Calcitonin gene-related peptide analogs

Abstract

Provided are calcitonin gene-related peptide (CGRP) analogs that are potent agonists of the CGRP receptor.

Description

Technical Field

[0001] This invention relates to CGRP peptide analogs as CGRP receptor agonists. Background Technology

[0002] Calcitonin gene-related peptide (CGRP) is a neuropeptide widely recognized for its key roles in various physiological processes such as vasodilation, neurotransmission regulation, and nociception.

[0003] CGRP is a member of the calcitonin peptide family. The main CGRP receptor is formed by the co-expression of a calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein-1 (RAMP1). These receptors are distributed throughout the cardiovascular system, particularly in blood vessels. Although CGRP has been identified as a potent vasodilator, there is limited evidence that sufficient endogenous CGRP is released to affect physiological blood pressure regulation, despite the presence of CGRP-containing nerves surrounding all cardiovascular tissues. CGRP receptor antagonists and antibodies developed as migraine treatments have minimal effects on blood pressure in healthy individuals. Evidence for the role of CGRP in cardiovascular protection comes from studies administering CGRP in hypertensive rodent models. Therefore, CGRP is known as a potent vasodilator that can lower blood pressure, and thus may be used to treat hypertension and potentially provide benefits for hypertension-driven heart disease.

[0004] Literature indicates that CGRP, in addition to vasodilation, possesses various pharmacological effects. It triggers activation of AMP kinase (AMPK) in muscle and liver, leading to lipolysis and / or lipid oxidation, reducing food intake, inhibiting gastric emptying, altering intestinal function, and increasing glycolysis while inhibiting glycogen synthesis. The net physiological significance of these effects is not fully understood. AMPK activation, lipid oxidation, and reduced food intake may be beneficial for metabolic diseases, while glycolysis and inhibition of glycogen synthesis are thought to mediate insulin resistance.

[0005] The clinical applicability of natural CGRP is limited by challenges related to its pharmacokinetics, stability (short half-life), and off-target effects. Therefore, ongoing efforts are underway to identify CGRP analogs with improved properties. Acylated CGRP compounds with extended activity are disclosed, for example, in WO 2011 / 051312. Acylation is known to increase half-life, but at the cost of reduced potency of the acylated compound.

[0006] CGRP analogues in this field have different pharmacological characteristics, and altering or removing amino acids from the N-terminal portion of CGRP1-37 is largely known to produce CGRP receptor antagonists (e.g., CGRP receptor antagonists). 8-37 CGRP 12-37 CGRP 27-37 ). Summary of the Invention

[0007] The inventors have developed CGRP peptide analogs that are agonists of the CGRP receptor, with potency (EC50) comparable to or better than clinically relevant agonist CGRP peptide compounds.

[0008] One aspect is providing sequences (CGRP) 1-37 CGRP peptide analogues: X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF (SEQ ID NO:1), Where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X? 31 Is it Asp or Asn, X 35 It is either Glu or Lys, and the carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:1, wherein the positions are X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X31 Is it Asp or His; X 34 It is Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the CGRP receptor.

[0009] In a preferred embodiment of this disclosure, the peptide analog comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

[0010] definition

[0011] In this article, 'CGRP peptide analog', 'CGRP analog' and 'peptide analog' can be used interchangeably.

[0012] The terms "about" and "approximately" used herein are synonyms. In one embodiment, "about" and "approximately" refer to the listed quantity, value, or duration ± 5%, ± 4.5%, ± 4%, ± 3.5%, ± 3%, ± 2.5%, ± 2%, ± 1.75%, ± 1.5%, ± 1.25%, ± 1%, ± 0.9%, ± 0.8%, ± 0.7%, ± 0.6%, ± 0.5%, ± 0.4%, ± 0.3%, ± 0.2%, ± 0.1%, ± 0.09%, ± 0.08%, ± 0.07%, ± 0.06%, ± 0.05%, ± 0.04%, ± 0.03%, ± 0.02%, or ± 0.01%. In one embodiment, "about" and "about" refer to the listed amount, value, or duration ±2.5%, ±2%, ±1.75%, ±1.5%, ±1.25%, ±1%, ±0.9%, ±0.8%, ±0.7%, ±0.6%, ±0.5%. In one embodiment, "about" and "about" refer to the listed amount, value, or duration ±1%. In one embodiment, "about" and "about" refer to the listed amount, value, or duration ±0.5%. In one embodiment, "about" and "about" refer to the listed amount, value, or duration ±0.1%. In the context of amount or dose, the terms "about" and "about" refer to the listed amount or dose ±10%, ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, ±1.5%, ±1%, ±0.5%.

[0013] "Amino acid residue" can be a natural or non-natural amino acid residue linked by a peptide bond or a bond other than a peptide bond. Amino acid residues can be D-configured or L-configured. An amino acid residue comprises an amino-terminal portion (NH2) and a carboxyl-terminal portion (COOH), separated by a central portion comprising a carbon atom or a chain of carbon atoms, at least one of which contains at least one side chain or functional group. NH2 refers to the amino group present at the amino terminus of an amino acid or peptide, and COOH refers to the carboxyl group present at the carboxyl terminus of an amino acid or peptide. The general term amino acid includes both natural and non-natural amino acids. Natural amino acids listed in J. Biol. Chem., 243:3552-59 (1969) and adopted in the standard nomenclature of 37 CFR, Part 1.822(b)(2) belong to the group of amino acids listed herein: Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N, and C. Non-natural amino acids are those amino acids not listed immediately above, including modified amino acid residues.

[0014] "Equivalent amino acid residues" refer to amino acid residues that can replace another amino acid residue in a polypeptide without significantly altering the polypeptide's structure and / or function. Therefore, equivalent amino acids share similar properties, such as the size of their side chains, side chain polarity (polar or nonpolar), hydrophobicity (hydrophobic or hydrophilic), charge (acidic, neutral, or basic), and the side chain organization of the carbon molecule (aromatic / aliphatic). Thus, "equivalent amino acid residues" can be considered "conserved amino acid substitutions."

[0015] Within the meaning of the term "equivalent amino acid substitution" as used herein, in one embodiment, an amino acid may be substituted by another amino acid from the group of amino acids specified below: i) Amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Tyr, Cys) ii) Amino acids with nonpolar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Pro, Met) iii) Amino acids with aliphatic side chains (Gly, Ala Val, Leu, Ile) iv) Amino acids with cyclic side chains (Phe, Tyr, Trp, His, Pro) v) Amino acids with aromatic side chains (Phe, Tyr, Trp) vi) Amino acids with acidic side chains (Asp, Glu) vii) Amino acids with basic side chains (Lys, Arg, His) viii) Amino acids with amide side chains (Asn, Gln) ix) Amino acids with hydroxyl side chains (Ser, Thr) x) Amino acids with sulfur-containing side chains (Cys, Met). xi) Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr) xii) Hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and xiii) Hydrophobic amino acids (Leu, Ile, Val) If the L or D form (optical isomer) is not specified, it should be understood that the amino acid in question has a natural L form, see Pure & Appl. Chem. Vol. (56(5) pp 595-624 (1984), or a D form, and thus the peptide formed may consist of amino acids in the L, D or mixed L and D forms.

[0016] A "functional variant" of a peptide is a peptide that can perform essentially the same function as the peptide from which it originates. In particular, a functional variant can bind to essentially the same molecule as the peptide from which it originates.

[0017] In this document, "conservative substitution" refers to a change in the amino acid composition of a peptide that does not significantly alter its activity, wherein residues are replaced by structurally similar substitutes. Therefore, a "conservative substitution variant" of a particular amino acid sequence refers to the substitution of an amino acid that is not critical to protein activity, or the substitution of an amino acid with another amino acid having similar properties (e.g., acidic, basic, positively or negatively charged, polar or nonpolar), such that even the substitution of a critical amino acid does not significantly alter activity. Conservative substitutions of functionally similar amino acids are well known in the art. The following six groups each contain amino acids that are conserved substitutes for each other: 1) alanine, serine, and threonine; 2) aspartic acid and glutamic acid; 3) asparagine and glutamine; 3a) asparagine, glutamine, and histidine; 4) arginine and lysine; 5) isoleucine, leucine, methionine, and valine; and 6) phenylalanine, tyrosine, and tryptophan. Those skilled in the art will understand that the above substitutions are not the only possible conserved substitutions. For example, all charged amino acids can be considered as conserved substitutes for each other, regardless of whether they are positively or negatively charged. In addition, alterations, additions, or deletions of a single amino acid or a small percentage of amino acids in the coding sequence can also be considered "conservative substitution variants".

[0018] An agonist is a compound that activates a receptor to produce a biological response. The CGRP receptor agonist used herein is a compound that acts as an agonist on one or more CGRP receptors. In some embodiments, the CGRP receptor agonist used herein is a compound that acts as an agonist on one or more CGRP receptors comprising CLR, RAMP1, and RCP. CGRP receptors may be of human or mouse origin, such as from mice or rats. In some embodiments, the CGRP receptor agonist used herein is a compound that acts as an agonist on the islet amyloid-1 (amylin-1) receptor. In some embodiments, the CGRP receptor agonist used herein is a compound that acts as an agonist on both the CGRP receptor and the islet amyloid-1 receptor.

[0019] "Affinity" refers to the binding between a receptor and its ligand.

[0020] "Efficacy" is the ability to produce a maximum receptor response.

[0021] Half maximum effective concentration (EC50 or EC50) 50 EC50 is a measure of the concentration at which a compound or drug induces half the biological response between baseline and maximum after a specified exposure time. Therefore, EC50 gives the concentration at which the half-maximal response, or 50% effect, is achieved. It is commonly used as a measure of drug potency. Drug potency depends on the drug's affinity and efficacy. EC50 is a measure of concentration expressed in molar units (M), where 1 M equals 1 mol / L.

[0022] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient for the purpose of combating a condition, disease, or ailment. The term is intended to encompass the full spectrum of treatment for a given condition suffered by a patient or subject. Patients to be treated are preferably mammals, particularly humans. However, treatment of animals such as mice, rats, dogs, cats, horses, cattle, sheep, and pigs is also within the scope of this context. Patients to be treated can be of various ages. The terms 'subject,' 'individual,' and 'patient' are used interchangeably herein.

[0023] As used herein, the term "therapeutic effective amount" refers to an amount sufficient to cure, alleviate, prevent, reduce the risk of, or partially prevent the clinical manifestations of a given disease or condition and its complications. An amount sufficient to achieve this is defined as a "therapeutic effective amount." The effective amount for each purpose will depend on the severity of the disease or injury, as well as the subject's weight and general condition. It should be understood that determining an appropriate dose can be accomplished using routine experiments by constructing a value matrix and testing the different points in the matrix, all within the general skill of a trained physician or veterinarian. The terms 'amount' and 'dose' are used interchangeably herein. While a particular dose will depend on the molecular structure and chemical properties of a particular compound, those skilled in the art will understand from the disclosure herein that an appropriate dose can be determined using conventional techniques. The amount of compound administered to achieve the desired level or concentration will depend on many well-known factors, such as the compound's half-life and the frequency and manner of administration.

[0024] In this article, "prolonged effect" means a half-life or T½ longer than that of the corresponding natural CGRP. The half-life of natural CGRP is less than 30 minutes, while modifications via fatty acylation have been shown to have a T½ as long as 8 days. T½ can be determined by the method described in WO 2011 / 051312A1. Invention Details

[0026] Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family, existing in two isoforms: αCGRP and βCGRP. αCGRP is a 37-amino acid peptide formed by alternative splicing of the calcitonin gene, particularly in the central and peripheral nervous systems, and acts as a potent vasodilator and modulator of cerebrovascular nociception. βCGRP is encoded by the second CGRP gene and is primarily expressed in the enteric sensory system. Human βCGRP shares 34 amino acids with human αCGRP. The sequence identity between α-CGRP and β-CGRP is 92% in humans and 97% in rats.

[0027] Both CGRP isoforms act on the CGRP receptor, which is composed of a 7-transmembrane calcitonin-like receptor (CLR), receptor activity-modifying protein type 1 (RAMP1), and receptor component protein (RCP). All three components are essential for optimal receptor function. Its primary second messenger is cyclic adenosine monophosphate (cAMP). Pancreatic amyloid-1 receptor is also considered to act as a CGRP receptor. Natural CGRP has a half-life of less than 30 minutes and a short duration of pharmacological action after infusion.

[0028] The sequences of α-CGRP and β-CGRP in humans, rats, and mice are as follows: ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF (α-hCGRP; SEQ ID NO: 3); ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (β-hCGRP; SEQ ID NO:4); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (α-rCGRP; SEQ ID NO:5); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (β-rCGRP; SEQ ID NO:6), SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (α-mCGRP; SEQ ID NO:7); and SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (β-mCGRP; SEQ ID NO:8).

[0029] The common sequence of SEQ ID NO:1 covers CGRP from, for example, the following species: pigs, mice, humans, dogs, and rats; in α and β forms where applicable: X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF (SEQ ID NO:1), Where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X? 31 Is it Asp or Asn, X 35 It is either Glu or Lys.

[0030] Natural CGRP has an intramolecular disulfide bond between two cysteine ​​residues at positions 2 and 7 at its N-terminus, and the carboxyl group on its C-terminal amino acid residue is amidated.

[0031] The CGRP peptide analogs disclosed herein

[0032] Mentioning CGRP peptide "CGRP" 1-37 "Refers to a peptide sequence with 37 consecutive amino acids, where each amino acid residue is represented as X1 to X2 from the N-terminus to the C-terminus." 37 Therefore, the amino acid mentioned at position X1 refers to the amino acid at position 1, which is also the N-terminal amino acid. (The mention of X...) 37 The amino acid mentioned is the one at position 37, which is also a C-terminal amino acid. Similarly, X is mentioned... 10 The amino acid mentioned is the amino acid at position 10, counting from the N-terminus.

[0033] One aspect of this disclosure is to provide sequences (CGRP) 1-37 CGRP peptide analogues: X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF (SEQ ID NO:1), Where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X? 31 Is it Asp or Asn, X 35 It is either Glu or Lys, and the carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO.1, wherein the positions are X1, X3 to X6 and X8 to X 37 Any part contains one or more individual amino acid substitutions. The peptide analogue contains at least one amino acid substitution selected from the following: X1 is either Gly or His. X3 is His, Arg, Gly, Met, or Lys. X4 is Ile X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr? X 14 Is it His, Glu, or Asp? X 17 It's Ala. X 19 It's His. X 22 Is it Ile, Leu, or Val? X 23 Is it Ser or His? X 24 Is it Arg or His? X 25 Is it Lys, Asn, Asp, Glu, Arg, or His? X 26 It's His. X 27 It's His. X 28 It's His. X 29 It's His. X 31 Is it Asp or His? X 34 It is Pro, and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0034] One aspect of this disclosure is to provide sequences (CGRP) 1-37 Peptide analogues of calcitonin gene-related peptide (CGRP): X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF (SEQ ID NO:1), Where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X 31 Is it Asp or Asn, X 35It is either Glu or Lys, and the carboxyl group in the C-terminal amino acid residue is optionally amidated. Or functional variants thereof, which are also present at positions X1, X3 to X6 and X8 to X of the peptide. 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His; X 10 Is it Asn, Gln, or Thr; X 14 It is His; X 17 It is Ala; X 19 It is His; X 22 It is Ile; X 23 It is His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Arg, or His; X 28 It is His; X 34 It's Pro; and X 35 It is His; wherein the peptide analogue is an agonist of the GCRP receptor.

[0035] In some embodiments of this disclosure, the CGRP peptide (CGRP 1-37 The α-CGRP is selected from human α-CGRP (SEQ ID NO:3), human β-CGRP (SEQ ID NO:4), rat α-CGRP (rCGRP; SEQ ID NO:5), rat β-CGRP (SEQ ID NO:6), mouse α-CGRP (SEQ ID NO:7) and mouse β-CGRP (SEQ ID NO:8), or functional variants thereof.

[0036] In some embodiments, peptide analogs of CGRP peptides are provided, having sequences selected from the following (CGRP... 1-37 ): SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF (SEQ ID NO: 3); ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 4); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (SEQ ID NO:5); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (SEQ ID NO: 6), SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (SEQ ID NO:7); and SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (SEQ ID NO:8), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2 to SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0037] In some embodiments, peptide analogs of β-CGRP peptides are provided, having sequences selected from the following (CGRP... 1-37 ): SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 4); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (SEQ ID NO: 6), SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (SEQ ID NO:8), The carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 and SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0038] In some embodiments, peptide analogs of β-CGRP peptides are provided, having the sequence (CGRP... 1-37 )

[0039] SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:2, which is also present at positions X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0040] In some embodiments, functional variations of any one of SEQ ID NO:1 to SEQ ID NO:8 are located at positions X1, X3 to X6, and X8 to X 37Each of the following contains one, two, three, four, five, or six single amino acid substitutions. In some embodiments, functional variants of any of SEQ ID NO:1 to SEQ ID NO:8 are in X1, X3 to X6, and X8 to X... 37 It contains one, two, three, four, five or six single conserved amino acid substitutions at any point.

