EP4638466A1

EP4638466A1 - Novel cyclic peptide inhibitors of psd-95

Info

Publication number: EP4638466A1
Application number: EP23836470.7A
Authority: EP
Inventors: Flora ALEXOPOULOU; Fabian HINK; Joseph Matthew ROGERS; Kristian STRØMGAARD
Original assignee: Københavns Universitet
Current assignee: Københavns Universitet
Priority date: 2022-12-20
Filing date: 2023-12-20
Publication date: 2025-10-29
Also published as: WO2024133413A1; TW202440612A; CN120380008A

Abstract

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

Description

Novel cyclic peptide inhibitors of PSD-95

Technical field

The present disclosure relates to novel cyclic peptides which can act as inhibitors of protein-protein interactions, specifically by inhibiting the PDZ domains of PSD-95, such as PDZ2, and their use in treatment of excitotoxicity-related diseases and neuropathic pain.

Background

The postsynaptic density-95 protein (PSD-95) is a highly abundant scaffolding protein at the postsynaptic density (PSD) regulating assembling and/or dissociation of protein complexes for the transmission of neuronal stimuli. PSD-95 belongs to the family of the PSD membrane-associated guanylate kinase (MAGLIK) scaffolding proteins. All PSD- MAGLIK family members share the same protein-interacting domains and are consisted by three N-terminal PSD-95, discs-large, zona occludens-1 (ZO-1) (PDZ) domains followed by a Src homology 3 (SH3) and a non-enzymatic guanylate kinase (GK) domain. The biological functions of PSD-MAGUK proteins have been related to synaptic trafficking and anchoring of the ionotropic glutamate receptors, thus modulating synaptic plasticity of glutamatergic postsynaptic neurons.

Through its PDZ domains, PSD-95 regulates both the a-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid receptors (AMPARs), indirectly via for example stargazin, and the N-methyl-D-aspartate receptors (NMDARs). PSD-95 binds directly the C-terminal tail of the GluN2 subunits of NMDARs, via a canonical binding mode, and regulates receptor signaling and surface expression. Additionally, PDZ-mediated interactions of PSD-95 associate NMDARs with intracellular signaling proteins as for example the neuronal nitric oxide synthase (nNOS). Importantly, nNOS binds to the PDZ domains of PSD-95 via an internal motif (non-canonical binding mode) that is structurally constrained within a p-hairpin of nNOS.

The ternary complex between NMDAR, PSD-95 and nNOS plays an important role in the mechanism of neuronal excitotoxicity and cell death during acute ischemic stroke (AIS) (Fig. 1). Binding of glutamate to NMDARs induces Ca²⁺-mediated neuronal signal transmission which plays a fundamental role in synaptic plasticity and cell survival. An excessive synaptic release of glutamate during AIS activates an increased Ca²⁺ influx which leads to cytotoxicity and neuronal damage. One of the mechanisms causing Ca²⁺-dependent excitotoxicity is mediated by the NMDAR/PSD-95/nNOS ternary complex. In particular, simultaneous binding of nNOS and NMDARs to PSD-95 through PDZ-mediated interactions, brings nNOS in close proximity to NMDARs and its subsequent activation by the increased local concentration of Ca²⁺. Activated nNOS leads to neuronal cell death through excessive synthesis of nitric oxide (NO).

Direct inhibition of NMDAR for treatment of AIS has failed due to inefficient neuroprotection and serious side effects. Thus, following studies focused on the downstream targeting of NMDAR via modulation of PSD-95 as an alternative neuroprotective strategy for AIS treatment. This approach was encouraged by findings demonstrating that abolishment of PSD-95-mediated interactions decreased synthesis of NO yet retained NMDAR activity. To date, two peptide-based approaches have been clinically investigated as potential therapies targeting the NMDAR/PSD-95/nNOS receptor complex for stroke treatment: Nerinetide (NA-1) and AVLX-144 target the PDZ domains of PSD-95 through mimicking binding of the C-terminal PDZ binding region of GluN2B, thus dissociating NMDAR and nNOS and preventing NO synthesis without blocking NMDAR signaling.

Summary

In order to address the stated problem of providing inhibitors of protein-protein interactions by specifically targeting the PDZ domains of PSD-95, the present disclosure describes a novel class of cyclic peptides capable of non-canonical binding to PDZ domains of PSD-95, such as the PDZ2 domain of PSD-95, thereby inhibiting its protein-protein interaction with GluN2B for treatment of ischemic stroke and neuropathic pain, methods of manufacture and methods of use of said peptides.

