHKLKVISKSMGTSTGA
TANHGTSAVAITSHDYLGQETLTEIQTSPETSMREVKADGASTPRLREQDCGEPASPAASISRL
SGEQVDGKGQAGSVSESARSEGRISPKSDITDTGLAQSNNLQVPSSSEPSSLKGSTSLLVHPVS
GVRKEQGGGCHSDT

For purposes of interpreting Table 4, please refer to the following legend:

Ac—Acylation
p-Cl-dF=para-Chlorine, D-Phenylalanine
4cl=Chlorinated Phenylalanine
_dF=para-Chlorine, D-Phenylalanine
_dR=D-Arginine
_dY=D-Tyrosine
_dA=D-Alanine
_hR=homoarginine
pY=Phosphoroylated Tyrosine
pS=Phosphoroylated Serine
pE=Pyroglutamic acid
PEG=Polyetheythlene Glycol
PEG{number kD}=Polyetheythlene Glycol with a molecular weight near {number} in kilodaltons.
Nle=Noraleucine
N_le=Noraleucine
Y_m=methoxy-tyrosine.
Y_M=methoxy-tyrosine.
K_m=methylated-lysine.
Aib=α-aminoisobutyric acid
Abu=ALPHA-AMINOBUTYRIC ACID
Gab=γ-aminobutyric acid;
Dip=β,β-diphenyl-L-alanine;
*=indicates cyclization between residues (lactam ring)
dHis=D-His
w=D-Tryptophan
Dnp=di-nitro-phenol
Mca=methoxycoumarin 4 acetic acid
Sar=sarcosine
Sta=statine
Ste=Stearyl
Pyr=pyroglutamic acid
Fam=carboxyfluoresceine
LC=−(NH₂—(CH₂)₅—C═O)—
TAMRA=carboxytetramethylrhodamine
T*=N-acetyl galactosamine labeled Thr
NH₂=amidation of carboxy terminus
Orn=ornithine
K(W)=Trp residue which is coupled to the side chain of a Lys
Y(OMe)=methylated Tyrosine
Cit=citrulline
C6=hexanoyl
Nva=Norvaline
In some embodiments, analogs of the present invention (including any polypeptide sequence identified in Tables 1, 2, 3, or 4) are either be N-terminal acylated or an N-terminal free-amine In some embodiments, analogs of the present invention are either either a c-terminal amine or a c-terminal acid. These terminal groups do not preclude additional solubilization and/or stabilization attachments such a poly-ethylene glycol.

The following examples are provided to describe the invention in greater detail. They are intended to illustrate, not to limit, the invention. Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety.

EXAMPLES

Example 1: Chemical Scheme to Synthesize Helical Polypeptides

This example describes how the polypeptide analogs may be designed prior to manufacture. The sequence of human vasoactive intestinal peptide (VIP) is given below, using the standard one-letter code for proteinogenic amino acid residues. For purposes of interpretation “position 1” of the sequence below is the N-terminal histidine. Each amino acid residue is numbered in sequence from the N-terminal end of the polypeptide to the C-terminal. Therefore, “position 28” of the sequence below is the C-terminal asparagine.

	(SEQ ID NO: 10)
	HSDAVFTDNYTRLRKQMAVKKYLNSILN

Design A. A family of the following VIP analogues were synthesized each containing at least two alpha to β³replacements per seven α-amino acid residues of VIP:

	(SEQ ID NO: 1342)
	HSDAV FTDNY TRLRK Q L AVK KYLN A ILN

	(SEQ ID NO: 1342)
	HSDAV FTDNY T RL R K QL A VK K YLN A I LN

	(SEQ ID NO: 1342)
	HSDAV FTDNY T RL R K QL A VK K Y LN A ILN

	(SEQ ID NO: 1342)
	HSDAV FTDN Y TRL R K Q L AVK K YL N A I LN

	(SEQ ID NO: 1343)
	HSDAV FTDNY T RL Z K QL X VK K YLN X IL N

	(SEQ ID NO: 1344)
	HSDAV FTDNY T RL Z K QL X VK Z YLN X I LN

	(SEQ ID NO: 1345)
	HSDAV FTDNY X RL Z K QL X VK K YLN X I LN

	(SEQ ID NO: 1346)
	HSDAV FTDNY X RL Z K QL X VK Z YLN X I LN

	(SEQ ID NO: 1347)
	HSDAV FTDNY T RLR Z QL X VK K Y LN X ILN

	(SEQ ID NO: 1348)
	HSDAV FTDNY X RLR Z QL X VK K Y LN X ILN

	(SEQ ID NO: 1349)
	HSDAV FTDN Y TRL Z K Q L AVK Z YL X A I LN

	(SEQ ID NO: 1350)
	HSDAV FTDN Y TRL Z K Q X AVK K YL X A I LN

	(SEQ ID NO: 1351)
	HSDAV FTDN Y TRL Z K Q X AVK Z YL X A I LN

In each of sequences above, at least one β-3 residue has been replaced by a cyclic or heterocyclic residue. In some embodiments, based upon the above sequences, X=ACPC, Z=APC; uncharged side chains replaced by ACPC, basic side chains replaced by APC, Protected β3-amino acids); the positions indicated with bold and underlined letters are those at which β-to-β3 replacement has occurred. Reagents for α/β-Peptide synthesis (Fmoc on the backbone nitrogen and appropriate protecting groups on side chains, when necessary) will be obtained from commercial suppliers or prepared via reported methods in Horne et. al. PNAS, Sep. 1, 2009, vol. 106, no. 35, 14751-14756. Each β3-amino acid residue bore the side chain of the β-amino acid found at that site in the VIP sequence. Thus, for example, analogues that contain a β-residue at position 10 of the sequence had a β3-homotyrosine at this position, in place of the tyrosine at position 10 of VIP itself. The analogues shown above were synthesized manually by microwave-assisted Fmoc solid phase peptide synthesis on NovaSyn TGR resin. Coupling steps were carried out with a three-fold excess of the appropriate protected α- or β3-amino acid, using HBTU and HOBt to mediate amide bond formation. Piperidine was used for Fmoc deprotection steps. Each peptide was cleaved from resin by treatment with 94:2.5:2.5 TFA/H2O/triisopropylsilane, precipitated by addition of cold ethyl ether, and purified by reverse phase HPLC on a prep-C18 column using gradients between 0.1% TFA in water and 0.1% TFA in acetonitrile. The identity and purity of the HSDAVFTDNYXRLZKQLXVKZYLNXILN (Compound 8) was determined by MALDI-TOF-MS and analytical HPLC, respectively. Data from the MALDI-TOF-MS analysis showing the expected mass values is shown in FIG. 1. The sample was examined by MALDI-TOF to determine molecular weight. A 50:50 mixture of acetonitrile/water was used to dissolve alpha cyano-cinnamic acid matrix together with a 5 uM aliquot of sample. The sample was dried on an appropriate sample plate and examined in positive, reflectron mode with a 25 KV voltage, 100 mV electronic gain and a laser frequency of 60 Hz. The resulting spectra demonstrated an observed mass (mass/charge, m/z) of 3351.4 which compares favorably with the expected mass of 3350.79. In addition, the observed doubly charged species, (Z=2) of 1675.684 was also observed and compares favorably to the expected ‘+2’ peak of 1675.395.
Design B (prophetic). A family of analogues will be prepared, each containing two alpha to β³replacements per seven α-amino acid residues of VIP. Each β³-amino acid residue will bear the side chain of the α-amino acid found at that site in the VIP sequence. Thus, for example, analogues that contain a β-residue at position 4 of the sequence will have β³-homoalanine at this position, in place of the alanine at position 4 of VIP itself. The analogues to be prepared are shown below; the positions indicated with bold and underlined letters are those at which α-to-β³replacement has occurred.