[0041] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises at least one amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It is Pro. In some embodiments, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises two or more amino acid substitutions selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

[0042] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises one or more amino acid substitutions selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It is His and X 14 Yes, it is His. In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises one or more amino acid substitutions selected from the following: X 10 It's Asp, X 19 It is His and X 14 Yes, it is His. In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises one or more amino acid substitutions selected from the following: X 10 It is Glu, X 19 It is His and X 14 It's His.

[0043] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises X 10 It is either Asp or Glu. In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises X.10 It is Asp. In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 contains X. 10 It's Glu.

[0044] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises X 19 It's His.

[0045] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises X 14 It's His.

[0046] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 includes X1, which is Gly.

[0047] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 contains X3 which is His.

[0048] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:1 to SEQ ID NO:8 comprises X 34 It's Pro.

[0049] In some implementations, the presence of sequence CGRP is mentioned. 1-37 CGRP peptides include CGRP peptides consisting of 37 consecutive amino acids. 1-37 A CGRP peptide consisting of a sequence. In some embodiments, a bCGRP sequence of 37 consecutive amino acids is provided. 1-37 Peptide analogs composed of CGRP.

[0050] In some embodiments, a peptide analog is provided comprising a sequence of bCGRP having 37 consecutive amino acids. 1-37 CGRP and the N-terminal region of N-terminal peptides composed of a single N-terminal amino acid and 2 to 30 consecutive amino acids.

[0051] In some embodiments, a peptide analog is provided, which is composed of a sequence of bCGRP having 37 consecutive amino acids. 1-37 It consists of CGRP and the N-terminal region of an N-terminal peptide composed of a single N-terminal amino acid and 2 to 30 consecutive amino acids.

[0052] In some embodiments, the peptides of this disclosure have peptide sequences selected from the following: HCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:9); SCNTATCVTQRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:10); SCNTATCVTTRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:11); SCNTATCVTHRLAGLLSRSGGMHKSNFVPTNVGSKAF(SEQ ID NO:12); SCNTATCVTHRLAGLLSRSGGMVHSNFVPTNVGSKAF(SEQ ID NO:13); SCNTATCVTHRLAGLLSRSGGMVKNNFVPTNVGSKAF(SEQ ID NO:14); SCNTATCVTHRLAGLLSRSGGMVKRNFVPTNVGSKAF(SEQ ID NO:15); SCNTATCVTHRLAGLLSRSGGMVKHNFVPTNVGSKAF(SEQ ID NO:16); SCNTATCVTHRLAGLLSRSGGMVKSNFHPTNVGSKAF(SEQ ID NO:17); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSHAF(SEQ ID NO:18), GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:19); SCHTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:20); SCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:21); SCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:22); SCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:23); SCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:24); SCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:25); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:26); SCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:27); SCNTATCVTHRLAGLLSRSGGMVKSHFVPTNVGSKAF(SEQ ID NO:28); SCNTATCVTHRLAGLLSRSGGMVKSNHVPTNVGSKAF(SEQ ID NO:29); SCNTATCVTHRLAGLLSRSGGMVKSNFVHTNVGSKAF(SEQ ID NO:30); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTHVGSKAF(SEQ ID NO:31); SCRTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:32); SCGTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:33); SCKTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:34); SCMTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:35); SCNIATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:36); SCNTATCVTARLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:37); SCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:38); SCNTATCVTGRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:39); SCNTATCVTSRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:40); SCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:41); GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:42); SCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:43); SCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:44); GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:45); SCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:46); SCNTATCVTHRLAGLLSRSGGVVKSNFVPTNVGSKAF(SEQ ID NO:47); SCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSKAF(SEQ ID NO:48); SCNTATCVTHRLAGLLSRSGGMVKDNFVPTNVGSKAF(SEQ ID NO:49); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTDVGSKAF(SEQ ID NO:50); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSEAF(SEQ ID NO:51); SCNTATCVTHRLADLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:52); SCNTATCVTHRLAGLLSRSGGMSKSNFVPTNVGSKAF(SEQ ID NO:53); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSSAF(SEQ ID NO:54); SCHTATCVTDRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:55); SCNIATCVTHRLAGLLSRHGGMVKSNFHPTNVGSKAF(SEQ ID NO:56); SCNIATCVTDRLAGLLSRSGGMVKKNFVPTNVGSKAF(SEQ ID NO:57); SCNIATCVTHRLAGLLSRSGGIVKSNFHPTNVGSKAF(SEQ ID NO:58); SCNTATCVTDRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:59); SCNTATCVTQRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:60); SCNTATCVTHRLAHLLSRSGGIVKRNFVPTNVGSKAF(SEQ ID NO:61); SCNTATCVTHRLAHLLARHGGMVKSNFVPTNVGSKAF(SEQ ID NO:62; GCNTATCVTHRLAHLLSRSGGMVKHNFVPTNVGSKAF(SEQ ID NO:63); GCHTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:64); SCNTATCVTHRLAGLLSRSGGLVKSNFHPTNVGPKAF(SEQ ID NO:65); SCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGPKAF(SEQ ID NO:66); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:67); GCHTATCVTNRLAHLLARHGGIVKKNFVPTNVGPKAF(SEQ ID NO:68); GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:69); GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:70); GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:71); GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:72; GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:73); GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:74); GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:75); GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:76); GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:77); GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:78); GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:79); GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF(SEQ ID NO:80); GCNTATCVTHRLADLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:81); GCNTATCVTHRLAELLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:82); GCNTATCVTHRLAGLLSRSGGMVKENFVPTNVGSKAF(SEQ ID NO:83); GCHTATCVTHRLADLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:84); GCHTATCVTHRLAELLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:85); GCHTATCVTHRLAGLLSRSGGMVKENFVPTNVGSKAF (SEQ ID NO:86); GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSKAF (SEQ ID NO:87); GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSRAF (SEQ ID NO:88); and GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:89); The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0053] Preferably, the peptide analogue of any one of SEQ ID NO:9 to SEQ ID NO:89 does not contain amino acid substitutions at one or more amino acid residues indicated in bold in the amino acid sequence. The amino acid residues indicated in bold in SEQ ID NO:9 to SEQ ID NO:89 are non-natural substitutions of this disclosure.

[0054] In some embodiments, the functional variant of any one of SEQ ID NO:9 to SEQ ID NO:89 is located at positions X1, X3 to X6, and X8 to X9. 37 Each of the following contains one, two, three, four, five, or six single amino acid substitutions. In some embodiments, the functional variant of any of SEQ ID NO:9 to SEQ ID NO:89 is present at positions X1, X3 to X6, and X8 to X... 37 It contains one, two, three, four, five or six single conserved amino acid substitutions at any point.

[0055] In some embodiments, the functional variant of any one of SEQ ID NO:9 to SEQ ID NO:89 is located at one or more positions other than one or more amino acid residues indicated in bold in the amino acid sequence of any one of SEQ ID NO:9 to SEQ ID NO:89, at positions X1, X3 to X6 and X8 to X9. 37 It contains one, two, three, four, five, or six single amino acid substitutions at any point.

[0056] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises at least one amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It is Pro. In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises at least one amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 His and X1 are Gly.

[0057] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises X 10 It is either Asp or Glu.

[0058] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises X 10 It is ASP.

[0059] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises X 19 It's His.

[0060] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises X 14 It's His.

[0061] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 includes X1 which is Gly.

[0062] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 contains X3 which is His.

[0063] In a preferred embodiment, the peptide analog of any one of SEQ ID NO:9 to SEQ ID NO:89 comprises X 34 It's Pro.

[0064] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8, wherein the carboxyl group of the C-terminal amino acid residue is amidated. The peptide described herein contains one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0065] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0066] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0067] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. The peptide described herein contains one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, the peptide may contain one or more single amino acid substitutions selected from the following: X 10 Is it Asp or Glu, X? 19 It's His, X 14It's His, X1 is Gly, X3 is His and X 34 It's Pro. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0068] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide described herein comprises one or more single amino acid substitutions selected from the following: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0069] In some embodiments, the peptide analogs of this disclosure comprise one amino acid substitution, such as two single amino acid substitutions, such as three single amino acid substitutions, such as four single amino acid substitutions, such as five single amino acid substitutions, such as six single amino acid substitutions, such as seven single amino acid substitutions, such as eight single amino acid substitutions, such as nine single amino acid substitutions, wherein each substitution is independently selected from: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0070] In some embodiments, the peptide analogs of this disclosure comprise at least two single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0071] In some embodiments, the peptide analogs disclosed herein comprise substitutions of two or more single amino acids selected from the following: X 10 Is it Asp or Glu, X? 19 It's His, X1 is Gly, X 14 It's His, X3 is His and X 34 It's Pro.

[0072] In some embodiments, the peptide analogs of this disclosure comprise at least three single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0073] In some embodiments, the peptide analogs of this disclosure comprise substitutions of three or more single amino acids selected from the following: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

[0074] In a preferred embodiment, the peptide analog of this disclosure comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

[0075] In a preferred embodiment, the peptide analog of this disclosure comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It is His, X1 is Gly and X3 is His.

[0076] In a preferred embodiment, the peptide analog of this disclosure comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly and X 34 It's Pro.

[0077] In a preferred embodiment, the peptide analog of this disclosure comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 His and X1 are Gly.

[0078] In a preferred embodiment, the peptide analog of this disclosure comprises at least one amino acid substitution selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X 34 It's Pro.

[0079] In some embodiments, the peptide analogs of this disclosure comprise at least one amino acid substitution selected from the group consisting of: X 19 It's His, X 10 It's Asp, X 10 It is Glu, X 14 It's His, X 25 It's His, X 25 It's Arg, X 28 It's His, X 35 It is Ser, X1 is His, and X 23 It's His.

[0080] In some embodiments, the peptide analogs of this disclosure comprise a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It's His, X3 is His, X 25 It's His, X 28 It is His, X1 is His, X 23 It's His, X 24 It's His, X 35 It's His, X 26 It's His, X 27 It's His, X 29 It is His, and X 31 It's His.

[0081] In some embodiments, the peptide analogs of this disclosure comprise a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It's His, X 25 It's His, X 28 It is His, X1 is His, and X 23 It's His.

[0082] In a preferred embodiment, the peptide analog of this disclosure comprises a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It is His and X3 is His.

[0083] In some embodiments, the peptide analogs of this disclosure have a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide described herein comprises one or more single amino acid substitutions selected from the following: X 19 It's His, X 14 It is His and X3 is His. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0084] In some embodiments, the peptide analogs disclosed herein comprise a substitution: X 19 It's His.

[0085] In some embodiments, the peptide analogs of this disclosure comprise X 19 It is a His substitution, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0086] In some embodiments, the peptide analogs of this disclosure contain a substitution at position 14, wherein X 14 It could be His, Glu, or Asp.

[0087] In some embodiments, the peptide analogs of this disclosure comprise X 14 It is a replacement for His.

[0088] In some embodiments, the peptide analogs of this disclosure comprise X 14 It is a His substitution, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0089] In some embodiments, the peptide analogs of this disclosure comprise X 19 It's His and X 14 It is a replacement for His.

[0090] In some embodiments, the peptide analogs of this disclosure comprise X 19 His and X3 are replacements for His.

[0091] In some embodiments, the peptide analogs of this disclosure comprise X 14 His and X3 are replacements for His.

[0092] In some embodiments, the peptide analogs of this disclosure comprise X 19 Is it His, X 14 His and X3 are replacements for His.

[0093] In the preferred embodiment, X 19 Is it His, X 14 His and X3 are one or more of His.

[0094] In some embodiments, the peptide analogs disclosed herein contain X3 as a substitution for His.

[0095] In some embodiments, the peptide analogs of this disclosure comprise a His substitution for X3, and further comprise one or more amino acid substitutions selected from the following: X1 is Gly or His; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0096] In some embodiments, the peptide analogs of this disclosure comprise X3, which is His and X 10 It is a substitute for Asp or Glu.

[0097] In some embodiments, the peptide analogs disclosed herein comprise X3, which is His, X 10 Is it Asp or Glu and X? 19 It is a replacement for His.

[0098] In some embodiments, the peptide analogs of this disclosure comprise X1 being a substitution of Gly. In a preferred embodiment, X1 is Gly.

[0099] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide described therein contains X1, which is an amino acid substitution of Gly. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0100] In some embodiments, the peptide analogs of this disclosure comprise X1 being a Gly substitution, and further comprise one or more amino acid substitutions selected from the following: X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0101] In some embodiments, the peptide analogs of this disclosure comprise X1 being a substitution of Gly and X19 Is it His, X 14 His and X3 are one or more of His.

[0102] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly and X 19 It is a replacement for His.

[0103] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly and X 14 It is a replacement for His.

[0104] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 19 It's His and X 14 It is a replacement for His.

[0105] In some embodiments, the peptide analogs disclosed herein comprise X1 being a Gly and X3 being a His substitution.

[0106] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 19 His and X3 are replacements for His.

[0107] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 14 His and X3 are replacements for His.

[0108] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 19 Is it His, X 14 His and X3 are replacements for His.

[0109] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly and X 34 It is a replacement for Pro.

[0110] In some embodiments, the peptide analogs of this disclosure comprise X1 being a Gly substitution, and X3 being His, X 10 Is it Asp or Glu, X? 19 It's His and X 14 It is one or more of His.

[0111] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly and X 10 It is a replacement for Asp.

[0112] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly and X 10 It is a substitute for Glu.

[0113] In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 10 Is it Asp or Glu and X? 19 It is a replacement for His. In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 10 Is it Asp or Glu and X? 14 It is a replacement for His. In some embodiments, the peptide analogs disclosed herein comprise X1 being Gly, X 10 Is it Asp or Glu, X? 19 It's His and X 14 It is a replacement for His.

[0114] In some embodiments, the peptide analogs disclosed herein contain X1 as a substitution for His.

[0115] In some embodiments, the peptide analogs of this disclosure contain a substitution at position 10, wherein X 10 It is a negatively charged amino acid selected from Asp or Glu. In a preferred embodiment, X 10 It is either Asp or Glu.

[0116] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8 and SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide contains a substitution at position 10, wherein X 10 It is a negatively charged amino acid selected from Asp or Glu. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0117] In some embodiments, the peptide analogs of this disclosure comprise X 10It is either Asp or Glu and X1 is a substitute for Gly.

[0118] In some embodiments, the peptide analogs of this disclosure comprise X 10 It is a replacement for Asp.

[0119] In some embodiments, the peptide analogs of this disclosure comprise X 10 It is a substitute for Glu.

[0120] In some embodiments, the peptide analogs of this disclosure comprise X 10 It is a substitution of Asp, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0121] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp, and X 19 It is His, X3 is His and X 14 It is one or more of His.

[0122] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X 19 It's His.

[0123] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X3 is His.

[0124] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X 14 It's His.

[0125] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It's Asp, X 19 It is His and X3 is His.

[0126] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X1 is Gly.

[0127] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X 34 It's Pro.

[0128] In some embodiments, the peptide analogs of this disclosure comprise X 10 It is a Glu substitution, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0129] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It's Glu and X 19 It's His.

[0130] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 Glu and X3 are His.

[0131] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It's Glu and X 14 It's His.

[0132] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Glu, X 19 It is His and X3 is His.

[0133] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 Glu and X1 are Gly.

[0134] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asp and X 34 It's Pro.

[0135] In some embodiments, the peptide analogs of this disclosure comprise X 34 It is a substitution of Pro, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; and X 35 Is it His, Glu, Arg, or Ser? In some embodiments, the peptide analogs of this disclosure comprise X 34 It's a replacement for the Pro, and the X. 14 Is it His, X 19 It is His, X1 is Gly, X3 is His and X 10 It is one or more of Asp or Glu.

[0136] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 The Pro and X1 are Gly.

[0137] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34It's Pro and X 14 It's His.

[0138] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 It's Pro and X 19 It's His.

[0139] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 The Pro and X3 are His.

[0140] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 It's Pro, X 14 It's His and X 19 It's His.

[0141] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 It's Pro; and X 10 It is either Asp or Glu.

[0142] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 34 It's Pro; X1 is Gly, X3 is His and X 10 It is either Asp or Glu.

[0143] In some embodiments, the peptide analogs of this disclosure comprise X 14 It is a substitute for Glu or Asp, for example, where X 14 It is Glu, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0144] In some embodiments, the peptide analogs of this disclosure comprise X 14 It is a substitute for Glu or Asp, and X 19 X1 is one or more of His, X2 is Gly, and X3 is His.

[0145] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 14 Is it Glu or Asp, and X? 19 It's His.