In one aspect, the present disclosure is directed to a peptide comprising the amino acid sequence

IETTFX1X2X3RIETSFX4C (SEQ ID NO: 1) wherein:

Xi 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 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or the functional variant thereof.

In another aspect, the present disclosure is directed to a composition comprising the peptide as described herein.

In another aspect, the present disclosure is directed to a polynucleotide encoding the peptide as described herein.

In another aspect, the present disclosure is directed to a vector comprising a polynucleotide as described herein.

In another aspect, the present disclosure is directed to a host cell comprising the polynucleotide as described herein or the vector as described herein.

In another aspect, the present disclosure is directed 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.

In another aspect, the present disclosure is directed 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 in prevention and/or treatment of an excitotoxicity-related disease in a subject.

In another aspect, the present disclosure is directed to a method of preventing and/or treating an excitotoxicity-related disease and/or neuropathic pain, said method comprising administering a therapeutically effective amount of the peptide as described herein, the composition as described herein, the polynucleotide as described herein, the vector as described herein, or the host cell as described herein, to a subject in need thereof.

In another aspect, the present disclosure is directed to the use of the peptide as described herein, the composition as described herein, the polynucleotide as described herein, the vector as described herein, or the host cell as described herein, for the manufacture of a medicament for the treatment and/or prevention of an excitotoxicity- related disease and/or neuropathic pain in a subject.

In another aspect, the present disclosure is directed to a method for manufacturing a peptide as described herein, said method comprising the steps of: a) preparing a peptide using solid-phase peptide synthesis (SPPS); and b) cyclization of said peptide via thioether cyclization.

Description of Drawings

Figure 1 : The role of PSD-95 in acute ischemic stroke. The excessive release of glutamate during stroke activates the NMDAR and induces a Ca²⁺ inward flux. The formation of the ternary complex through PDZ-mediated interactions of PSD-95 with NMDAR and nNOS leads to activation of nNOS and cytotoxicity.

Figure 2: RaPID selection of PDZ2/PSD-95 peptide binders. Higher recovery rate of total cDNA after binding to PDZ-immobilized beads (positive), relative to just streptavidin beads (negative), suggests enrichment for PDZ2 binders.

Figure 3: NGS analysis reveals enrichment of PDZ2/PSD-95 peptide binders with ‘TTF’ motifs. A) Next-generation sequencing (NGS) of positive RaPID selection rounds show a progressive enrichment for particular cyclic peptide sequences that are related through a ‘TTF’ motif. B) NGS of negative selection rounds show low enrichment of ‘TTF’ peptides indicating PDZ2 selective binding.

Figure 4: Binding of TAMRA-GluN2B C-terminal probe to PDZ2. A saturation fluorescence polarization assay was performed for the determination of the binding affinity of the TAMRA-GluN2B C-terminal peptide (C_probe = 500 nM) to A) PDZ2-Avi- BTN and B) His10-SUMO-PDZ2-Avi-BTN constructs. Data are presented as average ± SD, n = 3.

Figure 5: Potent binding of peptide 3 to PDZ2/PSD-95. A) Concentration-response curves of RaPID-identified peptides and analogues as measured in a competition fluorescence polarization (FP) assay for binding against PDZ2 (CPDZ2 = 4 pM) using the TAMRA-GluN2B peptide probe (C_probe = 25 nM). B) IC50 and C) values of peptide inhibitors. Data are presented as average ± SD, n = 3. n.d., not-determined, K < 0.3 pM.

Figure 6: qPCR analysis of input and recovered libraries. A) Number of DNA molecules before and after binding to PDZ2. B) Recovery rates of bound libraries.

Figure 7: Deep mutational scanning of peptide 3. Heat maps of enrichment scores (E) of peptide mutants selected for binding against PDZ2 (CPDZ2 = 1000 nM).

Figure 8: Potent binding of peptides 3 and 12 to PDZ2/PSD-95. A) Concentrationresponse curves of RaPID-identified peptide inhibitor 3 and its mutant 12 (N9W) as measured in a competition fluorescence polarization (FP) assay for binding against PDZ2 (CPDZ2 = 4 pM) using the TAMRA-GluN2B peptide probe (C_prObe = 25 nM). B) IC50 and C) K\ values of peptide inhibitors. Data are presented as average ± SD, n = 3. n.d., not-determined, K < 0.3 pM.

