Novel cyclopeptide inhibitors of PSD-95

Abstract

The present disclosure relates to novel cyclic peptides that can act as inhibitors of protein-protein interactions, particularly by inhibition of the PDZ2 domain of PSD-95, for use in the treatment of excitotoxicity-related diseases and neuropathic pain.

Description

Technical Field

[0001] The present disclosure relates to novel cyclic peptides that can act as inhibitors of protein-protein interactions, particularly by inhibiting the PDZ domain of PSD-95, such as PDZ2, and to the use of these cyclic peptides in the treatment of excitotoxicity-related diseases and neuropathic pain. Background Art

[0002] Postsynaptic density protein 95 (PSD-95) is an extremely abundant postsynaptic density (PSD) scaffolding protein that regulates the assembly and / or dissociation of protein complexes to transmit neuronal stimuli. PSD-95 belongs to the family of PSD membrane-associated guanylate kinase (MAGUK) scaffolding proteins. All PSD-MAGUK family members share the same protein interaction domains and consist of: three N-terminal PSD-95, discs-large, zonula occludens-1 (ZO-1) (PDZ) domains, followed by Src homology 3 (SH3) and non-enzymatic guanylate kinase (GK) domains. The biological functions of PSD-MAGUK proteins are related to the synaptic trafficking and anchoring of ionotropic glutamate receptors and thus regulate the synaptic plasticity of glutamatergic postsynaptic neurons.

[0003] Through its PDZ domain, PSD-95 indirectly regulates the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) via, for example, stargazin and N-methyl-D-aspartic acid receptor (NMDAR). PSD-95 directly binds to the C-terminal tail of the GluN2 subunit of NMDAR via a canonical binding mode and regulates receptor signaling and surface expression. In addition, PDZ-mediated PSD-95 interactions associate NMDAR with intracellular signaling proteins (e.g., neuronal nitric oxide synthase (nNOS)). Importantly, nNOS binds to the PDZ domain of PSD-95 via an internal motif (non-canonical binding mode), which is structurally restricted within the β-hairpin of nNOS.

[0004] The ternary complex between NMDAR, PSD-95 and nNOS plays an important role in the mechanisms of neuronal excitotoxicity and cell death during acute ischemic stroke (AIS) ( Figure 1 ). The binding of glutamate to NMDAR induces Ca 2+ -mediated neuronal signaling, which plays an important role in synaptic plasticity and cell survival. The excessive synaptic release of glutamate during AIS activates increased Ca 2+ influx, leading to cytotoxicity and neuronal damage. One cause of Ca 2+The mechanism of dependent excitotoxicity is mediated by the NMDAR / PSD-95 / nNOS ternary complex. Specifically, nNOS and NMDAR bind to PSD-95 simultaneously through PDZ-mediated interactions, bringing nNOS and NMDAR into close proximity, and are subsequently activated by an increase in local Ca 2+ concentration. Activated nNOS causes neuronal cell death by overproducing nitric oxide (NO).

[0005] Due to low neuroprotective efficiency and severe side effects, directly inhibiting NMDAR to treat AIS has failed. Therefore, the following research has focused on targeting NMDAR downstream via modulating PSD-95 as an alternative neuroprotective strategy for AIS treatment. The research results show that eliminating PSD-95-mediated interactions reduces NO synthesis but preserves NMDAR activity, which encourages this approach. To date, two peptide-based methods have been clinically studied as potential therapies targeting the NMDAR / PSD-95 / nNOS receptor complex for stroke treatment: Nerinetide (NA-1) and AVLX-144 target the PDZ domain of PSD-95 by mimicking the binding of the C-terminal PDZ-binding region of GluN2B, thus dissociating NMDAR and nNOS and preventing NO synthesis without blocking NMDAR signaling. Summary of the Invention

[0006] To address the problem of providing inhibitors of protein-protein interactions by specifically targeting the PDZ domain of PSD-95, the present disclosure describes a class of novel cyclic peptides that can non-canonically bind to the PDZ domain of PSD-95 (such as the PDZ2 domain of PSD-95), thereby inhibiting its protein-protein interaction with GluN2B for treating ischemic stroke and neuropathic pain; methods for manufacturing and using said peptides.

[0007] In one aspect, the present disclosure relates to a peptide comprising the amino acid sequence

[0008] IETTFX1X2X3RIETSFX4C (SEQ ID NO:1)

[0009] wherein:

[0010] X1 is independently selected from the group consisting of A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0011] X2 is independently selected from the group consisting of G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0012] X3 is independently selected from the group consisting of N, C, F, G, H, L, R, W, and Y;

[0013] X4 is independently selected from the group consisting of T, F, G, H, I, L, N, S, V, W, and Y;

[0014] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0015] In another aspect, the present disclosure relates to a composition comprising a peptide as described herein.

[0016] In another aspect, the present disclosure relates to a polynucleotide encoding a peptide as described herein.

[0017] In another aspect, the present disclosure relates to a vector comprising a polynucleotide as described herein.

[0018] In another aspect, the present disclosure relates to a host cell comprising a polynucleotide as described herein or a vector as described herein.

[0019] In another aspect, the present disclosure relates to a peptide as described herein, a composition as described herein, a polynucleotide as described herein, a vector as described herein, or a host cell as described herein, for use as a medicament.

[0020] In another aspect, the present disclosure relates to a peptide as described herein, a composition as described herein, a polynucleotide as described herein, a vector as described herein, or a host cell as described herein, for preventing and / or treating excitotoxicity-related diseases in a subject.

[0021] In another aspect, the present disclosure relates to a method for preventing and / or treating excitotoxicity-related diseases and / or neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as described herein, a composition as described herein, a polynucleotide as described herein, a vector as described herein, or a host cell as described herein.

[0022] In another aspect, the present disclosure relates to the use of a peptide as described herein, a composition as described herein, a polynucleotide as described herein, a vector as described herein, or a host cell as described herein in the preparation of a medicament for treating and / or preventing excitotoxicity-related diseases and / or neuropathic pain in a subject.

[0023] In another aspect, the present disclosure relates to a method for manufacturing a peptide as described herein, the method comprising the steps of:

[0024] a) using solid-phase peptide synthesis (SPPS) to prepare the peptide; and

[0025] b) Cyclize the peptide via thioether cyclization.

[0026] Brief Description of the Drawings

[0027] Figure 1 : Role of PSD-95 in acute ischemic stroke. Excessive release of glutamate during stroke activates NMDAR and induces Ca 2+ inward flow. Formation of a ternary complex through the PDZ-mediated interaction of PSD-95 with NMDAR and nNOS leads to nNOS activation and cytotoxicity.

[0028] Figure 2 : RaPID selection of PDZ2 / PSD-95 peptide conjugates. Higher recovery of total cDNA after binding to PDZ immobilized beads (positive) compared to streptavidin beads only (negative) indicates enrichment of PDZ2 conjugates.

[0029] Figure 3 : NGS analysis reveals enrichment of PDZ2 / PSD-95 peptide conjugates with the "TTF" motif. A) Next-generation sequencing (NGS) of the positive RaPID selection rounds shows progressive enrichment of specific cyclic peptide sequences related to the "TTF" motif. B) NGS of the negative selection rounds shows low enrichment of "TTF" peptides, indicating PDZ2 selective binding.

[0030] Figure 4 : Binding of TAMRA-GluN2B C-terminal probe to PDZ2. Saturation fluorescence polarization assays were performed to determine the binding affinity of TAMRA-GluN2B C-terminal peptide (C 探针 = 500 nM) to A) PDZ2-Avi-BTN and B) His10-SUMO-PDZ2-Avi-BTN constructs. Data are represented as mean ± SD, n = 3.

[0031] Figure 5 : Efficient binding of peptide 3 to PDZ2 / PSD-95. A) Concentration-response curves of peptides and analogs identified by RaPID, as measured in a competitive fluorescence polarization (FP) assay using the TAMRA-GluN2B peptide probe (C 探针 = 25 nM) with respect to binding to PDZ2 (C PDZ2 = 4 μM). B) IC 50 and C) K i values of the peptide inhibitor. Data are represented as mean ± SD, n = 3. n.d., not determined, K i < 0.3 μM.

[0032] Figure 6: qPCR analysis of the input and recovery libraries. A) Number of DNA molecules before and after binding to PDZ2. B) Recovery rate of the binding library.

[0033] Figure 7 : Deep mutational scanning of peptide 3. Heat map of the enrichment fraction (E) of peptide mutants selected for binding to PDZ2 (CPDZ2 = 1000 nM).

[0034] Figure 8 : Potent binding of peptides 3 and 12 to PDZ2 / PSD-95. A) Concentration-response curves of the peptide inhibitor 3 identified by RaPID and its mutant 12 (N9W), as measured in a competitive fluorescence polarization (FP) assay for binding to PDZ2 (C 探针 = 25 nM) using a TAMRA-GluN2B peptide probe (C PDZ2 = 4 μM). B) IC 50 and C) K i values of the peptide inhibitors. Data are represented as mean ± SD, n = 3. n.d., not determined, K i < 0.3 μM. Detailed Description

[0035] Definitions

[0036] "Amino acid residue" can be a natural or unnatural amino acid residue linked by a peptide bond or a bond different from a peptide bond. The amino acid residue can be in the D-configuration or the L-configuration. An amino acid residue contains an amino-terminal portion (NH2) and a carboxyl-terminal portion (COOH) separated by a central portion containing a carbon atom or a chain of carbon atoms, with at least one of them containing at least one side chain or functional group. NH2 refers to the amino group present at the amino terminus of an amino acid or a peptide, and COOH refers to the carboxyl group present at the carboxyl terminus of an amino acid or a peptide. The general term amino acid includes both natural and unnatural amino acids. Natural amino acids in the standard nomenclature listed in J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., Section 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. Unnatural amino acids are those not listed above. In addition, unnatural amino acid residues include, but are not limited to, modified amino acid residues, stereoisomers of L-amino acid residues, and D-amino acid residues.

[0037] "Equivalent amino acid residue" means an amino acid residue that can replace another amino acid residue in a polypeptide without substantially altering the structure and / or functionality of the polypeptide. Thus, equivalent amino acids have similar properties such as the volume of the side chain, the polarity of the side chain (polar or nonpolar), the hydrophobicity (hydrophobic or hydrophilic), the pH (acidic, neutral or basic), and the side chain organization of the carbon molecule (aromatic / aliphatic). Thus, "equivalent amino acid residue" can be regarded as "conservative amino acid substitution".

[0038] Within the meaning of the term "equivalent amino acid substitution" as applied herein, in one embodiment, within the amino acid groups indicated below, one amino acid can replace another amino acid:

[0039] Amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Pro, and Cys); amino acids with nonpolar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Tyr, and Met); amino acids with aliphatic side chains (Gly, Ala, Val, Leu, Ile); amino acids with cyclic side chains (Trp, His, Pro); amino acids with aromatic side chains (Phe, Tyr, Trp); amino acids with acidic (such as negatively charged) side chains (Asp, Glu); amino acids with basic (such as positively charged) side chains (Lys, Arg, His); amino acids with amide side chains (Asn, Gln); amino acids with hydroxyl side chains (Ser, Thr); amino acids with sulfur-containing side chains (Cys, Met); neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr); hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp); and hydrophobic amino acids (Leu, Ile, Val).

[0040] When the L or D form (optical isomer) is not specified, it is understood that the amino acids discussed have the natural L form, see Pure & Appl. Chem. Vol. 56(5), pp. 595 - 624 (1984), or the D form, such that the resulting peptide can be composed of L-form, D-form amino acids, or a sequence of mixed L-form and D-form.

[0041] A "functional variant" of a peptide is a peptide that can perform substantially the same function as the peptide of which it is a functional variant. Specifically, the functional variant can bind the same molecule as the peptide of which it is a functional variant, preferably with the same affinity.

[0042] The term "cell-penetrating peptide" (CPP) refers to a peptide characterized by the ability to cross the plasma membrane of mammalian cells and thereby facilitate the intracellular delivery of cargo molecules such as peptides, proteins, or oligonucleotides linked thereto.

[0043] The term "detectable moiety" refers to a moiety that can be detected by an analytical means. The detectable moiety is optionally selected from the group consisting of fluorophores, radiocontrast agents, MRI contrast agents, and radioisotopes.

[0044] As used herein, the term "effective amount" refers to an amount sufficient to achieve a desired result or to have an effect on an undesired condition. For example, a "therapeutically effective amount" refers to an amount sufficient to achieve a desired therapeutic result or to have an effect on an undesired symptom, but generally not sufficient to cause adverse side effects.

[0045] The terms "peptide", "polypeptide", or "protein" refer to polymers of amino acid residues preferably joined only by peptide bonds, whether produced naturally or synthetically. As used herein, the term "peptide" encompasses proteins, peptides, and polypeptides, where the protein, peptide, or polypeptide may or may not be post-translationally modified. Peptides are generally shorter in length than proteins and are single-stranded.

[0046] The term "PDZ" refers to postsynaptic density protein-95 (PSD-95), Drosophila homolog disc large tumor suppressor (DlgA), zonula occludens-1 protein (zo-1).

[0047] The term "PSD-95" refers to the protein PSD-95 (postsynaptic density protein 95), also known as SAP-90 (synapse-associated protein 90), which is a protein encoded by the DLG4 (disc large homolog 4) gene in humans and can be human PSD-95 (Uniprot: P78352).

[0048] A "subject in need thereof" refers to a subject who can benefit from the present invention. In one embodiment, the subject in need thereof is a subject suffering from an excitotoxicity-related disease and / or neuropathic pain. The subject to be treated is preferably a mammal, particularly a human. However, the treatment of animals such as mice, rats, dogs, cats, cows, horses, sheep, and pigs is also within the scope of the present invention.

[0049] As used herein, the term "treatment / treating" refers to the management and care of a patient for the purpose of combating a condition, disease or disorder. The term is intended to cover the full spectrum of treatment for an established disease or disorder suffered by a patient and also refers to curative, prophylactic / preventative and palliative therapies, such as the administration of the peptide or composition for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of a condition, partially arresting the clinical manifestation, disease or disorder; curing or eradicating a condition, disease or disorder; improving or alleviating a condition or symptoms, and alleviating (whether in part or in whole), whether detectable or not; and / or preventing or reducing the risk of acquiring a condition, disease or disorder, where "preventing / prevention" should be understood to refer to the management and care of a patient to impede the development of a condition, disease or disorder and includes the administration of an active compound to prevent or reduce the risk of onset of symptoms or complications. As used herein, the term "palliative" and variations thereof refer to a reduction in the degree and / or undesired manifestations of a physiological condition or symptoms, and / or a slowing or prolongation of the course of progression, as compared to not administering the composition of the present invention.

[0050] A "treatment effect / therapeutic effect" is exhibited if there is a change in the condition being treated, as measured by the criteria that constitute the definition of the term "treating / treatment". A "change" exists in the condition being treated if there is at least a 5% improvement, preferably a 10% improvement, more preferably at least 25%, even more preferably at least 50% (such as at least 75%), and most preferably at least 100% improvement. The change can be based on an improvement in the severity of the condition being treated in a subject, or on a difference in the frequency of the improved condition in a population of subjects treated with and without a bioactive agent or in combination with the pharmaceutical composition of the present invention and a bioactive agent.

[0051] Peptide

[0052] In one aspect, the present disclosure relates to a peptide comprising the amino acid sequence

[0053] IETTFX1X2X3RIETSFX4C (SEQ ID NO:1)

[0054] wherein:

[0055] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W and Y;

[0056] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0057] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0058] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0059] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0060] In some embodiments, the present disclosure relates to a peptide comprising the amino acid sequence

[0061] IETTFX1X2X3RIETSFX4C (SEQ ID NO:1)

[0062] wherein:

[0063] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0064] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0065] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0066] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0067] or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the peptide comprises the amino acid sequence

[0069] XIETTFX1X2X3RIETSFX4C (SEQ ID NO:165)

[0070] wherein:

[0071] X is any amino acid;

[0072] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0073] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0074] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0075] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0076] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0077] In some embodiments, the peptide comprises the amino acid sequence

[0078] XIETTFX1X2X3RIETSFX4C (SEQ ID NO:165)

[0079] wherein:

[0080] X is any amino acid;

[0081] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0082] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0083] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0084] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the peptide comprises the amino acid sequence

[0087] X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2)

[0088] wherein:

[0089] X D is a D-amino acid or glycine;

[0090] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0091] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0092] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0093] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0094] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0095] In some embodiments, the peptide comprises the amino acid sequence

[0096] X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2)

[0097] wherein:

[0098] X D is D-amino acid or glycine;

[0099] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0100] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0101] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0102] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0103] or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the peptide comprises the amino acid sequence

[0105] X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2)

[0106] wherein:

[0107] X D is D-phenylalanine or glycine;

[0108] X1 is independently selected from the group consisting of: A, F, H, I, N, Q, S, T, V, W, and Y;

[0109] X2 is independently selected from the group consisting of: F, G, H, N, and Q;

[0110] X3 is independently selected from the group consisting of N, G, H, and W;

[0111] X4 is independently selected from the group consisting of T, F, G, H, and W;

[0112] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0113] In some embodiments, the peptide comprises the amino acid sequence

[0114] X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2)

[0115] wherein:

[0116] X D is D-phenylalanine or glycine;

[0117] X1 is independently selected from the group consisting of A, F, H, I, N, Q, S, T, V, W, and Y;

[0118] X2 is independently selected from the group consisting of F, G, H, N, and Q;

[0119] X3 is independently selected from the group consisting of N, G, H, and W;

[0120] X4 is independently selected from the group consisting of T, F, G, H, and W;

[0121] or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the peptide is cyclized. In some embodiments, the peptide is cyclized as described in the section "Cyclic Peptides".

[0123] In some embodiments, X1 is A. In other embodiments, X1 is F. In other embodiments, X1 is H. In other embodiments, X1 is I. In other embodiments, X1 is L. In other embodiments, X1 is N. In other embodiments, X1 is Q. In other embodiments, X1 is S. In other embodiments, X1 is T. In other embodiments, X1 is V. In other embodiments, X1 is W. In other embodiments, X1 is Y.

[0124] In some embodiments, X2 is G. In other embodiments, X2 is A. In other embodiments, X2 is D. In other embodiments, X2 is E. In other embodiments, X2 is F. In other embodiments, X2 is H. In other embodiments, X2 is K. In other embodiments, X2 is L. In other embodiments, X2 is N. In other embodiments, X2 is Q. In other embodiments, X2 is R. In other embodiments, X2 is S. In other embodiments, X2 is W. In other embodiments, X2 is Y.

[0125] In some embodiments, X3 is N. In other embodiments, X3 is C. In other embodiments, X3 is F. In other embodiments, X3 is G. In other embodiments, X3 is H. In other embodiments, X3 is L. In other embodiments, X3 is R. In other embodiments, X3 is W. In other embodiments, X3 is Y.

[0126] In some embodiments, X4 is T. In other embodiments, X4 is F. In other embodiments, X4 is G. In other embodiments, X4 is H. In other embodiments, X4 is I. In other embodiments, X4 is L. In other embodiments, X4 is N. In other embodiments, X4 is S. In other embodiments, X4 is V. In other embodiments, X4 is W. In other embodiments, X4 is Y.