	(SEQ ID NO: 10)
	HS D AVF T DN Y TRL R KQ M AVK K YL N SIL N

	(SEQ ID NO: 10)
	HS D AV F TDN Y TR L RKQ M AV K KYL N SI L N

	(SEQ ID NO: 10)
	H SD A VFT D NY T RLR K QM A VKK Y LN S ILN

	(SEQ ID NO: 10)
	HSD A VF T DNY T RL R KQM A VK K YLN S IL N

	(SEQ ID NO: 10)
	H S DA V FTD N YT R LRK Q MA V KKY L NS I LN

	(SEQ ID NO: 10)
	H SDA V FT D NYT R LR K QMA V KK Y LNS I LN

	(SEQ ID NO: 10)
	H S DAV F TD N YTR L RK Q LAV K KY L NAI L N

	(SEQ ID NO: 1342)
	HSDAVFTDNY T RL R KQL A VK K YLN A ILN

	(SEQ ID NO: 1342)
	HSDAVFTDNY T RL R KQL A VK K YLN A IL N

	(SEQ ID NO: 1342)
	HSDAVFTDN Y TRL R KQ L AVK K YL N AIL N

	(SEQ ID NO: 1344)
	HSDAVFTDNY T RL Z KQL X VK Z YLN X IL N

	(SEQ ID NO: 1345)
	HSDAVFTDNY X RL Z KQL X VK K YLN X IL N

	(SEQ ID NO: 1346)
	HSDAVFTDNY X RL Z KQL X VK Z YLN X IL N

	(SEQ ID NO: 1349)
	HSDAVFTDN Y TRL Z KQ L AVK Z YL X AIL N

	(SEQ ID NO: 1350)
	HSDAVFTDN Y TRL Z KQ X AVK K YL X AIL N

	(SEQ ID NO: 1351)
	HSDAVFTDN Y TRL Z KQ X AVK Z YL X AIL N

	(SEQ ID NO: 1367)
	HSDAVFTDNY X RL R KQL A VK K YLN A ILN

	(SEQ ID NO: 1368)
	HSDAVFTDNY T RL Z KQL A VK K YLN A ILN

	(SEQ ID NO: 1369)
	HSDAVFTDNY T RL R KQL X VK K YLN A ILN

	(SEQ ID NO: 1370)
	HSDAVFTDNY T RL R KQL A VK Z YLN A ILN

	(SEQ ID NO: 1371)
	HSDAVFTDNY T RL R KQL A VK K YLN X ILN

	(SEQ ID NO: 1346)
	HSDAVFTDNY X RL Z KQL X VK Z YLN X ILN

	(SEQ ID NO: 1372)
	HSDAVF TD NYTRLR R Q L A ARR YLN A I KK

In each of sequences above, at least one β-3 residue has been replaced by a cyclic or heterocyclic residue. In some embodiments, based upon the above sequences, X=ACPC, Z=APC; uncharged side chains replaced by ACPC, basic side chains replaced by APC, Protected β³-amino acids). α/β-Peptide synthesis (Fmoc on the backbone nitrogen and appropriate protecting groups on side chains, when necessary) will be obtained from commercial suppliers or prepared via reported methods. Each β^3-peptide will be prepared manually by microwave-assisted Fmoc solid phase peptide synthesis on NovaSyn TGR resin. Coupling steps will be carried out with a three-fold excess of the appropriate protected α- or β³-amino acid, using HBTU and HOBt to mediate amide bond formation. Piperidine will be used for Fmoc deprotection steps. Each peptide will be cleaved from resin by treatment with 94:2.5:2.5:1 TFA/H2O/ethanedithiol/triisopropylsilane, precipitated by addition of cold ethyl ether, and purified by reverse phase HPLC on a prep-C18 column using gradients between 0.1% TFA in water and 0.1% TFA in acetonitrile. The identity and purity of the final products will be determined by MALDI-TOF-MS and analytical HPLC, respectively.
Design and Synthesis of VPAC₁-selective VIP analogues. VPAC₁-selective VIP analogues will be synthesized in accordance with the protocol outlined above. The predicted α-helical portion of VIP polypeptide is from positions 10-28 which are depicted in FIG. 6. The amino acid residues will be substituted with non-natural amino acid residues. β³-amino acid residue positions indicated in bold and underline, and, on the helical wheel diagrams shown in FIG. 7 (which correspond to the positions on the diagram depicted in FIG. 6), β³-amino acid residue positions indicated as solid dots. In some species, the non-polar β³-residues (e.g., β³-hAla, β³-hVal) will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while basic β³-residues (such as β³-hLys or β³-hArg) will be replaced by APC:

	(SEQ ID NO: 435)
	HSDAV FTDN Y ARL R K Q M AVK K AL N S IL A

	(SEQ ID NO: 435)
	HSDAV FTDN Y AR L RK Q M AV K KAL N S I L A

	(SEQ ID NO: 435)
	HSDAV FTDNY A RLR K QM A VK K A LN S ILA

	(SEQ ID NO: 435)
	HSDAV FTDNY A RL R K QM A VK K ALN S IL A

	(SEQ ID NO: 435)
	HSDAV FTDNY A R LRK Q MA V K KA L NS I LA

	(SEQ ID NO: 435)
	HSDAV FTDNY A R LR K QMA V K K A LNS I LA

	(SEQ ID NO: 435)
	HSDAV FTDNY AR L RK Q MAV K KA L NS I L A

	(SEQ ID NO: 434)
	HADAV FTAAY ARLRK QMAAK KALAA IAA

α/β-Peptide analogues below will be synthesized:

	(SEQ ID NO: 434)
	HADAV FTAA Y ARL R K Q M AAK K AL A A IA A

	(SEQ ID NO: 434)
	HADAV FTAA Y AR L RK Q M AA K KAL A A I A A

	(SEQ ID NO: 434)
	HADAV FTAAY A RLR K QM A AK K A LA A IAA

	(SEQ ID NO: 434)
	HADAV FTAAY A RL R K QM A AK K ALA A IA A

	(SEQ ID NO: 434)
	HADAV FTAAY A R LRK Q MA A K KA L AA I AA

	(SEQ ID NO: 434)
	HADAV FTAAY A R LRK QMA A K K A LAA I AA

	(SEQ ID NO: 434)
	HADAV FTAAY AR L RK Q MAA K KA L AA I A A

Designs Targeted Toward the VPAC2 Receptor-Selective Analogues.