[0146] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 14 It is either Glu or Asp, and X1 is Gly.

[0147] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 14 It is either Glu or Asp, and X3 is His.

[0148] In some embodiments, the peptide analogs of this disclosure comprise X 10 It is a substitution of Asn, and also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0149] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asn, and X3 is His, X 14 Is it His, X 19 His and X1 are one or more of Gly.

[0150] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asn, X3 is His, X 14 It's His and X 19 It's His.

[0151] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 X1 is Asn, X3 is His, and X1 is Gly.

[0152] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 10 It is Asn and X1 is Gly.

[0153] In some embodiments, the peptide analogs of this disclosure comprise X 17 It is a substitution of Ala and one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0154] In some embodiments, the peptide analogs of this disclosure comprise X 17 It is a replacement for Ala, and X1 is Gly, X3 is His, X 10 Is it Asp or Asn, X 19 It's His, X 14 It's His and X 34 It is one or more of the Pro components.

[0155] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 17 It's Ala and X 10 It is ASP.

[0156] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 17 It's Ala and X 10 It is Asn.

[0157] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 17 It is Ala; and X 19 Is it His and / or X? 14 It's His.

[0158] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 17 Ala and X1 are Gly.

[0159] In some embodiments, the peptide analogs of this disclosure comprise X 22 It is a substitution of Ile or Leu and one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0160] In some embodiments, the peptide analogs of this disclosure comprise X 22 It is a replacement for Ile and X1 is Gly, X 19 Is it His, X 14 It is His, X3 is His, X 10 It is Asn, X 24 It is Arg, X 28 Is it His, X 17 It's Ala and X 34 It is one or more of the Pro components.

[0161] In some embodiments, the peptide analogs of this disclosure comprise X 22 It is a replacement for Leu and X1 is Gly, X 28 It's His and X 34 It is one or more of the Pro components.

[0162] In some embodiments, the peptide analogs of this disclosure comprise X 24 The substitution is His, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0163] In some embodiments, the peptide analogs of this disclosure comprise a substitution of Ile for X4, and the peptide analogs further comprise one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0164] In some embodiments, the peptide analogs of this disclosure comprise X4 being a substitution of Ile and X 10 It is Asp, X 19 Is it His, X 28 It's His and X 22 It is one or more of Ile.

[0165] In some embodiments, the peptide analogs disclosed herein comprise the following substitutions: X 24 It's Arg and X 35 It's Arg.

[0166] In some embodiments, the peptide analogs of this disclosure comprise X 25 It is a substitute for Asp or Glu, for example, where X 25 It is Glu, and one or more amino acids selected from the following substitutions: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0167] In some embodiments, the peptide analogs of this disclosure comprise X 25 X3 is a substitute for Glu, and X1 is one or more of His and Gly.

[0168] In some embodiments, the peptide analogs of this disclosure comprise X 24 It is a replacement for Arg, provided that X 25 Not Lys. In some implementations, when X 24When it is Arg, then X 25 It's not Lys.

[0169] In some embodiments, the peptide analogs of this disclosure comprise X 31 It is a substitution of Asp, and one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 28 It is His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

[0170] In some embodiments, the peptide analogs of this disclosure comprise X 35 It is a substitution of His or Arg and a substitution of one or more amino acids selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 28 It is His; X 31 It is Asp; and X 34 It's Pro.

[0171] In some embodiments, the peptide analogs of this disclosure comprise at least one amino acid substitution selected from the following: X1 is His, X... 10 It is Thr, X 14 It's His, X 19 It's His, X 23It's His, X 25 Is it Arg or His, and X? 28 It's His.

[0172] In some embodiments of this disclosure, the peptide analog comprises at least one amino acid substitution introducing a His amino acid residue without reducing the potency of the substituted peptide analog. In some embodiments of this disclosure, the peptide analog comprises at least one amino acid substitution introducing a His amino acid residue while maintaining or even increasing the potency of the substituted peptide analog.

[0173] The isoelectric point (pI) is the pH value at which a particular molecule is electrically neutral due to the balance of positive and negative charges. In proteins and peptides, this depends on the charged groups of the seven amino acids and the dissociation constants (pKa) of the NH+ and COO- groups at the peptide terminals.

[0174] Histidine is unique among natural amino acids because its side chain (R group) contains an imidazole group, which can function as both a weak acid and a weak base. The pKa of the histidine side chain is 6.10, meaning that histidine is positively charged when protonated (at lower pH) and neutral when deprotonated (at higher pH). Therefore, the introduction or removal of one or more histidine residues can determine the activity of CGRP peptide analogs in biological processes where pH changes can affect their charge state and function, such as during ischemic conditions.

[0175] Ischemia is a condition where insufficient blood supply to tissues leads to a shortage of oxygen and nutrients. When tissue is ischemia occurs, cellular metabolism shifts from aerobic (oxygen-dependent) to anaerobic (oxygen-independent) pathways in an attempt to generate ATP (adenosine triphosphate), the cell's primary energy source. During anaerobic metabolism, glucose is metabolized to produce ATP, but lactic acid is also produced as a byproduct. In the absence of sufficient oxygen, the accumulation of lactic acid and other metabolic byproducts leads to a decrease in tissue pH.

[0176] In some embodiments of this disclosure, the peptide analogue comprises amino acid substitutions that are beneficial to CGRP receptor efficacy, binding affinity, or effectiveness, but does not contain amino acid substitutions at positions that are detrimental to CGRP receptor efficacy, binding affinity, or effectiveness.

[0177] The amino acids at positions X2 and X7 in the peptide analog cannot be substituted. The amino acids at positions X2 and X7 in the peptide analog are Cys.

[0178] In some embodiments of this disclosure, the amino acids at positions X5 and X6 are not substituted; for example, X5 is Ala and X6 is Thr.

[0179] In some embodiments of this disclosure, the amino acid at any of positions X4, X5, and X6 is not substituted; for example, X4 is Thr, X5 is Ala, and X6 is Thr.

[0180] In some embodiments of this disclosure, the amino acid at any of positions X4, X5, X6, and X8 is not substituted; for example, X4 is Thr, X5 is Ala, X6 is Thr, and X8 is Val.

[0181] In some embodiments of this disclosure, the peptide analog comprises one or more of the following: X4 is Thr, X5 is Ala, X6 is Thr, X8 is Val, X9 is Thr, X... 16 It's Leu, X 17 It is Ser, X 22 It's Met, X 30 It is Thr and X 32 It's Val.

[0182] In some embodiments of this disclosure, the peptide analog does not contain amino acid substitutions selected from the following: X4 is Asp, X5 is Asp, X6 is Asp, X8 is Asp, X9 is Asp, X... 17 It is Asp and X 22 It is ASP.

[0183] In some embodiments of this disclosure, in the peptide analogue, X4 is not Asp or Glu; X5 is not Asp, Glu, or Arg; and X6 is not Asp, Glu, Arg, or His.

[0184] In some embodiments of this disclosure, in the peptide analogue, X 17 It is Ser; for example, X in it 17 Not Asp, Arg, or Ile.

[0185] In some embodiments of this disclosure, in the peptide analogue, X 22 It is Met; for example, where X is... 22 Not Asp, Gln, or His.

[0186] In some embodiments of this disclosure, in the peptide analogue, X 16 It's Leu, X 30 It is Thr and X 32 It is Val; for example, X in it. 16 X 30 and X 32 None of them are His.

[0187] In some embodiments of this disclosure, in the peptide analogue, X 10Not Arg or Lys.

[0188] In some embodiments of this disclosure, in the peptide analogue, X 14 It's not Ile.

[0189] In some embodiments of this disclosure, in the peptide analogue, X 19 It's not Asp or Glu.

[0190] In some embodiments of this disclosure, a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is included in positions X1, X3 to X6, and X8 to X9. 37 One to six individual amino acid substitutions at any point in the mixture.

[0191] In some embodiments of this disclosure, functional variations of any one of SEQ ID NO:1 to SEQ ID NO:89 are at positions X1, X3 to X6, and X8 to X9. 37 Any part contains 1 to 5, for example 1 to 4, for example 1 to 3, for example 1 to 2 single amino acid substitutions.

[0192] In some embodiments of this disclosure, functional variations of any one of SEQ ID NO:1 to SEQ ID NO:89 are at positions X1, X3 to X6, and X8 to X9. 37 Any part of it contains 6, for example 5, for example 4, for example 3, for example 2, for example 1 single amino acid substitution.

[0193] In some embodiments of this disclosure, a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is located at positions X4, X5, X6, X8, X9, X 11 X 21 X 13 X 15 X 16 X 18 X 20 X 21 X 26 X 27 X 29 To X 33 X 36 and X 37 Any part of it contains 1 to 6 single amino acid substitutions, such as 1 to 5, 1 to 4, 1 to 3, 1 to 2 single amino acid substitutions, such as containing 1, 2, 3, 4, 5 or 6 single amino acid substitutions; For example, at positions X5, X6, X8, X9, X 11 X 12 X 13X 15 X 16 X 18 X 20 X 21 X 30 X 32 X 33 X 36 and X 37 Any place in the middle; For example, at positions X8, X9, X 11 X 12 X 13 X 15 X 16 X 18 X 20 X 21 X 30 X 32 X 33 X 36 and X 37 Any place in the middle; For example, at position X 11 X 12 X 13 X 15 X 18 X 20 X 21 X 33 X 36 and X 37 Any place in the middle; For example, at position X 11 X 12 X 13 X 15 X 18 X 20 X 21 and X 33 Any place in the middle.

[0194] In some embodiments of this disclosure, functional variations of any one of SEQ ID NO:1 to SEQ ID NO:89 are at positions X1, X3 to X6, and X8 to X9. 37 Each of the contents contains 1 to 6 conserved amino acid substitutions.

[0195] In some embodiments, the peptide analogs of this disclosure are GCRP receptor agonists. In some embodiments, the peptide analogs of this disclosure are GCRP receptor agonists at systemic pH. Typically, systemic acid-base balance is well regulated, with arterial pH between 7.36 and 7.44; intracellular pH is typically about 7.2. In some embodiments, the peptide analogs of this disclosure are GCRP receptor agonists at physiological pH (e.g., pH about 7.4, pH about 7.2 to 7.6, pH about 7.3 to 7.5).

[0196] In some embodiments, the peptide analogs of this disclosure are agonists of the GCRP receptor under ischemic conditions, ischemic pH, or acidic pH.

[0197] In some embodiments, the peptide analogs of this disclosure have binding affinity for the GCRP receptor.

[0198] In some embodiments, the peptide analogs of this disclosure have an efficacy (EC50) equal to or greater than that of the polypeptide consisting of the amino acid sequence SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2) to the GCRP receptor, having an acyl group linked to an N-terminal amino acid and a linker HOOC(CH2)16CO-isoGlu-AEEA.

[0199] In some embodiments, the peptide analogs of this disclosure have an efficacy (EC50) comparable to that of a polypeptide consisting of the amino acid sequence ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:3).

[0200] In some embodiments, the peptide analogs of this disclosure have a sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:26 and SEQ ID NO:90 to SEQ ID NO:92. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His; X 10 Is it Asn, Gln, or Thr; X 14 It is His; X 17 It is Ala; X 19 It is His; X 22 It is Ile; X 23 It is His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Arg, or His; X 28 It is His; X 34It's Pro; and X 35 It's His. Or its functional variants, which are located at positions X4, X5, X6, X8, X9, X 11 X 21 X 13 X 15 X 16 X 18 X 20 X 21 X 26 X 27 X 29 To X 33 X 36 and X 37 Any part of it contains one or more single amino acid substitutions. The carboxyl group in the C-terminal amino acid residue is amidated.

[0201] In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 The (nM) value is 16 nM or lower, for example, less than 16 nM.

[0202] In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 The (nM) value is from 0.01 to 16 nM, for example, 0.1 to 16 nM, for example, 1 to 16 nM. In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 (nM) values ​​range from >6 nM to 16 nM.

[0203] In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 The value is at least 0.5 times the EC50 value of the polypeptide consisting of the amino acid sequence SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2) linked to the N-terminal amino acid HOOC(CH2)16CO-isoGlu-AEEA; For example, EC 50 The value is at least 0.8 times, for example at least 0.75 times, for example at least 1 time, for example at least 1.5 times, for example at least 2 times, for example at least 2.5 times, for example at least 3 times, for example at least 3.5 times, for example at least 4 times, for example at least 5 times, of the EC50 value of HOOC(CH2)16CO-isoGlu-AEEA-SEQ ID NO:2. For example, EC 50The value is HOOC(CH2)16CO-isoGlu-AEEA-SEQ ID The EC50 value of NO:2 is 0.5 to 10 times; for example, 0.5 to 0.6 times, 0.6 to 0.7 times, 0.7 to 0.8 times, 0.8 to 0.9 times, 0.9 to 1.0 times, 1.0 to 1.1 times, 1.1 to 1.2 times, 1.2 to 1.3 times, 1.3 to 1.4 times, 1.4 to 1.5 times, 1.5 to 1.6 times, 1.6 to 1.7 times, 1.7 to 1.8 times, 1.8 to 1.9 times, 1.9 to 2.0 times, 2 to 3 times, 3 to 4 times, 4 to 5 times, 5 to 6 times, 6 to 7 times, 7 to 8 times, 8 to 9 times, 9 to 10 times, for example, HOOC(CH2)16CO-isoGlu-AEEA-SEQ ID The EC50 value of NO:2 is 0.5 to 5 times, for example 0.5 to 4 times, for example 0.5 to 3 times, for example 0.5 to 2 times, for example 0.5 to 1.5 times, for example 1.0 to 10 times, for example 1.0 to 5 times.

[0204] In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 The (nM) value is 6 nM or lower, such as 5 nM or lower, such as 4 nM or lower, such as 3 nM or lower, such as 2 nM or lower, such as 1 nM or lower, such as 0.5 nM or lower, such as 0.1 nM or lower.

[0205] In some embodiments, the peptide analogues of this disclosure are agonists of the GCRP receptor, whose EC50... 50 The (nM) value is 0.01 to 6 nM, for example 0.1 to 6 nM, for example 1 to 6 nM.

[0206] In a preferred embodiment, the peptide analog of the present disclosure contains an intramolecular disulfide bond between the Cys amino acid residue at position 2 (X2) and the Cys amino acid residue at position 7 (X7).

[0207] In some embodiments, the peptide analogs of this disclosure contain a disulfide bond with a linker, such as a methylene linker, between the Cys amino acid residue at position 2 (X2) and the Cys amino acid residue at position 7 (X7), for example -S-[CH2]-S.

[0208] Preferably, the peptide analog contains a disulfide bond, such as -SS- or -S-[CH2]-S, between Cys amino acid residues at positions 2 (X2) and 7 (X7).

[0209] In some embodiments, the peptide analogs of this disclosure contain Cys amino acid residues at position 2 (X2) and position 7 (X7).

[0210] The carboxyl group of the C-terminal amino acid residue in CGRP peptides or peptide analogs is amidated (-COOH amidated to -CONH2), for example, at position X. 37 The amino acids at that location are amidated.

[0211] In some embodiments of this disclosure, the one or more amino acid substitutions are conservative or non-conservative substitutions.

[0212] In some embodiments of this disclosure, the one or more amino acid substitutions are conservative substitutions.

[0213] N-terminal modification

[0214] This disclosure provides information with sequence (CGRP) 1-37 The present disclosure provides peptide analogs of CGRP peptides, or CGRP peptide analogs having one or more specified amino acid substitutions as disclosed herein, which are agonists of the CGRP receptor. In some embodiments, peptide analogs of the present disclosure are provided having an N-terminal region of an amino group linked by a peptide bond to the N-terminal amino acid of the CGRP peptide, the N-terminal region being a short peptide.

[0215] One aspect of this disclosure is to provide sequences (CGRP) 1-37 CGRP peptide analogues: X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF (SEQ ID NO:1), where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X 31 Is it Asp or Asn, X 35 It is either Glu or Lys, and the carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:1, wherein the positions are X1, X3 to X6 and X8 to X 37Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0216] In some embodiments, this disclosure provides a sequence (CGRP) having any one of SEQ ID NO:2 to SEQ ID NO:8. 1-37 CGRP peptide analogs, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2 to SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0217] In some embodiments, this disclosure provides sequences selected from the following (CGRP) 1-37 β-CGRP peptide analogues: SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:4), SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (SEQ ID NO:6), and SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (SEQ ID NO:8), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 and SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0218] In one particular embodiment, this disclosure provides a peptide analog of SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:2, which includes positions X1, X3 to X6 and X8 to X 37 One or more single amino acid substitutions at any point in the mixture. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0219] In some embodiments, this disclosure provides a sequence (CGRP) having any one of SEQ ID NO:1 to SEQ ID NO:8. 1-37 CGRP peptide analogs, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide analogues described herein contain one or more amino acid substitutions selected from the following: X1 is Gly, X... 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X 34 It's Pro. The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0220] In some embodiments, this disclosure provides a sequence (CGRP) having any one of SEQ ID NO:9 to SEQ ID NO:89. 1-37 CGRP peptide analogs, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:81, wherein the position is X1, X3 to X6 and X8 to X 37Any part of it contains one or more single amino acid substitutions. The peptide analogues thereon optionally contain one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0221] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide analogues described herein contain one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0222] In some embodiments, the peptide of this disclosure has a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group of the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide described herein contains one or more single amino acid substitutions selected from the following: X1 is Gly, X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X 34 It's Pro. The peptide analogue comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analogue. The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0223] In some embodiments, reference to a peptide analog having a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:89 means a peptide analog having a peptide sequence consisting of an amino acid sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:89.