[0127] In some embodiments, the D - amino acid is D - phenylalanine. Those skilled in the art will understand that other D - amino acids may also be suitable for generating cyclic peptides. In some embodiments, X D is glycine. In some embodiments, X D is selected from the group consisting of D - phenylalanine and glycine, preferably D - phenylalanine.

[0128] In some embodiments, the peptide comprises, or consists of, an amino acid sequence selected from the group consisting of:

[0129] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0130] X D IETTFAGWRIETSFTC (SEQ ID NO:4);

[0131] X D IETTFFGNRIETSFTC (SEQ ID NO:5);

[0132] X DIETTFHGNRIETSFTC (SEQ ID NO:6);

[0133] X D IETTFIGNRIETSFTC (SEQ ID NO:7);

[0134] X D IETTFLGNRIETSFTC (SEQ ID NO:8);

[0135] X D IETTFNGNRIETSFTC (SEQ ID NO:9);

[0136] X D IETTFQGNRIETSFTC (SEQ ID NO:10);

[0137] X D IETTFSGNRIETSFTC (SEQ ID NO:11);

[0138] X D IETTFTGNRIETSFTC (SEQ ID NO:12);

[0139] X D IETTFVGNRIETSFTC (SEQ ID NO:13);

[0140] X D IETTFWGNRIETSFTC (SEQ ID NO:14);

[0141] X D IETTFYGNRIETSFTC (SEQ ID NO:15); X D IETTFAANRIETSFTC (SEQ ID NO:16); X D IETTFADNRIETSFTC (SEQ ID NO:17); X D IETTFAENRIETSFTC (SEQ ID NO:18); X D IETTFAFNRIETSFTC (SEQ ID NO:19); X D IETTFAHNRIETSFTC (SEQ ID NO:20); X D IETTFAKNRIETSFTC (SEQ ID NO:21); X D IETTFALNRIETSFTC (SEQ ID NO:22); X DIETTFANNRIETSFTC (SEQ ID NO:23); X D IETTFAQNRIETSFTC (SEQ ID NO:24); X D IETTFARNRIETSFTC (SEQ ID NO:25); X D IETTFASNRIETSFTC (SEQ ID NO:26); X D IETTFAWNRIETSFTC (SEQ ID NO:27); X D IETTFAYNRIETSFTC (SEQ ID NO:28); X D IETTFAGCRIETSFTC (SEQ ID NO:29); X D IETTFAGFRIETSFTC (SEQ ID NO:30); X D IETTFAGGRIETSFTC (SEQ ID NO:31); X D IETTFAGHRIETSFTC (SEQ ID NO:32); X D IETTFAGLRIETSFTC (SEQ ID NO:33); X D IETTFAGRRIETSFTC (SEQ ID NO:34); X D IETTFAGYRIETSFTC (SEQ ID NO:35); X D IETTFAGNRIETSFFC (SEQ ID NO:36); X D IETTFAGNRIETSFGC (SEQ ID NO:37); X D IETTFAGNRIETSFHC (SEQ ID NO:38); X D IETTFAGNRIETSFIC (SEQ ID NO:39); X D IETTFAGNRIETSFLC (SEQ ID NO:40); X D IETTFAGNRIETSFNC (SEQ ID NO:41); X D IETTFAGNRIETSFSC (SEQ ID NO:42); X D IETTFAGNRIETSFVC (SEQ ID NO:43); X D IETTFAGNRIETSFWC (SEQ ID NO:44); X DIETTFAGNRIETSFYC (SEQ ID NO:45);

[0142] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or a functional variant thereof.

[0143] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0144] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0145] X D IETTFAGWRIETSFTC (SEQ ID NO:4);

[0146] X D IETTFFGNRIETSFTC (SEQ ID NO:5);

[0147] X D IETTFHGNRIETSFTC (SEQ ID NO:6);

[0148] X D IETTFIGNRIETSFTC (SEQ ID NO:7);

[0149] X D IETTFLGNRIETSFTC (SEQ ID NO:8);

[0150] X D IETTFNGNRIETSFTC (SEQ ID NO:9);

[0151] X D IETTFQGNRIETSFTC (SEQ ID NO:10);

[0152] X D IETTFSGNRIETSFTC (SEQ ID NO:11);

[0153] X D IETTFTGNRIETSFTC (SEQ ID NO:12);

[0154] X D IETTFVGNRIETSFTC (SEQ ID NO:13);

[0155] X DIETTFWGNRIETSFTC (SEQ ID NO:14);

[0156] X D IETTFYGNRIETSFTC (SEQ ID NO:15);

[0157] X D IETTFAANRIETSFTC (SEQ ID NO:16);

[0158] X D IETTFADNRIETSFTC (SEQ ID NO:17);

[0159] X D IETTFAENRIETSFTC (SEQ ID NO:18);

[0160] X D IETTFAFNRIETSFTC (SEQ ID NO:19);

[0161] X D IETTFAHNRIETSFTC (SEQ ID NO:20);

[0162] X D IETTFAKNRIETSFTC (SEQ ID NO:21);

[0163] X D IETTFALNRIETSFTC (SEQ ID NO:22);

[0164] X D IETTFANNRIETSFTC (SEQ ID NO:23);

[0165] X D IETTFAQNRIETSFTC (SEQ ID NO:24);

[0166] X D IETTFARNRIETSFTC (SEQ ID NO:25);

[0167] X D IETTFASNRIETSFTC (SEQ ID NO:26);

[0168] X D IETTFAWNRIETSFTC (SEQ ID NO:27);

[0169] X DIETTFAYNRIETSFTC (SEQ ID NO:28);

[0170] X D IETTFAGCRIETSFTC (SEQ ID NO:29);

[0171] X D IETTFAGFRIETSFTC (SEQ ID NO:30);

[0172] X D IETTFAGGRIETSFTC (SEQ ID NO:31);

[0173] X D IETTFAGHRIETSFTC (SEQ ID NO:32);

[0174] X D IETTFAGLRIETSFTC (SEQ ID NO:33);

[0175] X D IETTFAGRRIETSFTC (SEQ ID NO:34);

[0176] X D IETTFAGYRIETSFTC (SEQ ID NO:35);

[0177] X D IETTFAGNRIETSFFC (SEQ ID NO:36);

[0178] X D IETTFAGNRIETSFGC (SEQ ID NO:37);

[0179] X D IETTFAGNRIETSFHC (SEQ ID NO:38);

[0180] X D IETTFAGNRIETSFIC (SEQ ID NO:39);

[0181] X D IETTFAGNRIETSFLC (SEQ ID NO:40);

[0182] X D IETTFAGNRIETSFNC (SEQ ID NO:41);

[0183] X DIETTFAGNRIETSFSC (SEQ ID NO:42);

[0184] X D IETTFAGNRIETSFVC (SEQ ID NO:43);

[0185] X D IETTFAGNRIETSFWC (SEQ ID NO:44);

[0186] X D IETTFAGNRIETSFYC (SEQ ID NO:45);

[0187] or a pharmaceutically acceptable salt thereof.

[0188] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0189] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0190] X D IETTFAGWRIETSFTC (SEQ ID NO:4);

[0191] X D IETTFFGNRIETSFTC (SEQ ID NO:5);

[0192] X D IETTFHGNRIETSFTC (SEQ ID NO:6);

[0193] X D IETTFNGNRIETSFTC (SEQ ID NO:9);

[0194] X D IETTFQGNRIETSFTC (SEQ ID NO:10);

[0195] X D IETTFSGNRIETSFTC (SEQ ID NO:11);

[0196] X D IETTFVGNRIETSFTC (SEQ ID NO:13);

[0197] X D IETTFYGNRIETSFTC (SEQ ID NO:15);

[0198] X D IETTFAHNRIETSFTC (SEQ ID NO:20);

[0199] X D IETTFANNRIETSFTC (SEQ ID NO:23);

[0200] X D IETTFAGNRIETSFGC (SEQ ID NO:37);

[0201] X D IETTFAGNRIETSFHC (SEQ ID NO:38);

[0202] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0203] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0204] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0205] X D IETTFAGWRIETSFTC (SEQ ID NO:4);

[0206] X D IETTFFGNRIETSFTC (SEQ ID NO:5);

[0207] X D IETTFHGNRIETSFTC (SEQ ID NO:6);

[0208] X D IETTFNGNRIETSFTC (SEQ ID NO:9);

[0209] X D IETTFQGNRIETSFTC (SEQ ID NO:10);

[0210] X D IETTFSGNRIETSFTC (SEQ ID NO:11);

[0211] X D IETTFVGNRIETSFTC (SEQ ID NO:13);

[0212] X DIETTFYGNRIETSFTC (SEQ ID NO:15);

[0213] X D IETTFAHNRIETSFTC (SEQ ID NO:20);

[0214] X D IETTFANNRIETSFTC (SEQ ID NO:23);

[0215] X D IETTFAGNRIETSFGC (SEQ ID NO:37);

[0216] X D IETTFAGNRIETSFHC (SEQ ID NO:38);

[0217] or a pharmaceutically acceptable salt thereof.

[0218] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFTC (SEQ ID NO:3) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0219] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGWRIETSFTC (SEQ ID NO:4) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0220] In some embodiments, the peptide comprises the amino acid sequence X D IETTFFGNRIETSFTC (SEQ ID NO:5) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0221] In some embodiments, the peptide comprises the amino acid sequence X D IETTFHGNRIETSFTC (SEQ ID NO:6) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0222] In some embodiments, the peptide comprises the amino acid sequence X DIETTFIGNRIETSFTC (SEQ ID NO:7) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0223] In some embodiments, the peptide comprises the amino acid sequence X D IETTFLGNRIETSFTC (SEQ ID NO:8) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0224] In some embodiments, the peptide comprises the amino acid sequence X D IETTFNGNRIETSFTC (SEQ ID NO:9) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0225] In some embodiments, the peptide comprises the amino acid sequence X D IETTFQGNRIETSFTC (SEQ ID NO:10) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0226] In some embodiments, the peptide comprises the amino acid sequence X D IETTFSGNRIETSFTC (SEQ ID NO:11) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0227] In some embodiments, the peptide comprises the amino acid sequence X D IETTFTGNRIETSFTC (SEQ ID NO:12) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0228] In some embodiments, the peptide comprises the amino acid sequence X D IETTFVGNRIETSFTC (SEQ ID NO:13) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0229] In some embodiments, the peptide comprises the amino acid sequence XD IETTFWGNRIETSFTC (SEQ ID NO: 14 or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0230] In some embodiments, the peptide comprises the amino acid sequence X D IETTFYGNRIETSFTC (SEQ ID NO: 15 or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0231] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAANRIETSFTC (SEQ ID NO: 16) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0232] In some embodiments, the peptide comprises the amino acid sequence X D IETTFADNRIETSFTC (SEQ ID NO: 17) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0233] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAENRIETSFTC (SEQ ID NO: 18) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0234] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAFNRIETSFTC (SEQ ID NO: 19) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0235] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAHNRIETSFTC (SEQ ID NO: 20) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof).

[0236] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAKNRIETSFTC (SEQ ID NO:21) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0237] In some embodiments, the peptide comprises the amino acid sequence X D IETTFALNRIETSFTC (SEQ ID NO:22) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0238] In some embodiments, the peptide comprises the amino acid sequence X D IETTFANNRIETSFTC (SEQ ID NO:23) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0239] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAQNRIETSFTC (SEQ ID NO:24) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0240] In some embodiments, the peptide comprises the amino acid sequence X D IETTFARNRIETSFTC (SEQ ID NO:25) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0241] In some embodiments, the peptide comprises the amino acid sequence X D IETTFASNRIETSFTC (SEQ ID NO:26) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0242] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAWNRIETSFTC (SEQ ID NO:27) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0243] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAYNRIETSFTC (SEQ ID NO:28) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0244] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGCRIETSFTC (SEQ ID NO:29) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0245] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGFRIETSFTC (SEQ ID NO:30) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0246] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGGRIETSFTC (SEQ ID NO:31) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0247] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGHRIETSFTC (SEQ ID NO:32) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0248] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGLRIETSFTC (SEQ ID NO:33) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0249] In some embodiments, the peptide comprises the amino acid sequence X DIETTFAGRRIETSFTC (SEQ ID NO:34) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0250] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGYRIETSFTC (SEQ ID NO:35) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0251] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFFC (SEQ ID NO:36) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0252] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFGC (SEQ ID NO:37) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0253] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFHC (SEQ ID NO:38) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0254] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFIC (SEQ ID NO:39) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0255] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFLC (SEQ ID NO:40) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0256] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFNC (SEQ ID NO:41) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same

[0257] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFSC (SEQ ID NO:42) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same

[0258] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFVC (SEQ ID NO:43) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same

[0259] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFWC (SEQ ID NO:44) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same

[0260] In some embodiments, the peptide comprises the amino acid sequence X D IETTFAGNRIETSFYC (SEQ ID NO:45) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same

[0261] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consists of:

[0262] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0263] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0264] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0265] fIETTFHGNRIETSFTC (SEQ ID NO:49);

[0266] fIETTFIGNRIETSFTC (SEQ ID NO:50);

[0267] fIETTFLGNRIETSFTC (SEQ ID NO:51);

[0268] fIETTFNGNRIETSFTC (SEQ ID NO:52);

[0269] fIETTFQGNRIETSFTC (SEQ ID NO:53);

[0270] fIETTFSGNRIETSFTC (SEQ ID NO:54);

[0271] fIETTFTGNRIETSFTC (SEQ ID NO:55);

[0272] fIETTFVGNRIETSFTC (SEQ ID NO:56);

[0273] fIETTFWGNRIETSFTC (SEQ ID NO:57);

[0274] fIETTFYGNRIETSFTC (SEQ ID NO:58);

[0275] fIETTFAANRIETSFTC (SEQ ID NO:59);

[0276] fIETTFADNRIETSFTC (SEQ ID NO:60);

[0277] fIETTFAENRIETSFTC (SEQ ID NO:61);

[0278] fIETTFAFNRIETSFTC (SEQ ID NO:62);

[0279] fIETTFAHNRIETSFTC (SEQ ID NO:63);

[0280] fIETTFAKNRIETSFTC (SEQ ID NO:64);

[0281] fIETTFALNRIETSFTC (SEQ ID NO:65);

[0282] fIETTFANNRIETSFTC (SEQ ID NO:66);

[0283] fIETTFAQNRIETSFTC (SEQ ID NO:67);

[0284] fIETTFARNRIETSFTC (SEQ ID NO:68);

[0285] fIETTFASNRIETSFTC (SEQ ID NO:69);

[0286] fIETTFAWNRIETSFTC (SEQ ID NO:70);

[0287] fIETTFAYNRIETSFTC (SEQ ID NO:71);

[0288] fIETTFAGCRIETSFTC (SEQ ID NO:72);

[0289] fIETTFAGFRIETSFTC (SEQ ID NO:73);

[0290] fIETTFAGGRIETSFTC (SEQ ID NO:74);

[0291] fIETTFAGHRIETSFTC (SEQ ID NO:75);

[0292] fIETTFAGLRIETSFTC (SEQ ID NO:76);

[0293] fIETTFAGRRIETSFTC (SEQ ID NO:77);

[0294] fIETTFAGYRIETSFTC (SEQ ID NO:78);

[0295] fIETTFAGNRIETSFFC (SEQ ID NO:79);

[0296] fIETTFAGNRIETSFGC (SEQ ID NO:80);

[0297] fIETTFAGNRIETSFHC (SEQ ID NO:81);

[0298] fIETTFAGNRIETSFIC (SEQ ID NO:82);

[0299] fIETTFAGNRIETSFLC (SEQ ID NO:83);

[0300] fIETTFAGNRIETSFNC (SEQ ID NO:84);

[0301] fIETTFAGNRIETSFSC (SEQ ID NO:85);

[0302] fIETTFAGNRIETSFVC (SEQ ID NO:86);

[0303] fIETTFAGNRIETSFWC (SEQ ID NO:87);

[0304] fIETTFAGNRIETSFYC (SEQ ID NO:88);

[0305] or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0306] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0307] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0308] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0309] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0310] fIETTFHGNRIETSFTC (SEQ ID NO:49);

[0311] fIETTFIGNRIETSFTC (SEQ ID NO:50);

[0312] fIETTFLGNRIETSFTC (SEQ ID NO:51);

[0313] fIETTFNGNRIETSFTC (SEQ ID NO:52);

[0314] fIETTFQGNRIETSFTC (SEQ ID NO:53);

[0315] fIETTFSGNRIETSFTC (SEQ ID NO:54);

[0316] fIETTFTGNRIETSFTC (SEQ ID NO:55);

[0317] fIETTFVGNRIETSFTC (SEQ ID NO:56); fIETTFWGNRIETSFTC (SEQ ID NO:57); fIETTFYGNRIETSFTC (SEQ ID NO:58); fIETTFAANRIETSFTC (SEQ ID NO:59); fIETTFADNRIETSFTC (SEQ ID NO:60); fIETTFAENRIETSFTC (SEQ ID NO:61); fIETTFAFNRIETSFTC (SEQ ID NO:62); fIETTFAHNRIETSFTC (SEQ ID NO:63); fIETTFAKNRIETSFTC (SEQ ID NO:64); fIETTFALNRIETSFTC (SEQ ID NO:65); fIETTFANNRIETSFTC (SEQ ID NO:66); fIETTFAQNRIETSFTC (SEQ ID NO:67); fIETTFARNRIETSFTC (SEQ ID NO:68); fIETTFASNRIETSFTC (SEQ ID NO:69); fIETTFAWNRIETSFTC (SEQ ID NO:70); fIETTFAYNRIETSFTC (SEQ ID NO:71); fIETTFAGCRIETSFTC (SEQ ID NO:72); fIETTFAGFRIETSFTC (SEQ ID NO:73); fIETTFAGGRIETSFTC (SEQ ID NO:74); fIETTFAGHRIETSFTC (SEQ ID NO:75); fIETTFAGLRIETSFTC (SEQ ID NO:76); fIETTFAGRRIETSFTC (SEQ ID NO:77); fIETTFAGYRIETSFTC (SEQ ID NO:78); fIETTFAGNRIETSFFC (SEQ ID NO:79); fIETTFAGNRIETSFGC (SEQ ID NO:80); fIETTFAGNRIETSFHC (SEQ ID NO:81); fIETTFAGNRIETSFIC (SEQ ID NO:82); fIETTFAGNRIETSFLC (SEQ ID NO:83); fIETTFAGNRIETSFNC (SEQ ID NO:84); fIETTFAGNRIETSFSC (SEQ ID NO:85); fIETTFAGNRIETSFVC (SEQ ID NO:86);

[0318] fIETTFAGNRIETSFWC (SEQ ID NO:87);

[0319] fIETTFAGNRIETSFYC (SEQ ID NO:88);

[0320] or a pharmaceutically acceptable salt thereof.