Detailed description

Definitions

An “amino acid residue” can be a natural or non-natural amino acid residue linked by peptide bonds or bonds different from peptide bonds. The amino acid residues can be in D-configuration or L-configuration. An amino acid residue comprises an amino terminal part (NH2) and a carboxy terminal part (COOH) separated by a central part comprising a carbon atom, or a chain of carbon atoms, at least one of which comprises at least one side chain or functional group. NH2 refers to the amino group present at the amino terminal end of an amino acid or peptide, and COOH refers to the carboxy group present at the carboxy terminal end of an amino acid or peptide. The generic term amino acid comprises both natural and non-natural amino acids. Natural amino acids of standard nomenclature as 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 herewith: Y,G,F,M,A,S,I,L,T,V,P,K,H,Q,E,W,R,D,N and C. Non-natural amino acids are those not listed immediately above. Also, non-natural amino acid residues include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues.

An “equivalent amino acid residue” refers to an amino acid residue capable of replacing another amino acid residue in a polypeptide without substantially altering the structure and/or functionality of the polypeptide. Equivalent amino acids thus have similar properties such as bulkiness of the side-chain, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic) and side chain organization of carbon molecules (aromatic/aliphatic). As such, “equivalent amino acid residues” can be regarded as “conservative amino acid substitutions”.

Within the meaning of the term “equivalent amino acid substitution” as applied herein, one amino acid may be substituted for another, in one embodiment, within the groups of amino acids indicated herein below:

Amino acids having polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Pro, and Cys); Amino acids having non-polar side chains (Gly, Ala, Vai, Leu, lie, Phe, Trp, Tyr and Met); Amino acids having aliphatic side chains (Gly, Ala Vai, Leu, lie); Amino acids having cyclic side chains (Trp, His, Pro); Amino acids having aromatic side chains (Phe, Tyr, Trp); Amino acids having acidic, such as negatively charged side chains (Asp, Glu); Amino acids having basic, such as positively charged side chains (Lys, Arg, His); Amino acids having amide side chains (Asn, Gin); Amino acids having hydroxy side chains (Ser, Thr); Amino acids having sulphur-containing side chains (Cys, Met); Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr); Hydrophilic, acidic amino acids (Gin, Asn, Glu, Asp); and Hydrophobic amino acids (Leu, lie, Vai).

Where the L or D form (optical isomers) has not been specified it is to be understood that the amino acid in question has the natural L form, cf. Pure & Appl. Chem. Vol. (56(5) pp 595-624 (1984) or the D form, so that the peptides formed may be constituted of amino acids of L form, D form, or a sequence of mixed L forms and D forms. A “functional variant” of a peptide is a peptide capable of performing essentially the same functions as the peptide it is a functional variant of. In particular, a functional variant can bind the same molecules, preferably with the same affinity, as the peptide it is a functional variant of.

The term “cell penetrating peptide” (CPP) refers to a peptide characterised by the ability to cross the plasma membrane of mammalian cells, and thereby ability to facilitate the intracellular delivery of cargo molecules, such as peptides, proteins or oligonucleotides to which it is linked.

The term “detectable moiety” refers to a moiety, which can be detected by analytical means. A detectable moiety may be selected from the group consisting of fluorophores, radiocontrasts, MRI contrast agents and radioisotopes.

The term “effective amount”, as used herein, refers to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.

The term "peptide", "polypeptide" or “protein” refers to a polymer of amino acid residues preferably joined exclusively by peptide bonds, whether produced naturally or synthetically. The term “peptide” as used herein covers proteins, peptides and polypeptides, wherein said proteins, peptides or polypeptides may or may not have been post-translationally modified. A peptide is usually shorter in length than a protein, and single-chained.

The term “PDZ” refers to postsynaptic density protein-95 (PSD-95), drosophila homologue discs large tumor suppressor (DlgA), zonula occludens-1 protein (zo-1).

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 that in humans is encoded by the DLG4 (discs large homolog 4) gene, and may be human PSD-95 (Uniprot: P78352). A “subject in need thereof” refers to an individual who may benefit from the present invention. In one embodiment, said subject in need thereof is an individual suffering from an excitotoxicity-related disease and/or neuropathic pain. The subject to be treated is preferably a mammal, in particular a human being. Treatment of animals, such as mice, rats, dogs, cats, cows, horses, sheep and pigs, is, however, also within the scope of the present invention.