VPAC₁-selective VIP analogues will be synthesized in accordance with the protocol outlined above. α-helical portion of VIP polypeptide sequences will be substituted with non-natural amino acid residues where β³-amino acid residue positions indicated in bold and underlined. In some species, the non-polar β³-residues (e.g., β³-hAla, β³-hVal) will be replaced by (S,S)-trans-2-aminocyclopentanecarboxylic acid ((S,S)-ACPC), while basic β³-homo residues (such as β³-hLys or β³-hArg) will be replaced by the pyrrolidine analogue of (S,S)-ACPC, which is designated APC (Note: Ac=acetyl; N^le=norleucine; K*---D* indicates that the side chains of these two residues may be linked via an amide bond.)
a/b-Peptide analogues will be synthesized:

	(SEQ ID NO: 1373)
	Ac-HSDAV FTEN Y TKL R K Q N ^le AVK KYL N D LK K GG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTEN Y TK L RK Q N ^le AVK KYLND L K KGG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY T KLR K QN^le A VK K* Y LN D* LKK G G T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY T KL R K QN^le A VK K* YLN D* LK K GG T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY T K LRK Q N^leAVK KY L ND L KKG G T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY T K LR K QN^leA V K K* Y LND* L KK G G T

	(SEQ ID NO: 1373)
	Ac-HSDAV FTENY TK L RK Q N^leAV K KY L ND L K KG G T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTEN Y TKL R K R N ^le AAK N ^le YL N N LK K GG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTEN Y TK L RK R N ^le AA K N^leYL N N L K KGG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY T KLR K RN^le A AK N^le Y LN N LKK G G T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY T KL R K RN^le A AK N ^le YLN N LK K GG T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY T K LRK R N^leA A K N^leY L NN L KKG G T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY T K LR K RN^leA A K N^le Y LNN L KK G G T

	(SEQ ID NO: 1374)
	Ac-HSDAV FTENY TK L RK R N^leAA K N^leY L NN L K KG G T

wherein Ac=acetyl; N^le=norleucine; K*---D* indicates that the side chains of these two residues may be linked via an amide bond.

One purpose of this study will be to demonstrate that the analogs of the application may be designed to increase the half-life of the polypeptide as compared to the half-life of the naturally encoded protein by introducing non-natural amino acid analogs that are resistant to degradation and/or induce an equivalent or increased bioactivity as compared to the naturally encoded polypeptide sequence upon which the analog is based or derived through the possible incorporation of conformationally-constrained residues.

Example 2: Structural Analysis of Helical Polypeptides

Structural Analysis A

This example describes how a VIP analogue was characterized after chemical synthesis and and purification.
Circular Dichroism Spectroscopy. Circular dichroism measurements were carried out on a Aviv 202SF Circular Dichroism Spectrophotometer (FIG. 2). Samples of each peptide were prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in a phosphate-buffered solution at a pH of 7.5 for a final concentration of about 14 μM. The analogue was transferred a 0.1 cm path length cell for measurement. Wavelength scans were carried out with a 1 nm step and 8 sec averaging time, in quadruplicate at 23° C. All spectra were corrected against buffer measured in the same cell.
The data of FIG. 2 demonstrate the expected circular dichroism measurements of an alpha-beta hybrid polypeptide. The results are consistent with previously published data of an alpha-beta hybrid polypeptide that has similar backbone length and similar beta-amino acid percent and similar sample concentration.

Structural Analysis B (Prophetic)

This prophetic example describes how the polypeptide analogs of this invention may be characterized after manufacture through structural conformational assays such as circular dichroism (CD) and Nuclear magnetic resonance (NMR).
Circular Dichroism Spectroscopy. Circular dichroism measurements will be carried out on an Aviv 202SF Circular Dichroism Spectrophotometer. Samples of each peptide will be prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in a pH buffered solution. Spectra will be recorded in a 1 mm cell with a step size of 1 nm and an averaging time of 5 sec. All spectra will be background corrected against buffer measured in the same cell. Thermal melts will be carried out in 1-degree increments with an equilibration time of 2 min between each temperature change. Thermal unfolding data will be fit to a simple two state folding model Shortle, D. Meeker, A. K. Freire, E. Biochemistry 1988, 27, 4761-4768) using GraphPad Prism.
Nuclear Magnetic Resonance: Structure elucidation of the proposed analogs can also be accomplished based on analyses of heteronuclear NMR experimental data. Global backbone structural information complementing the local structure information provided by backbone chemical-shift assignments can be obtained from nuclear Overhauser effect spectroscopy (NOESY) which yield atomic distance constraints together with residual dipolar coupling (RDC) experiments which provide orientation restraint information. Together, these techniques can be used to provide valuable structural information regarding the positioning and alignment of the amino acids within the polypeptide analog. Samples of each peptide or analog will be prepared with a determined UV absorbance in the range of 0.1-1.0 at 280 nm in an appropriate pH buffered solution. Each preparation will then be used to conduct NOESY and RDC experiments using standard NMR equipment (i.e. Bruker NMR) and data analysis software (i.e. Talos+). Further structural insight can be ascertained by comparing the results of NMR experiments in the presence and absence of the intended binding partner.
One purpose of this study is to evidence that the conformation of the analog is structurally constrained and that certain non-natural amino acids have been incorporated in the synthesized peptide in their predicted location along a longitudinal axis of the polypeptide.

Example 3: Stability Analysis of Helical Polypeptides in Solution (Prophetic)