[0321] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0322] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0323] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0324] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0325] fIETTFHGNRIETSFTC (SEQ ID NO:49);

[0326] fIETTFNGNRIETSFTC (SEQ ID NO:52);

[0327] fIETTFQGNRIETSFTC (SEQ ID NO:53);

[0328] fIETTFSGNRIETSFTC (SEQ ID NO:54);

[0329] fIETTFVGNRIETSFTC (SEQ ID NO:56);

[0330] fIETTFYGNRIETSFTC (SEQ ID NO:58);

[0331] fIETTFAHNRIETSFTC (SEQ ID NO:63);

[0332] fIETTFANNRIETSFTC (SEQ ID NO:66);

[0333] fIETTFAGNRIETSFGC (SEQ ID NO:80);

[0334] fIETTFAGNRIETSFHC (SEQ ID NO:81);

[0335] or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or a functional variant thereof.

[0336] In some embodiments, the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0337] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0338] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0339] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0340] fIETTFHGNRIETSFTC (SEQ ID NO:49);

[0341] fIETTFNGNRIETSFTC (SEQ ID NO:52);

[0342] fIETTFQGNRIETSFTC (SEQ ID NO:53);

[0343] fIETTFSGNRIETSFTC (SEQ ID NO:54);

[0344] fIETTFVGNRIETSFTC (SEQ ID NO:56);

[0345] fIETTFYGNRIETSFTC (SEQ ID NO:58);

[0346] fIETTFAHNRIETSFTC (SEQ ID NO:63);

[0347] fIETTFANNRIETSFTC (SEQ ID NO:66);

[0348] fIETTFAGNRIETSFGC (SEQ ID NO:80);

[0349] fIETTFAGNRIETSFHC (SEQ ID NO:81);

[0350] or a pharmaceutically acceptable salt thereof.

[0351] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFTC (SEQ ID NO:46) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0352] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGWRIETSFTC (SEQ ID NO:47) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0353] In some embodiments, the peptide comprises the amino acid sequence fIETTFFGNRIETSFTC (SEQ ID NO:48) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0354] In some embodiments, the peptide comprises the amino acid sequence fIETTFHGNRIETSFTC (SEQ ID NO:49) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0355] In some embodiments, the peptide comprises the amino acid sequence fIETTFIGNRIETSFTC (SEQ ID NO:50) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0356] In some embodiments, the peptide comprises the amino acid sequence fIETTFLGNRIETSFTC (SEQ ID NO:51) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0357] In some embodiments, the peptide comprises the amino acid sequence fIETTFNGNRIETSFTC (SEQ ID NO:52) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0358] In some embodiments, the peptide comprises the amino acid sequence fIETTFQGNRIETSFTC (SEQ ID NO:53) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0359] In some embodiments, the peptide comprises the amino acid sequence fIETTFSGNRIETSFTC (SEQ ID NO:54) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0360] In some embodiments, the peptide comprises the amino acid sequence fIETTFTGNRIETSFTC (SEQ ID NO:55) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0361] In some embodiments, the peptide comprises the amino acid sequence fIETTFVGNRIETSFTC (SEQ ID NO:56) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0362] In some embodiments, the peptide comprises the amino acid sequence fIETTFWGNRIETSFTC (SEQ ID NO:57) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0363] In some embodiments, the peptide comprises the amino acid sequence fIETTFYGNRIETSFTC (SEQ ID NO:58) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0364] In some embodiments, the peptide comprises the amino acid sequence fIETTFAANRIETSFTC (SEQ ID NO:59) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0365] In some embodiments, the peptide comprises the amino acid sequence fIETTFADNRIETSFTC (SEQ ID NO:60) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0366] In some embodiments, the peptide comprises the amino acid sequence fIETTFAENRIETSFTC (SEQ ID NO:61) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0367] In some embodiments, the peptide comprises the amino acid sequence fIETTFAFNRIETSFTC (SEQ ID NO:62) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0368] In some embodiments, the peptide comprises the amino acid sequence fIETTFAHNRIETSFTC (SEQ ID NO:63) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0369] In some embodiments, the peptide comprises the amino acid sequence fIETTFAKNRIETSFTC (SEQ ID NO:64) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0370] In some embodiments, the peptide comprises the amino acid sequence fIETTFALNRIETSFTC (SEQ ID NO:65) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0371] In some embodiments, the peptide comprises the amino acid sequence fIETTFANNRIETSFTC (SEQ ID NO:66) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0372] In some embodiments, the peptide comprises the amino acid sequence fIETTFAQNRIETSFTC (SEQ ID NO:67) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0373] In some embodiments, the peptide comprises the amino acid sequence fIETTFARNRIETSFTC (SEQ ID NO:68) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0374] In some embodiments, the peptide comprises the amino acid sequence fIETTFASNRIETSFTC (SEQ ID NO:69) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0375] In some embodiments, the peptide comprises the amino acid sequence fIETTFAWNRIETSFTC (SEQ ID NO:70) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0376] In some embodiments, the peptide comprises the amino acid sequence fIETTFAYNRIETSFTC (SEQ ID NO:71) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0377] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGCRIETSFTC (SEQ ID NO:72) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0378] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGFRIETSFTC (SEQ ID NO:73) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0379] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGGRIETSFTC (SEQ ID NO:74) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0380] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGHRIETSFTC (SEQ ID NO:75) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0381] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGLRIETSFTC (SEQ ID NO:76) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0382] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGRRIETSFTC (SEQ ID NO:77) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0383] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGYRIETSFTC (SEQ ID NO:78) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0384] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFFC (SEQ ID NO:79) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0385] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFGC (SEQ ID NO:80) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0386] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFHC (SEQ ID NO:81) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0387] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFIC (SEQ ID NO:82) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0388] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFLC (SEQ ID NO:83) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0389] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFNC (SEQ ID NO:84) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0390] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFSC (SEQ ID NO:85) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0391] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFVC (SEQ ID NO:86) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0392] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFWC (SEQ ID NO:87) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0393] In some embodiments, the peptide comprises the amino acid sequence fIETTFAGNRIETSFYC (SEQ ID NO:88) or a functional variant thereof, where f is D-phenylalanine, where the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0394] In some embodiments, the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of:

[0395] [fIETTFAGNRIETSFTC] (SEQ ID NO:120); [fIETTFAGWRIETSFTC] (SEQ ID NO:121); [fIETTFFGNRIETSFTC] (SEQ ID NO:122); [fIETTFHGNRIETSFTC] (SEQ ID NO:123); [fIETTFIGNRIETSFTC] (SEQ ID NO:124); [fIETTFLGNRIETSFTC] (SEQ ID NO:125); [fIETTFNGNRIETSFTC] (SEQ ID NO:126); [fIETTFQGNRIETSFTC] (SEQ ID NO:127); [fIETTFSGNRIETSFTC] (SEQ ID NO:128); [fIETTFTGNRIETSFTC] (SEQ ID NO:129); [fIETTFVGNRIETSFTC] (SEQ ID NO:130); [fIETTFWGNRIETSFTC] (SEQ ID NO:131); [fIETTFYGNRIETSFTC] (SEQ ID NO:132); [fIETTFAANRIETSFTC] (SEQ ID NO:133); [fIETTFADNRIETSFTC] (SEQ ID NO:134); [fIETTFAENRIETSFTC] (SEQ ID NO:135); [fIETTFAFNRIETSFTC] (SEQ ID NO:136); [fIETTFAHNRIETSFTC] (SEQ ID NO:137); [fIETTFAKNRIETSFTC] (SEQ ID NO:138); [fIETTFALNRIETSFTC] (SEQ ID NO:139); [fIETTFANNRIETSFTC] (SEQ ID NO:140); [fIETTFAQNRIETSFTC] (SEQ ID NO:141); [fIETTFARNRIETSFTC] (SEQ ID NO:142); [fIETTFASNRIETSFTC] (SEQ ID NO:143); [fIETTFAWNRIETSFTC] (SEQ ID NO:144); [fIETTFAYNRIETSFTC] (SEQ ID NO:145); [fIETTFAGCRIETSFTC] (SEQ ID NO:146); [fIETTFAGFRIETSFTC] (SEQ ID NO:147);[fIETTFAGGRIETSFTC] (SEQ ID NO:148); [fIETTFAGHRIETSFTC] (SEQ ID NO:149);

[0396] [fIETTFAGLRIETSFTC] (SEQ ID NO:150);

[0397] [fIETTFAGRRIETSFTC] (SEQ ID NO:151);

[0398] [fIETTFAGYRIETSFTC] (SEQ ID NO:152);

[0399] [fIETTFAGNRIETSFFC] (SEQ ID NO:153);

[0400] [fIETTFAGNRIETSFGC] (SEQ ID NO:154);

[0401] [fIETTFAGNRIETSFHC] (SEQ ID NO:155);

[0402] [fIETTFAGNRIETSFIC] (SEQ ID NO:156);

[0403] [fIETTFAGNRIETSFLC] (SEQ ID NO:157);

[0404] [fIETTFAGNRIETSFNC] (SEQ ID NO:158);

[0405] [fIETTFAGNRIETSFSC] (SEQ ID NO:159);

[0406] [fIETTFAGNRIETSFVC] (SEQ ID NO:160);

[0407] [fIETTFAGNRIETSFWC] (SEQ ID NO:161); and

[0408] [fIETTFAGNRIETSFYC] (SEQ ID NO:162),

[0409] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0410] In some embodiments, the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of:

[0411] [fIETTFAGNRIETSFTC](SEQ ID NO:120);

[0412] [fIETTFAGWRIETSFTC](SEQ ID NO:121);

[0413] [fIETTFFGNRIETSFTC](SEQ ID NO:122);

[0414] [fIETTFHGNRIETSFTC](SEQ ID NO:123);

[0415] [fIETTFIGNRIETSFTC](SEQ ID NO:124);

[0416] [fIETTFLGNRIETSFTC](SEQ ID NO:125);

[0417] [fIETTFNGNRIETSFTC](SEQ ID NO:126);

[0418] [fIETTFQGNRIETSFTC](SEQ ID NO:127);

[0419] [fIETTFSGNRIETSFTC](SEQ ID NO:128);

[0420] [fIETTFTGNRIETSFTC](SEQ ID NO:129);

[0421] [fIETTFVGNRIETSFTC](SEQ ID NO:130);

[0422] [fIETTFWGNRIETSFTC](SEQ ID NO:131);

[0423] [fIETTFYGNRIETSFTC](SEQ ID NO:132);

[0424] [fIETTFAANRIETSFTC](SEQ ID NO:133);

[0425] [fIETTFADNRIETSFTC](SEQ ID NO:134);

[0426] [fIETTFAENRIETSFTC](SEQ ID NO:135);

[0427] [fIETTFAFNRIETSFTC](SEQ ID NO:136);

[0428] [fIETTFAHNRIETSFTC](SEQ ID NO:137);

[0429] [fIETTFAKNRIETSFTC](SEQ ID NO:138);

[0430] [fIETTFALNRIETSFTC](SEQ ID NO:139);

[0431] [fIETTFANNRIETSFTC](SEQ ID NO:140);

[0432] [fIETTFAQNRIETSFTC](SEQ ID NO:141);

[0433] [fIETTFARNRIETSFTC](SEQ ID NO:142);

[0434] [fIETTFASNRIETSFTC](SEQ ID NO:143);

[0435] [fIETTFAWNRIETSFTC](SEQ ID NO:144);

[0436] [fIETTFAYNRIETSFTC](SEQ ID NO:145);

[0437] [fIETTFAGCRIETSFTC](SEQ ID NO:146);

[0438] [fIETTFAGFRIETSFTC](SEQ ID NO:147);

[0439] [fIETTFAGGRIETSFTC](SEQ ID NO:148);

[0440] [fIETTFAGHRIETSFTC](SEQ ID NO:149);

[0441] [fIETTFAGLRIETSFTC](SEQ ID NO:150);

[0442] [fIETTFAGRRIETSFTC] (SEQ ID NO:151);

[0443] [fIETTFAGYRIETSFTC] (SEQ ID NO:152);

[0444] [fIETTFAGNRIETSFFC] (SEQ ID NO:153);

[0445] [fIETTFAGNRIETSFGC] (SEQ ID NO:154);

[0446] [fIETTFAGNRIETSFHC] (SEQ ID NO:155);

[0447] [fIETTFAGNRIETSFIC] (SEQ ID NO:156);

[0448] [fIETTFAGNRIETSFLC] (SEQ ID NO:157);

[0449] [fIETTFAGNRIETSFNC] (SEQ ID NO:158);

[0450] [fIETTFAGNRIETSFSC] (SEQ ID NO:159);

[0451] [fIETTFAGNRIETSFVC] (SEQ ID NO:160);

[0452] [fIETTFAGNRIETSFWC] (SEQ ID NO:161); and [fIETTFAGNRIETSFYC] (SEQ ID NO:162),

[0453] or a pharmaceutically acceptable salt thereof.

[0454] In some embodiments, the peptide is [fIETTFAGNRIETSFTC] (SEQ ID NO:120) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or a functional variant thereof.

[0455] In some embodiments, the peptide is [fIETTFAGWRIETSFTC] (SEQ ID NO:121) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or a functional variant thereof.

[0456] In some embodiments, the peptide is [fIETTFFGNRIETSFTC] (SEQ ID NO:122) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0457] In some embodiments, the peptide is [fIETTFHGNRIETSFTC] (SEQ ID NO:123) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0458] In some embodiments, the peptide is [fIETTFIGNRIETSFTC] (SEQ ID NO:124) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0459] In some embodiments, the peptide is [fIETTFLGNRIETSFTC] (SEQ ID NO:125) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0460] In some embodiments, the peptide is [fIETTFNGNRIETSFTC] (SEQ ID NO:126) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0461] In some embodiments, the peptide is [fIETTFQGNRIETSFTC] (SEQ ID NO:127) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0462] In some embodiments, the peptide is [fIETTFSGNRIETSFTC] (SEQ ID NO:128) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0463] In some embodiments, the peptide is [fIETTFTGNRIETSFTC] (SEQ ID NO:129) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0464] In some embodiments, the peptide is [fIETTFVGNRIETSFTC] (SEQ ID NO: 130) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0465] In some embodiments, the peptide is [fIETTFWGNRIETSFTC] (SEQ ID NO: 131) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0466] In some embodiments, the peptide is [fIETTFYGNRIETSFTC] (SEQ ID NO: 132) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0467] In some embodiments, the peptide is [fIETTFAANRIETSFTC] (SEQ ID NO: 133) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0468] In some embodiments, the peptide is [fIETTFADNRIETSFTC] (SEQ ID NO: 134) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0469] In some embodiments, the peptide is [fIETTFAENRIETSFTC] (SEQ ID NO: 135) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0470] In some embodiments, the peptide is [fIETTFAFNRIETSFTC] (SEQ ID NO: 136) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0471] In some embodiments, the peptide is [fIETTFAHNRIETSFTC] (SEQ ID NO: 137) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0472] In some embodiments, the peptide is [fIETTFAKNRIETSFTC] (SEQ ID NO: 138) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0473] In some embodiments, the peptide is [fIETTFALNRIETSFTC] (SEQ ID NO: 139) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0474] In some embodiments, the peptide is [fIETTFANNRIETSFTC] (SEQ ID NO: 140) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0475] In some embodiments, the peptide is [fIETTFAQNRIETSFTC] (SEQ ID NO: 141) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0476] In some embodiments, the peptide is [fIETTFARNRIETSFTC] (SEQ ID NO: 142) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0477] In some embodiments, the peptide is [fIETTFASNRIETSFTC] (SEQ ID NO: 143) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0478] In some embodiments, the peptide is [fIETTFAWNRIETSFTC] (SEQ ID NO: 144) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0479] In some embodiments, the peptide is [fIETTFAYNRIETSFTC] (SEQ ID NO: 145) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0480] In some embodiments, the peptide is [fIETTFAGCRIETSFTC] (SEQ ID NO:146) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0481] In some embodiments, the peptide is [fIETTFAGFRIETSFTC] (SEQ ID NO:147) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0482] In some embodiments, the peptide is [fIETTFAGGRIETSFTC] (SEQ ID NO:148) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0483] In some embodiments, the peptide is [fIETTFAGHRIETSFTC] (SEQ ID NO:149) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0484] In some embodiments, the peptide is [fIETTFAGLRIETSFTC] (SEQ ID NO:150) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0485] In some embodiments, the peptide is [fIETTFAGRRIETSFTC] (SEQ ID NO:151) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0486] In some embodiments, the peptide is [fIETTFAGYRIETSFTC] (SEQ ID NO:152) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0487] In some embodiments, the peptide is [fIETTFAGNRIETSFFC] (SEQ ID NO:153) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0488] In some embodiments, the peptide is [fIETTFAGNRIETSFGC] (SEQ ID NO:154) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0489] In some embodiments, the peptide is [fIETTFAGNRIETSFHC] (SEQ ID NO:155) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0490] In some embodiments, the peptide is [fIETTFAGNRIETSFIC] (SEQ ID NO:156) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0491] In some embodiments, the peptide is [fIETTFAGNRIETSFLC] (SEQ ID NO:157) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0492] In some embodiments, the peptide is [fIETTFAGNRIETSFNC] (SEQ ID NO:158) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0493] In some embodiments, the peptide is [fIETTFAGNRIETSFSC] (SEQ ID NO:159) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0494] In some embodiments, the peptide is [fIETTFAGNRIETSFVC] (SEQ ID NO:160) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0495] In some embodiments, the peptide is [fIETTFAGNRIETSFWC] (SEQ ID NO:161) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0496] In some embodiments, the peptide is [fIETTFAGNRIETSFYC](SEQ ID NO:162) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0497] In some embodiments, the peptide comprises at least 17 amino acid residues, such as at least 18 amino acid residues, such as at least 19 amino acid residues, such as at least 20 amino acid residues, such as at least 21 amino acid residues, such as at least 22 amino acid residues, such as at least 23 amino acid residues, such as at least 24 amino acid residues, such as at least 25 amino acid residues, such as at least 26 amino acid residues, such as at least 27 amino acid residues, such as at least 28 amino acid residues, such as at least 29 amino acid residues, such as at least 30 amino acid residues, such as at least 31 amino acid residues, such as at least 32 amino acid residues, such as at least 33 amino acid residues, such as at least 34 amino acid residues, such as at least 35 amino acid residues, such as at least 36 amino acid residues, such as at least 37 amino acid residues.

[0498] In some embodiments, the peptide comprises no more than 50 amino acid residues, such as no more than 45 amino acid residues, such as no more than 40 amino acid residues, such as no more than 35 amino acid residues, such as no more than 30 amino acid residues, such as no more than 29 amino acid residues, such as no more than 28 amino acid residues, such as no more than 27 amino acid residues, such as no more than 26 amino acid residues, such as no more than 25 amino acid residues, such as no more than 24 amino acid residues, such as no more than 23 amino acid residues, such as no more than 22 amino acid residues, such as no more than 21 amino acid residues, such as no more than 20 amino acid residues, such as no more than 19 amino acid residues, such as no more than 18 amino acid residues, such as no more than 17 amino acid residues.

[0499] In some embodiments, the peptide comprises a range of 17 to 50 amino acid residues, such as a range of 19 to 45 amino acid residues, such as a range of 17 to 40 amino acid residues, such as a range of 17 to 35 amino acid residues, such as a range of 17 to 30 amino acid residues, such as a range of 17 to 25 amino acid residues, such as a range of 17 to 23 amino acid residues, such as a range of 17 to 20 amino acid residues, such as a range of 17 to 18 amino acid residues.