The terms “treatment” and “treating” as used herein refer to the management and care of a patient for the purpose of combating a condition, disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, and refer equally to curative therapy, prophylactic or preventative therapy and ameliorating or palliative therapy, such as administration of the peptide or composition for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, partially arresting the clinical manifestations, disease or disorder; curing or eliminating the condition, disease or disorder; amelioration or palliation of the condition or symptoms, and remission (whether partial or total), whether detectable or undetectable; and/or preventing or reducing the risk of acquiring the condition, disease or disorder, wherein “preventing” or “prevention” is to be understood to refer to the management and care of a patient for the purpose of hindering the development of the condition, disease or disorder, and includes the administration of the active compounds to prevent or reduce the risk of the onset of symptoms or complications. The term "palliation", and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering compositions of the present invention.

A "treatment effect" or "therapeutic effect" is manifested if there is a change in the condition being treated, as measured by the criteria constituting the definition of the terms "treating" and "treatment." There is a "change" in the condition being treated if there is at least 5% improvement, preferably 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 improvements in the severity of the treated condition in an individual, or on a difference in the frequency of improved conditions in populations of individuals with and without treatment with the bioactive agent, or with the bioactive agent in combination with a pharmaceutical composition of the present invention.

Peptides

IETTFX1X2X3RIETSFX4C (SEQ ID NO: 1) wherein:

Xi 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;

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 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or the functional variant thereof.

In some embodiments, the present disclosure is directed to a peptide comprising the amino acid sequence

IETTFX1X2X3RIETSFX4C (SEQ ID NO: 1) wherein:

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. In some embodiments, the peptide comprises the amino acid sequence XIETTFX1X2X3RIETSFX4C (SEQ ID NO: 165) wherein:

Xis any amino acid;

In some embodiments, the peptide comprises the amino acid sequence XIETTFX1X2X3RIETSFX4C (SEQ ID NO: 165) wherein:

Xis any amino acid;

X4 is independently selected from the group consisting of: T, F, G, H, I, L, N, S, V, W and Y; or pharmaceutically acceptable salt thereof.

In some embodiments, the peptide comprises the amino acid sequence

XDIETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein:

XD is a D-amino acid, or glycine;

In some embodiments, the peptide comprises the amino acid sequence XDIETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein:

XD is a D-amino acid, or glycine;

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.

XD is a D-phenylalanine, or glycine;

Xi 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;

X4 is independently selected from the group consisting of: T, F, G, H, and W; 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 the functional variant thereof.

XD is a D-phenylalanine, or glycine;

Xi 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;

X4 is independently selected from the group consisting of: T, F, G, H, and W; or a pharmaceutically acceptable salt thereof.

In some embodiments, the peptide is cyclized. In some embodiments the peptide is cyclized as described in the section “Cyclic peptides”.

In some embodiments, Xi is A. In other embodiments, Xi is F. In other embodiments, Xi is H. In other embodiments, Xi is I. In other embodiments, Xi is L. In other embodiments, Xi is N. In other embodiments, Xi is Q. In other embodiments, Xi is S. In other embodiments, Xi is T. In other embodiments, Xi is V. In other embodiments, Xi is W. In other embodiments, Xi is Y.

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. 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.

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.

In some embodiments, the D-amino acid is D-phenylalanine. The skilled person will understand that other D-amino acid may also be suitable for generating a cyclic peptide. In some embodiments XD is glycine. In some embodiments XD is selected from the group consisting of: d-phenylalanine and glycine, preferably d-phenylalanine.