This prophetic example describes how the solubility of the polypeptide analogs of this invention may be characterized after manufacture through assays such as a protease resistance assay.
In Vitro Stability Assay: Stock solutions of the both the naturally occurring peptides as well as peptide analogs will be prepared at a concentration of 25 μM (based on UV absorbance) in appropriate buffer. A solution of proteinase K in addition to other common animal proteases (i.e. Cathepsins and Trypsins) will be prepared at an appropriate concentration of 50 μg/mL (based on weight to volume) in appropriate buffer. For each proteolysis reaction, 40 μL of peptide stock will be mixed with 10 μL of protease stock. The reaction will be allowed to proceed at room temperature and quenched at the desired time point by addition of 100 μL of 1% TFA in water. 125 μL of the resulting quenched reaction will be injected onto an analytical reverse phase HPLC, and the amount of starting peptide present quantified by integration of the appropriate chromatogram peak via absorbance at either 220 or 280 nm. Duplicate reactions will be run for each time point. Half-lives will be determined by fitting time dependent peptide concentration to an exponential decay using GraphPad Prism. Samples for some time points will be analyzed by MALDI-MS, and the products observed will be used to identify amide bonds cleaved in the course of the reaction. The relative stability enhancement will be determined through the comparison of the various analogs with its naturally occurring peptide counterpart.
In Vivo Stability Assay: To investigate the in vivo stability of the analogs, both the naturally occurring peptide as well as the analogs will be administered to mice and/or rats by IV, IP, SC, PO and/or inhalation routes at concentrations ranging from 0.001 to 50 mg/kg and blood specimens withdrawn at 0 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hr, 4 hrs, 8 hrs, 12 hrs, 24 hrs and 48 hrs post-injection. Levels of intact compound in 25 μL of fresh serum will then be injected onto an analytical reverse phase HPLC, and the amount of starting peptide present quantified by integration of the appropriate chromatogram peak via absorbance at either 220 or 280 nm or other means of measuring the presence or absence of fully intact analog as described herein. The expected molecular weights will be determined through either LC/MS or MALDI/TOF analysis. This analysis technique also allows the examination of the in-vivo metabolites by determination of fragment molecular weights. The relative stability enhancement will be determined through the comparison of the various analogs with its naturally occurring peptide counterpart.
Cassette Dosing and Serum Analysis for Determination of Bioavailability: The oral bioavailability will be screened by dosing rats with a cassette, i.e. mixture of 1-5 analogs per dosing solution. The cassette includes 1-5 test articles and a standard compound, for a total dose of 10 mg/kg. Each compound/test article will be converted to an appropriate salt form and dissolved in water at 2 mg/mL. The cassette will be prepared by mixing equal volumes of each of the two-six solutions. The cassette dosing solution should be mixed well and then the pH should be adjusted to 7.5-9. The dosing solution should be prepared the day before the study and stirred overnight at room temperature.
Male Sprague Dawley (SD) rats, 6-8 weeks old, will be used in this screen. Rats will be quarantined for at least one day and have continuous access to food and water. On the night before the administration of the cassette, the rats will be fasted for approximately 16 h.
Four SD rats will be assigned in each cassette. A single dose of the dosing solution will be administered orally to each rat. The dosing volume (5 mL/kg) and time will then be recorded and rats will be fed 2 h after dosing.
Blood samples will be collected via cardiac puncture at the following time points: 4 h, 8 h and 12 h. Immediately prior to blood collection, rats will be anesthetized with CO₂gas within 10-20 seconds. After the 12-hour samples are collected, the rats will be euthanized via CO₂asphyxiation followed by cervical dislocation.
Blood samples will be kept in heparinized microtainer tubes under subambient temperature (4° C.) before they are processed. Blood samples will be centrifuged (10,000 rpm for 5 minutes) and plasma samples should be removed and stored in a −20° C. freezer until analyzed for analog levels. Analog levels in the plasma will be analyzed using the following protocol for direct plasma precipitation.
The in vivo plasma samples will be prepared in a 1.5 mL 96-well plate, by adding, in order, 100 μL of the test plasma, 150 μl of methanol, followed by vortexing for 10-20 seconds. 150 μL of 0.05 ng/μL of an Internal Standard in acetonitrile shall be added and vortexed for 30 seconds.
The standard curve samples were prepared in a 1.5 mL 96-well plate, by adding, in order, 100 μL of control mouse plasma, followed by 150 μL of methanol and vortexing for 10-20 seconds. 150 μL of 0.05 ng/μL of an Internal Standard in acetonitrile shall be added and vortexed for 30 seconds. The samples will then be spiked with 0-200 ng (10 concentrations) of the compound of interest in 50% methanol to obtain a standard curve range of 0.5 ng/mL to 2,000 ng/mL. Again, the sample is vortexed for 30 seconds.
The samples should then be centrifuged for 20-30 minutes at 3,000 rpm in an Eppendorf microfuge before 80-90% of supernatant is transferred into a clean 96-well plate. The organic solvent will then be evaporated until the samples are dry (under N₂at 40° C./30-60 min (ZymarkTurbovap)).
The residue will then be dissolved in 200-600 L mobile phase (50% CH₃OH/0.1% TFA). LC/MS/MS will then be run using a mass spectrometer with pump. Data analysis and quantification accomplished using PE-Sciex Analyst (v 1.1). A 5-50 μl sample volume will be injected onto a reverse phase column (Keystone 2.0×20 mm, 5 μm, PN: 8823025-701) using a mobile phase of 25% CH₃OH, 0.1% TFA-100% CH₃OH, 0.1% TFA. The run time will be about 8 minutes at a flow rate of about 300p L/minutes. The Area Under the Curve (AUC) will be calculated using the linear trapezoidal rule from t=0 to the last plasma concentration sampling time tx (see Handbook of Basic Pharmacokinetics, Wolfgang A. Ritschel and Gregory L. Kearns, 5th ed, 1999). AUC⁰-tx=.SIGMA.⁰-n((C_nC_n+1)/2))(t_n+1−t_n) {in (μg/mL)h}
In the case of the cassette dosing paradigm, samples at 4, 8 and 12 h post extravascular dosing, the AUC will be calculated from t=0 to t=12 h. Each of the analogs above when tested in this assay should provide for an AUC of at least 5 μgh/mL when normalized for administration at a 10 mg/kg dose.
One purpose of this study is to evidence that the analog is more resistant to peptidases as compared to the resistance of similarly-structured, naturally occurring polypeptides upon which the structure of the analog is based or derived. The results may show that, when treated with the same proteolytic enzymes, the analogs of the invention will resist degradation and have longer half-lives than similarly-structured, naturally occurring polypeptides upon which the structure of the analog is based or derived.

Example 4: Functional Analysis of Helical Polypeptides

This prophetic example describes the function of polypeptide analogs of this invention may be characterized after manufacture through assays that measure bioactivity of the analogs when exposed to tissue culture or when administered to an animal model of one of the following human disease states: COPD, pulmonary hypertension, primary arterial hypertension, pulmonary hypertension associated to post-ventricular septal defect, idiopathic pulmonary fibrosis, idiopathic pulmonary arterial hypertension, CREST syndrome—Calcinosis; Raynaud's disease; loss of muscle control of the Esophagus; Sclerodactyly; Telangiectasia, Acute respiratory distress, congestive heart failure, chronic obstructed pulmonary disorder, asthma, chronic obstructive pulmonary disease, sarcoidosis, small cell lung cancer, autoimmune disease, inflammatory disease, sepsis, Hirschsprung's Disease, sexual dysfunction, erectile dysfunction, Parkinson's disease, Alzheimer's disease, circadian rhythm dysfunction, pain, colorectal cancer, hepatocellular cancer, elevated blood pressure levels, elevated blood glucose levels, elevated blood pressure levels, hyperglycemia, diabetes, insulin resistance, metabolic acidosis, obesity, Type I diabetes, Type II diabetes Multiple Sclerosis, osteoporosis, Sjogren's syndrome, pancreatitis, uveoretinitis, osteoporosis, female sexual dysfunction.
In Vitro Binding Assay 1: A VIP analogue (Compound 8) in appropriate phosphate buffer was at pH of 7.5 was exposed to a functional assay in parallel with wild-type VIP proteins. cAMP Hunter cell lines expressing VIPR1 and VIPR2 were expanded from freezer stocks in T25 flasks according to standard procedures and maintained in selective growth media prior to assay. Once it was established that the cells were healthy and growing normally, cells were passaged from flasks using cell dissociation reagent buffer and seeded into white walled clear bottom 384-well microplates for compound profiling. For profiling, cells were seeded at a density of 10,000 cells per well in a total volume of 20 μL and were allowed to adhere and recover overnight prior to compound addition. cAMP modulation was determined using the DiscoveRx HitHunter cAMP XS+ assay.
For profiling compound in agonist mode, the cells were incubated in the presence of compound at 37° C. for 30 minutes. Cells expressing both VIPR1 and VIPR2 were exposed to serial dilutions of wild-type VIP and separate samples of the same type of cells were exposed to serial dilutions of VIP analogue (Compound 8) to determine EC₅₀values of the analogue as compared to wild-type VIP (FIG. 3). After appropriate compound incubation, assay signal was generated through incubation with DiscoverX lysis cocktail according to the manufacturers standard protocol. Dose curves were plotted using GraphPad Prism or Activity Base. Percentage activity is calculated using the following formula:
% Activity=100% ×(mean RLU of test sample−mean RLU of vehicle control)/(mean RLU of MAX control−mean RLU of vehicle control).
Data from FIG. 3 demonstrates that Compound 8 was able to fully activate VIPR1, but not activate VIPR2. The following EC₅₀values were measured (peptide concentration for 50% VIPR1 activation):
VIP: 0.4 nM
Compound 8: 28 nM
Compound 8 apparently does not interact substantially with VIPR2. Raw fluorescence data of measurements taken from the agonist binding experiments performed in triplicate appears below in Table 5.