[0500] Cyclic peptide

[0501] In some embodiments, the peptide is cyclized, i.e., the peptide is a cyclic peptide. In some embodiments, the peptide is backbone-cyclized. In some embodiments, the peptide is "head-to-tail" cyclized, i.e., the N-terminal amino acid residue is linked to the C-terminal amino acid residue. In one embodiment, the N-terminal amino acid residue is linked to the C-terminal amino acid residue via a peptide bond. In one embodiment, the N-terminal amino acid residue is linked to the C-terminal amino acid residue via a non-peptide chemical linker. For example, in one embodiment, the peptide comprises a chloroacetylated N-terminal amino acid residue, wherein the chloroacetylated N-terminal residue forms a linkage with the side chain of a C-terminal cysteine.

[0502] Affinity for PSD-95

[0503] To date, there has been a limited number of efforts to develop non-canonical PSD-95 inhibitors that bind to PDZ via internal binding motifs. Through the integration of genetic code reprogramming facilitated by flexizyme (flexible tRNA-aminoacylating ribozyme) and mRNA display, the "Random non-standard Peptide Integration Discovery" (RaPID) system has provided a powerful platform for the rapid discovery of novel peptide drug candidates targeting various therapeutically relevant proteins. Here, the present inventors applied the RaPID technology to target PSD-95 for the first time. Specifically, RaPID was applied to synthesize a trillion-member library of unnatural thioether-cyclized peptides, and these peptides were subsequently screened against the PDZ2 domain of PSD-95, aiming to identify novel non-canonical PSD-95 peptide inhibitors.

[0504] Thus, in some embodiments, the peptide is capable of binding to PSD-95.

[0505] PSD-95 directly binds to the C-terminal tail of the NMDAR GluN2 subunit via a canonical binding mode and regulates receptor signaling and surface expression. Thus, by competing for binding to PSD-95, the peptides described herein can inhibit the interaction between the C-terminal tail of the GluN2 subunit of NMDAR and PSD-95.

[0506] Thus, in some embodiments, the peptide is capable of inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95.

[0507] In some embodiments, the peptide inhibits the binding of GluN2B to the PDZ2 domain of PSD-95 with a K iThe value is less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, such as less than 2 μM, such as less than 1 μM, such as less than 0.9 μM, such as less than 0.8 μM, such as less than 0.7 μM, such as less than 0.6 μM, such as less than 0.5 μM, such as less than 0.4 μM, such as less than 0.35 μM, such as less than 0.3 μM, preferably less than 0.3 μM.

[0508] In some embodiments, the IC of the peptide inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95 50 The value is less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, preferably less than 3 μM.

[0509] Peptide modification

[0510] In some embodiments, the peptide is conjugated to a cell-penetrating peptide (CPP).

[0511] In some embodiments, the peptide is further conjugated to a moiety.

[0512] In some embodiments, the moiety is selected from the group consisting of PEG, monosaccharide, fluorophore, chromophore, radioactive compound, and cell-penetrating peptide.

[0513] In some embodiments, the moiety is a detectable moiety.

[0514] In some embodiments, the peptide is further modified by glycosylation, PEGylation, amidation, esterification, acylation, acetylation, and / or alkylation.

[0515] In some embodiments, one or more of these amino acid residues are alkylated, such as methylated.

[0516] In some embodiments, the N-terminal amino acid residue of the peptide is chloroacetylated.

[0517] Polynucleotide, vector, and cell

[0518] In one aspect of the invention, there is provided a nucleic acid construct encoding and capable of expressing a peptide comprising an amino acid sequence as defined herein. The nucleic acid construct is to be understood as a genetically engineered nucleic acid. The nucleic acid construct can be a non-replicating and linear nucleic acid, a circular expression vector, or an autonomously replicating plasmid. In one aspect, the invention relates to a polynucleotide encoding a corresponding linear sequence of a cyclic peptide as defined herein.

[0519] In one aspect, the present invention relates to a vector comprising the polynucleotide.

[0520] In one aspect, the present invention relates to a host cell comprising the polynucleotide or the vector. In some embodiments, the host cell is a bacterial cell. In some embodiments, the host cell is a mammalian cell. In some embodiments, the host cell is a human cell.

[0521] Medical use

[0522] In one aspect, the present disclosure relates to a peptide, composition, polynucleotide, vector or host cell as defined herein for use as a medicament. In some embodiments, the present disclosure relates to a cyclic peptide as defined herein for use as a medicament.

[0523] In one aspect, the present disclosure relates to a method of preventing and / or treating excitotoxicity-related diseases and / or neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide, composition, polynucleotide, vector or host cell as defined herein.

[0524] In one aspect, the present disclosure relates to the use of a peptide, composition, polynucleotide, vector or host cell as defined herein in the preparation of a medicament for treating and / or preventing excitotoxicity-related diseases and / or neuropathic pain in a subject.

[0525] Excitotoxicity-related diseases

[0526] In one aspect, the present disclosure relates to a peptide, composition, polynucleotide, vector or host cell as defined herein for preventing and / or treating excitotoxicity-related diseases in a subject. In some embodiments, the present disclosure relates to a cyclic peptide as defined herein for preventing and / or treating excitotoxicity-related diseases in a subject.

[0527] The ternary complex between N-methyl-D-aspartic acid receptor (NMDAR), postsynaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) plays an important role in the excitotoxic mechanism of cell death. Since the peptides of the present disclosure are capable of inhibiting the binding of GluN2B to PSD-95 and thus preventing / interrupting the formation of excessive NO that causes excitotoxicity, these peptides can be used to treat excitotoxicity-related diseases.

[0528] A number of indications such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders are associated with excitotoxicity (Gardoni, F. et al., 2006, European Journal of Pharmacology, 545, 2-10). In some embodiments, the excitotoxicity-related disease is stroke, such as ischemic stroke. In some embodiments, the excitotoxicity-related disease is an ischemic or traumatic injury of the CNS, such as spinal cord injury and traumatic brain injury. In some embodiments, the excitotoxicity-related disease is epilepsy. In some embodiments, the excitotoxicity-related disease is a neurodegenerative disease of the CNS. In some embodiments, the neurodegenerative disease of the CNS is selected from the group consisting of Alzheimer's disease, Huntington's disease and Parkinson's disease.

[0529] Neuropathic pain

[0530] In one aspect, the present disclosure relates to a peptide, composition, polynucleotide, vector or host cell as defined herein for preventing and / or treating neuropathic pain in a subject. In some embodiments, the present disclosure relates to a cyclic peptide as defined herein for preventing and / or treating neuropathic pain in a subject.

[0531] Neuropathic pain is a type of pain that includes several forms of chronic pain and is caused by a dysfunction of the nerves rather than somatic tissues. Neuropathic pain is pain that results from a dysfunction of the central or peripheral nervous system, may also be the result of damage to the peripheral nerves or central nervous system regions, may be caused by a disease, or may be idiopathic. Symptoms of neuropathic pain include burning, stabbing, electric shock, pins and needles, paresthesia, numbness, stiffness, numbness in the limbs, a feeling of body distortion, allodynia (pain caused by a normally harmless stimulus), hyperalgesia (abnormal sensitivity to pain), hyperpathia (an exaggerated pain response that persists long after the pain stimulus has ceased), phantom limb pain and spontaneous pain.

[0532] PSD-95 has been shown to be involved in the central mechanisms of neuropathic pain (Tao, F. et al., 2003, Neuroscience, 731-739; Florio, S.K. et al., 2009, British Journal of Pharmacology, 158, 494-506). Since the peptides of the present disclosure inhibit PSD-95, these peptides can be used to treat neuropathic pain.

[0533] Administration

[0534] According to the present disclosure, a peptide as defined herein or a composition comprising a peptide is administered to a subject in need of treatment in a pharmaceutically effective dose or a therapeutically effective amount. The dosage requirements will vary with the particular pharmaceutical composition employed, the route of administration, and the particular subject being treated, depending on the severity and nature of the disorder and the weight and general condition of the subject. Those skilled in the art will also recognize that the optimal amount and interval of individual doses of the peptide compound will be determined by the nature and extent of the condition being treated, the form, route, and site of administration, and the particular patient being treated, and such optimal values can be determined by conventional techniques. Those skilled in the art will also understand that the optimal course of treatment can be determined by using routine therapeutic course determination tests, i.e., the number of doses of the compound administered per day over a specified number of days.

[0535] Pharmaceutical composition

[0536] Although the peptides of the present disclosure may be administered as the native peptides, it is preferred to present these peptides in the form of a pharmaceutical formulation. Accordingly, the present disclosure further provides a pharmaceutical formulation comprising a peptide of the present disclosure or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor. Thus, in one aspect, the present disclosure relates to a composition comprising a peptide as defined herein, such as a pharmaceutical composition. These pharmaceutical formulations can be prepared by conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0537] Item

[0538] 1. A peptide comprising the amino acid sequence

[0539] IETTFX1X2X3RIETSFX4C (SEQ ID NO:1)

[0540] wherein:

[0541] X1 is independently selected from the group consisting of A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0542] X2 is independently selected from the group consisting of G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0543] X3 is independently selected from the group consisting of N, C, F, G, H, L, R, W, and Y;

[0544] X4 is independently selected from the group consisting of T, F, G, H, I, L, N, S, V, W, and Y;

[0545] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0546] 2. The peptide according to item 1, wherein the peptide comprises the amino acid sequence

[0547] X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2)

[0548] wherein:

[0549] X D is a D-amino acid or glycine;

[0550] X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y;

[0551] X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y;

[0552] X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y;

[0553] X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y;

[0554] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0555] 3. The peptide according to item 2, wherein

[0556] X D is D-phenylalanine;

[0557] X1 is independently selected from the group consisting of: A, F, H, I, N, Q, S, T, V, W, and Y;

[0558] X2 is independently selected from the group consisting of: F, G, H, N, and Q;

[0559] X3 is independently selected from the group consisting of: N, G, H, and W;

[0560] X4 is independently selected from the group consisting of: T, F, G, H, and W;

[0561] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0562] 4. A peptide according to any one of the preceding items, wherein the peptide is cyclized.

[0563] 5. A peptide according to any one of the preceding items, wherein the peptide is backbone-cyclized.

[0564] 6. A peptide according to any one of the preceding items, wherein the peptide comprises a chloroacetylated N-terminal residue.

[0565] 7. A peptide according to any one of the preceding items, wherein the chloroacetylated N-terminal residue forms a linkage with the side chain of the C-terminal cysteine.

[0566] 8. A peptide according to any one of the preceding items, wherein X1 is A.

[0567] 9. A peptide according to any one of items 1 to 7, wherein X1 is F.

[0568] 10. A peptide according to any one of items 1 to 7, wherein X1 is H.

[0569] 11. A peptide according to any one of items 1 to 7, wherein X1 is I.

[0570] 12. A peptide according to any one of items 1 to 7, wherein X1 is L.

[0571] 13. A peptide according to any one of items 1 to 7, wherein X1 is N.

[0572] 14. A peptide according to any one of items 1 to 7, wherein X1 is Q.

[0573] 15. A peptide according to any one of items 1 to 7, wherein X1 is S.

[0574] 16. A peptide according to any one of items 1 to 7, wherein X1 is T.

[0575] 17. A peptide according to any one of items 1 to 7, wherein X1 is V.

[0576] 18. A peptide according to any one of items 1 to 7, wherein X1 is W.

[0577] 19. A peptide according to any one of items 1 to 7, wherein X1 is Y.

[0578] 20. A peptide according to any one of items 1 to 19, wherein X2 is G.

[0579] 21. A peptide according to any one of items 1 to 19, wherein X2 is A.

[0580] 22. A peptide according to any one of items 1 to 19, wherein X2 is D.

[0581] 23. The peptide according to any one of Items 1 to 19, wherein X2 is E.

[0582] 24. The peptide according to any one of Items 1 to 19, wherein X2 is F.

[0583] 25. The peptide according to any one of Items 1 to 19, wherein X2 is H.

[0584] 26. The peptide according to any one of Items 1 to 19, wherein X2 is K.

[0585] 27. The peptide according to any one of Items 1 to 19, wherein X2 is L.

[0586] 28. The peptide according to any one of Items 1 to 19, wherein X2 is N.

[0587] 29. The peptide according to any one of Items 1 to 19, wherein X2 is Q.

[0588] 30. The peptide according to any one of Items 1 to 19, wherein X2 is R.

[0589] 31. The peptide according to any one of Items 1 to 19, wherein X2 is S.

[0590] 32. The peptide according to any one of Items 1 to 19, wherein X2 is W.

[0591] 33. The peptide according to any one of Items 1 to 19, wherein X2 is Y.

[0592] 34. The peptide according to any one of Items 1 to 33, wherein X3 is N.

[0593] 35. The peptide according to any one of Items 1 to 33, wherein X3 is C.

[0594] 36. The peptide according to any one of Items 1 to 33, wherein X3 is F.

[0595] 37. The peptide according to any one of Items 1 to 33, wherein X3 is G.

[0596] 38. The peptide according to any one of Items 1 to 33, wherein X3 is H.

[0597] 39. The peptide according to any one of Items 1 to 33, wherein X3 is L.

[0598] 40. The peptide according to any one of Items 1 to 33, wherein X3 is R.

[0599] 41. The peptide according to any one of Items 1 to 33, wherein X3 is W.

[0600] 42. The peptide according to any one of Items 1 to 33, wherein X3 is Y.

[0601] 43. A peptide according to any one of items 1 to 42, wherein X4 is T.

[0602] 44. A peptide according to any one of items 1 to 42, wherein X4 is F.

[0603] 45. A peptide according to any one of items 1 to 42, wherein X4 is G.

[0604] 46. A peptide according to any one of items 1 to 42, wherein X4 is H.

[0605] 47. A peptide according to any one of items 1 to 42, wherein X4 is I.

[0606] 48. A peptide according to any one of items 1 to 42, wherein X4 is L.

[0607] 49. A peptide according to any one of items 1 to 42, wherein X4 is N.

[0608] 50. A peptide according to any one of items 1 to 42, wherein X4 is S.

[0609] 51. A peptide according to any one of items 1 to 42, wherein X4 is V.

[0610] 52. A peptide according to any one of items 1 to 42, wherein X4 is W.

[0611] 53. A peptide according to any one of items 1 to 42, wherein X4 is Y.

[0612] 54. A peptide according to any one of the foregoing items, wherein the peptide comprises, or consists of, an amino acid sequence selected from the group consisting of:

[0613] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0614] X D IETTFAGWRIETSFTC (SEQ ID NO:4); X D IETTFFGNRIETSFTC (SEQ ID NO:5); X D IETTFHGNRIETSFTC (SEQ ID NO:6); X D IETTFIGNRIETSFTC (SEQ ID NO:7); X D IETTFLGNRIETSFTC (SEQ ID NO:8); X D IETTFNGNRIETSFTC (SEQ ID NO:9); X DIETTFQGNRIETSFTC (SEQ ID NO:10); X D IETTFSGNRIETSFTC (SEQ ID NO:11); X D IETTFTGNRIETSFTC (SEQ ID NO:12); X D IETTFVGNRIETSFTC (SEQ ID NO:13); X D IETTFWGNRIETSFTC (SEQ ID NO:14); X D IETTFYGNRIETSFTC (SEQ ID NO:15); X D IETTFAANRIETSFTC (SEQ ID NO:16); X D IETTFADNRIETSFTC (SEQ ID NO:17); X D IETTFAENRIETSFTC (SEQ ID NO:18); X D IETTFAFNRIETSFTC (SEQ ID NO:19); X D IETTFAHNRIETSFTC (SEQ ID NO:20); X D IETTFAKNRIETSFTC (SEQ ID NO:21); X D IETTFALNRIETSFTC (SEQ ID NO:22); X D IETTFANNRIETSFTC (SEQ ID NO:23); X D IETTFAQNRIETSFTC (SEQ ID NO:24); X D IETTFARNRIETSFTC (SEQ ID NO:25); X D IETTFASNRIETSFTC (SEQ ID NO:26); X D IETTFAWNRIETSFTC (SEQ ID NO:27); X D IETTFAYNRIETSFTC (SEQ ID NO:28); X D IETTFAGCRIETSFTC (SEQ ID NO:29); X D IETTFAGFRIETSFTC (SEQ ID NO:30); X D IETTFAGGRIETSFTC (SEQ ID NO:31); X DIETTFAGHRIETSFTC (SEQ ID NO:32); X D IETTFAGLRIETSFTC (SEQ ID NO:33); X D IETTFAGRRIETSFTC (SEQ ID NO:34);

[0615] X D IETTFAGYRIETSFTC (SEQ ID NO:35);

[0616] X D IETTFAGNRIETSFFC (SEQ ID NO:36);

[0617] X D IETTFAGNRIETSFGC (SEQ ID NO:37);

[0618] X D IETTFAGNRIETSFHC (SEQ ID NO:38);

[0619] X D IETTFAGNRIETSFIC (SEQ ID NO:39);

[0620] X D IETTFAGNRIETSFLC (SEQ ID NO:40);

[0621] X D IETTFAGNRIETSFNC (SEQ ID NO:41);

[0622] X D IETTFAGNRIETSFSC (SEQ ID NO:42);

[0623] X D IETTFAGNRIETSFVC (SEQ ID NO:43);

[0624] X D IETTFAGNRIETSFWC (SEQ ID NO:44);

[0625] X D IETTFAGNRIETSFYC (SEQ ID NO:45);

[0626] or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0627] 55. A peptide according to any one of the preceding items, wherein the peptide comprises, or consists of, an amino acid sequence selected from the group consisting of:

[0628] X D IETTFAGNRIETSFTC (SEQ ID NO:3);

[0629] X D IETTFAGWRIETSFTC (SEQ ID NO:4);

[0630] X D IETTFFGNRIETSFTC (SEQ ID NO:5);

[0631] X D IETTFHGNRIETSFTC (SEQ ID NO:6);

[0632] X D IETTFNGNRIETSFTC (SEQ ID NO:9);

[0633] X D IETTFQGNRIETSFTC (SEQ ID NO:10);

[0634] X D IETTFSGNRIETSFTC (SEQ ID NO:11);

[0635] X D IETTFVGNRIETSFTC (SEQ ID NO:13);

[0636] X D IETTFYGNRIETSFTC (SEQ ID NO:15);

[0637] X D IETTFAHNRIETSFTC (SEQ ID NO:20);

[0638] X D IETTFANNRIETSFTC (SEQ ID NO:23);

[0639] X D IETTFAGNRIETSFGC (SEQ ID NO:37);

[0640] X D IETTFAGNRIETSFHC (SEQ ID NO:38);

[0641] or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0642] 56. The peptide according to any one of the preceding items, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFTC (SEQ ID NO:3) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0643] 57. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGWRIETSFTC (SEQ ID NO:4) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0644] 58. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFFGNRIETSFTC (SEQ ID NO:5) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0645] 59. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFHGNRIETSFTC (SEQ ID NO:6) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0646] 60. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFIGNRIETSFTC (SEQ ID NO:7) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0647] 61. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFLGNRIETSFTC (SEQ ID NO:8) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0648] 62. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFNGNRIETSFTC (SEQ ID NO:9) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0649] 63. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFQGNRIETSFTC (SEQ ID NO:10) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0650] 64. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFSGNRIETSFTC (SEQ ID NO:11) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0651] 65. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFTGNRIETSFTC (SEQ ID NO:12) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0652] 66. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFVGNRIETSFTC (SEQ ID NO:13) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0653] 67. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFWGNRIETSFTC (SEQ ID NO:14) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consisting of the same

[0654] 68. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFYGNRIETSFTC (SEQ ID NO: 15 or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same).