[0224] In some embodiments, reference to a peptide analog having a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:89 means a peptide analog consisting of a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:89 and an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide sequence.

[0225] In some embodiments, this disclosure provides a sequence (CGRP) having any one of SEQ ID NO:9 to SEQ ID NO:89. 1-37 ) is a peptide analog of CGRP, comprising an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of an amino acid residue at position 1 (X1) of any one of SEQ ID NO: 9 to 89.

[0226] In some embodiments, the peptide analogs disclosed herein comprise an N-terminal single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which are linked by peptide bonds to the amino group of the amino acid residue at position 1 (X1) of the peptide analog.

[0227] In some embodiments of this disclosure, the N-terminal region is composed of naturally occurring amino acid residues. In some embodiments of this disclosure, the N-terminal region is composed of naturally occurring amino acid residues independently selected from Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N, and C.

[0228] In some embodiments, the N-terminal peptide consists of 2 to 30 naturally occurring amino acid residues, such as 2 to 30 naturally occurring amino acid residues selected from Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N, and C.

[0229] In some embodiments, the N-terminal peptide consists of 2 to 30 consecutive amino acids independently selected from Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Met, and Orn. ​​In some embodiments, the N-terminal peptide consists of 4 to 30 consecutive amino acid residues independently selected from Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, and Met; for example, amino acid residues independently selected from Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn, and Met; for example, Glu, Lys, and Met.

[0230] In some embodiments, the N-terminal peptide consists of six consecutive Lys amino acids (Lys6). In some embodiments, the N-terminal peptide consists of six consecutive Ala amino acids (Ala6).

[0231] In some embodiments, the N-terminal single amino acid is Lys.

[0232] In some embodiments, the N-terminal single amino acid is an aromatic amino acid. In some embodiments, the N-terminal single amino acid is an aromatic amino acid selected from Trp, Tyr, Phe, and 3-(1-naphthyl)alanine.

[0233] In some embodiments, the peptide analogs disclosed herein comprise: A non-aromatic amino acid, an N-terminal single amino acid, an N-terminal dipeptide, or an N-terminal tripeptide, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog, or An N-terminal peptide consisting of 2 to 30 consecutive amino acids and containing one or more amino acids selected from the following: Gly (G), Pro (P), Phe (F) and Val (V), which are linked by peptide bonds to the amino group of the amino acid residue at position 1 (X1) of the peptide analog.

[0234] In some embodiments, the peptide analogs of this disclosure include an N-terminal region that is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the CGRP peptide, wherein the N-terminal region is: The N-terminal single amino acid that is not an aromatic amino acid and is not Lys(K), an N-terminal dipeptide, an N-terminal tripeptide, or An N-terminal peptide consisting of 2 to 30 consecutive amino acid residues and containing one or more amino acids selected from the following: Gly (G), Pro (P), Phe (F), and Val (V).

[0235] The amino group attached to the amino acid residue at position 1 (X1) of the peptide analog via a peptide bond is equivalent to the amino group attached to the N-terminal amino acid residue of the CGRP peptide analog via a peptide bond.

[0236] In some embodiments, the N-terminal peptide consists of 2 to 30 consecutive amino acid residues and includes at least one amino acid selected from the group consisting of Gly, Pro, Phe, and Val. In some embodiments, the N-terminal peptide consists of 3 to 30 consecutive amino acid residues and includes at least one amino acid selected from the group consisting of Gly, Pro, Phe, and Val. In some embodiments, the N-terminal peptide consists of 4 to 30 consecutive amino acid residues and includes at least one amino acid selected from the group consisting of Gly, Pro, Phe, and Val.

[0237] In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 3 consecutive amino acid residues, for example 3 to 4, for example 4 to 5, for example 5 to 6, for example 6 to 7, for example 7 to 8, for example 8 to 9, for example 9 to 10, for example 10 to 11, for example 11 to 12, for example 12 to 13, for example 13 to 14, for example 14 to 15, for example 15 to 16, for example 16 to 17, for example 17 to 18, for example 18 to 19, for example 19 to 20, for example 20 to 21, for example 21 to 22, for example 22 to 23, for example 23 to 24, for example 24 to 25, for example 25 to 26, for example 26 to 27, for example 27 to 28, for example 28 to 29, for example 29 to 30 consecutive amino acid residues.

[0238] In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 30 consecutive amino acid residues, such as 2 to 25, 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 consecutive amino acid residues.

[0239] In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 25 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 20 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 15 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 10 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 9 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 5 consecutive amino acid residues. In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 4 consecutive amino acid residues.

[0240] In some embodiments of this disclosure, the N-terminal peptide is composed of 2 consecutive amino acid residues, such as 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, or 30 consecutive amino acid residues.

[0241] In some embodiments of this disclosure, the N-terminal peptide consists of 2 to 30, for example 3 to 30, for example 4 to 30 consecutive amino acids, and includes one or more amino acids selected from the following: Gly, Pro, Phe and Val.

[0242] In some embodiments of this disclosure, the N-terminal peptide comprises one or more amino acids selected from the group consisting of Gly and Pro.

[0243] In some embodiments of this disclosure, the N-terminal peptide comprises at least one amino acid selected from the group consisting of Gly and Pro.

[0244] In some embodiments of this disclosure, the N-terminal peptide comprises one amino acid selected from the group consisting of Gly and Pro. In some embodiments of this disclosure, the N-terminal peptide comprises two amino acids selected from the group consisting of Gly and Pro. In some embodiments of this disclosure, the N-terminal peptide comprises two or more amino acids selected from the group consisting of Gly and Pro. In some embodiments of this disclosure, the N-terminal peptide comprises three amino acids selected from the group consisting of Gly and Pro. In some embodiments of this disclosure, the N-terminal peptide comprises three or more amino acids selected from the group consisting of Gly and Pro.

[0245] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Gly amino acid. In some embodiments of this disclosure, the N-terminal peptide comprises one Gly amino acid, such as one or more Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises two Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises two or more Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises three Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises three or more Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises four Gly amino acids, such as four or more Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises five Gly amino acids, such as five or more Gly amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises six Gly amino acids, such as six or more Gly amino acids.

[0246] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Pro amino acid. In some embodiments of this disclosure, the N-terminal peptide comprises one Pro amino acid, such as one or more Pro amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises two Pro amino acids, such as two or more Pro amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises three Pro amino acids, such as three or more Pro amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises four Pro amino acids, such as four or more Pro amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises five Pro amino acids, such as five or more Pro amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises six Pro amino acids, such as six or more Pro amino acids.

[0247] In some embodiments of this disclosure, the N-terminal peptide comprises one or more amino acids selected from the following: Phe and Val.

[0248] In some embodiments of this disclosure, the N-terminal peptide comprises at least one amino acid selected from the group consisting of Phe and Val.

[0249] In some embodiments of this disclosure, the N-terminal peptide comprises two amino acids selected from the group consisting of Phe and Val. In some embodiments of this disclosure, the N-terminal peptide comprises two or more amino acids selected from the group consisting of Phe and Val. In some embodiments of this disclosure, the N-terminal peptide comprises three amino acids selected from the group consisting of Phe and Val. In some embodiments of this disclosure, the N-terminal peptide comprises three or more amino acids selected from the group consisting of Phe and Val.

[0250] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Phe amino acid.

[0251] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Phe amino acid. In some embodiments of this disclosure, the N-terminal peptide comprises one Phe amino acid, for example, one or more Phe amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises two Phe amino acids, for example, two or more Phe amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises three Phe amino acids, for example, three or more Phe amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises four Phe amino acids, for example, four or more Phe amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises five Phe amino acids, for example, five or more Phe amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises six Phe amino acids, for example, six or more Phe amino acids.

[0252] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Val amino acid.

[0253] In some embodiments of this disclosure, the N-terminal peptide comprises at least one Val amino acid. In some embodiments of this disclosure, the N-terminal peptide comprises one Val amino acid, for example, one or more Val amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises two Val amino acids, for example, two or more Val amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises three Val amino acids, for example, three or more Val amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises four Val amino acids, for example, four or more Val amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises five Val amino acids, for example, five or more Val amino acids. In some embodiments of this disclosure, the N-terminal peptide comprises six Val amino acids, for example, six or more Val amino acids.

[0254] In some embodiments of this disclosure, the N-terminal single amino acid or the N-terminal peptide does not contain any amino acid with a charged side chain selected from Arg, His, Lys, Asp, and Glu.

[0255] In some embodiments of this disclosure, the N-terminal single amino acid or the N-terminal peptide comprises at most one amino acid having a charged side chain selected from Arg, His, Lys, Asp, and Glu.

[0256] In some embodiments of this disclosure, the N-terminal single amino acid or the N-terminal peptide comprises an amino acid selected from Arg, His, Lys, Asp, and Glu, having a charged side chain.

[0257] In some embodiments of this disclosure, the N-terminal single amino acid or the N-terminal peptide comprises up to two amino acids having charged side chains selected from Arg, His, Lys, Asp, and Glu.

[0258] In some embodiments of this disclosure, the N-terminal peptide comprises one and no more than one Lys amino acid.

[0259] In some embodiments of this disclosure, the N-terminal single amino acid or the N-terminal peptide comprises up to two amino acids having charged side chains selected from Arg, His, Lys, Asp, and Glu.

[0260] In some embodiments of this disclosure, the N-terminal peptide comprises one or more His amino acids. In some embodiments of this disclosure, the N-terminal peptide is a single His amino acid or the N-terminal peptide comprises one His amino acid. In some embodiments of this disclosure, the N-terminal peptide comprises two His amino acids.

[0261] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of one or more amino acids independently selected from or composed of Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys.

[0262] In a preferred embodiment of this disclosure, the N-terminal peptide consists of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys.

[0263] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of one or more amino acids independently selected from or composed of Ser, Gly, Arg, Phe, and Val.

[0264] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of one or more amino acids independently selected from or composed of Ala, Pro, Glu, and Lys.

[0265] In some embodiments of this disclosure, the N-terminal peptide is composed of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys, wherein each of the 2 to 30 amino acids selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys is present at most twice.

[0266] In some embodiments of this disclosure, the N-terminal peptide is composed of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys, wherein the N-terminal peptide comprises up to 2 Ser amino acids, up to 2 Gly amino acids, up to 2 Arg amino acids, up to 2 Phe amino acids, up to 2 Val amino acids, up to 2 Ala amino acids, up to 2 Pro amino acids, up to 2 Glu amino acids, up to 2 Leu amino acids, and up to 2 Lys amino acids.

[0267] In some embodiments of this disclosure, the N-terminal peptide is composed of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys, wherein each of the 2 to 30 amino acids selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys is present only once.

[0268] In some embodiments of this disclosure, the N-terminal peptide is composed of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys, wherein the N-terminal peptide comprises at most one Ser amino acid, at most one Gly amino acid, at most one Arg amino acid, at most one Phe amino acid, at most one Val amino acid, at most one Ala amino acid, at most one Pro amino acid, at most one Glu amino acid, at most one Leu amino acid, and at most one Lys amino acid.

[0269] In some embodiments of this disclosure, the N-terminal single amino acid is not an aromatic amino acid.

[0270] In some embodiments of this disclosure, the N-terminal single amino acid is selected from the following amino acids: Gly, Pro, and Val. In some embodiments of this disclosure, the N-terminal single amino acid is Gly. In some embodiments of this disclosure, the N-terminal single amino acid is Pro. In some embodiments of this disclosure, the N-terminal single amino acid is Val.

[0271] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of the following sequences: X -9 X -8 X -7 X -6 X -5 X -4 X -3 X -2 X -1 (SEQ ID NO:233) Where X -1 The amino group of X1 of the CGRP peptide or peptide analog is linked via a peptide bond: X -9 Selected from: Nonexistent, Ser, and Gly X -8 Selected from: Nonexistent, Gly, and Ser. X -7 Selected from: Nonexistent, Ser, and Gly X -6 Selected from: Nonexistent, Gly, Ser, Lys, and Ala. X -5 Selected from: Nonexistent, Ser, Gly, Lys, and Ala. X -4 Selected from: Nonexistent, Gly, Ser, Lys, Ala, Arg, and Leu. X -3 Selected from: Nonexistent, Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X -2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala; Optionally, the N-terminal peptide comprises at least one amino acid selected from the group consisting of Gly, Pro, Phe, and Val.

[0272] In some embodiments of this disclosure, the N-terminal peptide comprises sequence X. -4 X -3 X -2 X -1 (SEQ ID NO:234) or composed of it, Where X -1 The amino group of X1 of the CGRP peptide or peptide analog is linked to the peptide via a peptide bond, wherein: X -4 Selected from: Gly, Ser, Lys, Ala, Arg, and Leu. X -3 Selected from: Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X -2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala; Optionally, the N-terminal peptide comprises at least one amino acid selected from the group consisting of Gly, Pro, Phe, and Val.

[0273] In some embodiments of this disclosure, the N-terminal peptide comprises sequence X. -3 X -2 X -1 Or composed of, Where X -1 The amino group of X1 of the CGRP peptide or peptide analog is linked to the peptide via a peptide bond. Where X -3 X -2 and X -1 Each is independently selected from Ser, Gly, Arg, Phe, Val, Pro, Glu, Ala, Leu, and Lys.

[0274] In some embodiments of this disclosure, the N-terminal peptide comprises sequence X. -3 X -2 X -1 Or composed of, Where X -1 The amino group of X1 of the CGRP peptide or peptide analog is linked to the peptide via a peptide bond, wherein... X -3 Selected from: Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X-2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala.

[0275] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of sequences selected from or composed of the following: SG S GS G S G G S RS F R V PA S and SGSGSGSG S (SEQ ID NO:235).

[0276] It should be understood that in a sequence of more than one amino acid, the last amino acid mentioned is the amino acid that is linked by a peptide bond to the amino group of the N-terminal amino acid (X1) of the CGRP peptide or peptide analog (e.g., sequence RS). F In F , and sequence PA S In S ).

[0277] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of sequences selected from or formed therefrom: SGS, GSG, SG, GS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240).

[0278] In some embodiments of this disclosure, the N-terminal peptide is composed of sequences selected from the following: SGS, GSG, SG, GS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240).

[0279] In some embodiments of this disclosure, the N-terminal peptide is composed of sequences selected from the following: RSF, RSFG (SEQ ID NO:237), KSF, and GKSF (SEQ ID NO:240). In some embodiments of this disclosure, the N-terminal peptide is composed of RSF or RSFG (SEQ ID NO:237).

[0280] In some embodiments of this disclosure, the N-terminal peptide is composed of sequences selected from the following: RV, RVG, LRV, LLRV (SEQ ID NO:238), KVG, and GKVG (SEQ ID NO:239). In some embodiments of this disclosure, the N-terminal peptide is composed of sequences selected from the following: RV, RVG, LRV, and LLRV (SEQ ID NO:238).

[0281] In some embodiments of this disclosure, the N-terminal peptide consists of a sequence selected from the following: S-(GS) n (GS) n G-(SG) n (SG) n (S) n (G) n (ES) n and (RV) n , where n is an integer from 2 to 12; (PAS) n (RSF) n (KSF) n (LRV) n (RVG) n and (KVG) n , where n is an integer from 2 to 8; and (RSFG) n (GKSF) n (LLRV) n and (GKVG) n , where n is an integer from 2 to 6.

[0282] In some embodiments of this disclosure, the N-terminal peptide comprises or consists of a sequence selected from or composed of the following: S-(GS) n (GS) n G-(SG) n (SG) n (S) n and (G) n , where n is an integer from 2 to 12; for example

[0283] Where n is an integer from 2 to 11, for example 2 to 10, for example 2 to 9, for example 2 to 8, for example 2 to 7, for example 2 to 6, for example 2 to 5, for example 2 to 4, for example 2 to 3; for example where n=1, for example where n=2, for example where n=3, for example where n=4, for example where n=5, for example where n=6, for example where n=7, for example where n=8, for example where n=9, for example where n=10, for example where n=11, for example where n=12.