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

XDIETTFAGNRIETSFTC (SEQ ID NO: 3); X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5); XDIETTFHGNRIETSFTC (SEQ ID NO: 6); XDIETTFIGNRIETSFTC (SEQ ID NO: 7); XDIETTFLGNRIETSFTC (SEQ ID NO: 8); XDIETTFNGNRIETSFTC (SEQ ID NO: 9); XDIETTFQGNRIETSFTC (SEQ ID NO: 10); XDIETTFSGNRIETSFTC (SEQ ID NO: 11); XDIETTFTGNRIETSFTC (SEQ ID NO: 12); XDIETTFVGNRIETSFTC (SEQ ID NO: 13); X_DI ETTFWGN RI ETSFTC (SEQ ID NO: 14); XDIETTFVGNRIETSFTC (SEQ ID NO: 15); XDIETTFAANRI ETSFTC (SEQ ID NO: 16); XDIETTFADNRI ETSFTC (SEQ ID NO: 17); XDIETTFAENRI ETSFTC (SEQ ID NO: 18); XDIETTFAFNRIETSFTC (SEQ ID NO: 19); XDIETTFAHNRIETSFTC (SEQ ID NO: 20); XDIETTFAKNRIETSFTC (SEQ ID NO: 21); XDIETTFALNRIETSFTC (SEQ ID NO: 22); XDIETTFANNRIETSFTC (SEQ ID NO: 23); XDIETTFAQNRIETSFTC (SEQ ID NO: 24); XDIETTFARNRIETSFTC (SEQ ID NO: 25); XDIETTFASNRIETSFTC (SEQ ID NO: 26); X_DI ETTFAWN RI ETSFTC (SEQ ID NO: 27); XDIETTFAYNRIETSFTC (SEQ ID NO: 28); XDIETTFAGCRI ETSFTC (SEQ ID NO: 29); XDIETTFAGFRI ETSFTC (SEQ ID NO: 30); X_DI ETTFAGGRI ETSFTC (SEQ ID NO: 31); XDIETTFAGHRIETSFTC (SEQ ID NO: 32); XDIETTFAGLRI ETSFTC (SEQ ID NO: 33); XDIETTFAGRRI ETSFTC (SEQ ID NO: 34); XDIETTFAGYRI ETSFTC (SEQ ID NO: 35); XDIETTFAGNRIETSFFC (SEQ ID NO: 36);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37); XDIETTFAGNRIETSFHC (SEQ ID NO: 38); XDIETTFAGNRIETSFIC (SEQ ID NO: 39); XDIETTFAGNRIETSFLC (SEQ ID NO: 40); XDIETTFAGNRIETSFNC (SEQ ID NO: 41); XDIETTFAGNRIETSFSC (SEQ ID NO: 42); XDIETTFAGNRIETSFVC (SEQ ID NO: 43); X_DI ETTFAGN RI ETSFWC (SEQ ID NO: 44); XDIETTFAGNRIETSFYC (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 the functional variant thereof.

XDIETTFAGNRIETSFTC (SEQ ID NO: 3);

XDIETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5); XDIETTFHGNRIETSFTC (SEQ ID NO: 6); XDIETTFIGNRIETSFTC (SEQ ID NO: 7); XDIETTFLGNRIETSFTC (SEQ ID NO: 8); XDIETTFNGNRIETSFTC (SEQ ID NO: 9); XDIETTFQGNRIETSFTC (SEQ ID NO: 10); XDIETTFSGNRIETSFTC (SEQ ID NO: 11); XDIETTFTGNRIETSFTC (SEQ ID NO: 12); XDIETTFVGNRIETSFTC (SEQ ID NO: 13); X_DI ETTFWGN RI ETSFTC (SEQ ID NO: 14); XDIETTFVGNRIETSFTC (SEQ ID NO: 15); XDIETTFAANRI ETSFTC (SEQ ID NO: 16); XDIETTFADNRI ETSFTC (SEQ ID NO: 17); XDIETTFAENRI ETSFTC (SEQ ID NO: 18); XDIETTFAFNRI ETSFTC (SEQ ID NO: 19); XDIETTFAHNRI ETSFTC (SEQ ID NO: 20); XDIETTFAKNRI ETSFTC (SEQ ID NO: 21); XDIETTFALNRI ETSFTC (SEQ ID NO: 22); XDIETTFANNRI ETSFTC (SEQ ID NO: 23); XDIETTFAQNRI ETSFTC (SEQ ID NO: 24); XDIETTFARNRI ETSFTC (SEQ ID NO: 25); XDIETTFASNRI ETSFTC (SEQ ID NO: 26); X_DI ETTFAWN RI ETSFTC (SEQ ID NO: 27); XDIETTFAYNRI ETSFTC (SEQ ID NO: 28); XDIETTFAGCRI ETSFTC (SEQ ID NO: 29); XDIETTFAGFRI ETSFTC (SEQ ID NO: 30); X_DI ETTFAGGRI ETSFTC (SEQ ID NO: 31); XDIETTFAGHRIETSFTC (SEQ ID NO: 32); XDIETTFAGLRI ETSFTC (SEQ ID NO: 33); XDIETTFAGRRI ETSFTC (SEQ ID NO: 34); XDIETTFAGYRI ETSFTC (SEQ ID NO: 35); XDIETTFAGNRIETSFFC (SEQ ID NO: 36);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37); XDIETTFAGNRIETSFHC (SEQ ID NO: 38); XDIETTFAGNRIETSFIC (SEQ ID NO: 39); XDIETTFAGNRIETSFLC (SEQ ID NO: 40);