[0655] 69. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAANRIETSFTC (SEQ ID NO: 16) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0656] 70. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFADNRIETSFTC (SEQ ID NO: 17) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0657] 71. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAENRIETSFTC (SEQ ID NO: 18) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0658] 72. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAFNRIETSFTC (SEQ ID NO: 19) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0659] 73. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAHNRIETSFTC (SEQ ID NO: 20) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0660] 74. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFAKNRIETSFTC (SEQ ID NO:21) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0661] 75. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFALNRIETSFTC (SEQ ID NO:22) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0662] 76. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFANNRIETSFTC (SEQ ID NO:23) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0663] 77. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAQNRIETSFTC (SEQ ID NO:24) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0664] 78. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFARNRIETSFTC (SEQ ID NO:25) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0665] 79. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFASNRIETSFTC (SEQ ID NO:26) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0666] 80. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFAWNRIETSFTC (SEQ ID NO:27) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0667] 81. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAYNRIETSFTC (SEQ ID NO:28) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0668] 82. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGCRIETSFTC (SEQ ID NO:29) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0669] 83. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGFRIETSFTC (SEQ ID NO:30) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0670] 84. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGGRIETSFTC (SEQ ID NO:31) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0671] 85. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGHRIETSFTC (SEQ ID NO:32) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0672] 86. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFAGLRIETSFTC (SEQ ID NO:33) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0673] 87. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGRRIETSFTC (SEQ ID NO:34) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0674] 88. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGYRIETSFTC (SEQ ID NO:35) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0675] 89. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFFC (SEQ ID NO:36) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0676] 90. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFGC (SEQ ID NO:37) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0677] 91. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFHC (SEQ ID NO:38) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or a composition comprising the same.

[0678] 92. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFAGNRIETSFIC (SEQ ID NO:39) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0679] 93. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFLC (SEQ ID NO:40) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0680] 94. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFNC (SEQ ID NO:41) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0681] 95. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFSC (SEQ ID NO:42) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0682] 96. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFVC (SEQ ID NO:43) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0683] 97. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X D IETTFAGNRIETSFWC (SEQ ID NO:44) or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0684] 98. The peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence X DIETTFAGNRIETSFYC (SEQ ID NO:45) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0685] 99. The peptide according to any one of the foregoing items, wherein X D is selected from the group consisting of: D-phenylalanine and glycine, preferably D-phenylalanine.

[0686] 100. The peptide according to any one of items 1 to 54, wherein the peptide comprises, or consists of, an amino acid sequence selected from the group consisting of:

[0687] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0688] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0689] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0690] fIETTFHGNRIETSFTC (SEQ ID NO:49); fIETTFIGNRIETSFTC (SEQ ID NO:50); fIETTFLGNRIETSFTC (SEQ ID NO:51); fIETTFNGNRIETSFTC (SEQ ID NO:52); fIETTFQGNRIETSFTC (SEQ ID NO:53); fIETTFSGNRIETSFTC (SEQ ID NO:54); fIETTFTGNRIETSFTC (SEQ ID NO:55); fIETTFVGNRIETSFTC (SEQ ID NO:56); fIETTFWGNRIETSFTC (SEQ ID NO:57); fIETTFYGNRIETSFTC (SEQ ID NO:58); fIETTFAANRIETSFTC (SEQ ID NO:59); fIETTFADNRIETSFTC (SEQ ID NO:60); fIETTFAENRIETSFTC (SEQ ID NO:61); fIETTFAFNRIETSFTC (SEQ ID NO:62); fIETTFAHNRIETSFTC (SEQ ID NO:63); fIETTFAKNRIETSFTC (SEQ ID NO:64); fIETTFALNRIETSFTC (SEQ ID NO:65); fIETTFANNRIETSFTC (SEQ ID NO:66); fIETTFAQNRIETSFTC (SEQ ID NO:67); fIETTFARNRIETSFTC (SEQ ID NO:68); fIETTFASNRIETSFTC (SEQ ID NO:69); fIETTFAWNRIETSFTC (SEQ ID NO:70); fIETTFAYNRIETSFTC (SEQ ID NO:71); fIETTFAGCRIETSFTC (SEQ ID NO:72); fIETTFAGFRIETSFTC (SEQ ID NO:73); fIETTFAGGRIETSFTC (SEQ ID NO:74); fIETTFAGHRIETSFTC (SEQ ID NO:75); fIETTFAGLRIETSFTC (SEQ ID NO:76); fIETTFAGRRIETSFTC (SEQ ID NO:77); fIETTFAGYRIETSFTC (SEQ ID NO:78); fIETTFAGNRIETSFFC (SEQ ID NO:79);

[0691] fIETTFAGNRIETSFGC (SEQ ID NO:80);

[0692] fIETTFAGNRIETSFHC (SEQ ID NO:81);

[0693] fIETTFAGNRIETSFIC (SEQ ID NO:82);

[0694] fIETTFAGNRIETSFLC (SEQ ID NO:83);

[0695] fIETTFAGNRIETSFNC (SEQ ID NO:84);

[0696] fIETTFAGNRIETSFSC (SEQ ID NO:85);

[0697] fIETTFAGNRIETSFVC (SEQ ID NO:86);

[0698] fIETTFAGNRIETSFWC (SEQ ID NO:87);

[0699] fIETTFAGNRIETSFYC (SEQ ID NO:88);

[0700] or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0701] 101. A peptide according to any one of items 1 to 55, wherein the peptide comprises an amino acid sequence selected from the group consisting of, or consisting of:

[0702] fIETTFAGNRIETSFTC (SEQ ID NO:46);

[0703] fIETTFAGWRIETSFTC (SEQ ID NO:47);

[0704] fIETTFFGNRIETSFTC (SEQ ID NO:48);

[0705] fIETTFHGNRIETSFTC (SEQ ID NO:49);

[0706] fIETTFNGNRIETSFTC (SEQ ID NO:52);

[0707] fIETTFQGNRIETSFTC (SEQ ID NO:53);

[0708] fIETTFSGNRIETSFTC (SEQ ID NO:54);

[0709] fIETTFVGNRIETSFTC (SEQ ID NO:56);

[0710] fIETTFYGNRIETSFTC (SEQ ID NO:58);

[0711] fIETTFAHNRIETSFTC (SEQ ID NO:63);

[0712] fIETTFANNRIETSFTC (SEQ ID NO:66);

[0713] fIETTFAGNRIETSFGC (SEQ ID NO:80);

[0714] fIETTFAGNRIETSFHC (SEQ ID NO:81);

[0715] or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

[0716] 102. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFTC (SEQ ID NO:46) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0717] 103. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGWRIETSFTC (SEQ ID NO:47) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0718] 104. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFFGNRIETSFTC (SEQ ID NO:48) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the foregoing.

[0719] 105. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFHGNRIETSFTC (SEQ ID NO: 49) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0720] 106. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFIGNRIETSFTC (SEQ ID NO: 50) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0721] 107. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFLGNRIETSFTC (SEQ ID NO: 51) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0722] 108. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFNGNRIETSFTC (SEQ ID NO: 52) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0723] 109. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFQGNRIETSFTC (SEQ ID NO: 53) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0724] 110. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFSGNRIETSFTC (SEQ ID NO: 54) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0725] 111. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFTGNRIETSFTC (SEQ ID NO:55) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0726] 112. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFVGNRIETSFTC (SEQ ID NO:56) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0727] 113. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFWGNRIETSFTC (SEQ ID NO:57) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0728] 114. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFYGNRIETSFTC (SEQ ID NO:58) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0729] 115. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAANRIETSFTC (SEQ ID NO:59) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0730] 116. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFADNRIETSFTC (SEQ ID NO:60) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0731] 117. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAENRIETSFTC (SEQ ID NO: 61) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0732] 118. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAFNRIETSFTC (SEQ ID NO: 62) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0733] 119. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAHNRIETSFTC (SEQ ID NO: 63) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0734] 120. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAKNRIETSFTC (SEQ ID NO: 64) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0735] 121. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFALNRIETSFTC (SEQ ID NO: 65) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0736] 122. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFANNRIETSFTC (SEQ ID NO: 66) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0737] 123. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAQNRIETSFTC (SEQ ID NO: 67) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0738] 124. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFARNRIETSFTC (SEQ ID NO: 68) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0739] 125. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFASNRIETSFTC (SEQ ID NO: 69) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0740] 126. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAWNRIETSFTC (SEQ ID NO: 70) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0741] 127. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAYNRIETSFTC (SEQ ID NO: 71) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0742] 128. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGCRIETSFTC (SEQ ID NO: 72) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0743] 129. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGFRIETSFTC (SEQ ID NO:73) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0744] 130. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGGRIETSFTC (SEQ ID NO:74) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0745] 131. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGHRIETSFTC (SEQ ID NO:75) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0746] 132. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGLRIETSFTC (SEQ ID NO:76) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0747] 133. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGRRIETSFTC (SEQ ID NO:77) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0748] 134. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGYRIETSFTC (SEQ ID NO:78) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0749] 135. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFFC (SEQ ID NO:79) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0750] 136. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFGC (SEQ ID NO:80) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0751] 137. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFHC (SEQ ID NO:81) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0752] 138. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFIC (SEQ ID NO:82) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0753] 139. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFLC (SEQ ID NO:83) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0754] 140. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFNC (SEQ ID NO:84) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists thereof.

[0755] 141. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFSC (SEQ ID NO:85) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0756] 142. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFVC (SEQ ID NO:86) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0757] 143. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFWC (SEQ ID NO:87) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0758] 144. A peptide according to any one of items 1 to 54, wherein the peptide comprises the amino acid sequence fIETTFAGNRIETSFYC (SEQ ID NO:88) or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant, or consists of the same.

[0759] 145. A peptide according to any one of items 1 to 54, wherein the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of:

[0760] [fIETTFAGNRIETSFTC] (SEQ ID NO:120);

[0761] [fIETTFAGWRIETSFTC] (SEQ ID NO:121);

[0762] [fIETTFFGNRIETSFTC] (SEQ ID NO:122);

[0763] [fIETTFHGNRIETSFTC] (SEQ ID NO:123);

[0764] [fIETTFIGNRIETSFTC] (SEQ ID NO:124);

[0765] [fIETTFLGNRIETSFTC](SEQ ID NO:125);

[0766] [fIETTFNGNRIETSFTC](SEQ ID NO:126);

[0767] [fIETTFQGNRIETSFTC](SEQ ID NO:127); [fIETTFSGNRIETSFTC](SEQ ID NO:128); [fIETTFTGNRIETSFTC](SEQ ID NO:129); [fIETTFVGNRIETSFTC](SEQ ID NO:130); [fIETTFWGNRIETSFTC](SEQ ID NO:131); [fIETTFYGNRIETSFTC](SEQ ID NO:132); [fIETTFAANRIETSFTC](SEQ ID NO:133); [fIETTFADNRIETSFTC](SEQ ID NO:134); [fIETTFAENRIETSFTC](SEQ ID NO:135); [fIETTFAFNRIETSFTC](SEQ ID NO:136); [fIETTFAHNRIETSFTC](SEQ ID NO:137); [fIETTFAKNRIETSFTC](SEQ ID NO:138); [fIETTFALNRIETSFTC](SEQ ID NO:139); [fIETTFANNRIETSFTC](SEQ ID NO:140); [fIETTFAQNRIETSFTC](SEQ ID NO:141); [fIETTFARNRIETSFTC](SEQ ID NO:142); [fIETTFASNRIETSFTC](SEQ ID NO:143); [fIETTFAWNRIETSFTC](SEQ ID NO:144); [fIETTFAYNRIETSFTC](SEQ ID NO:145); [fIETTFAGCRIETSFTC](SEQ ID NO:146); [fIETTFAGFRIETSFTC](SEQ ID NO:147); [fIETTFAGGRIETSFTC](SEQ ID NO:148); [fIETTFAGHRIETSFTC](SEQ ID NO:149); [fIETTFAGLRIETSFTC](SEQ ID NO:150); [fIETTFAGRRIETSFTC](SEQ ID NO:151); [fIETTFAGYRIETSFTC](SEQ ID NO:152); [fIETTFAGNRIETSFFC](SEQ ID NO:153); [fIETTFAGNRIETSFGC](SEQ ID NO:154);[fIETTFAGNRIETSFHC](SEQ ID NO:155); [fIETTFAGNRIETSFIC](SEQ ID NO:156); [fIETTFAGNRIETSFLC](SEQ ID NO:157);

[0768] [fIETTFAGNRIETSFNC](SEQ ID NO:158);

[0769] [fIETTFAGNRIETSFSC](SEQ ID NO:159);

[0770] [fIETTFAGNRIETSFVC](SEQ ID NO:160);

[0771] [fIETTFAGNRIETSFWC](SEQ ID NO:161); and

[0772] [fIETTFAGNRIETSFYC](SEQ ID NO:162),

[0773] or a functional variant thereof, wherein the functional variant comprises one or two single amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or a functional variant thereof.

[0774] 146. A peptide according to any one of items 1 to 54, wherein the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of:

[0775] [fIETTFAGNRIETSFTC](SEQ ID NO:120);

[0776] [fIETTFAGWRIETSFTC](SEQ ID NO:121);

[0777] [fIETTFFGNRIETSFTC](SEQ ID NO:122);

[0778] [fIETTFHGNRIETSFTC](SEQ ID NO:123);

[0779] [fIETTFIGNRIETSFTC](SEQ ID NO:124);

[0780] [fIETTFLGNRIETSFTC](SEQ ID NO:125);

[0781] [fIETTFNGNRIETSFTC](SEQ ID NO:126);

[0782] [fIETTFQGNRIETSFTC] (SEQ ID NO:127);

[0783] [fIETTFSGNRIETSFTC] (SEQ ID NO:128);

[0784] [fIETTFTGNRIETSFTC] (SEQ ID NO:129);

[0785] [fIETTFVGNRIETSFTC] (SEQ ID NO:130);

[0786] [fIETTFWGNRIETSFTC] (SEQ ID NO:131);

[0787] [fIETTFYGNRIETSFTC] (SEQ ID NO:132);

[0788] [fIETTFAANRIETSFTC] (SEQ ID NO:133);

[0789] [fIETTFADNRIETSFTC] (SEQ ID NO:134);

[0790] [fIETTFAENRIETSFTC] (SEQ ID NO:135);

[0791] [fIETTFAFNRIETSFTC] (SEQ ID NO:136);

[0792] [fIETTFAHNRIETSFTC] (SEQ ID NO:137);

[0793] [fIETTFAKNRIETSFTC] (SEQ ID NO:138);

[0794] [fIETTFALNRIETSFTC] (SEQ ID NO:139);

[0795] [fIETTFANNRIETSFTC] (SEQ ID NO:140);

[0796] [fIETTFAQNRIETSFTC] (SEQ ID NO:141);

[0797] [fIETTFARNRIETSFTC] (SEQ ID NO:142);

[0798] [fIETTFASNRIETSFTC](SEQ ID NO:143);

[0799] [fIETTFAWNRIETSFTC](SEQ ID NO:144);

[0800] [fIETTFAYNRIETSFTC](SEQ ID NO:145);

[0801] [fIETTFAGCRIETSFTC](SEQ ID NO:146);

[0802] [fIETTFAGFRIETSFTC](SEQ ID NO:147);

[0803] [fIETTFAGGRIETSFTC](SEQ ID NO:148);

[0804] [fIETTFAGHRIETSFTC](SEQ ID NO:149);

[0805] [fIETTFAGLRIETSFTC](SEQ ID NO:150);

[0806] [fIETTFAGRRIETSFTC](SEQ ID NO:151);

[0807] [fIETTFAGYRIETSFTC](SEQ ID NO:152);

[0808] [fIETTFAGNRIETSFFC](SEQ ID NO:153);

[0809] [fIETTFAGNRIETSFGC](SEQ ID NO:154);

[0810] [fIETTFAGNRIETSFHC](SEQ ID NO:155);

[0811] [fIETTFAGNRIETSFIC](SEQ ID NO:156);

[0812] [fIETTFAGNRIETSFLC](SEQ ID NO:157);

[0813] [fIETTFAGNRIETSFNC](SEQ ID NO:158);

[0814] [fIETTFAGNRIETSFSC] (SEQ ID NO:159);

[0815] [fIETTFAGNRIETSFVC] (SEQ ID NO:160);

[0816] [fIETTFAGNRIETSFWC] (SEQ ID NO:161); and

[0817] [fIETTFAGNRIETSFYC] (SEQ ID NO:162),

[0818] or a pharmaceutically acceptable salt thereof.

[0819] 147. The peptide according to any one of the preceding items, wherein the peptide comprises at least 17 amino acid residues, such as at least 18 amino acid residues, such as at least 19 amino acid residues, such as at least 20 amino acid residues, such as at least 21 amino acid residues, such as at least 22 amino acid residues, such as at least 23 amino acid residues, such as at least 24 amino acid residues, such as at least 25 amino acid residues, such as at least 26 amino acid residues, such as at least 27 amino acid residues, such as at least 28 amino acid residues, such as at least 29 amino acid residues, such as at least 30 amino acid residues, such as at least 31 amino acid residues, such as at least 32 amino acid residues, such as at least 33 amino acid residues, such as at least 34 amino acid residues, such as at least 35 amino acid residues, such as at least 36 amino acid residues, such as at least 37 amino acid residues.

[0820] 148. The peptide according to any one of the preceding items, wherein the peptide comprises no more than 50 amino acid residues, such as no more than 45 amino acid residues, such as no more than 40 amino acid residues, such as no more than 35 amino acid residues, such as no more than 30 amino acid residues, such as no more than 29 amino acid residues, such as no more than 28 amino acid residues, such as no more than 27 amino acid residues, such as no more than 26 amino acid residues, such as no more than 25 amino acid residues, such as no more than 24 amino acid residues, such as no more than 23 amino acid residues, such as no more than 22 amino acid residues, such as no more than 21 amino acid residues, such as no more than 20 amino acid residues, such as no more than 19 amino acid residues, such as no more than 18 amino acid residues, such as no more than 17 amino acid residues.

[0821] 149. A peptide according to any one of the preceding items, wherein the peptide comprises a range of 17 to 50 amino acid residues, such as a range of 19 to 45 amino acid residues, such as a range of 17 to 40 amino acid residues, such as a range of 17 to 35 amino acid residues, such as a range of 17 to 30 amino acid residues, such as a range of 17 to 25 amino acid residues, such as a range of 17 to 23 amino acid residues, such as a range of 17 to 20 amino acid residues, such as a range of 17 to 18 amino acid residues.

[0822] 150. A peptide according to any one of the preceding items, wherein the peptide is conjugated to a cell-penetrating peptide (CPP).