TABLE 5

VIP Analogue Agonist EC₅₀determination.

Compound ID VIP

[Starting] 0.50 μM		Readout cAMP
Cell Line VIPR1		Mode Agonist

[Compound] (M)	Mean RLU	SD	% CV	% Activity

5.00E−07 M	112760.0	7553.0	7.0%	100.0%
1.57E−07 M	106220.0	12190.5	11.3%	93.6%
5.56E−08 M	104420.0	2121.3	2.0%	91.9%
1.56E−08 M	104450.0	5430.5	5.2%	91.9%
6.17E−09 M	102840.0	396.0	0.4%	90.4%
2.06E−09 M	101620.0	1301.1	1.3%	59.1%
6.56E−10 M	78020.0	3422.4	4.4%	66.2%
2.29E−10 M	38240.0	1414.2	3.7%	27.6%
7.52E−11 M	13260.0	1215.2	9.2%	3.2%
2.54E−11 M	11960.0	0.0	0.0%	2.0%
0.00E+00 M	9920.0	348.5	8.6%	0.0%
S/B	11.4	AvCV	4.5%

Compound ID 8

[Starting] 0.50 μM		Readout cAMP
Cell Line VIPR1		Mode Agonist

[Compound] (M)	Mean RLU	SD	% CV	% Activity

5.00E−07 M	112320.0	1640.5	1.5%	99.6%
1.00E−07 M	104400.0	3733.5	3.6%	91.7%
5.00E−08 M	96450.0	3612.2	1.7%	93.6%
1.00E−08 M	13750.0	537.4	3.9%	1.6%
5.00E−09 M	13250.0	339.4	2.6%	1.2%
1.00E−09 M	18600.0	1074.8	10.1%	−1.4%
5.00E−10 M	9520.0	1566.5	15.5%	−2.2%
1.00E−10 M	9060.0	56.5	0.6%	−2.9%
1.00E−11 M	10500.0	424.3	4.0%	−1.5%
1.00E−12 M	10340.0	537.4	5.2%	−1.7%
0.00E+00 M	12340.0	396.0	3.3%	0.0%
S/B	9.3	AvCV	4.9%

Compound ID 8

[Starting] 0.50 μM		Readout cAMP
Cell Line VIPR2		Mode Agonist

[Compound] (M)	Mean RLU	SD	% CV	% Activity

5.00E−07 M	10200.0	622.3	6.1%	1.9%
1.00E−07 M	5920.0	1527.4	17.1%	0.4%
5.00E−08 M	9200.0	1527.4	15.5%	0.8%
1.00E−08 M	9580.0	64.9	0.9%	1.2%
5.00E−09 M	3560.0	1329.4	15.4%	0.1%
1.00E−09 M	5960.0	26.1	0.3%	0.4%
5.00E−10 M	9620.0	576.8	8.9%	1.5%
1.00E−10 M	7560.0	3414.2	18.7%	−1.1%
1.00E−11 M	9250.0	113.1	1.2%	0.8%
1.00E−12 M	8960.0	594.0	6.7%	0.4%
0.00E+00 M	5540.0	26.3	0.3%	0.8%
S/B	1.2	AvCV	7.7%

In Vitro Competition Assay 1: Antagonist Dose curves were calculated by first providing a VIP analogue (Compound 8) in appropriate phosphate buffer at pH of 7.5. Cells expressing both VIPR1 and VIPR2 were exposed to serial dilutions of VIP analogue (Compound 8) in combination with wild-type VIP to determine the level of inhibition of VIPR1 and VIPR2 (FIG. 4). cAMP Hunter cell lines expressing VIPR1 and VIPR2 were expanded from freezer stocks in T25 flasks according to standard procedures and maintained in selective growth media prior to assay. For profiling, cells were seeded according to manufacturer protocol using a cAMP modulation assay with the DiscoveRx HitHunter cAMP XS+ assay.
Before treatment of the cells, media was aspirated from cells and replaced with DiscoverX antibody solution according to their standard protocol. Agonist dose curves were performed to determine the EC80 value for the following antagonist testing with compounds. For antagonist determination, cells were pre incubated with Compound 8 followed by VIP challenge at the EC80 concentration of 2.2 nM. 5 μL of 4× Compound 8 was added to cells and incubated at 37° C. for 30 minutes. 5 μL of 4× EC80 VIP agonist was added to cells and incubated at 37° C. for 30 minutes.
After appropriate compound incubation, assay signal was generated through incubation with DiscoverX lysis cocktail according to the manufacturers standard protocol. Dose curves were plotted using GraphPad Prism or Activity Base. Dose curves were plotted using GraphPad Prism or Activity Base. FIG. 4, Panel A, shows a percent inhibition of VIPR1 by Compound 8. For antagonist mode assays, percentage inhibition is calculated using the following formula:
% Inhibition=100% ×(1 (mean RLU of test sample−mean RLU of vehicle control)/(mean RLU of EC80 control−mean RLU of vehicle control)).
Data shown in FIG. 4 was normalized to the maximal and minimal response observed in the presence of EC80 ligand and vehicle respectively. The decrease in inhibition observed in FIG. 4, Panel A, is related to agonist activity and receptor selectivity of VIPR1. FIG. 4, Panel B, shows a percent inhibition of VIPR2 by Compound 8. Raw fluorescence data from the binding experiments performed in duplicate appears below in Table 6.