XDIETTFAGNRIETSFNC (SEQ ID NO: 41);

XDIETTFAGNRIETSFSC (SEQ ID NO: 42);

XDIETTFAGNRIETSFVC (SEQ ID NO: 43);

X_DI ETTFAGN RI ETSFWC (SEQ ID NO: 44);

XDIETTFAGNRIETSFYC (SEQ ID NO: 45); or a pharmaceutically acceptable salt thereof.

XDIETTFAGNRIETSFTC (SEQ ID NO: 3); X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5);

XDIETTFHGNRIETSFTC (SEQ ID NO: 6);

XDIETTFNGNRIETSFTC (SEQ ID NO: 9);

XDIETTFQGNRIETSFTC (SEQ ID NO: 10);

XDIETTFSGNRIETSFTC (SEQ ID NO: 11);

XDIETTFVGNRIETSFTC (SEQ ID NO: 13);

XDIETTFYGNRIETSFTC (SEQ ID NO: 15);

XDIETTFAHNRI ETSFTC (SEQ ID NO: 20);

XDIETTFANNRI ETSFTC (SEQ ID NO: 23);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38); 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 the functional variant thereof.

XDIETTFAGNRIETSFTC (SEQ ID NO: 3);

X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4);

XDIETTFFGNRIETSFTC (SEQ ID NO: 5);

XDIETTFHGNRIETSFTC (SEQ ID NO: 6);

XDIETTFNGNRIETSFTC (SEQ ID NO: 9);

XDIETTFQGNRIETSFTC (SEQ ID NO: 10); XDIETTFSGNRIETSFTC (SEQ ID NO: 11);

XDIETTFVGNRIETSFTC (SEQ ID NO: 13);

XDIETTFYGNRIETSFTC (SEQ ID NO: 15);

XDIETTFAHNRIETSFTC (SEQ ID NO: 20);