[0823] 151. A peptide according to any one of the preceding items, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, such as 2 individual amino acid substitutions, such as 1 individual amino acid substitution.

[0824] 152. A peptide according to any one of the preceding items, wherein the peptide is capable of binding to PSD-95.

[0825] 153. A peptide according to any one of the preceding items, wherein the peptide is capable of inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95.

[0826] 154. A peptide according to any one of the preceding items, wherein the K of the peptide inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95 i value is less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, such as less than 2 μM, such as less than 1 μM, such as less than 0.9 μM, such as less than 0.8 μM, such as less than 0.7 μM, such as less than 0.6 μM, such as less than 0.5 μM, such as less than 0.4 μM, such as less than 0.35 μM, such as less than 0.3 μM, preferably less than 0.3 μM.

[0827] 155. A peptide according to any one of the preceding items, wherein the IC of the peptide inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95 50 value is less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, preferably less than 3 μM.

[0828] 156. A peptide according to any one of the preceding items, wherein the peptide further binds to a moiety.

[0829] 157. The peptide according to item 156, wherein the moiety is selected from the group consisting of PEG, monosaccharide, fluorophore, chromophore, radioactive compound, and cell-penetrating peptide.

[0830] 158. The peptide according to any one of items 156 to 157, wherein the moiety is a detectable moiety.

[0831] 159. The peptide according to any one of the foregoing items, wherein the peptide is further modified by glycosylation, PEGylation, amidation, esterification, acylation, acetylation, and / or alkylation.

[0832] 160. The peptide according to any one of the foregoing items, wherein one or more of the amino acid residues are alkylated, such as methylated.

[0833] 161. A composition comprising the peptide according to any one of the foregoing items.

[0834] 162. The composition according to item 161, wherein the composition is a pharmaceutical composition.

[0835] 163. A polynucleotide encoding the peptide as defined in any one of items 1 to 160.

[0836] 164. A vector comprising the polynucleotide as defined in item 163.

[0837] 165. A host cell comprising the polynucleotide according to item 163 or the vector according to item 164.

[0838] 166. The host cell according to item 165, wherein the host cell is a bacterial cell.

[0839] 167. The host cell according to item 165, wherein the host cell is a mammalian cell.

[0840] 168. The host cell according to item 165, wherein the host cell is a human cell.

[0841] 169. The peptide as defined in any one of items 1 to 160, the composition as defined in any one of items 161 to 162, the polynucleotide as defined in item 163, the vector as defined in item 164, or the host cell as defined in any one of items 165 to 168, which is used as a drug.

[0842] A peptide as defined in any one of Items 1 to 160, a composition as defined in any one of Items 161 to 162, a polynucleotide as defined in Item 163, a vector as defined in Item 164, or a host cell as defined in any one of Items 165 to 168, for use in preventing and / or treating excitotoxicity-related diseases in a subject.

[0843] 171. The peptide, composition, polynucleotide, vector or host cell for use according to Item 170, wherein the excitotoxicity-related disease is stroke, such as ischemic stroke.

[0844] 172. The peptide, composition, polynucleotide, vector or host cell for use according to the use described in Item 170, wherein the excitotoxicity-related disease is an ischemic or traumatic injury of the CNS, such as spinal cord injury and traumatic brain injury.

[0845] 173. The peptide, composition, polynucleotide, vector or host cell for use according to the use described in Item 170, wherein the excitotoxicity-related disease is epilepsy.

[0846] 174. The peptide, composition, polynucleotide, vector or host cell for use according to the use described in Item 170, wherein the excitotoxicity-related disease is a neurodegenerative disease of the CNS.

[0847] 175. The peptide, composition, polynucleotide, vector or host cell for use according to the use described in Item 174, wherein the neurodegenerative disease of the CNS is selected from the group consisting of Alzheimer's disease, Huntington's disease, and Parkinson's disease.

[0848] 176. A peptide as defined in any one of Items 1 to 160, a composition as defined in any one of Items 161 to 162, a polynucleotide as defined in Item 163, a vector as defined in Item 164, or a host cell as defined in any one of Items 165 to 168, for use in preventing and / or treating neuropathic pain in a subject.

[0849] 177. A method for preventing and / or treating excitotoxicity-related diseases and / or neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide according to any one of Items 1 to 160, a composition according to any one of Items 161 to 162, a polynucleotide according to Item 163, a vector according to Item 164, or a host cell according to any one of Items 165 to 168.

[0850] Use of a peptide according to any one of items 1 to 160, a composition according to any one of items 161 to 162, a polynucleotide according to item 163, a vector according to item 164, or a host cell according to any one of items 165 to 168 in the preparation of a medicament for the treatment and / or prevention of excitotoxicity-related diseases and / or neuropathic pain in a subject.

[0851] 179. A method for manufacturing a peptide according to any one of items 1 to 160, the method comprising the steps of:

[0852] a) using solid-phase peptide synthesis (SPPS) to prepare the peptide; and

[0853] b) cyclizing the peptide via thioether cyclization.

[0854] 180. The method according to item 179, the method further comprising a step after step b), wherein a fluorophore is bound to the peptide.

[0855] Examples

[0856] Example 1: Materials and Methods

[0857] Flexizyme tRNA aminoacylation

[0858] Prepare flexizyme and ini tRNA CAU in buffer (HEPES-KOH pH 7.6) to a final concentration of approximately 41.6 μM. Heat the mixture to 95 °C for 2 min and then cool at RT for 5 min. Subsequently, add MgCl2 (0.75 M) and leave the solution at RT for 5 min. Add N-ClAc-D-Phe-CME (5 mM) and incubate the reaction on ice for 2 h. Precipitate the aminoacylated tRNA in acidic buffer (0.23 M NaOAc pH 5.2) by adding 2× volume of ethanol. After centrifugation (12,000 rpm, 15 min), wash the precipitate with 70% ethanol, 0.1 M NaOAc pH 5.2 and centrifuge (12,000 rpm, 5 min).

[0859] Transcription

[0860] The DNA library was transcribed overnight at 37 °C in a mixture of 10×T7 buffer, dithiothreitol (DTT, 10 mM), MgCl2 (30 mM), NTP (7.5 mM), T7 RNA polymerase (0.05× volume, ThermoFisher, catalog #10753931), and RNasinRPlus ribonuclease inhibitor (0.015× volume, Promega, catalog #N2615). 1× volume of 0.6 M NaCl 50 mM ethylenediaminetetraacetic acid (EDTA) was added to the mRNA mixture and the mRNA was then purified by phenol / chloroform extraction. First, 1× volume of phenol:chloroform:isoamyl alcohol (25:24:1) was added and the mixture was centrifuged (13,000 rpm, 10 min). 1× volume of chloroform-isoamyl alcohol (24:1) was added to the aqueous phase, followed by centrifugation (13,000 rpm, 10 min) and the mRNA was precipitated with 0.8× volume of isopropanol. After centrifugation (13,000 rpm, 5 min), the pellet was resuspended in 0.3 M NaCl and precipitated again with 0.8× volume of isopropanol, and centrifuged (13,000 rpm, 5 min). Finally, the pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min).

[0861] Puromycin ligation

[0862] Puromycin ligation was performed by preparing a solution of pur-linker (1.5 μM), mRNA library (1 μM), ATP (1 mM, New England Biolabs, catalog #NEB-P0756S), 10x T4 RNA ligase buffer (0.1× volume, New England Biolabs, catalog #B0216L), and T4 ssRNA ligase 1 (0.1× volume, New England Biolabs, catalog #NEB-M0204S). The reaction was carried out at RT for 30 min and the pur-mRNA was then purified after phenol-chloroform extraction. First, 1× volume of 0.6 M NaCl 10 mM EDTA was added, followed by 1× volume of phenol:chloroform:isoamyl alcohol (25:24:1). The mixture was centrifuged (13,000 rpm, 10 min) and 1x volume of chloroform-isoamyl alcohol (24:1) was added to the aqueous phase. After centrifugation (13,000 rpm, 10 min), 2× volume of ethanol was added and the mixture was centrifuged (13,000 rpm, 15 min). The pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min).

[0863] PURE translation

[0864] The PURE translation mixture consists of SolA and SolB solutions (PUREfrex, catalog #PF201-10-EX) and a 1 mM amino acid mixture without Met. For the first RaPID round, in vitro translation was performed in 25 μL of the translation mixture supplemented with 1250 pmol of ClAc-d-Phe-initRNACAU using 25 pmol of puromycin-linked mRNA library. Subsequently, the translation mixture was incubated at 37 °C for 40 min. Then, 5 μL of 100 mM EDTA pH 8.0 was added to the solution to dissociate ribosomes from the mRNA-peptide conjugate, and the solution was incubated at 37 °C for 30 min. For subsequent selection rounds, the same procedure was followed, except that the amount of the translation mixture was adjusted to 5 μL.

[0865] Reverse transcription

[0866] Reverse transcription (RT) was prepared in the translation solution (25 μL) by adding RT-Premix solution (7.6 μL, 1), Mg(OAc)2 (16.4 mM), 0.006× volume of RNasinRPlus ribonuclease inhibitor (Promega, catalog #N2615), and 0.03× volume of RTasesuperscript IV (ThermoFisher, catalog #15387686). The reaction was incubated at 45 °C for 1 h. The RT solution was prepared for RaPID selection by a 1:1 dilution in 2× blocking buffer (Table 1).

[0867] RaPID positive selection

[0868] The protein was immobilized on magnetic beads (Dynabeads M-280, Invitrogen, catalog #11206D) to a final concentration of 200 nM when incubated with the peptide library. The bead slurry was then washed twice with the selection buffer (Table 1) and then incubated with the protein for 15 min at 4 °C with rotation. Next, biotin (25 mM) was added to the solution and the beads were incubated for an additional 15 min at 4 °C with rotation. The beads were washed with cold selection buffer (3×) and placed on ice until needed. For the first RaPID round, the protein beads were incubated directly with the peptide library and selection was carried out at 4 °C for 30 min. The beads were washed with cold selection buffer (Table 1) (3×) and the bound peptides were eluted in the elution PCR mixture (Table 1) by heating the beads at 95 °C for 5 min. The DNA concentration was determined by qPCR. Next, Phusion polymerase (New England Biolabs, catalog #NEB-M0530S) was added to the PCR mixture and the cDNA was PCR amplified. The amplified DNA was purified by phenol / chloroform extraction and ethanol precipitation. First, 0.1× volume of 3 M NaCl was added to the PCR reaction, followed by 1× volume of phenol:chloroform:isoamyl alcohol (25:24:1). The mixture was centrifuged (13,000 rpm, 10 min) and 1× volume of chloroform-isoamyl alcohol (24:1) was added to the aqueous phase. After centrifugation (13,000 rpm, 10 min), the DNA was precipitated with 2× volume of ethanol and centrifuged (13,000 rpm, 15 min). The pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min). Then, the purified DNA was used as the library for subsequent selection rounds.

[0869] RaPID negative selection

[0870] For the second and subsequent rounds of RaPID selection and the RaPID mutagenesis scan, a negative selection round is performed prior to incubating the library with protein beads. Three samples of negative beads are prepared by an initial wash with cold selection buffer (Table 1) in an amount equal to that used for positive selection. Subsequently, the beads of each sample are separated, and biotin (25 mM) is added to half of them, followed by incubation at 4 °C with rotation for 15 min. Then, the beads are washed with selection buffer (3×) and recombined. The first sample of negative beads is incubated with the blocked peptide-mRNA / cDNA library at 4 °C with rotation for 30 min. The recovered library is transferred to the next sample of negative beads, and the same procedure is performed twice. The library recovered from the three negative selections is used as the input for subsequent positive selection. Then, the pellet of negative beads is resuspended in 1% Triton X-100 and pooled. The bound peptides are eluted by heating at 95 °C for 5 min, and the samples are analyzed by qPCR.

[0871] Quantitative PCR

[0872] To monitor the selection process, quantitative PCR (qPCR) is used, enabling quantification of the amount of DNA molecules selected against the protein target and the DNA recovered after positive and negative selection rounds. Samples (1 μL) of the input and output libraries are added to 19 μL of qPCR master mix (Table 1), followed by the addition of 0.08 μL of Taq polymerase (VWR, catalog #733-1819). Then, the samples are analyzed using a MyGo Pro real-time PCR thermocycler (IT-IS Life Science Ltd.).

[0873] Solid-phase peptide synthesis (SPPS)

[0874] Reagents for SPPS were purchased from Iris Biotech GmbH (Marktredwitz, Germany). Peptides were synthesized by automated peptide synthesis using Prelude X (Gyros Protein Technologies, Tucson, AZ, USA). The reagents were prepared as stock solutions in DMF: Fmoc-protected amino acids (0.2 M), HCTU (0.5 M), DIPEA (1 M), and piperidine (20% v / v). Chain elongation of the Fmoc-protected resin was performed in a 10 mL glass reaction vessel with all steps continuously shaken at 300 rpm: deprotection (2×2 min, RT), condensation (2×7 min, 50 °C), and an intermediate wash step with DMF. For condensation, 5 eq of amino acid, 5 eq of HCTU, and 5 eq of DIPEA were used.

[0875] Peptide cleavage

[0876] The peptide was released from the solid support and simultaneously the acid-labile side-chain protecting groups were removed by incubating with a mixture of trifluoroacetic acid (TFA):triethylsilane:H2O (95:2.5:2.5) at RT for 3 h. The peptide was precipitated using cold diethyl ether.

[0877] Peptide purification

[0878] The peptide was purified using a preparative reversed-phase high performance liquid chromatography (HPLC) system (Waters) with a reversed-phase C18 column (Zorbax, 300SB-C18, 21.2×250 mm). A linear gradient was used, which used a binary buffer system of H2O:MeCN:TFA (A: 95:5:0.1; B: 5:95:0.1) at 20 mL / min. The collected fractions were characterized by liquid chromatography-mass spectrometry (LC-MS) with a reversed-phase C18 column (Zorbax Eclipse XBD-C18, 4.6×50 mm), using a binary buffer system consisting of H2O:MeCN:formic acid (A: 95:5:0.1; B: 5:95:0.1) at 0.75 mL / min. The purity of the collected fractions was determined at 214 nm on an analytical reversed-phase ultra high performance liquid chromatography (RP-UPLC) (Waters) system with a reversed-phase C18 column (Acquity UPLC BEH C18, 1.7 μm, 2.1×50 mm), using a binary buffer system of H2O:ACN:TFA (A: 95:5:0.1; B: 5:95:0.1) at 0.45 mL / min.

[0879] Thioether cyclization

[0880] N-terminal chloroacetylation was performed on the resin using a mixture of chloroacetic acid (0.5 M), Oxyma (0.5) and DIC (0.2 M) in DMF, and the resin was shaken at RT for 10 min. Subsequently, the chloroacetylated peptide was cleaved, and the crude peptide was dissolved in MeCN:H2O (1:1) and lyophilized. An alkaline buffer of MeCN:H2O (1:1) was prepared by slowly adding DIPEA and the pH was monitored with a pH meter. The crude peptide powder was dissolved in DMSO and added dropwise to the alkaline mixture of MeCN:H2O. The reaction was stirred for 15 - 30 min and then the peptide was directly injected into RP-HPLC for purification.

[0881] Fluorescent labeling

[0882] 5(6)-Carboxytetramethylrhodamine (5(6)-TAMRA, Anaspec, catalog #AS - 81124) labeling was performed on the resin by coupling a mixture of TAMRA with TAMRA:PyBOP:DIPEA (1.5:1.5:3) in NMP. The reaction was carried out overnight at RT.

[0883] Fluorescence polarization

[0884] The FP binding experiments were performed using a Safire2 microplate reader (Tecan). Samples were prepared in 50 mM HEPES, 100 mM NaCl (pH 7.4) and transferred to a flat-bottom black 384-well plate (Corning Life Science, catalog #3573). For saturation analysis, the protein was prepared in a 1:1 dilution and the TAMRA-labeled peptide probe was added to a final concentration of 500 nM. Dilutions were prepared in triplicate and the data were analyzed with a one-site binding model. For inhibition analysis, the unlabeled peptide was prepared in a 1:1 dilution, in the range of 0.24 - 500 μM. The unlabeled peptide competed with the TAMRA-probe (C = 25 nM) for binding to His10-SUMO-PDZ2-Avi-BTN (C = 4 μM). Experiments were performed in triplicate and the data were analyzed based on a sigmoidal dose-response curve. All data were analyzed using GraphPad Prism 9. The K i value was calculated according to Nikolvoska-Coleska et al. 26

[0885] Klenow PCR

[0886] Klenow PCR was used to generate a DNA library for RaPID mutagenesis scanning. A 2 μM forward primer (NNKX_F86) and a reverse primer (RaPID_HA_R) (Table 2) were prepared in NEBuffer 2 (New England BioLabs, GmbH, catalog #B7002S). The mixture was heated to 94 °C for 2 minutes, cooled to 50 °C at a rate of 0.2 °C / sec, held at that temperature for 2 min and then cooled to 37 °C at a rate of 0.2 °C / sec. Then, dNTP (0.25 μM) and 0.01× volume of Klenow (New England BioLabs, GmbH, catalog #M0210S) were added to the mixture and held at 37 °C for 30 min.

[0887] HA purification

[0888] HA purification was performed according to Vinogradov et al. 27Briefly, anti-HA magnetic beads (8 μL / pmol of mRNA library, ThermoFisher, catalog #88836) were washed in the selection buffer (Table 1) and then incubated with the peptide-mRNA / cDNA library for 1 h at 4 °C with rotation. Next, the supernatant was recovered and saved for subsequent NGS sequencing. The bound library was eluted by incubating the beads with HA peptide (2 mg / mL in water) at 37 °C for 15 min. The elution step was repeated, and the supernatants were pooled, blocked with 2× blocking buffer (Table 1) and used for RaPID mutagenesis scanning.

[0889] Table 1: Sequences of primers used for preparing the RaPID library.

[0890]

[0891]

[0892]

[0893] Table 2: Composition of buffers and reagent mixtures used for RaPID selection.

[0894]

[0895] Example 2: RaPID selection of PDZ2 / PSD-95

[0896] Based on the theoretical diversity of each NNK library ((4*4*2) n*NNK ), DNA libraries encoding 4 to 15 randomized amino acids (NNK4-15, N = A / C / G / T and K = G / T) were prepared. For NNK4-8, all possible DNA sequences were present in the final library. Due to the higher diversity of the larger libraries, the remaining library space was divided between NNK9-15 based on a rough ratio estimate to accommodate approximately equal diversity between the libraries (Table 3).

[0897] Table 3: Fractions of individual NNK libraries prepared for RaPID selection against PDZ2.

[0898]

[0899]

[0900] To generate cyclic peptides, enhanced flexible ribozyme (eFx) was used to perform genetic code reprogramming to load the initiator tRNA with the CME ester of N-terminal chloroacetylated D-Phe (ClAc-d-Phe-CME)( ini tRNA CAU)(Goto et al. 2008). Subsequently, aminoacylated ClAc-d-Phe- ini tRNA CAU was supplied to an in vitro translation system lacking Met and formyl donor. Subsequently, ClAc-d-Phe was incorporated at the starting position and a thioether cyclic peptide was generated after translation.