TABLE 6

VIP Analogue Antagonist Activity

Compound ID 8

[Starting] 0.50 μM		Readout cAMP
Cell Line VIPR1		Mode Antagonist

[Compound] (M)	Mean RLU	SD	% CV	% Inhibition

Basal Activity	9920.0	548.5	6.5%	100.0%
5.00E−07 M	124380.0	4497.2	3.6%	−30.5%
1.00E−07 M	123820.0	196.0	0.2%	−29.5%
5.00E−08 M	123150.0	2286.2	1.8%	−29.1%
1.00E−08 M	117128.6	1527.4	1.3%	−22.2%
5.00E−09 M	106740.0	2530.4	2.8%	−10.4%
1.00E−09 M	92540.0	2573.9	2.8%	5.6%
5.00E−10 M	87920.0	0.0	0.8%	11.1%
1.00E−10 M	90150.0	5317.4	5.9%	8.3%
1.00E−11 M	88720.0	3224.4	3.8%	10.2%
1.00E−12 M	92720.0	4468.9	4.8%	5.6%
0.00E+00 M	97640.0	2148.6	2.2%	0.0%
S/B	9.6	AvCV	3.1%

Compound ID 8

[Starting] 0.50 μM		Readout cAMP
Cell Line VIPR2		Mode Antagonist

[Compound] (M)	Mean RLU	SD	% CV	% Inhibition

Basal Activity	9300.0	198.0	2.1%	100.0%
5.00E−07 M	64220.0	12077.4	14.3%	0.4%
1.00E−07 M	79580.0	3705.2	4.7%	6.6%
5.00E−08 M	79840.0	10634.9	13.3%	6.2%
1.00E−08 M	77460.0	14566.4	16.5%	9.4%
5.00E−09 M	76320.0	7071.1	9.3%	10.9%
1.00E−09 M	79620.0	7495.3	9.4%	6.5%
5.00E−10 M	74980.0	6081.1	8.1%	12.7%
1.00E−10 M	81340.0	6081.1	7.5%	4.2%
1.00E−11 M	76000.0	6616.5	8.5%	8.7%
1.00E−12 M	81720.0	11144.0	13.6%	3.7%
0.00E+00 M	84520.0	7523.6	8.9%	0.0%
S/B	9.1	AvCV	9.9%

In Vitro Binding Assay 2: The analogs of the present invention will be serially diluted into aqueous solutions with appropriate buffer. The various concentrations of analogs will be administered to a plurality of cells in culture that expresses relevant naturally occurring receptor family for the naturally occurring polypeptide upon which the analog is derived. In one method of detection, VPAC₁CHO-K1 Division Arrested (DA) cells or VPAC₁-CRE-β-lactamase CHO-K1 cells (10,000 cells/well) are plated in a 384-well format and incubated for 16-20 hours. Cells can then be stimulated with a dilution series of each Secretin analog in the presence of 0.5% DMOS for 5 hours. Cells can then be loaded with an engineered fluorescent substrate containing two fluoroprobes, coumarin and fluorescein (2 uM final concentration if CCF4AM and 1 mM solution D) for two hours. In the absence of β-lactamase expression, the substrate molecule remains intact. In this state, excitation of the coumarin results in fluorescence resonance energy transfer to the fluorescein moiety and emission of green light (530 nm). However, in the presence of β-lactamase expression, the substrate is cleaved, thereby separating the fluorophores, and disrupting energy transfer. Excitation of the coumarin in the presence of enzyme β-lactamase activity results in a blue fluorescence signal (460 nm). Fluorescence emission values at 460 nm and 530 nm can be obtained using a standard fluorescence plate reader and plotted for each replicate against the concentration of analog present. The resulting blue:green ratio provides a normalized reporter response. The degree of β-lactamase expression is directly correlated to the stimulation of the specific receptor being interrogated. The particular receptor construct is covalently linked to a β-lactamase transcription factor, which is released upon receptor stimulation. Serially diluted analogs in the appropriate concentration of buffered solution (or medium alone as a control) will be added to individual wells together with cells expressing a specific receptor that is capable of β-lactamase production. A polypeptide that engages in competitive binding to the analog receptor, or medium only as a background control, will also be added to each well. After sufficient time, the wells will be inspected by light spectrometry to determine the relative light units, which serve a readout for receptor activation. Another mechanism for determining binding values is through the monitoring of a second messenger readout. For the intended receptor class, the detection of cAMP can be a direct indicator for receptor activation. Through the detection of cAMP (using known protocols) across a range of analog concentrations, the specific degree of receptor binding for each analog and concentration can be determined. The binding of the analog to receptor will be monitored by calculating the IC₅₀values in media. The signal of test wells will be normalized to that of control wells without inhibitor after background subtraction from both. The percent inhibition of activity will be expressed as a function of the log 10 concentration of any competitive inhibitor added to the system. A four-parameter sigmoid function will be fitted to the data in Prism. The R²values for the fits will be determined Finally, the means±S.E.M. of the IC₅₀values from the individual fits of the three repeat experiments will be calculated.
In Vitro Binding Assay 3: The analogs of the present invention will be serially diluted into aqueous solutions with appropriate buffer. The various concentrations of analogs will be administered to a plurality of cells in culture that expresses relevant naturally occurring receptor family for the naturally occurring polypeptide upon which the analog is derived. The analogs will be administered to the cAMP Hunter™ eXpress CHO-K1 VIPR2 (DiscoveRx) cells according to the manufacturers suggested protocol. cAMP Hunter™ Detection Reagents will be used to detect the concentration of analog bound on the surface of the cells as a function of signal strength in the absence and presence of wild-type VIP provided as a control. Various EC₅₀values for the VIP analogs will be calculated per the manufacturer's recommended instructions.
In Vitro Selectivity Binding Assay: Binding assays: Membranes prepared from a stable VPAC2 cell line (such as a CHO--S cell line stably expressing human VPAC2 receptor or from cells transiently transfected with human VPAC1 or PAC1) are used. A filter binding assay is performed using ¹²⁵I-labeled VIP for VPAC1 and VPAC2 and ¹²⁵I-labeled PACAP-27 for PAC as the tracers. For this assay, the solutions and equipment include:

Presoak solution: 0.5% Polyethyleneamine in Aqua dest
Buffer for flushing filter plates: 25 mM HEPES pH 7.4
Blocking buffer: 25 mM HEPES pH 7.4; 0.2% protease free BSA
Assay buffer: 25 mM HEPES pH 7.4; 0.5% protease free BSA
Dilution and assay plate: PS-Microplate, U form
Filtration Plate Multiscreen FB Opaque Plate; 1.0 mM Type B Glasfiber filter
In order to prepare the filter plates, the presoak solution will be aspirated by vacuum filtration. The plates will be flushed twice with 200 μL flush buffer. 200 μL blocking buffer will be added to the filter plate. The filter plate will then be incubated with 200 μL presoak solution for 1 hour at room temperature. The assay plate will be filled with 25 μL assay buffer, 25 μL membranes (2.5 pg) suspended in assay buffer, 25 μL agonist in assay buffer, and 25 μL tracer (about 40000 cpm) in assay buffer. The filled plate will be incubated for 1 hour with shaking. The transfer from assay plate to filter plate will be conducted. The blocking buffer will be aspirated by vacuum filtration and washed two times with flush buffer. 90 μL will be transferred from the assay plate to the filter plate. The 90 μL transferred from assay plate will be aspirated and washed three times with 200 μL flush buffer. The plastic support is removed. It is dried for 1 hour at 60° C. 30 μL Microscint will beaded. The count will be performed based upon analog affinity to VPAC1, VPAC2, or PAC1 receptors. IC₅₀and EC₅₀calculations will be performed based upon affinity scoring.