XDIETTFANNRIETSFTC (SEQ ID NO: 23);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38); or a pharmaceutically acceptable salt thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGWRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFFGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFHGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFIGNRIETSFTC (SEQ ID NO: 7) 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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFLGNRIETSFTC (SEQ ID NO: 8) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFNGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFQGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFSGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFTGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFVGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFWGNRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFYGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAANRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFADNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAENRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAFNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAHNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAKNRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFALNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFANNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAQNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFARNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFASNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAWNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAYNRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGCRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGFRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGGRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGHRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGLRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGRRIETSFTC (SEQ ID NO: 34) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGYRIETSFTC (SEQ ID NO: 35) 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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFFC (SEQ ID NO: 36) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFGC (SEQ ID NO: 37) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFHC (SEQ ID NO: 38) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFIC (SEQ ID NO: 39) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFLC (SEQ ID NO: 40) 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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFNC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFSC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFVC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFWC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFYC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFIGNRIETSFTC (SEQ ID NO: 50); flETTFLGNRIETSFTC (SEQ ID NO: 51); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFTGNRIETSFTC (SEQ ID NO: 55); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFWGNRIETSFTC (SEQ ID NO: 57); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAANRIETSFTC (SEQ ID NO: 59); flETTFADNRIETSFTC (SEQ ID NO: 60); flETTFAENRIETSFTC (SEQ ID NO: 61); flETTFAFNRIETSFTC (SEQ ID NO: 62); flETTFAHNRIETSFTC (SEQ ID NO: 63); fl ETTFAKNRI ETSFTC (SEQ ID NO: 64); fl ETTFALNRI ETSFTC (SEQ ID NO: 65); fl ETTFANNRI ETSFTC (SEQ ID NO: 66); fl ETTFAQNRI ETSFTC (SEQ ID NO: 67); fl ETTFARNRI ETSFTC (SEQ ID NO: 68); fl ETTFASNRI ETSFTC (SEQ ID NO: 69); fl ETTFAWNRI ETSFTC (SEQ ID NO: 70); fl ETTFAYNRI ETSFTC (SEQ ID NO: 71); fl ETTFAGCRI ETSFTC (SEQ ID NO: 72); fl ETTFAGFRI ETSFTC (SEQ ID NO: 73); fl ETTFAGGRI ETSFTC (SEQ ID NO: 74); flETTFAGHRIETSFTC (SEQ ID NO: 75); fl ETTFAGLRI ETSFTC (SEQ ID NO: 76); fl ETTFAGRRI ETSFTC (SEQ ID NO: 77); fl ETTFAGYRI ETSFTC (SEQ ID NO: 78); flETTFAGNRIETSFFC (SEQ ID NO: 79); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); flETTFAGNRIETSFIC (SEQ ID NO: 82); flETTFAGNRIETSFLC (SEQ ID NO: 83); flETTFAGNRIETSFNC (SEQ ID NO: 84); flETTFAGNRIETSFSC (SEQ ID NO: 85); flETTFAGNRIETSFVC (SEQ ID NO: 86); flETTFAGNRIETSFWC (SEQ ID NO: 87); flETTFAGNRIETSFYC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); fl ETTFAGWRI ETSFTC (SEQ I D NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); fl ETTFHGNRI ETSFTC (SEQ ID NO: 49); flETTFIGNRIETSFTC (SEQ ID NO: 50); flETTFLGNRIETSFTC (SEQ ID NO: 51); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFTGNRIETSFTC (SEQ ID NO: 55); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFWGNRIETSFTC (SEQ ID NO: 57); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAANRIETSFTC (SEQ ID NO: 59); flETTFADNRIETSFTC (SEQ ID NO: 60); flETTFAENRIETSFTC (SEQ ID NO: 61); flETTFAFNRIETSFTC (SEQ ID NO: 62); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFAKNRIETSFTC (SEQ ID NO: 64); flETTFALNRIETSFTC (SEQ ID NO: 65); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAQNRIETSFTC (SEQ ID NO: 67); flETTFARNRIETSFTC (SEQ ID NO: 68); flETTFASNRIETSFTC (SEQ ID NO: 69); flETTFAWNRIETSFTC (SEQ ID NO: 70); flETTFAYNRIETSFTC (SEQ ID NO: 71); flETTFAGCRIETSFTC (SEQ ID NO: 72); flETTFAGFRIETSFTC (SEQ ID NO: 73); flETTFAGGRIETSFTC (SEQ ID NO: 74); flETTFAGHRIETSFTC (SEQ ID NO: 75); flETTFAGLRIETSFTC (SEQ ID NO: 76); flETTFAGRRIETSFTC (SEQ ID NO: 77); flETTFAGYRIETSFTC (SEQ ID NO: 78); flETTFAGNRIETSFFC (SEQ ID NO: 79); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); flETTFAGNRIETSFIC (SEQ ID NO: 82); flETTFAGNRIETSFLC (SEQ ID NO: 83); flETTFAGNRIETSFNC (SEQ ID NO: 84); flETTFAGNRIETSFSC (SEQ ID NO: 85); flETTFAGNRIETSFVC (SEQ ID NO: 86); flETTFAGNRIETSFWC (SEQ ID NO: 87); flETTFAGNRIETSFYC (SEQ ID NO: 88); or a pharmaceutically acceptable salt thereof.

In some embodiments, the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); or a functional variant thereof, wherein f is D-fhenylalanine, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt of the peptide or the functional variant thereof.

In some embodiments, the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); or a pharmaceutically acceptable salt thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGWRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFFGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFHGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFIGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFLGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFNGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFQGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFSGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFTGNRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFVGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFWGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFYGNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAANRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFADNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAENRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAFNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAHNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAKNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFALNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFANNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAQNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFARNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFASNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAWNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAYNRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGCRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGFRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGGRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGHRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGLRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGRRIETSFTC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGYRIETSFTC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFFC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFGC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFHC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFIC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFLC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFNC (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 the functional variant thereof. In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFSC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFVC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFWC (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 the functional variant thereof.

In some embodiments, the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFYC (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 the functional variant thereof.

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

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124);

[flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127); [flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129);

[flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144);

[flETTFAYNRIETSFTC] (SEQ ID NO: 145);

[flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148);

[flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159);

[flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

[flETTFAGNRIETSFYC] (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 thereof the peptide or the functional variant thereof.