[0901] Regarding the puromycin tag of the mRNA sequence and the puromycin-mediated ligation of each cyclic peptide to its encoded mRNA during translation, the mRNA display protocol was followed. Complementary DNA was generated by reverse transcription and, using the resulting peptide-mRNA / cDNA conjugate, affinity selection was performed by incubating the library with biotinylated PDZ2 immobilized on streptavidin magnetic beads. Unbound peptides were washed, followed by thermal elution of the bound library, and the number of recovered DNA molecules was determined by quantitative PCR (qPCR). The bound cDNA was amplified by PCR such that the enriched bound cyclic peptides were resynthesized and these cyclic peptides were applied to the next round of affinity selection. For subsequent rounds, including "negative selection", the peptide library was incubated with biotin-streptavidin beads before selection against PDZ2. Using this method, non-specific peptide binders to biotin and streptavidin beads were discarded.

[0902] The progress of RaPID selection was monitored by calculating the library recovery rate using qPCR analysis of the input library and the libraries recovered from negative and positive selections. The recovery rate of positive selection increased after the second selection round, indicating enrichment of PDZ2-specific binders. Since higher fractions of positive selection compared to negative selection were observed in the fourth and fifth rounds, the selection was stopped and the libraries from positive and negative selections were prepared for next-generation sequencing (NGS) analysis ( Figure 2 ).

[0903] Example 3: Next-generation sequencing shows enrichment of hit peptides

[0904] Decoding of the library composition indicated a gradual enrichment of peptide sequences from the 2nd to the 5th rounds, mainly containing 15 randomized amino acids ( Figure 3 A, Table 4). Interestingly, all identified peptides included the "TTF" PDZ-binding motif present in the nNOS-binding sequence and, in some cases, two "TTF" or similar motifs were present in the same peptide. In addition, decoding of the DNA library from negative selection showed that the hit peptides had lower enrichment in the equivalent positive selection, indicating preferential binding to PDZ2 on streptavidin beads compared to streptavidin beads alone ( Figure 3 B). These promising findings enabled us to chemically synthesize the most enriched peptides by solid-phase peptide synthesis (SPPS) and verify their binding properties to PDZ2.

[0905] Table 4: Sequences of the most enriched peptides in the RaPID PDZ2 / PSD-95 selection.

[0906]

[0907] Example 4: Verification of PDZ2 binding of the hit peptides

[0908] Fluorescence polarization (FP) assays were applied to characterize the binding properties of the peptides identified by RaPID. To this end, the C-terminal binding motif of the GluN2B receptor was synthesized as a fluorescently labeled peptide (TAMRA-NNG-EKLSSIESDV–SEQ ID NO: 119). Saturation analysis of TAMRA-GluN2B showed similar binding affinities for the two tested PDZ2 constructs, biotinylated PDZ2 and ubiquitin-like / biotinylated PDZ2 (3.6 ± 0.3 μM and 2.0 ± 0.3 μM, respectively), which was in good correlation with the literature (Bach, A. et al. 2012) Figure 4 ).

[0909] To study the binding properties of the RaPID-enriched sequences 1, 2, 3, and 5 (Table 4), peptides were synthesized by SPPS. Notably, 1 contains an internal cysteine, and thus two possible thioether-linked analogs cyclized via the terminal or internal cysteine were investigated. Cyclization of 2 via its internal cysteine was not investigated because cyclization with the side chain of cysteine at the second position in the peptide sequence has been reported to be disfavored (Iwasaki et al. 2012). In addition, an unlabeled GluN2B peptide (6) was synthesized as a control. Due to the poor solubility of peptides 1 and 2, these peptides were synthesized with a Flag solubility tag, resulting in analogs 7, 8, and 9 (Table 5). To verify that the tag does not interfere with peptide binding, an analog of 3 labeled with Flag was synthesized, resulting in peptide 11. Finally, a linear analog of 3, peptide 12, was synthesized to evaluate the importance of the cyclic structure of the peptide.

[0910] Table 5: Comparison of the K i and IC 50 values. K i is expressed as mean ± SD, n = 3. IC 50 is expressed as mean ± SD, n = 3; N.B., not bound, IC 50 > 250 μM

[0911]

[0912] * Estimated value

[0913] ** K i Could not be calculated

[0914] Using TAMRA-GluN2B as a probe, the binding of unlabeled GluN2B peptide (6) and RaPID hit peptides (3 and 5) and analogs (7 - 11) to PDZ2 was characterized by FP competition assay. Peptide 3 was the most potent peptide binder to PDZ2 (IC 50 = 2.3 ± 0.1 μM, K i < 0.3 μM), with approximately ten-fold higher binding affinity compared to the control linear GluN2B peptide (6) (K i = 3.1 ± 0.2 μM). Notably, the K i value of 3 exceeded the linear range of the TMARA-GluN2B probe, and thus its exact binding affinity could not be determined. Linear peptide 11 showed decreased affinity compared to 3 (IC 50 = 13.1 ± 1.0, K i = 3.5 ± 0.3 μM), and a similar binding profile was observed for its Flag-tagged analog 10 (IC 50 = 3.8 ± 0.4 μM, K i = 0.3 ± 0.1 μM), indicating that the tag itself did not bind to PDZ2 or interfere with binding. Peptides 7 and 9 showed poor binding to PDZ2 (K i ~50 μM), however, the increased polarization indicated precipitation of the peptide at high concentration, and thus their exact binding affinity could not be determined. Peptides 5 and 8 did not bind to PDZ2 (Table 5, Figure 5 ).

[0915] Example 5: Structure-Activity Map Reveals Key Amino Acids for PDZ2 Binding

[0916] As measured by FP assay, peptide 3 showed the highest affinity for PDZ2 / PSD-95. Therefore, it was selected for structure-activity relationship studies, which aimed to better understand peptide binding and optimize its affinity. To this end, the RaPID system was applied to generate a peptide mutant library in which 15 internal residues in the peptide sequence were substituted with all 20 proteinogenic amino acids.

[0917] First, a site-saturation mutagenesis DNA library was designed (Chronopoulou and Labrou, 2011), in which the sequences encoding each wild-type amino acid were replaced with randomized NNK codons. Additionally, a DNA sequence encoding an influenza hemagglutinin (HA) tag was incorporated at the C-terminus of each peptide, enabling library purification prior to incubation with the protein target. The mRNA library was translated into peptide mutants, and the cDNA-linked peptides were purified based on the HA-tag affinity method. The peptide library was incubated with three PDZ2 samples immobilized in a titrated bead slurry. Final protein concentrations of 40, 200, and 1000 nM were evaluated, aiming to identify the optimal conditions under which peptide binding would reach equilibrium. Additionally, the library was selected against the beads to detect potential bead-binding peptides.

[0918] Following library selection, qPCR analysis of the input and recovered samples showed a 5-fold higher recovery of PDZ2 at 1000 nM concentration compared to the lower protein concentrations ( Figure 6 ). Nevertheless, recoveries similar to those observed during RaPID selection ( Figure 3 ) were also obtained.

[0919] The populations of all binding protein samples and the input library were decoded by NGS. Based on the profile analysis described by Rogers et al. 2018, the enrichment ratio (e) of the peptides was calculated by computing the fraction (e = F 结合 / F 输入 ) of the DNA reads (F) of the binding samples relative to the input samples. Subsequently, the enrichment fraction (E) of each mutant was determined based on the e of each mutant (e i ) relative to that of the wild type (e WT , E i = e i / e WT ).

[0920] By analyzing the library recovered from the selection against 1000 nM PDZ2, a nearly complete heatmap ( Figure 7 and the table below) representing the E scores of most peptide mutants was obtained.

[0921]

[0922]

[0923] R I E T S F T A -3,6 -6,8 -3,2 -7,5 -0,8 -5,8 -1,5 C -2,8 -6,2 -2,9 -7,5 -1,3 -3,5 -0,7 D -6,0 -3,8 -4,2 -4,5 -4,0 -2,3 E -2,7 -6,2 -3,5 -3,9 -4,2 F -3,4 -4,6 -3,0 -4,4 -5,0 -0,6 G -1,5 -7,4 -3,9 -3,2 -5,8 -3,7 1,0 H -3,9 -2 ,8 -1,1 -0,9 -2,7 -0,1 I -3,2 -1,7 -3,9 -4,4 -3,0 0,0 K -0,7 -6,2 -3,2 -5,5 -5,6 -6,3 -1,9 L -1,5 -3,3 -4,6 -6,3 -1,0 -3,8 -0,6 N -2,9 -5,4 -5,3 -2,6 -6,7 -5,9 -0,2 P -5,2 -4,8 -4,6 -5,8 -2,3 -5,0 -4,6 Q -3,0 -5,2 -0,8 -2,5 -2,8 R -7,0 -4,3 -5,1 -5,3 -5,5 -2,1 S -2,8 -3,4 -1,6 -3,7 -5,0 -0,2 T -1,6 -3,2 -0,8 -0,4 -5,6 V -2,2 -0,7 -2,3 -6,1 -4,0 -3,5 0,0 W -2,5 -6,4 -1,7 -4,6 -4,6 -3,2 0,6 Y -2,7 -6,4 -0,9 -6,1 -5,7 -3,7 -0,5 f -3,2 -1,5 -1,6 -3,7 0,2 -2,1 -1,0

[0924] It was observed that substitutions at most positions in the peptide sequence, including the nNOS “TTF” binding motif, were detrimental to binding to PDZ2. Changes at positions 6, 7, 8, and 15 appeared to be more tolerable, and the mutant N9W was particularly beneficial, as indicated by the highest E score. Importantly, the peptide sequences present in the bead samples were not relevant to the profile of the binding library.

[0925] References

[0926] Bach, A. et al. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl. Acad. Sci. U.S.A. 109, 3317–3322 (2012).

[0927] Chronopoulou, E.G. & Labrou, N.E. Site-saturation mutagenesis: a powerful tool for structure-based design of combinatorial mutation libraries. Curr. Protoc. protein Sci. Chapter 26, Unit 26.6 (2011).

[0928] Goto, Y. et al. Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides. ACS Chem. Biol. 3, 120–129 (2008)

[0929] Iwasaki, K., Goto, Y., Katoh, T. & Suga, H. Selective thioether macrocyclization of peptides having the N-terminal 2-chloroacetyl group and competing two or three cysteine residues in translation. Org. Biomol. Chem. 10, 5783–5786 (2012).

[0930] Rogers, J.M., Passioura, T. & Suga, H. Nonproteinogenic deep mutational scanning of linear and cyclic peptides. Proc. Natl. Acad. Sci. U.S.A. 115, 10959–10964 (2018).

Claims

1. A peptide comprising the amino acid sequence IETTFX1X2X3RIETSFX4C (SEQ ID NO:1) wherein: X1 is independently selected from the group consisting of A, F, H, I, L, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y; X3 is independently selected from the group consisting of N, C, F, G, H, L, R, W, and Y; X4 is independently selected from the group consisting of T, F, G, H, I, L, N, S, V, W, and Y; or a functional variant thereof, wherein the functional variant comprises 1 or 2 single amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

2. A peptide comprising the amino acid sequence IETTFX1X2X3RIETSFX4C (SEQ ID NO:1) wherein: X1 is independently selected from the group consisting of A, F, H, I, L, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y; X3 is independently selected from the group consisting of N, C, F, G, H, L, R, W, and Y; X4 is independently selected from the group consisting of T, F, G, H, I, L, N, S, V, W, and Y; or a pharmaceutically acceptable salt thereof.

3. The peptide according to claim 1, wherein the peptide comprises the following amino acid sequence, or consists of X D IETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein: X D is a D-amino acid, such as D-phenylalanine; X1 is independently selected from the group consisting of A, F, H, I, L, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y; X3 is independently selected from the group consisting of N, C, F, G, H, L, R, W, and Y; X4 is independently selected from the group consisting of T, F, G, H, I, L, N, S, V, W, and Y; or a pharmaceutically acceptable salt thereof.

4. The peptide according to claim 2, wherein X D is D-phenylalanine; X1 is independently selected from the group consisting of A, F, H, I, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of F, G, H, N, and Q; X3 is independently selected from the group consisting of N, G, H, and W; and X4 is independently selected from the group consisting of T, F, G, H, and W.

5. The peptide according to claim 1, wherein the peptide comprises an amino acid sequence selected from the group consisting of: X D IETTFAGNRIETSFTC (SEQ ID NO:3); X D IETTFAGWRIETSFTC (SEQ ID NO:4); X D IETTFFGNRIETSFTC (SEQ ID NO:5); X D IETTFHGNRIETSFTC (SEQ ID NO:6); X D IETTFIGNRIETSFTC (SEQ ID NO:7); X D IETTFLGNRIETSFTC (SEQ ID NO:8); X D IETTFNGNRIETSFTC (SEQ ID NO:9); X D IETTFQGNRIETSFTC (SEQ ID NO:10); X D IETTFSGNRIETSFTC (SEQ ID NO:11); X D IETTFTGNRIETSFTC (SEQ ID NO:12); X D IETTFVGNRIETSFTC (SEQ ID NO:13); X D IETTFWGNRIETSFTC (SEQ ID NO:14); X D IETTFYGNRIETSFTC (SEQ ID NO:15); X D IETTFAANRIETSFTC (SEQ ID NO:16); X D IETTFADNRIETSFTC (SEQ ID NO:17); X D IETTFAENRIETSFTC (SEQ ID NO:18); X D IETTFAFNRIETSFTC (SEQ ID NO:19); X D IETTFAHNRIETSFTC (SEQ ID NO:20); X D IETTFAKNRIETSFTC (SEQ ID NO:21); X D IETTFALNRIETSFTC (SEQ ID NO:22); X D IETTFANNRIETSFTC (SEQ ID NO:23); X D IETTFAQNRIETSFTC (SEQ ID NO:24); X D IETTFARNRIETSFTC (SEQ ID NO:25); X D IETTFASNRIETSFTC (SEQ ID NO:26); X D IETTFAWNRIETSFTC (SEQ ID NO:27); X D IETTFAYNRIETSFTC (SEQ ID NO:28); X D IETTFAGCRIETSFTC (SEQ ID NO:29); X D IETTFAGFRIETSFTC (SEQ ID NO:30); X D IETTFAGGRIETSFTC (SEQ ID NO:31); X D IETTFAGHRIETSFTC (SEQ ID NO:32); X D IETTFAGLRIETSFTC (SEQ ID NO:33); X D IETTFAGRRIETSFTC (SEQ ID NO:34); X D IETTFAGYRIETSFTC (SEQ ID NO:35); X D IETTFAGNRIETSFFC (SEQ ID NO:36); X D IETTFAGNRIETSFGC (SEQ ID NO:37); X D IETTFAGNRIETSFHC (SEQ ID NO:38); X D IETTFAGNRIETSFIC (SEQ ID NO:39); X D IETTFAGNRIETSFLC (SEQ ID NO:40); X D IETTFAGNRIETSFNC (SEQ ID NO:41); X D IETTFAGNRIETSFSC (SEQ ID NO:42); X D IETTFAGNRIETSFVC (SEQ ID NO:43); X D IETTFAGNRIETSFWC (SEQ ID NO:44); X D IETTFAGNRIETSFYC (SEQ ID NO:45); wherein X D is a D-amino acid, such as D-phenylalanine; or a functional variant thereof, wherein the functional variant comprises 1 or 2 single amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

6. The peptide according to claim 1, wherein the peptide comprises an amino acid sequence selected from the group consisting of: X D IETTFAGNRIETSFTC (SEQ ID NO:3); X D IETTFAGWRIETSFTC (SEQ ID NO:4); X D IETTFFGNRIETSFTC (SEQ ID NO:5); X D IETTFHGNRIETSFTC (SEQ ID NO:6); X D IETTFIGNRIETSFTC (SEQ ID NO:7); X D IETTFLGNRIETSFTC (SEQ ID NO:8); X D IETTFNGNRIETSFTC (SEQ ID NO:9); X D IETTFQGNRIETSFTC (SEQ ID NO:10); X D IETTFSGNRIETSFTC (SEQ ID NO:11); X D IETTFTGNRIETSFTC (SEQ ID NO:12); X D IETTFVGNRIETSFTC (SEQ ID NO:13); X D IETTFWGNRIETSFTC (SEQ ID NO:14); X D IETTFYGNRIETSFTC (SEQ ID NO:15); X D IETTFAANRIETSFTC (SEQ ID NO:16); X D IETTFADNRIETSFTC (SEQ ID NO:17); X D IETTFAENRIETSFTC (SEQ ID NO:18); X D IETTFAFNRIETSFTC (SEQ ID NO:19); X D IETTFAHNRIETSFTC (SEQ ID NO:20); X D IETTFAKNRIETSFTC (SEQ ID NO:21); X D IETTFALNRIETSFTC (SEQ ID NO:22); X D IETTFANNRIETSFTC (SEQ ID NO:23); X D IETTFAQNRIETSFTC (SEQ ID NO:24); X D IETTFARNRIETSFTC (SEQ ID NO:25); X D IETTFASNRIETSFTC (SEQ ID NO:26); X D IETTFAWNRIETSFTC (SEQ ID NO:27); X D IETTFAYNRIETSFTC (SEQ ID NO:28); X D IETTFAGCRIETSFTC (SEQ ID NO:29); X D IETTFAGFRIETSFTC (SEQ ID NO:30); X D IETTFAGGRIETSFTC (SEQ ID NO:31); X D IETTFAGHRIETSFTC (SEQ ID NO:32); X D IETTFAGLRIETSFTC (SEQ ID NO:33); X D IETTFAGRRIETSFTC (SEQ ID NO:34); X D IETTFAGYRIETSFTC (SEQ ID NO:35); X D IETTFAGNRIETSFFC (SEQ ID NO:36); X D IETTFAGNRIETSFGC (SEQ ID NO:37); X D IETTFAGNRIETSFHC (SEQ ID NO:38); X D IETTFAGNRIETSFIC (SEQ ID NO:39); X D IETTFAGNRIETSFLC (SEQ ID NO:40); X D IETTFAGNRIETSFNC (SEQ ID NO:41); X D IETTFAGNRIETSFSC (SEQ ID NO:42); X D IETTFAGNRIETSFVC (SEQ ID NO:43); X D IETTFAGNRIETSFWC (SEQ ID NO:44); X D IETTFAGNRIETSFYC (SEQ ID NO:45); wherein X D is a D-amino acid, such as D-phenylalanine; or a pharmaceutically acceptable salt thereof.

7. The peptide according to any one of the preceding claims, wherein the peptide comprises 17 to 23 amino acid residues.

8. The peptide according to any one of the preceding claims, wherein the peptide is cyclic.

9. The peptide according to any one of the preceding claims, wherein the peptide is cyclized.

10. The peptide according to any one of the preceding claims, wherein the peptide is backbone-cyclized.

11. The peptide according to any one of the preceding claims, wherein the peptide comprises a chloroacetylated N-terminal residue.

12. The peptide according to any one of the preceding claims, wherein the chloroacetylated N-terminal residue forms a linkage with the side chain of a C-terminal cysteine.