[0284] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (PAS). n Or from sequence (PAS) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0285] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (ES). n Or from sequence (ES) n Composition, where n is an integer from 2 to 12; for example, where n is an integer from 2 to 11, for example, 2 to 10, for example, 2 to 9, for example, 2 to 8, for example, 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8, for example, where n=9, for example, where n=10, for example, where n=11, for example, where n=12.

[0286] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (RSFG). n Or from the sequence (RSFG) n Composition, where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6.

[0287] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (RSF). n Or from sequence (RSF) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0288] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (GKSF). n Or from the sequence (GKSF) n Composition, where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6.

[0289] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (KSF). n Or from the sequence (KSF) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0290] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (LLRV). n Or from sequence (LLRV) n Composition, where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6.

[0291] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (LRV). n Or from sequence (LRV) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0292] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (RV). n Or from sequence (RV) n Composition, where n is an integer from 2 to 12; for example, where n is an integer from 2 to 11, for example, 2 to 10, for example, 2 to 9, for example, 2 to 8, for example, 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8, for example, where n=9, for example, where n=10, for example, where n=11, for example, where n=12.

[0293] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (RVG). n Or from sequence (RVG) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0294] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (GKVG). n Or from the sequence (GKVG) n Composition, where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6.

[0295] In some embodiments of this disclosure, the N-terminal peptide comprises a sequence (KVG). n Or from sequence (KVG) n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3; for example, where n=2, for example, where n=3, for example, where n=4, for example, where n=5, for example, where n=6, for example, where n=7, for example, where n=8.

[0296] In some embodiments of this disclosure, the N-terminal single amino acid, N-terminal dipeptide, N-terminal tripeptide, or N-terminal peptide contributes to one or more of the potency, binding affinity, or efficacy of the CGRP peptide against the CGRP receptor, such as increasing and / or maintaining one or more of the potency, binding affinity, or efficacy of the CGRP peptide against the CGRP receptor.

[0297] In some embodiments, the peptide analogs of this disclosure have a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8, wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8, which includes positions X1, X3 to X6 and X8 to X 37 One or more single amino acid substitutions at any location, for example, those contained at positions X1, X3 to X6, and X8 to X. 37 One, two, three, four, five, or six single amino acid substitutions at any point in the mixture. The peptide described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, the peptide described herein contains at least one amino acid substitution selected from the following: X1 is Gly, X... 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X 34 It's Pro. The peptide analogue comprises an N-terminal region which is linked by a peptide bond to the amino group of an amino acid residue at position 1 (X1) of the peptide analogue. The N-terminal region is selected from SGS, GSG, SG, GS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240). The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0298] In some embodiments, the peptide analogs of this disclosure have a peptide sequence selected from any one of SEQ ID NO:1 to SEQ ID NO:8, wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, the peptide described herein contains at least one amino acid substitution selected from the following: X1 is Gly, X... 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X. 34 It's Pro. The peptide analogue comprises an N-terminal region that is linked by a peptide bond to the amino group of an amino acid residue at position 1 (X1) of the peptide analogue, wherein the N-terminal region is selected from S-(GS). n (GS) n G-(SG) n (SG) n (S) n (G) n (ES) n and (RV) n , where n is an integer from 2 to 12; (PAS) n (RSF) n (KSF)n (LRV) n (RVG) n and (KVG) n , where n is an integer from 2 to 8; and (RSFG) n (GKSF) n (LLRV) n and (GKVG) n , where n is an integer from 2 to 6; The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0299] In some embodiments, the peptide analogs of this disclosure have a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, said peptide optionally comprises one or more single amino acid substitutions selected from the following: X1 is Gly, X 10 Is it Asp or Glu, X?19 It's His, X 14 It's His, X3 is His and X. 34 It's Pro. The peptide analogue comprises an N-terminal region which is linked by a peptide bond to the amino group of an amino acid residue at position 1 (X1) of the peptide analogue. The N-terminal region is selected from SGS, GSG, SG, GS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240). The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0300] In some embodiments, the peptide analogs of this disclosure have a peptide sequence selected from any one of SEQ ID NO:9 to SEQ ID NO:89, wherein the carboxyl group at the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any location may contain one or more single amino acid substitutions, for example at positions X1, X3 to X6, and X8 to X. 37 Any part of it contains one, two, three, four, five, or six single amino acid substitutions. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, said peptide optionally comprises one or more single amino acid substitutions selected from the following: X1 is Gly, X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X. 34 It's Pro. The peptide analogue comprises an N-terminal region that is linked by a peptide bond to the amino group of an amino acid residue at position 1 (X1) of the peptide analogue, wherein the N-terminal region is selected from S-(GS). n (GS) n G-(SG) n (SG) n (S) n (G) n (ES) n and (RV) n , where n is an integer from 2 to 12; (PAS) n (RSF) n (KSF) n (LRV) n (RVG) n and (KVG) n , where n is an integer from 2 to 8; and (RSFG) n (GKSF) n (LLRV) n and (GKVG) n , where n is an integer from 2 to 6; The peptide analogues mentioned therein are agonists of the GCRP receptor.

[0301] In a preferred embodiment, the N-terminal region is selected from SGS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240).

[0302] In some embodiments, the N-terminal region is selected from SGS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240).

[0303] In some embodiments, the N-terminal region is selected from SGS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF, and GKSF (SEQ ID NO:240).

[0304] In some embodiments of this disclosure, the N-terminal single amino acid, N-terminal dipeptide, N-terminal tripeptide, or N-terminal peptide is a linker, such as an inactive linker.

[0305] In some embodiments, the adapter does not substantially affect the potency of the CGRP peptide. In some embodiments, the adapter does not substantially affect the agonistic potency (EC50) of the CGRP peptide agonist.

[0306] In some embodiments, an N-terminal single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or an N-terminal peptide contributes to one or more of the potency, binding affinity, or efficacy of the CGRP peptide analog to the CGRP receptor, such as increasing and / or maintaining one or more of the potency, binding affinity, or efficacy of the CGRP peptide analog to the CGRP receptor.

[0307] In some implementations, the connector does not substantially affect the T½ of the CGRP peptide.

[0308] In some implementations, the connector has virtually no effect on the solubility of the CGRP peptide.

[0309] In some embodiments of this disclosure, the N-terminal single amino acid, N-terminal dipeptide, N-terminal tripeptide, or N-terminal peptide is a connector capable of linking the CGRP peptide analog to another entity.

[0310] In some embodiments of this disclosure, the N-terminal single amino acid, N-terminal dipeptide, N-terminal tripeptide, or N-terminal peptide is a connector capable of linking the CGRP peptide analog to another peptide or protein; for example, a therapeutic peptide, a therapeutic protein, a circulating peptide, or a circulating protein.

[0311] In some embodiments of this disclosure, the CGRP peptide analog comprises another peptide or protein attached to the N-terminus of the CGRP peptide analog; for example, attached to the N-terminus of a single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or the N-terminus of an N-terminal peptide.

[0312] In some embodiments of this disclosure, the CGRP peptide analog comprises a therapeutic peptide, therapeutic protein, circulating peptide, or circulating protein attached to the N-terminus of the CGRP peptide analog; for example, attached to the N-terminus of a single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or the N-terminus of an N-terminal peptide.

[0313] In some embodiments of this disclosure, the CGRP peptide analog comprises another peptide or protein connected to the N-terminus of the CGRP peptide analog via its C-terminus; for example, connected to the N-terminus of the CGRP peptide analog via its C-terminus as a single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or the N-terminus of an N-terminal peptide.

[0314] In some embodiments of this disclosure, the CGRP peptide analog comprises a therapeutic peptide, therapeutic protein, circulating peptide, or circulating protein connected via its C-terminus to the N-terminus of the CGRP peptide analog; for example, a single amino acid, an N-terminal dipeptide, an N-terminal tripeptide, or the N-terminus of an N-terminal peptide connected via its C-terminus to the N-terminus of the CGRP peptide analog.

[0315] The term "its C-terminus" in this document refers to the C-terminus of "another protein," such as the C-terminus of the therapeutic peptide, therapeutic protein, circulating peptide, or circulating protein.

[0316] In some embodiments of this disclosure, the other peptide or protein is albumin, an Fc domain, or an albumin-binding domain (ABD).

[0317] In some embodiments of this disclosure, the circulating protein or peptide is selected from albumin, the Fc domain, or the albumin-binding domain (ABD).

[0318] The crystallizable fragment domain (Fc domain) is the tail region where antibodies interact with cell surface receptors called Fc receptors and some proteins in the complement system. This region allows antibodies to activate the immune system, for example, by binding to Fc receptors. The albumin-binding domain (ABD) is a small triple-helical protein domain found in various surface proteins expressed by Gram-positive bacteria.

[0319] In some embodiments of this disclosure, peptide analogs having sequences selected from the following are provided: SGS-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 90); RSF-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 91); RV-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 92); SGSGSGSGS–GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:93); PAS-SCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:94); ES-SCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:95); KKKKKK-SCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:96); AAAAAA-SCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:97); PAS-GCNTATCVTHHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:98); SGSG-GCNTATCVTHHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:99); RSFG-GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO: 100); RVG-GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:101); PAS-SCHTATTCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:102; SGSG-SCHTATTCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:103); LRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:104); RSF-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:105); SGS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:106); SGSG-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:107); LLRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:108); SGS-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:109); RSF-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:110); RV-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:111; PAS-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:112; LRV-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:113; SGS-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:114); RSF-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:115); RV-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:116); PAS-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:117); LRV-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:118); SGS-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:119; RSF-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:120); RV-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:121); PAS-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:122; LRV-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:123; SGS-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:124); RSF-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:125); RV-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:126); PAS-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:127); LRV-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:128); SGS-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:129); RSF-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:130); RV-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:131); PAS-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:132; LRV-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:133; SGS-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:134); RSF-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:135); RV-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:136); PAS-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:137); LRV-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:138; SGS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:139); RSF-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:140); RV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:141); PAS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:142); LRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:143; SGS-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:144; RSF-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:145); RV-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:146); PAS-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:147: LRV-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:148); SGS-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:149); RSF-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:150); RV-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:151); PAS-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:152; LRV-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:153); SGS-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:154); RSF-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:155); RV-GCHTATCVTNRLAGLLRSSGGMVKSNFVPTNVGSKAF(SEQ ID NO:156); PAS-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:157) LRV-GCHTATTCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:158); SGS-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:159) RSF-GCNTATCVTHRLAHLLSRHGGMVKSNFVPPTNVGSKAF(SEQ ID NO:160); RV-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:161) PAS-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:162) LRV-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:163) SGS-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:164) RSF-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:165) RV-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:166) PAS-GCHTATTCVTHRLAHLLSRHGGMVKSNFVPPTNVGSKAF(SEQ ID NO:167); LRV-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:168) SGS-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:169) RSF-GCNTATCVTHRLAGLSRSGGLVKSNFVPTNVGSKAF(SEQ ID NO:170); RV-GCNTATCVTHRLAGLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO: 171); PAS-GCNTATCVTHRLAGLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO: 172); LRV-GCNTATCVTHRLAGLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO: 173); RVG-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 174); KVG-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 175); GKVG-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 176); K-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 177); KSF-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 178); KSF-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 179); and GKSF-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 180); The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:90 to SEQ ID NO:180, which includes positions X1, X3 to X6 and X8 to X 37 One or more single amino acid substitutions at any point in the mixture. The peptide may optionally contain one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala; X19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? The analogues mentioned above are agonists of the GCRP receptor.

[0320] Preferably, the peptide analogue of any one of SEQ ID NO:90 to SEQ ID NO:180 does not contain amino acid substitutions at one or more amino acid residues indicated in bold in the amino acid sequence.

[0321] In some embodiments, the functional variant of any one of SEQ ID NO:90 to SEQ ID NO:180 is located at positions X1, X3 to X6, and X8 to X 37 Each of the following contains one, two, three, four, five, or six single amino acid substitutions. In some embodiments, the functional variant of any of SEQ ID NO:90 to SEQ ID NO:180 is located at positions X1, X3 to X6, and X8 to X... 37 It contains one, two, three, four, five or six single conserved amino acid substitutions at any point.

[0322] In some embodiments, the functional variant of any one of SEQ ID NO:90 to SEQ ID NO:180 is located at positions X1, X3 to X6, and X8 to X6, other than one or more amino acid residues indicated in bold in the amino acid sequence of any one of SEQ ID NO:90 to SEQ ID NO:180. 37 It contains one, two, three, four, five, or six single amino acid substitutions at any point.

[0323] In some embodiments, the peptide analog of any one of SEQ ID NO:90 to SEQ ID NO:180 comprises at least one amino acid substitution selected from: X1 is Gly, X 10 Is it Asp or Glu, X? 19 It's His, X 14It's His, X3 is His and X. 34 It is Pro. In some embodiments, the peptide analog of any one of SEQ ID NO:90 to SEQ ID NO:180 comprises at least one amino acid substitution selected from: X1 is Gly, X 10 Is it Asp or Glu, X? 19 It's His and X 14 It's His.

[0324] CGRP peptide analogs with acylation / linkers

[0325] In some embodiments, the CGRP analogs disclosed herein comprise an acyl group (“Z”) linked to an amino group present in an amino acid residue of the CGRP analog.

[0326] In some embodiments, the CGRP analogs of this disclosure comprise a linker (“Y”) and an acyl group (“Z”) forming a YZ moiety attached to an amino group present on an amino acid residue in the CGRP analog.

[0327] In some embodiments of this disclosure, hydrogen has been removed from one of the amino groups present in the amino acid residues of the CGRP peptide analog, wherein a linker (“Y”) and an acyl group (“Z”) form a YZ moiety which is linked to an amino group present in the amino acid residues of the CGRP peptide analog “X”.

[0328] In some embodiments, the acyl group (referred to as Z) and / or the acyl group linked to the linker (referred to as Y) should have sufficient albumin-binding affinity. In some embodiments, the addition of the -YZ- moiety will increase the half-life of CGRP peptide X or CGRP peptide analogues (“prolongation effect”).

[0329] In some embodiments, the peptide analogs disclosed herein contain an acyl Z group.

[0330] In some embodiments, the peptide analogs disclosed herein comprise an acyl Z group attached to an amino group of an N-terminal amino acid residue of the peptide analog.

[0331] In some embodiments, the peptide analogs disclosed herein include a linker Y.

[0332] In some implementations, the connector Y is selected from the following formula:

[0333] Where m is an integer from 0 to 6, for example, m is 0, 1, 2, 3, 4, 5 or 6; n is an integer from 1 to 3, for example, n is 1, 2 or 3; s is an integer from 0 to 3, for example, where s is 0, 1, 2, or 3; and p is an integer from 1 to 23, for example, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23. Furthermore, the carbonyl end of the connector is attached to the N-terminal amino acid residue of the peptide analog.

[0334] In some embodiments, the peptide analogs of this disclosure comprise a connector Y, wherein the connector comprises one or more portions independently selected from: i. α-amino acids, γ-amino acids, and ω-amino acids, ii. Glu, γ-Glu, iso-Glu, β-Asp, Asp, β-Ala, Lys, γ-aminobutyric acid and Gly, and iii. [8-Amino-3,6-dioxanoic acid] n (AEEA) n ), where n is an integer from 1 to 20, such as an integer from 1 to 5, 1 to 4, 1 to 3 or 1 to 2; such as an integer from 1, 2, 3, 4 or 5, preferably 1 or 2.

[0335] In some embodiments, the peptide analogs disclosed herein comprise a linker Y selected from AEEA, 2AEEA, isoGlu-AEEA, isoGlu-2AEEA, γGlu-AEEA, and γGlu-2AEEA.

[0336] In some embodiments, the connector Y is attached to the amino group of the N-terminal amino acid residue of the peptide analog.

[0337] In some embodiments, the acyl group Z or the linker Y is attached to the amino group of the N-terminal amino acid residue of the CGRP peptide analog, wherein the amino group is selected from position X. -9 amino, X -8 amino, X -7 amino, X -6 amino, X -5 amino, X -4 amino, X -3 amino, X -2 amino, X -1 The amino group of X1 and the amino group of X2.

[0338] In some implementations, the amino terminus of the connector Y is linked to the acyl group Z.

[0339] In some implementations, the acyl group of Z is derived from fatty acids or fatty diacids.

[0340] In some implementations, the acyl group of Z is derived from a fatty diacid having α and ω carboxyl groups.

[0341] In some embodiments, the acyl group of Z contains the formula CH3(CH2). n The acyl group of CO-, where n is an integer from 4 to 24; for example, where n is an integer from 8 to 20, 10 to 20, 12 to 20, 14 to 20, or 14 to 18.

[0342] In some embodiments, the acyl group of Z comprises an acyl group of the formula COOH(CH2)nCO-, where n is an integer from 4 to 24; for example, where n is an integer from 8 to 20, 10 to 20, 12 to 20, 14 to 20, or 14 to 18.

[0343] In some implementations, the acyl group of Z is derived from a fatty acid or fatty acid diacid having 12-22 carbon atoms.