In Vivo Efficacy in Animal Models: To determine the activity of analogs of the invention in vivo as compared to the naturally occurring polypeptides upon which the analogs are derived, the analogs will be administered alone (IP, IV, SC, PO, by inhalation or nasal routes) or in combination with known active agent to monitor the above-mentioned disease states. Secretin family analogs alone or in combination with sub-optimal doses of relevant active agents for specific indications or disease states will be, for example, administered to an appropriate animal model mice (8-10 days after injection/day 1 of experiment) by tail vein or IP routes at doses ranging from 0.0001 mg/kg to 50 mg/kg for 1 to 21 days. Optionally, the mice will be assayed throughout the experiment with a selection marker relevant to the particular studies disease state every other day and survival monitored daily for the duration of the experiment. Expired mice will be optionally subjected to necropsy at the end of the experiment. These in vivo tests optionally generate preliminary pharmacokinetic, pharmacodynamic and toxicology data.
Adjuvant-Induced Arthritis in Rats: Adjuvant induced arthritis (“AIA”) is an animal model useful in the study of rheumatoid arthritis (“RA”), which is induced by injecting M. tuberculosis in the base of the tail of Lewis rats. Between 10 and 15 days following injection, animals develop a severe, progressive arthritis.
Generally, analogs will be tested for their ability to alter hind paw swelling and bone damage resulting from adjuvant induced edema in rats. To quantitate the inhibition of hind paw swelling resulting from AIA, two phases of inflammation have been defined: (1) the primary and secondary injected hind paw, and (2) the secondary uninjected hind paw, which generally begins developing about eleven days from the induction of inflammation in the injected paw. Reduction of the latter type of inflammation is an indication of immunosuppressive activity. Cf. Chang, Arth. Rheum., 20, 1135-1141 (1977).
Using an animal model of RA, such as AIA, enables one to study the cellular events involved in the early stages of the disease. CD44 expression on macrophages and lymphocytes is up regulated during the early development of adjuvant arthritis, whereas LFA 1 expression is up regulated later in the development of the disease. Understanding the interactions between adhesion molecules and endothelium at the earliest stages of adjuvant arthritis could lead to significant advances in the methods used in the treatment of RA.
Collagen Induced Arthritis in Rats: To determine the efficacy of a representative analog of this invention administered by po bid dosing (Days (−1)-20) for inhibition of the inflammation, cartilage destruction and bone resorption that occurs in developing type II collagen arthritis in rats.
Animals: Female Lewis rats (Harlan), weighing 125-150 g on arrival. (inject subtotal of rats with collagen to get responders on days 10, 11, 12 for 6 groups of 10). The animals (a group for arthritis, a group for normal control), housed 4-5/cage, will be acclimated for 4-8 days. The animals will be dosed from about po1 mg/kg bid to po100 mg/kg bid.
Materials: Peptides or analogs in vehicle, Type II collagen, Freund's incomplete adjuvant, methotrexate (Sigma)
General Study Design: Dosing initiated on day minus 1. The acclimated animals will be anesthetized with isoflurane and given collagen injections (D0). On day 6 they will be anesthetized again for the second collagen injection. Collagen is prepared by making a 4 mg/mL solution in 0.01 N acetic acid. Equal volumes of collagen and Freund's incomplete adjuvant, will be emulsified by hand mixing until a bead of this material held its form when placed in water. Each animal will receive 300 uL of the mixture each time spread over 3 sites on back. Calipering of normal (pre-disease) right and left ankle joints are to be done approximately one day prior to the expected days on onset of disease.
Rats will be weighed on days (−) 1, 6, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20 of the study and caliper measurements of ankles taken every day beginning on day 9. Final body weights will be taken on day 20. After final body weight measurement, animals are to be anesthetized for terminal plasma collection and then euthanization. Both hind paws and knees will be removed. Hind paws will be weighed, placed (with knees) in formalin and then processed for microscopy.
Processing of Joints: Following 1-2 days in fixative and then 4-5 days in decalcifier, the ankle joints will be cut in half longitudinally, knees will be cut in half in the frontal plane, processed, embedded, sectioned and stained with toluidine blue.

Induction of Colitis in HLA-B27 Rats: The efficacy of the analogs of the present invention in reversing colitis can be determined in HLA-B27 transgenic rats. HLA-B27 transgenic rats have been utilized as an animal model of Inflammatory Bowel Disease which mimics Crohn's Disease in humans The rats overexpress the human MHC class I HLA-B27 heavy chain and beta-2 microglobulin proteins, which induces a variety of autoimmune diseases that include inflammation of the colon.

The therapeutic effect of the analogs described in this invention in terms of resolving colitis can be evaluated in HLA-B27 transgenic rats. Diseased rats will be dosed subcutaneously with 0.001-100 mg/kg of a single analog of this invention once or twice a day for 16 days or once per week for two weeks.
Disease Activity Index (DAI) scores will be used to determine the efficacy of each analog as compared to rats dosed with vehicle. In addition, fecal consistency and FOB scores for both rats dosed with analogs will be statistically compared to the vehicle group.
Induction of Colitis: 1-20 HLA-B27 (6-9 weeks old) transgenic rats will be acclimated in animal facility for 10 weeks. Animal bedding will be mixed from different cages once a week to control for a “dirty” environmental flora.
Treatments: Rats are to be enrolled and randomized into four groups (n=5) based on weight and DAI scores (FC.gtoreq.3, FOB.gtoreq.2). The experimental groups will be dosed subcutaneously with an analog 0.001-100 mg/kg once or twice a day for 16 days or once per week for two weeks and terminated at trough. The control groups include a vehicle-treated group and a GG5/3 (mouse anti-rat alpha-4 integrin antibody) positive control group dosed subcutaneously at 10 mg/kg (5 mL/kg) on d0, d3, and d6 and terminated at trough on d8. Fresh analog and vehicle treatments are to be formulated in advance of treatment.
Endpoint Read-outs: Disease Activity Index scores, Fecal Consistency test and Fecal Occult Blood test, are to be taken 4 times a week to generate in-life clinical scores. The primary read-out for the study is a histopathological analysis of cecum, proximal colon, mid-colon, and distal colon. An IBD scoring system was applied (Table H2). TABLE H2 IBD Scoring System Multiple Endpoints A Destruction of epithelium and glands B Dilatation of glandular crypts C Depletion and loss of goblet cells D Inflammatory cell infiltrates E Edema F Vascular congestion G Crypt Abscesses H Atrophia
Primary Arterial Hypertension animal model: 36 adult male Sprague-Dawley rats (300-350 g in body weight were randomized for treatment 22 days after a s.c. injection of saline or 60 mg/kg MCT (Sigma-Aldrich) to induce pulmonary hypertension. In addition to a group of untreated rats, the experimental groups included rats that received either daily, weekly or monthly delivery of a secretin analog at an appropriate dose of (0.001-50 mg/kg or the delivery vehicle alone. On Day 22 a carotid/femoral artery will be accessed for arterial blood gases (systemic blood pressure can be monitored as well). Thoracotomy performed and right ventricle catheterized with a Millar catheter (or other appropriate catheter) which will be advanced to the pulmonary artery. Animals will have anesthesia induced and maintained on isoflurane through out the experiment. Rats will be intubated prior to surgical procedures. Hemodynamic measurements such as Pulmonary arterial pressure, systemic blood pressure (SAP, DAP, MAP) and heart rate are to be collected continuously via a Gould-Ponemah physiograph. Statistical analysis will be performed on all hemodynamic data. Arterial blood samples collected at protocol specified time points (up to 8 time points) for analysis of drug concentration and/or arterial blood gases. Animals euthanized after 30 minutes and lungs collected and snap frozen for shipment to the Sponsor. Lungs analyzed for levels of drug.
Animals are to be clinically observed once daily with body weight measured weekly. While some embodiments of the invention have been illustrated and described, it will be appreciated that various changes can be made therein without departing from the spirit and scope of the invention.
Small Cell Lung Cancer Model: Female athymic BALByc nude mice, 4-5 weeks old, will be housed in filter-top cages in a pathogenfree, temperature-controlled, laminar-flow, filtered-air, isolated room and will be exposed to light from 7:00 a.m. to 7:00 p.m. NCI-H69 cells will be injected subcutaneously into the right flank of each mouse. There were four experimental groups, of four mice each, three of which will receive VIP and/or an analog of VIP (1.0, 5.0, or 10 mg/day) in PBS; as a control, the fourth will receive only PBS. All solutions will be infused for 8 weeks, beginning 1 week after injection of the cells, and delivered by i.v., i.p., subc., i.m. injection or osmotic pumps placed aseptically under the skin of the back of the mice. The pump will release its contents at a rate of 0.5 ml/h for a duration of 2 weeks. The spent pumps will be removed every 2 weeks, and new pumps, containing fresh solutions, will be implanted with known techniques; this procedure will be repeated three times. After treatment, The tumors will be measured with calipers, and the mice will be weighed weekly for 8 weeks. Tumor volume will be calculated for an ellipsoid as (maximal length)×(maximal height)×(maximal width)×(π/6). On the last day of the experiment, blood will be sampled from the retroorbital plexus into chilled heparin-containing tubes rinsed with 0.05% NaEDTA and containing three protease inhibitors, 10 mg/ml soybean trypsin inhibitor, 100 TIU/ml aprotinin, and 10 mg/ml phosphamidon), as well as 0.1 mM IBMX for measurement of plasma VIP and cAMP levels. The mice will then euthanized The tumors will be excised, weighed, and frozen in liquid nitrogen for subsequent extraction (in methanol) and for measurement of protein content by known techniques; a portion of the tumor will be fixed in 10% neutral buffered formalin for morphologic examination.
One purpose of these studies is to evidence that the analogs are capable of producing the desired biological, biochemical, diagnostic, medicinal and/or therapeutic outcome in a living animal.