13. The peptide according to claim 1, wherein the peptide is cyclic and comprises the following amino acid sequence, or consists of X D IETTFX1X2X3RIETSFX4C (SEQ ID NO:2) Wherein: X D is a D-amino acid; X1 is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of: G, A, D, E, F, H, K, L, N, Q, R, S, W, and Y; X3 is independently selected from the group consisting of: N, C, F, G, H, L, R, W, and Y; X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W, and Y; or a pharmaceutically acceptable salt thereof.

14. The peptide according to claim 13, wherein X D is D-phenylalanine.

15. The peptide according to claim 13, wherein X D is D-phenylalanine; X1 is independently selected from the group consisting of: A, F, H, I, N, Q, S, T, V, W, and Y; X2 is independently selected from the group consisting of: F, G, H, N, and Q; X3 is independently selected from the group consisting of: N, G, H, and W; and X4 is independently selected from the group consisting of: T, F, G, H, and W.

16. The peptide according to any one of the preceding claims, wherein the peptide is head-to-tail cyclic.

17. The peptide according to any one of the preceding claims, wherein the peptide inhibits the binding of GluN2B to the PDZ2 domain of PSD-95 with a K i value of less than 0.3 μM.

18. The peptide according to any one of the preceding claims, wherein the IC 50 value of the peptide inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95 is less than 3 μM.

19. The peptide according to claim 1, wherein the peptide comprises an amino acid sequence selected from the group consisting of, or consists of: fIETTFAGNRIETSFTC (SEQ ID NO:46); fIETTFAGWRIETSFTC (SEQ ID NO:47); fIETTFFGNRIETSFTC (SEQ ID NO:48); fIETTFHGNRIETSFTC (SEQ ID NO:49); fIETTFIGNRIETSFTC (SEQ ID NO:50); fIETTFLGNRIETSFTC (SEQ ID NO:51); fIETTFNGNRIETSFTC (SEQ ID NO:52); fIETTFQGNRIETSFTC (SEQ ID NO:53); fIETTFSGNRIETSFTC (SEQ ID NO:54); fIETTFTGNRIETSFTC (SEQ ID NO:55); fIETTFVGNRIETSFTC (SEQ ID NO:56); fIETTFWGNRIETSFTC (SEQ ID NO:57); fIETTFYGNRIETSFTC (SEQ ID NO:58); fIETTFAANRIETSFTC (SEQ ID NO:59); fIETTFADNRIETSFTC (SEQ ID NO:60); fIETTFAENRIETSFTC (SEQ ID NO:61); fIETTFAFNRIETSFTC (SEQ ID NO:62); fIETTFAHNRIETSFTC (SEQ ID NO:63); fIETTFAKNRIETSFTC (SEQ ID NO:64); fIETTFALNRIETSFTC (SEQ ID NO:65); fIETTFANNRIETSFTC (SEQ ID NO:66); fIETTFAQNRIETSFTC (SEQ ID NO:67); fIETTFARNRIETSFTC (SEQ ID NO:68); fIETTFASNRIETSFTC (SEQ ID NO:69); fIETTFAWNRIETSFTC (SEQ ID NO:70); fIETTFAYNRIETSFTC (SEQ ID NO:71); fIETTFAGCRIETSFTC (SEQ ID NO:72); fIETTFAGFRIETSFTC (SEQ ID NO:73); fIETTFAGGRIETSFTC (SEQ ID NO:74); fIETTFAGHRIETSFTC (SEQ ID NO:75); fIETTFAGLRIETSFTC (SEQ ID NO:76); fIETTFAGRRIETSFTC (SEQ ID NO:77); fIETTFAGYRIETSFTC (SEQ ID NO:78); fIETTFAGNRIETSFFC (SEQ ID NO:79); fIETTFAGNRIETSFGC (SEQ ID NO:80); fIETTFAGNRIETSFHC (SEQ ID NO:81); fIETTFAGNRIETSFIC (SEQ ID NO:82); fIETTFAGNRIETSFLC (SEQ ID NO:83); fIETTFAGNRIETSFNC (SEQ ID NO:84); fIETTFAGNRIETSFSC (SEQ ID NO:85); fIETTFAGNRIETSFVC (SEQ ID NO:86); fIETTFAGNRIETSFWC (SEQ ID NO:87); fIETTFAGNRIETSFYC (SEQ ID NO:88); or a functional variant thereof, wherein f is D-phenylalanine, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

20. The peptide according to claim 1, wherein the peptide comprises an amino acid sequence selected from the group consisting of, or consists of: fIETTFAGNRIETSFTC (SEQ ID NO:46); fIETTFAGWRIETSFTC (SEQ ID NO:47); fIETTFFGNRIETSFTC (SEQ ID NO:48); fIETTFHGNRIETSFTC (SEQ ID NO:49); fIETTFIGNRIETSFTC (SEQ ID NO:50); fIETTFLGNRIETSFTC (SEQ ID NO:51); fIETTFNGNRIETSFTC (SEQ ID NO:52); fIETTFQGNRIETSFTC (SEQ ID NO:53); fIETTFSGNRIETSFTC (SEQ ID NO:54); fIETTFTGNRIETSFTC (SEQ ID NO:55); fIETTFVGNRIETSFTC (SEQ ID NO:56); fIETTFWGNRIETSFTC (SEQ ID NO:57); fIETTFYGNRIETSFTC (SEQ ID NO:58); fIETTFAANRIETSFTC (SEQ ID NO:59); fIETTFADNRIETSFTC (SEQ ID NO:60); fIETTFAENRIETSFTC (SEQ ID NO:61); fIETTFAFNRIETSFTC (SEQ ID NO:62); fIETTFAHNRIETSFTC (SEQ ID NO:63); fIETTFAKNRIETSFTC (SEQ ID NO:64); fIETTFALNRIETSFTC (SEQ ID NO:65); fIETTFANNRIETSFTC (SEQ ID NO:66); fIETTFAQNRIETSFTC (SEQ ID NO:67); fIETTFARNRIETSFTC (SEQ ID NO:68); fIETTFASNRIETSFTC (SEQ ID NO:69); fIETTFAWNRIETSFTC (SEQ ID NO:70); fIETTFAYNRIETSFTC (SEQ ID NO:71); fIETTFAGCRIETSFTC (SEQ ID NO:72); fIETTFAGFRIETSFTC (SEQ ID NO:73); fIETTFAGGRIETSFTC (SEQ ID NO:74); fIETTFAGHRIETSFTC (SEQ ID NO:75); fIETTFAGLRIETSFTC (SEQ ID NO:76); fIETTFAGRRIETSFTC (SEQ ID NO:77); fIETTFAGYRIETSFTC (SEQ ID NO:78); fIETTFAGNRIETSFFC (SEQ ID NO:79); fIETTFAGNRIETSFGC (SEQ ID NO:80); fIETTFAGNRIETSFHC (SEQ ID NO:81); fIETTFAGNRIETSFIC (SEQ ID NO:82); fIETTFAGNRIETSFLC (SEQ ID NO:83); fIETTFAGNRIETSFNC (SEQ ID NO:84); fIETTFAGNRIETSFSC (SEQ ID NO:85); fIETTFAGNRIETSFVC (SEQ ID NO:86); fIETTFAGNRIETSFWC (SEQ ID NO:87); fIETTFAGNRIETSFYC (SEQ ID NO:88); wherein f is D - phenylalanine, or a pharmaceutically acceptable salt thereof.

21. The peptide according to claim 1, wherein the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of: [fIETTFAGNRIETSFTC] (SEQ ID NO:120); [fIETTFAGWRIETSFTC] (SEQ ID NO:121); [fIETTFFGNRIETSFTC] (SEQ ID NO:122); [fIETTFHGNRIETSFTC] (SEQ ID NO:123); [fIETTFIGNRIETSFTC] (SEQ ID NO:124); [fIETTFLGNRIETSFTC] (SEQ ID NO:125); [fIETTFNGNRIETSFTC] (SEQ ID NO:126); [fIETTFQGNRIETSFTC] (SEQ ID NO:127); [fIETTFSGNRIETSFTC] (SEQ ID NO:128); [fIETTFTGNRIETSFTC] (SEQ ID NO:129); [fIETTFVGNRIETSFTC] (SEQ ID NO:130); [fIETTFWGNRIETSFTC] (SEQ ID NO:131); [fIETTFYGNRIETSFTC] (SEQ ID NO:132); [fIETTFAANRIETSFTC] (SEQ ID NO:133); [fIETTFADNRIETSFTC] (SEQ ID NO:134); [fIETTFAENRIETSFTC] (SEQ ID NO:135); [fIETTFAFNRIETSFTC] (SEQ ID NO:136); [fIETTFAHNRIETSFTC] (SEQ ID NO:137); [fIETTFAKNRIETSFTC] (SEQ ID NO:138); [fIETTFALNRIETSFTC] (SEQ ID NO:139); [fIETTFANNRIETSFTC] (SEQ ID NO:140); [fIETTFAQNRIETSFTC] (SEQ ID NO:141); [fIETTFARNRIETSFTC] (SEQ ID NO:142); [fIETTFASNRIETSFTC] (SEQ ID NO:143); [fIETTFAWNRIETSFTC] (SEQ ID NO:144); [fIETTFAYNRIETSFTC] (SEQ ID NO:145); [fIETTFAGCRIETSFTC] (SEQ ID NO:146); [fIETTFAGFRIETSFTC] (SEQ ID NO:147); [fIETTFAGGRIETSFTC] (SEQ ID NO:148); [fIETTFAGHRIETSFTC] (SEQ ID NO:149); [fIETTFAGLRIETSFTC] (SEQ ID NO:150); [fIETTFAGRRIETSFTC] (SEQ ID NO:151); [fIETTFAGYRIETSFTC] (SEQ ID NO:152); [fIETTFAGNRIETSFFC] (SEQ ID NO:153); [fIETTFAGNRIETSFGC] (SEQ ID NO:154); [fIETTFAGNRIETSFHC] (SEQ ID NO:155); [fIETTFAGNRIETSFIC] (SEQ ID NO:156); [fIETTFAGNRIETSFLC] (SEQ ID NO:157); [fIETTFAGNRIETSFNC] (SEQ ID NO:158); [fIETTFAGNRIETSFSC] (SEQ ID NO:159); [fIETTFAGNRIETSFVC] (SEQ ID NO:160); [fIETTFAGNRIETSFWC] (SEQ ID NO:161); and [fIETTFAGNRIETSFYC] (SEQ ID NO:162), or a functional variant thereof, wherein the functional variant comprises one or two individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or its functional variant.

22. The peptide according to claim 1, wherein the peptide is cyclic and consists of an amino acid sequence selected from the group consisting of: [fIETTFAGNRIETSFTC] (SEQ ID NO:120); [fIETTFAGWRIETSFTC] (SEQ ID NO:121); [fIETTFFGNRIETSFTC] (SEQ ID NO:122); [fIETTFHGNRIETSFTC] (SEQ ID NO:123); [fIETTFIGNRIETSFTC] (SEQ ID NO:124); [fIETTFLGNRIETSFTC] (SEQ ID NO:125); [fIETTFNGNRIETSFTC] (SEQ ID NO:126); [fIETTFQGNRIETSFTC] (SEQ ID NO:127); [fIETTFSGNRIETSFTC] (SEQ ID NO:128); [fIETTFTGNRIETSFTC] (SEQ ID NO:129); [fIETTFVGNRIETSFTC] (SEQ ID NO:130); [fIETTFWGNRIETSFTC] (SEQ ID NO:131); [fIETTFYGNRIETSFTC] (SEQ ID NO:132); [fIETTFAANRIETSFTC] (SEQ ID NO:133); [fIETTFADNRIETSFTC] (SEQ ID NO:134); [fIETTFAENRIETSFTC] (SEQ ID NO:135); [fIETTFAFNRIETSFTC] (SEQ ID NO:136); [fIETTFAHNRIETSFTC] (SEQ ID NO:137); [fIETTFAKNRIETSFTC] (SEQ ID NO:138); [fIETTFALNRIETSFTC] (SEQ ID NO:139); [fIETTFANNRIETSFTC] (SEQ ID NO:140); [fIETTFAQNRIETSFTC] (SEQ ID NO:141); [fIETTFARNRIETSFTC] (SEQ ID NO:142); [fIETTFASNRIETSFTC] (SEQ ID NO:143); [fIETTFAWNRIETSFTC] (SEQ ID NO:144); [fIETTFAYNRIETSFTC] (SEQ ID NO:145); [fIETTFAGCRIETSFTC] (SEQ ID NO:146); [fIETTFAGFRIETSFTC] (SEQ ID NO:147); [fIETTFAGGRIETSFTC] (SEQ ID NO:148); [fIETTFAGHRIETSFTC] (SEQ ID NO:149); [fIETTFAGLRIETSFTC] (SEQ ID NO:150); [fIETTFAGRRIETSFTC] (SEQ ID NO:151); [fIETTFAGYRIETSFTC] (SEQ ID NO:152); [fIETTFAGNRIETSFFC] (SEQ ID NO:153); [fIETTFAGNRIETSFGC] (SEQ ID NO:154); [fIETTFAGNRIETSFHC] (SEQ ID NO:155); [fIETTFAGNRIETSFIC] (SEQ ID NO:156); [fIETTFAGNRIETSFLC] (SEQ ID NO:157); [fIETTFAGNRIETSFNC] (SEQ ID NO:158); [fIETTFAGNRIETSFSC] (SEQ ID NO:159); [fIETTFAGNRIETSFVC] (SEQ ID NO:160); [fIETTFAGNRIETSFWC] (SEQ ID NO:161); and [fIETTFAGNRIETSFYC] (SEQ ID NO:162), or a pharmaceutically acceptable salt thereof.

23. The peptide according to any one of the preceding claims, wherein the peptide comprises at least 17 amino acid residues, such as at least 18 amino acid residues, such as at least 19 amino acid residues, such as at least 20 amino acid residues, such as at least 21 amino acid residues, such as at least 22 amino acid residues, such as at least 23 amino acid residues, such as at least 24 amino acid residues, such as at least 25 amino acid residues, such as at least 26 amino acid residues, such as at least 27 amino acid residues, such as at least 28 amino acid residues, such as at least 29 amino acid residues, such as at least 30 amino acid residues, such as at least 31 amino acid residues, such as at least 32 amino acid residues, such as at least 33 amino acid residues, such as at least 34 amino acid residues, such as at least 35 amino acid residues, such as at least 36 amino acid residues, such as at least 37 amino acid residues.

24. The peptide according to any one of the preceding claims, wherein the peptide comprises no more than 50 amino acid residues, such as no more than 45 amino acid residues, such as no more than 40 amino acid residues, such as no more than 35 amino acid residues, such as no more than 30 amino acid residues, such as no more than 29 amino acid residues, such as no more than 28 amino acid residues, such as no more than 27 amino acid residues, such as no more than 26 amino acid residues, such as no more than 25 amino acid residues, such as no more than 24 amino acid residues, such as no more than 23 amino acid residues, such as no more than 22 amino acid residues, such as no more than 21 amino acid residues, such as no more than 20 amino acid residues, such as no more than 19 amino acid residues, such as no more than 18 amino acid residues, such as no more than 17 amino acid residues.

25. The peptide according to any one of the preceding claims, wherein the peptide comprises an amino acid residue range of 17 to 50, such as an amino acid residue range of 19 to 45, such as an amino acid residue range of 17 to 40, such as an amino acid residue range of 17 to 35, such as an amino acid residue range of 17 to 30, such as an amino acid residue range of 17 to 25, such as an amino acid residue range of 17 to 23, such as an amino acid residue range of 17 to 20, such as an amino acid residue range of 17 to 18.

26. The peptide according to any one of the preceding claims, wherein the peptide binds to a cell-penetrating peptide (CPP).

27. The peptide according to any one of the preceding claims, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, such as 2 individual amino acid substitutions, such as 1 individual amino acid substitution.

28. The peptide according to any one of the preceding claims, wherein the peptide is capable of binding to PSD-95.

29. The peptide according to any one of the preceding claims, wherein the peptide is capable of inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95.

30. The peptide according to any one of the preceding claims, wherein the peptide inhibits the binding of GluN2B to the PDZ2 domain of PSD-95 with a K i value of less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, such as less than 2 μM, such as less than 1 μM, such as less than 0.9 μM, such as less than 0.8 μM, such as less than 0.7 μM, such as less than 0.6 μM, such as less than 0.5 μM, such as less than 0.4 μM, such as less than 0.35 μM, such as less than 0.3 μM, preferably less than 0.3 μM.

31. The peptide according to any one of the preceding claims, wherein the IC 50 value of the peptide for inhibiting the binding of GluN2B to the PDZ2 domain of PSD-95 is less than 100 μM, such as less than 75 μM, such as less than 50 μM, such as less than 25 μM, such as less than 20 μM, such as less than 15 μM, such as less than 10 μM, such as less than 5 μM, such as less than 4 μM, such as less than 3 μM, preferably less than 3 μM.

32. The peptide according to any one of the preceding claims, wherein the peptide further binds to a moiety.

33. The peptide according to claim 32, wherein the moiety is selected from the group consisting of PEG, monosaccharide, fluorophore, chromophore, radioactive compound, and cell-penetrating peptide.

34. The peptide according to any one of claims 32 to 33, wherein the moiety is a detectable moiety.

35. A composition comprising the peptide according to any one of the preceding claims.

36. A polynucleotide encoding the peptide according to any one of claims 1 to 34.

37. A vector comprising the polynucleotide according to claim 36.

38. A host cell comprising the polynucleotide according to claim 36 or the vector according to claim 37.

39. The peptide according to any one of claims 1 to 19, the composition according to claim 16, the polynucleotide according to claim 20, the vector according to claim 21, or the host cell according to claim 22, for use as a medicament.

40. The peptide according to any one of claims 1 to 34, the composition according to claim 35, the polynucleotide according to claim 36, the vector according to claim 37, or the host cell according to claim 38, for the prevention and / or treatment of excitotoxicity-related diseases in a subject, the excitotoxicity-related diseases being selected from the group consisting of: stroke, such as ischemic stroke; ischemic or traumatic injury of the CNS, such as spinal cord injury and traumatic brain injury; epilepsy; Alzheimer's disease; Huntington's disease, and Parkinson's disease, and / or for the prevention and / or treatment of neuropathic pain in a subject.

41. The peptide according to any one of claims 1 to 34, the composition according to claim 35, the polynucleotide according to claim 36, the vector according to claim 37, or the host cell according to claim 38, for the prevention and / or treatment of neuropathic pain in a subject.

42. A method for preventing and / or treating excitotoxicity-related diseases and / or neuropathic pain, the method comprising administering to a subject in need thereof a therapeutically effective amount of the peptide according to any one of claims 1 to 34, the composition according to claim 35, the polynucleotide according to claim 36, the vector according to claim 37, or the host cell according to claim 38.

43. Use of the peptide according to any one of claims 1 to 34, the composition according to claim 35, the polynucleotide according to claim 36, the vector according to claim 37, or the host cell according to claim 38 in the manufacture of a medicament for the treatment and / or prevention of excitotoxicity-related diseases and / or neuropathic pain in a subject.

44. A method for manufacturing the peptide according to any one of claims 1 to 34, the method comprising the steps of: c) using solid-phase peptide synthesis (SPPS) to prepare the peptide; and d) cyclizing the peptide via thioether cyclization.

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