[0344] In some embodiments, the acyl group of Z is derived from a fatty acid or fatty acid having 14 carbon atoms. In some embodiments, the acyl group of Z is derived from a fatty acid or fatty acid having 16 carbon atoms.

[0345] In some implementations, the acyl group of Z is derived from a fatty acid or fatty acid diacid with 18 carbon atoms.

[0346] In some implementations, the acyl group of Z is derived from a fatty acid or fatty acid diacid with 20 carbon atoms.

[0347] In some embodiments, the acyl group is selected from HOOC(CH2)14CO, HOOC(CH2)16CO, HOOC(CH2)18CO, CH3(CH2)14CO, CH3(CH2)16CO and CH3(CH2)18CO.

[0348] In a preferred embodiment, the N-terminal amino acid of the CGRP peptide analog disclosed herein comprises an acyl group and a linker.

[0349] In some embodiments, the N-terminal amino acid of the peptide analog of this disclosure comprises an acyl group and a linker selected from the following: HOOC(CH2)16CO-isoGlu-AEEA, HOOC(CH2)16CO-isoGlu-2AEEA, HOOC(CH2)14CO-isoGlu-AEEA, HOOC(CH2)14CO-isoGlu-2AEEA, HOOC(CH2)16CO-isoGlu-AEEA, and HOOC(CH2)16CO-isoGlu-2AEEA.

[0350] In some embodiments, the N-terminal amino acid of the peptide analog of this disclosure comprises an acyl group selected from the following: HOOC(CH2)16CO-isoGlu, HOOC(CH2)14CO-isoGlu, and HOOC(CH2)18CO-isoGlu.

[0351] In some embodiments, the N-terminal amino acid of the peptide analog of this disclosure comprises an acyl group selected from the following: CH3(CH2)14CO-γ-Glu, CH3(CH2)16CO-γGlu and CH3(CH2)18CO-γGlu.

[0352] In a preferred embodiment, the N-terminal amino acid of the CGRP peptide analog disclosed herein comprises HOOC(CH2)16CO-isoGlu-AEEA.

[0353] In some embodiments, the peptide analogs of this disclosure further comprise polyethylene glycol (PEG). In some embodiments, the CGRP peptide analogs of this disclosure further comprise biomarkers, such as fluorescent markers.

[0354] Composition and administration

[0355] The peptide analogues disclosed herein can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracerebrospinal injection or infusion, subcutaneous injection or implantation), by inhalation spray, nasal, vaginal, rectal, sublingual or local administration routes, and can be formulated alone or together in suitable dose-unit formulations containing conventional, non-toxic, pharmaceutically acceptable carriers, adjuvants and mediators suitable for each route of administration.

[0356] Although the peptide analogs disclosed herein can be administered alone, they are generally preferred to be presented as pharmaceutical formulations. Formulations typically comprise the active ingredient and one or more acceptable carriers thereof. Each carrier should be both pharmaceutically and physiologically acceptable in the sense of compatibility with other ingredients and harmlessness to the subject. Therapeutic formulations can be prepared by any method well known in the pharmaceutical field.

[0357] One aspect of the present invention is to provide a composition comprising the CGRP peptide analog of the present disclosure, and optionally further comprising a carrier.

[0358] A pharmaceutical composition comprising the CGRP peptide analog of the present disclosure, optionally comprising a pharmaceutically acceptable carrier, excipient, or diluent.

[0359] Medical use

[0360] Another aspect of the present invention is to provide CGRP peptide analogs, compositions, and pharmaceutical compositions according to the present disclosure, which are used as pharmaceuticals.

[0361] In some embodiments, CGRP peptide analogs of the present disclosure are provided for use in treating diseases selected from: cardiovascular diseases; neurological disorders; infections; kidney diseases; metabolic diseases; bone diseases; ischemic diseases; inflammatory diseases; gastrointestinal diseases; and pain, such as nociceptive pain and / or neuropathic pain.

[0362] In some embodiments, methods for treating diseases selected from: cardiovascular diseases; neurological disorders; infections; kidney diseases; metabolic diseases; bone diseases; ischemic diseases; inflammatory diseases; gastrointestinal diseases; and pain, such as nociceptive pain and / or neuropathic pain, are provided, said methods comprising one or more steps of administering a therapeutically effective amount of the disclosed CGRP peptide analogue to an individual in need.

[0363] In some embodiments, the use of the CGRP peptide analogs disclosed herein in the preparation of medicaments for treating diseases selected from: cardiovascular diseases; neurological disorders; infections; kidney diseases; metabolic diseases; bone diseases; ischemic diseases; inflammatory diseases; gastrointestinal diseases; and pain, such as nociceptive pain and / or neuropathic pain.

[0364] In some implementations, the cardiovascular disease is ischemic heart disease.

[0365] Example

[0366] Example 1: Peptide Synthesis

[0367] Peptide analogs can be produced, for example, by classical peptide synthesis methods, such as solid-phase peptide synthesis using t-Boc or Fmoc chemistry, or other established techniques, see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1999.

[0368] Peptide analogs can be covalently linked via disulfide bonds (—S—S—) between cysteine ​​residues at positions 2 and 7. Cyclation of the disulfide bonds can optionally occur in the presence of a suitable protecting group after peptide purification or before cleavage from the resin during solid-phase peptide synthesis. The disulfide bonds can be formed spontaneously by stirring the peptide in the presence of oxygen, or by treating the peptide with another suitable oxidant, such as iodine (I₂), optionally in the presence of a base.

[0369] To stabilize disulfide bonds, unprotected peptides can be used to directly initiate disulfide bond bonding procedures under mild, biocompatible reaction conditions (aqueous medium, low to ambient temperature, and mild pH). The key objective of this strategy is to insert minimal linkers (e.g., methylene groups) into the disulfide bonds while maintaining the structural integrity necessary for the peptide's biological activity.

[0370] WO 2011 / 051312 describes the synthesis of the CGRP analog HOOC(CH2)16CO-isoGlu-AEEA-SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2).

[0371] Example 2: Determining potency in cell-based assays

[0372] The potency of peptide analogs was determined in a cell-based CGRP receptor assay for cAMP accumulation using a cAMP detection kit (VKEY-BIO-A010012).

[0373] HEK293 cells were transfected with CGRP receptor subunits and frozen in aliquots.

[0374] The peptide analogue was dissolved in DMSO and serially diluted 10 times in 4-fold serial dilutions in assay buffer (HBSS (Gibco-14025-076), 20 mM HEPES, 0.1% HSA (Sigma-A1653), 500 μM IBMX (Sigma-I5879), pH 7.4).

[0375] 100 nL of solution was added to each well of a 384-well assay plate (PerkinElmer-6007299) using a liquid processor (Labcyte, Echo 555).

[0376] Thaw the cells, wash twice with HBSS, and resuspend them in assay buffer.

[0377] Add 5,000 cells to each well (in 10 μl).

[0378] Shake the test plate for 20 seconds, centrifuge (1000 rpm) for 10 seconds, and incubate (23°C) for 60 minutes.

[0379] Then add 10 μl of Eu2-labeled antibody / cAMP tracer solution to each well (50 μl Eu2-labeled antibody + 50 μl cAMP tracer in 5 ml detection buffer).

[0380] Shake the plate for 20 seconds, centrifuge (1000 rpm) for 10 seconds, incubate (23°C) for 1 hour, and then read the plate using an Envision microplate reader (Perkin Elmer).

[0381] All peptide analogs were assayed in duplicate, and the power (EC) was calculated using curve fitting (4-parameter nonlinear regression) with the aid of GraphPad Prism 10.1.0. 50 The values ​​are as follows. Each assay plate contains comparison sequences SEQ ID NO:2 (acylation) and SEQ ID NO:3 to account for differences between plates and assays.

[0382] Unless otherwise specified in the table below, all tested CGRP peptide analogs contained a linker / fatty acylation (HOOC(CH2)16CO-isoGlu-AEEA) attached to an N-terminal amino acid. Unless otherwise specified in the table below, all tested CGRP peptide analogs also had a C-terminal amidation (-NH2).

[0383] The results obtained using the above method are reproduced in the table below: ++++: EC 50 Below 6 nM +++: EC 50 >6 to 16 nM ++: EC 50 >16 to 200 nM +: EC 50 >200 nM EC 50 >1000 nM

Claims

1. A sequence (CGRP) 1-37 Peptide analogues of calcitonin gene-related peptide (CGRP): X1CX3TATCVTHRLAX 14 LLX 17 RSGGX 22 X 23 KX 25 NFVPTX 31 VGSX 35 AF(SEQ ID NO:1), Where X1 is Ala or Ser, X3 is Asp or Asn, X 14 Is it Asp or Gly, X 17 Is it Arg or Ser, X 22 Is it Val or Met, Χ 23 Is it Val or Leu, X 25 Is it Asp, Asn, or Ser, X 31 Is it Asp or Asn, X 35 It is either Glu or Lys, and the carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:1, wherein the positions are X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue contains at least one amino acid substitution selected from the following: X1 is either Gly or His. X3 is His, Arg, Gly, Met, or Lys. X4 is Ile. X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr? X 14 Is it His, Glu, or Asp? X 17 It's Ala. X 19 It's His. X 22 Is it Ile, Leu, or Val? X 23 Is it Ser or His? X 24 Is it Arg or His? X 25 Is it Lys, Asn, Asp, Glu, Arg, or His? X 26 It's His. X 27 It's His. X 28 It's His. X 29 It's His. X 31 Is it Asp or His? X 34 It is Pro, and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

2. The peptide analog of claim 1, wherein the peptide analog has a sequence selected from the group consisting of CGRP. 1-37 CGRP analogues: SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), ACDTATCVTHRLAGLLSRSGGVVKNNFVPTNVGSKAF (SEQ ID NO: 3); ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 4); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (SEQ ID NO:5); SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (SEQ ID NO:6), SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSEAF (SEQ ID NO:7); and SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (SEQ ID NO:8), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2 to SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

3. The peptide analog according to any one of the preceding claims, wherein the peptide analog has a sequence selected from the group consisting of CGRP. 1-37 β-CGRP analogues: SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), ACNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:4), SCNTATCVTHRLAGLLSRSGGVVKDNFVPTNVGSKAF (SEQ ID NO:6), and SCNTATCVTHRLADLLSRSGGVLKDNFVPTDVGSEAF (SEQ ID NO:8), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:6 and SEQ ID NO:8, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

4. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an analog of SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:2), The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of SEQ ID NO:2, wherein the positions are X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The peptide analogue described herein contains at least one amino acid substitution selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

5. The peptide analog according to any one of the preceding claims, having a peptide sequence selected from: HCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:9); SCNTATCVTQRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:10); SCNTATCVTTRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 11); SCNTATCVTHRLAGLLSRSGGMHKSNFVPTNVGSKAF (SEQ ID NO: 12); SCNTATCVTHRLAGLLSRSGGMVHSNFVPTNVGSKAF (SEQ ID NO:13); SCNTATCVTHRLAGLLSRSGGMVKNNFVPTNVGSKAF (SEQ ID NO:14); SCNTATCVTHRLAGLLSRSGGMVKRNFVPTNVGSKAF (SEQ ID NO:15); SCNTATCVTHRLAGLLSRSGGMVKHNFVPTNVGSKAF (SEQ ID NO:16); SCNTATCVTHRLAGLLSRSGGMVKSNFHPTNVGSKAF (SEQ ID NO: 17); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSHAF (SEQ ID NO:18), GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:19); SCHTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 20); SCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO: 21); SCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:22); SCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:23); SCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:24); SCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:25); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:26); SCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:27); SCNTATCVTHRLAGLLSRSGGMVKSHFVPTNVGSKAF(SEQ ID NO:28); SCNTATCVTHRLAGLLSRSGGMVKSNHVPTNVGSKAF(SEQ ID NO:29); SCNTATCVTHRLAGLLSRSGGMVKSNFVHTNVGSKAF(SEQ ID NO:30); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTHVGSKAF(SEQ ID NO:31); SCRTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:32); SCGTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:33); SCKTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:34; SCMTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:35); SCNIATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:36); SCNTATCVTARLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:37); SCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:38); SCNTATCVTGRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:39); SCNTATCVTSRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:40); SCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:41); GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:42); SCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:43); SCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:44); GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:45); SCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:46); SCNTATCVTHRLAGLLSRSGGVVKSNFVPTNVGSKAF(SEQ ID NO:47); SCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSKAF(SEQ ID NO:48); SCNTATCVTHRLAGLLSRSGGMVKDNFVPTNVGSKAF(SEQ ID NO:49); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTDVGSKAF(SEQ ID NO:50); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSEAF(SEQ ID NO:51); SCNTATCVTHRLADLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:52); SCNTATCVTHRLAGLLSRSGGMSKSNFVPTNVGSKAF(SEQ ID NO:53); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSSAF(SEQ ID NO:54); SCHTATCVTDRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:55); SCNIATCVTHRLAGLLSRHGGMVKSNFHPTNVGSKAF(SEQ ID NO:56); SCNIATCVTDRLAGLLSRSGGMVKKNFVPTNVGSKAF(SEQ ID NO:57); SCNIATCVTHRLAGLLSRSGGIVKSNFHPTNVGSKAF(SEQ ID NO:58); SCNTATCVTDRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:59); SCNTATCVTQRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:60); SCNTATCVTHRLAHLLSRSGGIVKRNFVPTNVGSKAF(SEQ ID NO:61); SCNTATCVTHRLAHLLARHGGMVKSNFVPTNVGSKAF(SEQ ID NO:62; GCNTATCVTHRLAHLLSRSGGMVKHNFVPTNVGSKAF(SEQ ID NO:63); GCHTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:64); SCNTATCVTHRLAGLLSRSGGLVKSNFHPTNVGPKAF(SEQ ID NO:65); SCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGPKAF(SEQ ID NO:66); SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:67); GCHTATCVTNRLAHLLARHGGIVKKNFVPTNVGPKAF(SEQ ID NO:68); GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:69); GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:70); GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:71); GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:72; GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:73); GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:74); GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:75); GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:76); GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:77); GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:78); GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:79); GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:80); GCNTATCVTHRLADLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:81); GCNTATCVTHRLAELLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:82); GCNTATCVTHRLAGLLSRSGGMVKENFVPTNVGSKAF (SEQ ID NO:83); GCHTATCVTHRLADLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:84); GCHTATCVTHRLAELLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:85); GCHTATCVTHRLAGLLSRSGGMVKENFVPTNVGSKAF (SEQ ID NO:86); GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSKAF (SEQ ID NO:87); GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSRAF (SEQ ID NO:88); and GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:89); The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any of SEQ ID NO:9 to SEQ ID NO:89, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. Optionally, the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog. The peptide analogues mentioned therein are agonists of the GCRP receptor.

6. The peptide analog of claim 5, wherein the peptide comprises one or more single amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

7. The peptide analog according to any one of claims 5 and 6, wherein the peptide analog having any one of SEQ ID NO:9 to SEQ ID NO:89 does not contain amino acid substitutions at one or more amino acid residues indicated in bold in the amino acid sequence of any one of SEQ ID NO:9 to SEQ ID NO:

89.

8. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least one single amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

9. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises 1 amino acid substitution, such as 2 single amino acid substitutions, such as 3 single amino acid substitutions, such as 4 single amino acid substitutions, such as 5 single amino acid substitutions, such as 6 single amino acid substitutions, such as 7 single amino acid substitutions, such as 8 single amino acid substitutions, such as 9 single amino acid substitutions, wherein each amino acid substitution is independently selected from: X1 is Gly or His; X3 is His, Arg, Gly, Met or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

10. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least two single amino acid substitutions selected from the group consisting of: X1 being Gly or His; X3 being His, Arg, Gly, Met, or Lys; X4 being Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

11. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises two or more single amino acid substitutions selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

12. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least three single amino acid substitutions selected from the group consisting of: X1 being Gly or His; X3 being His, Arg, Gly, Met, or Lys; X4 being Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

13. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises three or more single amino acid substitutions selected from the group consisting of: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly, X3 is His and X 34 It's Pro.

14. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least one single amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It is His, X1 is Gly and X3 is His; or selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X1 is Gly and X. 34 It is Pro; or selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 It's His, X3 is His and X. 34 It's Pro.

15. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least one single amino acid substitution selected from: X 10 Is it Asp or Glu, X? 19 It's His, X 14 His and X1 are Gly.

16. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises at least one amino acid substitution selected from: X 10 It's Asp, X 10 It is Glu, X 19 It's His, X 14 It's His, X 25 It's His, X 25 It's Arg, X 28 It's His, X 35 It is Ser, X1 is His, and X 23 It's His.

17. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It's His, X3 is His, X 25 It's His, X 28 It is His, X1 is His, X 23 It's His, X 24 It's His, X 35 It's His, X 26 It's His, X 27 It's His, X 29 It is His, and X 31 It's His.

18. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It's His, X 25 It's His, X 28 It is His, X1 is His, and X 23 It's His.

19. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises a His amino acid substitution for at least one amino acid selected from the group consisting of: X 19 It's His, X 14 It is His and X3 is His.

20. The peptide analog according to any one of the preceding claims, wherein X 19 It's His.

21. The peptide analog according to any one of the preceding claims, wherein X 19 It is His, and the peptide analog also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

22. The peptide analog according to any one of the preceding claims, wherein X 14 It could be His, Glu, or Asp.

23. The peptide analog according to any one of the preceding claims, wherein X 14 It's His.

24. The peptide analog according to any one of the preceding claims, wherein X 14 It is His, and the peptide analog also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

25. The peptide analog according to any one of the preceding claims, wherein X 19 It is His and X 14 It's His.

26. The peptide analog according to any one of the preceding claims, wherein X 19 It is His and X3 is His.

27. The peptide analog according to any one of the preceding claims, wherein X 14 It is His and X3 is His.

28. The peptide analog according to any one of the preceding claims, wherein X 19 It's His, X 14 It is His and X3 is His.

29. The peptide analog according to any one of the preceding claims, wherein X3 is His.

30. The peptide analog according to any one of the preceding claims, wherein X3 is His, and the peptide analog further comprises one or more amino acid substitutions selected from: X1 is Gly or His; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X3 represents His and X. 10 Is it Asp or Glu? For example, where X3 is His, X 10 Is it Asp or Glu and X? 19 It's His.

31. The peptide analog according to any one of the preceding claims, wherein X1 is Gly.

32. The peptide analog according to any one of the preceding claims, wherein X1 is Gly, and X 19 Is it His, X 14 His and X3 are one or more of His; For example, X1 is Gly and X 19 It is His; For example, X1 is Gly and X 14 It is His; For example, where X1 is Gly, X 19 It is His and X 14 It is His; For example, X1 is Gly and X3 is His; For example, where X1 is Gly, X 19 It is His and X3 is His; For example, where X1 is Gly, X 14 It is His and X3 is His; For example, where X1 is Gly, X 19 It's His, X 14 It is His and X3 is His.

33. The peptide analog according to any one of the preceding claims, wherein X1 is Gly, and the peptide analog further comprises one or more amino acid substitutions selected from: X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X1 is Gly, and X3 is His, X 10 Is it Asp or Glu, X? 19 It's His and X 14 It is one or more of His; For example, X1 is Gly and X 10 It's ASP. For example, X1 is Gly and X 10 It's Glu. For example, where X1 is Gly, X 10 Is it Asp or Glu and X? 19 It's His. For example, where X1 is Gly, X 10 Is it Asp or Glu and X? 14 It's His. For example, where X1 is Gly, X 10 Is it Asp or Glu, X? 19 It is His and X 14 It's His.

34. The peptide analog according to any one of the preceding claims, wherein X 10 It is a negatively charged amino acid selected from Asp or Glu.

35. The peptide analog according to any one of the preceding claims, wherein X 10 X1 is a negatively charged amino acid selected from Asp or Glu, and X1 is Gly.

36. The peptide analog according to any one of the preceding claims, wherein X 10 It is ASP.

37. The peptide analog according to any one of the preceding claims, wherein X 10 It's Glu.

38. The peptide analog according to any one of the preceding claims, wherein X 10 It is Asp, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 10 It is Asp, and X 19 It is His, X3 is His and X 14 It is one or more of His; For example, X 10 It is Asp and X 19 It is His; For example, X 10 It is Asp and X3 is His; For example, X 10 It is Asp and X 14 It is His; For example, X 10 It's Asp, X 19 It is His and X3 is His; For example, X 10 It is Asp and X1 is Gly.

39. The peptide analog according to any one of the preceding claims, wherein X 10 It is Glu, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 10 It is Asp, and X 19 It is His, X3 is His and X 14 It is one or more of His; For example, X 10 It is Glu and X 19 It is His; For example, X 10 Glu and X3 are His; For example, X 10 It is Glu and X 14 It is His; For example, X 10 It is Glu, X 19 It is His and X3 is His; For example, X 10 Glu and X1 are Gly.

40. The peptide analog according to any one of the preceding claims, wherein X 34 It is Pro, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; and X 35 Is it His, Glu, Arg, or Ser? For example, X 34 It's Pro; and X 14 Is it His, X 19 It is His, X1 is Gly, X3 is His and X 10 It is one or more of Asp or Glu; For example, X 34 The Pro and X1 both use Gly. For example, X 34 It's the Pro and X 14 It is His; For example, X 34 It's the Pro and X 19 It is His; For example, X 34 The Pro and X3 are His; For example, X 34 It's Pro, X 14 It is His and X 19 It is His; For example, X 34 It's Pro; and X 10 Is it Asp or Glu? For example, X 34 It's Pro; X1 is Gly, X3 is His and X 10 It is either Asp or Glu.

41. The peptide analog according to any one of the preceding claims, wherein X 14 It is either Glu or Asp, for example, where X 14 It is Glu, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 14 Is it Glu or Asp; and X 19 X1 is one or more of His, X2 is Gly, and X3 is one or more of His; For example, X 14 Is it Glu or Asp, and X? 19 It is His; For example, X 14 It is either Glu or Asp, and X1 is Gly; For example, X 14 It is either Glu or Asp, and X3 is His.

42. The peptide analog according to any one of the preceding claims, wherein X 10 It is Asn, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 10 It is Asn, and X3 is His, X 14 Is it His, X 19 His and X1 are one or more of Gly; For example, X 10 It is Asn, X3 is His, X 14 It is His and X 19 It is His; For example, X 10 X1 is Asn, X3 is His, and X1 is Gly; For example, X 10 It is Asn and X1 is Gly.

43. The peptide analog according to any one of the preceding claims, wherein X 17 It is Ala, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 17 It is Ala, and X1 is Gly, X3 is His, X 10 Is it Asp or Asn, X? 19 Is it His, X 14 It's His and X 34 It is one or more of the Pro components; For example, X 17 It is Ala and X 10 It is ASP; For example, X 17 It is Ala and X 10 It is Asn; For example, X 17 It is Ala; and X 19 Is it His and / or X? 14 It is His; For example, X 17 It is Ala and X1 is Gly.

44. The peptide analog according to any one of the preceding claims, wherein X 22 It is Ile or Leu, and the peptide analog further comprises one or more amino acid substitutions selected from: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 22 It's Ile, and X1 is Gly, X 19 Is it His, X 14 It is His, X3 is His, X 10 It is Asn, X 24 It is Arg, X 28 Is it His, X 17 It's Ala and X 34 It is one or more of the Pro components; For example, X 22 It's Leu, and X1 is Gly, X 28 It's His and X 34 It is one or more of the Pro components.

45. The peptide analog according to any one of the preceding claims, wherein X 24 It is His, and the peptide analog also contains one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

46. ​​The peptide analog according to any one of the preceding claims, wherein X4 is Ile, and the peptide analog further comprises one or more amino acid substitutions selected from: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X4 is Ile, and X 10 It is Asp, X 19 Is it His, X 28 It's His and X 22 It is one or more of Ile.

47. The peptide analog according to any one of the preceding claims, wherein X 24 It is Arg and X 35 It's Arg.

48. The peptide analog according to any one of the preceding claims, wherein X 25 It is either Asp or Glu, for example, where X 25 It is Glu, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 Is it His, Glu, Arg, or Ser? For example, X 25 X1 is Glu, X3 is His, and X1 is one or more of Gly.

49. The peptide analog according to any one of the preceding claims, wherein when X 24 When it is Arg, X 25 It's not Lys.

50. The peptide analog according to any one of the preceding claims, wherein X 31 It is Asp, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 28 It is His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

51. The peptide analog according to any one of the preceding claims, wherein X 35 It is His or Arg, and the peptide analog further comprises one or more amino acid substitutions selected from the following: X1 is Gly or His; X3 is His, Arg, Gly, Met, or Lys; X4 is Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 28 It is His; X 31 It is Asp; and X 34 It's Pro.

52. The peptide analog according to any one of the preceding claims, wherein the amino acids at positions X5 and X6 are not substituted; for example, wherein X5 is Ala and X6 is Thr.

53. The peptide analog according to any one of the preceding claims, wherein the amino acid at any one of positions X4, X5 and X6 is not substituted; for example, wherein X4 is Thr, X5 is Ala and X6 is Thr.

54. The peptide analog according to any one of the preceding claims, wherein the amino acid at any one of positions X4, X5, X6 and X8 is not substituted; for example, wherein X4 is Thr, X5 is Ala, X6 is Thr and X8 is Val.

55. The peptide analog according to any one of the preceding claims, wherein X4 is Thr, X5 is Ala, X6 is Thr, X8 is Val, X9 is Thr, X... 16 It is Leu, X 17 It is Ser, X 22 It is Met, X 30 It is Thr and X 32 It is one or more of Val.

56. The peptide analog according to any one of the preceding claims, wherein the peptide analog does not contain amino acid substitutions selected from the group consisting of: X4 being Asp, X5 being Asp, X6 being Asp, X8 being Asp, X9 being Asp, X... 17 It is Asp and X 22 It is ASP.

57. The peptide analog according to any one of the preceding claims, wherein X4 is not Asp or Glu; X5 is not Asp, Glu, or Arg; and X6 is not Asp, Glu, Arg, or His.

58. The peptide analog according to any one of the preceding claims, wherein X 17 It is Ser; for example, X in it 17 Not Asp, Arg, or Ile.

59. The peptide analog according to any one of the preceding claims, wherein X 22 It is Met; for example, where X is... 22 Not Asp, Gln, or His.

60. The peptide analog according to any one of the preceding claims, wherein X 16 It's Leu, X 30 It is Thr and X 32 It is Val; for example, X in it. 16 X 30 and X 32 Neither of them is His.

61. The peptide analog according to any one of the preceding claims, wherein X 10 Not Arg or Lys.

62. The peptide analog according to any one of the preceding claims, wherein X 14 It's not Ile.

63. The peptide analog according to any one of the preceding claims, wherein X 19 It's not Asp or Glu.

64. The peptide analog according to any one of the preceding claims, comprising at least one amino acid substitution selected from the group consisting of: X1 being His, X... 10 It is Thr, X 14 It's His, X 19 It's His, X 23 It's His, X 25 Is it Arg or His, and X? 28 It's His.

65. The peptide analog according to any one of the preceding claims, wherein a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is present at positions X1, X3 to X6, and X8 to X9. 37 Any part contains 1 to 6 single amino acid substitutions, such as 1 to 5, 1 to 4, 1 to 3, or 1 to 2 single amino acid substitutions.

66. The peptide analog according to any one of the preceding claims, wherein a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is present at positions X1, X3 to X6, and X8 to X9. 37 Any part of it contains 6, for example 5, for example 4, for example 3, for example 2, for example 1 single amino acid substitution.

67. The peptide analog according to any one of the preceding claims, wherein a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is located at positions X4, X5, X6, X8, X9, X... 11 X 12 X 13 X 15 X 16 X 18 X 20 X 21 X 26 X 27 X 29 To X 33 X 36 and X 37 Any place in the middle; For example, at positions X5, X6, X8, X9, X 11 X 12 X 13 X 15 X 16 X 18 X 20 X 21 X 30 X 32 X 33 X 36 and X 37 Any place in the middle; For example, at positions X8, X9, X 11 X 12 X 13 X 15 X 16 X 18 X 20 X 21 X 30 X 32 X 33 X 36 and X 37 Any place in the middle; For example, at position X 11 X 12 X 13 X 15 X 18 X 20 X 21 X 33 X 36 and X 37 Any place in the middle; For example, at position X 11 X 12 X 13 X 15 X 18 X 20 X 21 and X 33 any place It contains 1 to 6, for example 1 to 5, for example 1 to 4, for example 1 to 3, for example 1 to 2 single amino acid substitutions. For example, it may contain 1, 2, 3, 4, 5, or 6 single amino acid substitutions.

68. The peptide analog according to any one of the preceding claims, wherein a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is present at positions X1, X3 to X6, and X8 to X9. 37 Any part contains 1 to 4, for example 1 to 3, for example 1 to 2, for example 1 single amino acid substitution.

69. The peptide analog according to any one of the preceding claims, wherein a functional variant of any one of SEQ ID NO:1 to SEQ ID NO:89 is present at positions X1, X3 to X6, and X8 to X9. 37 Any part contains 1 to 5, for example, one, two, three, four, five or six single conserved amino acid substitutions.

70. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an agonist of the human GCRP receptor.

71. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an agonist of the GCRP receptor at systemic pH or physiological pH.

72. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an agonist of the GCRP receptor, and its EC50... 50 A (nM) value of 16 nM or lower, such as less than 16 nM, e.g., EC 50 The (nM) value is 0.01 to 16 nM, for example 0.1 to 16 nM, for example 1 to 16 nM, for example >6 nM to 16 nM.

73. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an agonist of the GCRP receptor, and its EC50... 50 Values ​​of 6 nM or lower, such as 5 nM or lower, such as 4 nM or lower, such as 3 nM or lower, such as 2 nM or lower, such as 1 nM or lower, such as 0.5 nM or lower, such as 0.1 nM or lower; For example, EC 50 The value ranges from 0.01 to 6 nM, for example, 0.1 to 6 nM, or 1 to 6 nM; For example, EC 50 The value ranges from 0.01 to 1.0, for example, 0.1 to 1.0 nM.

74. The peptide analog according to any one of the preceding claims, wherein the peptide analog is an agonist of the GCRP receptor, and its EC50... 50 The value is the EC of a polypeptide consisting of the amino acid sequence SEQ ID NO:2, which is linked to the N-terminal amino acid HOOC(CH2)16CO-isoGlu-AEEA. 50 At least 0.5 times the value; For example, EC 50 EC of HOOC(CH2)16CO-isoGlu-AEEA-SEQ ID NO:2 50 The value is at least 0.75 times, for example at least 1 time, for example at least 1.5 times, for example at least 2 times, for example at least 2.5 times, for example at least 3 times, for example at least 3.5 times, for example at least 4 times, for example at least 5 times; For example, EC 50 EC with value HOOC(CH2)16CO-isoGlu-AEEA-SEQ ID NO:2 50 Values ​​of 0.5 to 10 times, for example 0.5 to 5 times, for example 0.5 to 4 times, for example 0.5 to 3 times, for example 0.5 to 2 times, for example 0.5 to 1.5 times, for example 1.0 to 10 times, for example 1.0 to 5 times.

75. The peptide analog according to any one of the preceding claims, wherein an intramolecular disulfide bond (-SS-) is contained between the Cys amino acid residue at position 2 (X2) and the Cys amino acid residue at position 7 (X7).

76. The peptide analog according to any one of the preceding claims, wherein the Cys amino acid residue at position 2 (X2) and the Cys amino acid residue at position 7 (X7) contain a disulfide bond with a linker such as a methylene linker, for example -S-[CH2]-S-.

77. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises an N-terminal region selected from a single N-terminal amino acid and an N-terminal peptide consisting of 2 to 30 consecutive amino acids, which is linked by a peptide bond to an amino group of an amino acid residue at position 1 (X1) of the peptide analog.

78. The peptide analog according to any one of the preceding claims, wherein the N-terminal region is composed of naturally occurring amino acid residues independently selected from Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N and C.

79. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises an N-terminal single amino acid; an N-terminal dipeptide; or an N-terminal tripeptide, which is attached by a peptide bond to the amino group of the amino acid residue at position 1 (X1) of the peptide analog.

80. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises an N-terminal peptide consisting of 4 to 30 consecutive amino acid residues, said amino acid residues being independently selected from Ala, Leu, Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, and Met; for example, independently selected from the amino acid residues Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn, and Met; for example, Glu, Lys, and Met.

81. The peptide analog according to any one of the preceding claims, wherein the peptide analog comprises an N-terminal single amino acid of Lys; or an N-terminal single amino acid selected from Trp, Tyr, Phe and 3-(1-naphthyl)alanine.

82. The peptide analog according to any one of the preceding claims, comprising an N-terminal region, said N-terminal region being linked by a peptide bond to an amino group of an amino acid residue at position 1 (X1) of the CGRP peptide, wherein said N-terminal region is: It is neither an aromatic amino acid nor a single N-terminal amino acid of Lys(K). N-terminal dipeptide or N-terminal tripeptide, or An N-terminal peptide consisting of 2 to 30 consecutive amino acid residues and containing one or more amino acids selected from the following: Gly (G), Pro (P), Phe (F), and Val (V).

83. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises 2 to 3 consecutive amino acid residues, for example 3 to 4, for example 4 to 5, for example 5 to 6, for example 6 to 7, for example 7 to 8, for example 8 to 9, for example 9 to 10, for example 10 to 11, for example 11 to 12, for example 12 to 13, for example 13 to 14, for example 14 to 15, for example 15 to 16, for example 16 to 17, for example 17 to 18, for example 18 to 19, for example 19 to 20, for example 20 to 21, for example 21 to 22, for example 22 to 23, for example 23 to 24, for example 24 to 25, for example 25 to 26, for example 26 to 27, for example 27 to 28, for example 28 to 29, for example 29 to 30 consecutive amino acid residues; For example, the N-terminal peptide described herein is composed of 2 to 30 consecutive amino acid residues, such as 2 to 25, 2 to 20, 2 to 19, 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3 consecutive amino acid residues. For example, the N-terminal peptide described herein is composed of 2 consecutive amino acid residues, such as 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, or 30 consecutive amino acid residues. For example, the N-terminal peptide described therein consists of 2 to 20 consecutive amino acid residues, such as 2 to 15 consecutive amino acid residues, such as 2 to 10 consecutive amino acid residues, such as 2 to 5 consecutive amino acid residues.

84. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises one or more amino acids selected from the group consisting of Gly and Pro; for example, wherein the N-terminal peptide comprises at least one Gly amino acid; for example, wherein the N-terminal peptide comprises at least one Pro amino acid.

85. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises one or more amino acids selected from the group consisting of Phe and Val; for example, wherein the N-terminal peptide comprises at least one Phe amino acid; for example, wherein the N-terminal peptide comprises at least one Val amino acid.

86. The peptide analog according to any one of the preceding claims, wherein the N-terminal single amino acid or the N-terminal peptide does not contain any amino acid having a charged side chain selected from Arg, His, Lys, Asp, and Glu; for example, wherein the N-terminal single amino acid or the N-terminal peptide contains an amino acid having a charged side chain selected from Arg, His, Lys, Asp, and Glu.

87. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises at least one His amino acid; for example, it comprises one His amino acid.

88. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises one or more amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys; For example, the N-terminal peptide described therein is composed of 2 to 30 amino acids independently selected from Ser, Gly, Arg, Phe, Val, Ala, Pro, Glu, Leu, and Lys.

89. The peptide analog according to any one of the preceding claims, wherein the N-terminal single amino acid is not an aromatic amino acid selected from Trp, Tyr, Phe and 3-(l-naphthyl)alanine; for example, wherein the N-terminal single amino acid is selected from the amino acids Gly, Pro and Val.

90. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises or is composed of the following sequence: X -9 X -8 X -7 X -6 X -5 X -4 X -3 X -2 X -1 (SEQ ID NO:233), Where X -1 The peptide is linked to the amino group of X1 of the peptide analog via a peptide bond. in: X -9 Selected from: Nonexistent, Ser, and Gly X -8 Selected from: Nonexistent, Gly, and Ser. X -7 Selected from: Nonexistent, Ser, and Gly X -6 Selected from: Nonexistent, Gly, Ser, Lys, and Ala. X -5 Selected from: Nonexistent, Ser, Gly, Lys, and Ala. X -4 Selected from: Nonexistent, Gly, Ser, Lys, Ala, Arg, and Leu. X -3 Selected from: Nonexistent, Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X -2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala; The optional N-terminal peptide contains at least one amino acid selected from the following: Gly, Pro, Phe, and Val.

91. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises or is composed of the following sequence: X -4 X -3 X -2 X -1 (SEQ ID NO:234), Where X -1 The peptide is linked to the amino group of X1 of the peptide analog via a peptide bond. in: X -4 Selected from: Gly, Ser, Lys, Ala, Arg, and Leu. X -3 Selected from: Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X -2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala; Optionally, the N-terminal peptide comprises at least one amino acid selected from the following: Gly, Pro, Phe, and Val.

92. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises or is composed of the following sequence: X -3 X -2 X -1 , Where X -1 The peptide is linked to the amino group of X1 of the peptide analog via a peptide bond. Where X -3 X -2 and X -1 Each of them is independently selected from Ser, Gly, Arg, Phe, Val, Pro, Glu, Ala, Leu, and Lys.

93. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises or is composed of the following sequence: X -3 X -2 X -1 , Where X -1 The peptide is linked to the amino group of X1 of the peptide analog via a peptide bond. in: X -3 Selected from: Ser, Gly, Arg, Pro, Lys, Ala, and Leu. X -2 Selected from: Gly, Ser, Arg, Ala, Glu, Lys, Phe, and Val, and X -1 Selected from: Ser, Gly, Phe, Val, Lys, and Ala.

94. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises or consists of a sequence selected from the following: SGS, GSG, SG, GS, RSF, RSFG (SEQ ID NO:237), RV, RVG, LRV, LLRV (SEQ ID NO:238), ES, PAS, SGSG (SEQ ID NO:236), SGSGSGSGS (SEQ ID NO:235), KVG, GKVG (SEQ ID NO:239), KSF and GKSF (SEQ ID NO:239) NO:240).

95. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises a sequence selected from: S-(GS) n (GS) n G-(SG) n (SG) n (S) n (G) n (ES) n and (RV) n , where n is an integer from 2 to 12; (PAS) n (RSF) n (KSF) n (LRV) n (RVG) n and (KVG) n , where n is an integer from 2 to 8; and (RSFG) n (GKSF) n (LLRV) n and (GKVG) n , where n is an integer from 2 to 6.

96. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises a sequence selected from: S-(GS) n (GS) n G-(SG) n (SG) n (S) n and (G) n , where n is an integer from 2 to 12; for example, n is an integer from 2 to 11, for example, 2 to 10, for example, 2 to 9, for example, 2 to 8, for example, 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3.

97. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide is composed of a sequence (PAS). n Composition, where n is an integer from 2 to 8; for example, where n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3.

98. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide is derived from the sequence (ES). n Composition, where n is an integer from 2 to 12; for example, where n is an integer from 2 to 11, for example, 2 to 10, for example, 2 to 9, for example, 2 to 8, for example, 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3.

99. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises a sequence selected from: (RSFG) n , where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, or from 2 to 4, or from 2 to 3; (RSF) n , where n is an integer from 2 to 8; for example, n is an integer from 2 to 7, from 2 to 6, from 2 to 5, from 2 to 4, or from 2 to 3. (GKSF) n , where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; and (KSF) n , where n is an integer from 2 to 8; for example, n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3.

100. The peptide analog according to any one of the preceding claims, wherein the N-terminal peptide comprises a sequence selected from: (LLRV) n , where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, or from 2 to 4, or from 2 to 3; (LRV) n , where n is an integer from 2 to 8; for example, n is an integer from 2 to 7, from 2 to 6, from 2 to 5, from 2 to 4, or from 2 to 3. (RV) n , where n is an integer from 2 to 12; for example, n is an integer from 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, or 2 to 3. (RVG) n , where n is an integer from 2 to 8; for example, n is an integer from 2 to 7, from 2 to 6, from 2 to 5, from 2 to 4, or from 2 to 3. (GKVG) n , where n is an integer from 2 to 6; for example, where n is an integer from 2 to 5, for example, 2 to 4, for example, 2 to 3; and (KVG) n , where n is an integer from 2 to 8; for example, n is an integer from 2 to 7, for example, 2 to 6, for example, 2 to 5, for example, 2 to 4, for example, 2 to 3.

101. The peptide analog according to any one of claims 94 to 99, wherein n=1, for example, wherein n=2, for example, wherein n=3, for example, wherein n=4, for example, wherein n=5, for example, wherein n=6, for example, wherein n=7, for example, wherein n=8, for example, wherein n=9, for example, wherein n=10, for example, wherein n=11, for example, wherein n=12.

102. The peptide analog according to any one of the preceding claims, having a sequence selected from: SGS-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:90); RSF-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:91); and RV-GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:92); SGSGSGSGS–GCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:93); PAS-SCNTATCVTHRLAGLSRSGGMVKSNFVPTNVGSKAF (SEQ ID NO:94); ES-SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:95); KKKKKK-SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:96); AAAAAA-SCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:97); PAS-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:98); SGSG-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:99); RSFG-GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:100; RVG-GCHTATCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:101); PAS-SCHTATTCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:102; SGSG-SCHTATTCVTNRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:103); LRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:104); RSF-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:105); SGS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:106); SGSG-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:107); LLRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:108); SGS-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:109); RSF-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:110); RV-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:111; PAS-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:112; LRV-GCNTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:113; SGS-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:114); RSF-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:115); RV-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:116); PAS-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:117); LRV-GCNTATCVTHRLAHLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:118); SGS-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:119; RSF-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:120); RV-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:121); PAS-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:122; LRV-GCNTATCVTHRLAGLLARSGGMVKSNFVPTNVGSKAF(SEQ ID NO:123; SGS-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:124); RSF-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:125); RV-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:126); PAS-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:127); LRV-GCNTATCVTHRLAGLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:128); SGS-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:129); RSF-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:130); RV-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:131); PAS-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:132; LRV-GCNTATCVTHRLAGLLSRSGGIVKSNFVPTNVGSKAF(SEQ ID NO:133; SGS-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:134); RSF-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:135); RV-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:136); PAS-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:137); LRV-GCNTATCVTHRLAGLLSRSGGMVRKNFVPTNVGSKAF(SEQ ID NO:138; SGS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:139); RSF-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:140); RV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:141); PAS-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:142); LRV-GCNTATCVTHRLAGLLSRSGGMVKSNFVPTNVGPKAF(SEQ ID NO:143; SGS-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:144; RSF-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:145); RV-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:146); PAS-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:147: LRV-GCNTATCVTERLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:148); SGS-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:149); RSF-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:150); RV-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:151); PAS-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:152); LRV-GCNTATCVTDRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:153); SGS-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:154); RSF-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:155); RV-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:156); PAS-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:157; LRV-GCHTATCVTNRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:158); SGS-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:159); RSF-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:160); RV-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:161); PAS-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF(SEQ ID NO:162); LRV-GCNTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:163); SGS-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:164); RSF-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:165); RV-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:166); PAS-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:167); LRV-GCHTATCVTHRLAHLLSRHGGMVKSNFVPTNVGSKAF (SEQ ID NO:168); SGS-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:169); RSF-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:170); RV-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:171); PAS-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:172); LRV-GCNTATCVTHRLAGLLSRSGGLVKSNFVPTNVGSKAF (SEQ ID NO:173); RVG-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:174); KVG-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:175); GKVG-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:176); K-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:177); KSF-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:178); KSF-GCNTATCVTHRLAGLLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO:179); and GKSF-GCNTATCVTHRLAGLSRSGGMVRSNFVPTNVGSRAF (SEQ ID NO: 180); The carboxyl group in the C-terminal amino acid residue is amidated. Or a functional variant of any one of SEQ ID NO:90 to SEQ ID NO:180, wherein the position is X1, X3 to X6 and X8 to X 37 Any part of it contains one or more single amino acid substitutions. The analogues mentioned above are agonists of the GCRP receptor.

103. The peptide analog of claim 102, wherein the peptide comprises one or more single amino acid substitutions selected from the group consisting of: X1 being Gly or His; X3 being His, Arg, Gly, Met, or Lys; X4 being Ile; X 10 Is it Ala, Asn, Asp, Gln, Glu, Gly, Ser, or Thr; X 14 Is it His, Glu, or Asp; X 17 It is Ala;X 19 It is His; X 22 Is it Ile, Leu, or Val; X 23 Is it Ser or His; X 24 Is it Arg or His; X 25 Is it Lys, Asn, Asp, Glu, Arg, or His; X 26 It is His; X 27 It is His; X 28 It is His; X 29 It is His; X 31 Is it Asp or His; X 34 It's Pro; and X 35 It is His, Glu, Arg, or Ser.

104. The peptide analog according to any one of claims 102 and 103, wherein the peptide analog of any one of SEQ ID NO:90 to SEQ ID NO:180 does not contain amino acid substitutions at one or more amino acid residues indicated in bold in the amino acid sequence.

105. The peptide analog according to any one of the preceding claims, comprising an acyl group Z.

106. The peptide analog according to any one of the preceding claims, comprising an acyl group Z of an amino group attached to an N-terminal amino acid residue of the peptide analog.

107. The peptide analog according to any one of the preceding claims, comprising a linker Y.

108. The peptide analog according to any one of the preceding claims, comprising a linker Y selected from: and Where m is an integer from 0 to 6, for example, m is 0, 1, 2, 3, 4, 5 or 6; n is an integer from 1 to 3, for example, n is 1, 2 or 3; s is an integer from 0 to 3, for example, where s is 0, 1, 2, or 3; and p is an integer from 1 to 23, for example, p is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23. Furthermore, the carbonyl end of the connector is attached to the N-terminal amino acid residue of the peptide analog.

109. A peptide analog according to any one of the preceding claims, comprising a connector Y, wherein the connector comprises one or more portions independently selected from: a. α-amino acids, γ-amino acids, and ω-amino acids, b. Glu, γ-Glu, iso-Glu, β-Asp, Asp, β-Ala, Lys, γ-aminobutyric acid, and Gly, and c. [8-Amino-3,6-dioxanoic acid] n (AEEA) n ), where n is an integer from 1 to 20, such as an integer from 1 to 5, 1 to 4, 1 to 3 or 1 to 2; such as an integer from 1, 2, 3, 4 or 5, preferably 1 or 2.

110. The peptide analog according to any one of the preceding claims, comprising a linker selected from: AEEA, 2AEEA, isoGlu-AEEA, isoGlu-2AEEA, γGlu-AEEA, and γGlu-2AEEA.

111. The peptide analog according to any one of the preceding claims, comprising a linker Y of an amino group attached to an N-terminal amino acid residue of the peptide analog.

112. The peptide analog according to any one of the preceding claims, wherein the acyl group Z or the linker Y is attached to the amino group of the N-terminal amino acid residue of the peptide analog, which is selected from X. -9 amino, X -8 amino, X -7 amino, X -6 amino, X -5 amino, X -4 amino, X -3 amino, X -2 amino, X -1 The amino group of X1 and the amino group of X2.

113. The peptide analog according to any one of the preceding claims, wherein the amino terminus of the linker Y is linked to the acyl group Z.

114. The peptide analog according to any one of the preceding claims, wherein the acyl group of Z is derived from a fatty acid or fatty acid diacid.

115. The CGRP analogue according to any one of the preceding claims, wherein the acyl group of Z comprises the formula CH3(CH2). n An acyl group of CO-, where n is an integer from 4 to 24; or where the acyl group of Z contains the formula COOH(CH2). n The acyl group of CO-, where n is an integer from 4 to 24; For example, n can be an integer from 8 to 20, 10 to 20, 12 to 20, 14 to 20, or 14 to 18.

116. The peptide analog according to any one of the preceding claims, wherein the acyl group of Z is derived from a fatty acid or fatty acid having 12-22 carbon atoms; for example, a fatty acid or fatty acid having 14, 16, 18 or 20 carbon atoms.

117. The peptide analog according to any one of the preceding claims, wherein the N-terminal amino acid of the peptide analog comprises an acyl group selected from the group consisting of HOOC(CH2)14CO, HOOC(CH2)16CO, HOOC(CH2)18CO, CH3(CH2)14CO, CH3(CH2)16CO and CH3(CH2)18CO.

118. The peptide analog according to any one of the preceding claims, wherein the N-terminal amino acid of the peptide analog comprises an acyl group and a linker selected from the group consisting of HOOC(CH2)16CO-isoGlu-AEEA, HOOC(CH2)16CO-isoGlu-2AEEA, HOOC(CH2)14CO-isoGlu-AEEA, HOOC(CH2)14CO-isoGlu-2AEEA, HOOC(CH2)18CO-isoGlu-AEEA, and HOOC(CH2)18CO-isoGlu-2AEEA.

119. The peptide analog according to any one of the preceding claims, wherein the N-terminal amino acid of the peptide analog comprises an acyl group selected from HOOC(CH2)16CO-isoGlu, HOOC(CH2)14CO-isoGlu and HOOC(CH2)18CO-isoGlu.

120. The peptide analog according to any one of the preceding claims, wherein the N-terminal amino acid of the peptide analog comprises an acyl group selected from CH3(CH2)14CO-γ-Glu, CH3(CH2)16CO-γ-Glu and CH3(CH2)18CO-γ-Glu.

121. A composition comprising a peptide analog according to any one of the preceding claims, optionally further comprising a carrier.

122. A pharmaceutical composition comprising a peptide analog according to any one of the preceding claims, optionally further comprising a pharmaceutically acceptable carrier, excipient, or diluent.

123. The peptide analog, composition, and pharmaceutical composition according to any one of the preceding claims, used as a medicine.

124. A method of treating a peptide analog, composition, or pharmaceutical composition according to any one of the preceding claims for the treatment of a disease selected from: cardiovascular diseases, such as ischemic heart disease; neurological disorders; infections; kidney diseases; metabolic diseases; bone diseases; ischemic diseases; inflammatory diseases; gastrointestinal diseases; and pain, such as nociceptive pain and / or neuropathic pain.

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