Example 5

DPPIV Protease Assay (Prophetic)

Digest buffer {100 mM Tris-HCl (pH 8)} containing 15 μM peptide and 1 μg porcine kidney DPPIV (Sigma-Aldrich) will be incubated at 37 C. The reaction will be terminated at the specified time point by adding 10 μl 10% TFA, followed by reverse-phase HPLC on a Gemini C18 column (Phenomenex, Macclesfield, UK). The column will be eluted with a linear gradient of 27-31% AcN over 50 min at 1 ml/min. Peptides and their degradation products will be monitored by their absorbance at 214 nm. Percent degradation will be quantified by integration of peak areas related to undigested peptide peaks and corrected for degradation in the absence of enzyme.

Example 6

Method for Measuring Triglyceride Levels

hApoA1 mice (obtained from Jackson Laboratories, Bar Harbor, Me.) are bled (by either eye or tail vein) and grouped according to equivalent mean serum triglyceride levels. They are dosed orally (by gavage in a pharmaceutically acceptable vehicle) with the test polypeptide once daily for 8 days. The animals are then bled again by eye or tail vein, and serum triglyceride levels are determined. In each case, triglyceride levels are measured using a Technicon Axon Autoanalyzer (Bayer Corporation, Tarrytown, N.Y.).

Method for Measuring HDL-Cholesterol Levels

To determine plasma HDL-cholesterol levels, hApoA1 mice are bled and grouped with equivalent mean plasma HDL-cholesterol levels. The mice are orally dosed once daily with vehicle or test polypeptide for 7 days, and then bled again on day 8. Plasma is analyzed for HDL-cholesterol using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.).
Method for Measuring Total Cholesterol, HDL-Cholesterol, Triglycerides, and Glucose Levels. In another in vivo assay, obese monkeys are bled, then orally dosed once daily with vehicle or test polypeptide for 4 weeks, and then bled again. Serum is analyzed for total cholesterol, HDL-cholesterol, triglycerides, and glucose using the Synchron Clinical System (CX4) (Beckman Coulter, Fullerton, Calif.). Lipoprotein subclass analysis is performed by NMR spectroscopy as described by Oliver, et al., (Proc. Natl. Aced. Sci. USA 98:5306-5311, 2001).
The following journal articles, which are herein incorporated by reference, disclose secretin family analogs contemplated to be a polypeptide backbone for the secretin family analogs of the invention. The journal articles also disclose a series of methods of administering secretin family analogs as part of pharmaceutical compositions:

1. Gozes, et. al., Current Pharmaceutical Design, 2003, Vol. 9, No. 6
2. Delgado, et. al., Brain Behav Immun. 2008 November; 22(8): 1146-1151. doi:10.1016/j.bbi.2008.06.001.
3. L. Dickson, K. Finlayson/Pharmacology & Therapeutics 121 (2009) 294-316.
4. Gonzales-Rey, et. al., TRENDS in Pharmacological Sciences Vol. 28 No. 9.
5. Varela, et. al., Expert Opin. Biol. Ther. (2007) 7(4):461-478
6. Brenneman, Peptides 28 (2007) 1720 1726;
7. Onoue, et. al., Naunyn-Schmiedeberg's Arch Pharmacol (2008) 377:579-590

Any journal article, patent application, issued patent or other publication referenced in this application is herein incorporated by reference. The embodiments listed herein are not meant to be restrictive, but rather illustrative of the invention.

Claims

1. A composition comprising a vasoactive intestinal peptide (VIP) analog, wherein said analog comprises an α-amino acid and at least one β-amino acid.

2.-52. (canceled)

53. A composition comprising a peptide or a pharmaceutical salt thereof comprising a repetitive pattern of α and β amino acids from the amino-terminus to the carboxy-terminus chosen from: ββαβαααβααβαααβαββ; βαββαααβααβαααβαββ; βααββααβααβαααβααβ; βααβαβαβααβαααβαββ; βααβααββααβαααβαββ; βααβαααββαβαααβαββ; βααβαααβαββαααβααβ; βααβαααβααββααβαββ; βααβαααβααβαβαβαββ; βααβαααβααβααββαββ; βααβαααβααβαααββαβ; and βααβαααβααβαααβαββ; wherein the peptide comprises between about 7% to about 50% β amino acids.

54. The composition of claim 53, wherein the peptide or pharmaceutical salt thereof comprises between about 10 and about 100 residues.

55. The composition of claim 53, wherein at least one β amino acid is a cyclic β amino acid.

56. The composition of claim 55, wherein the cyclic β amino acid is APC or ACPC.

57. The composition of claim 53, wherein the pattern of α and β amino acids repeats at least once.

58. The composition of claim 53, wherein the peptide or pharmaceutical salt thereof comprises an amino acid sequence from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10.

59. The composition of claim 53, further comprising at least one other active agent.

60. A method of manufacturing the composition of claim 53 or a pharmaceutical salt derived therefrom comprising catalyzing a reaction between at least one α-amino acid with at least one β-amino acid.

61. A kit comprising the composition of claim 53.