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124);

[flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127);

[flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129);

[flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144);

[flETTFAYNRIETSFTC] (SEQ ID NO: 145);

[flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148); [flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159);

[flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

[flETTFAGNRIETSFYC] (SEQ ID NO: 162), or a pharmaceutically acceptable salt thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGWRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFFGNRIETSFTC] (SEQ ID NO: 122) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFHGNRIETSFTC] (SEQ ID NO: 123) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFIGNRIETSFTC] (SEQ ID NO: 124) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFLGNRIETSFTC] (SEQ ID NO: 125) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFNGNRIETSFTC] (SEQ ID NO: 126) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFQGNRIETSFTC] (SEQ ID NO: 127) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFSGNRIETSFTC] (SEQ ID NO: 128) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFTGNRIETSFTC] (SEQ ID NO: 129) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFVGNRIETSFTC] (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 thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFWGNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFYGNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAANRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFADNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAENRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAFNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAHNRIETSFTC] (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 thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFAKNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFALNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFANNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAQNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFARNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFASNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAWNRIETSFTC] (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 thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFAYNRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGCRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGFRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGGRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGHRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGLRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGRRIETSFTC] (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 thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFAGYRIETSFTC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFFC] (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 thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFGC] (SEQ ID NO: 154) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFHC] (SEQ ID NO: 155) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFIC] (SEQ ID NO: 156) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFLC] (SEQ ID NO: 157) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFNC] (SEQ ID NO: 158) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof. In some embodiments, the peptide is [flETTFAGNRIETSFSC] (SEQ ID NO: 159) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFVC] (SEQ ID NO: 160) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFWC] (SEQ ID NO: 161) or a functional variant thereof, wherein the functional variant comprises 1 or 2 individual amino acid substitutions, or a pharmaceutically acceptable salt thereof the peptide or the functional variant thereof.

In some embodiments, the peptide is [flETTFAGNRIETSFYC] (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 thereof the peptide or the functional variant thereof.

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.

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.

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

Cyclic peptides

In some embodiments, the peptide is cyclized, i.e. the peptide is a cyclic peptide. In some embodiments, the peptide is back bone cyclized. In some embodiment, 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 chloro-acetylated N-terminal amino acid residue, wherein the chloro-acetylated N- terminal residue forms a link with the side chain of a C-terminal cysteine.

Affinity for PSD-95

The number of efforts to develop non-canonical PSD-95 inhibitors that bind to PDZ through internal binding motifs has so far been limited. By integrating genetic code reprogramming facilitated by the flexizymes (flexible tRNA-aminoacylating ribozymes) and mRNA display, the ‘Random non-standard Peptides Integrated Discovery’ (RaPID) system has provided a powerful platform for the rapid discovery of novel peptide drug candidates targeting various therapeutically relevant proteins. Here, the inventors have applied for the first time the RaPID technology for targeting PSD-95. In particular, RaPID was applied for the synthesis of a trillion-membered library of non-natural thioether cyclized peptides and their subsequent screening against the PDZ2 domain of PSD-95 aiming to identify novel non-canonical PSD-95 peptide inhibitors.

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

PSD-95 binds directly the C-terminal tail of the GluN2 subunits of NMDARs, 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 of the C-terminal tail of the GluN2 subunits of NMDARs with PSD-95.

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

In some embodiments, the peptide has a Ki value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, such as less than 2 pM, such as less than 1 pM, such as less than 0.9 pM, such as less than 0.8 pM, such as less than 0.7 pM, such as less than 0.6 pM, such as less than 0.5 pM, such as less than 0.4 pM, such as less than 0.35 pM, such as less than 0.3 pM, preferably less than 0.3 pM.

In some embodiments, the peptide has a IC50 value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 of less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, preferably less than 3 pM.

Peptide modifications

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

In some embodiments, the peptide is further conjugated to a moiety. In some embodiments, the moiety is selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds, and cellpenetrating peptides.

In some embodiments, the moiety is a detectable moiety.

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

In some embodiments, one or more of the amino acid residues are alkylated, such as methylated.

In some embodiment, the N-terminal amino acid residue of the peptide is chloroacetylated.

Polynucleotides, vectors and cells

In one aspect of the present invention there is provided a nucleic acid construct encoding for and being capable of expressing a peptide comprising an amino acid sequence as defined herein. By nucleic acid construct is understood a genetically engineered nucleic acid. The nucleic acid construct may be a non-replicating and linear nucleic acid, a circular expression vector or an autonomously replicating plasmid.

In one aspect, the present invention concerns a polynucleotide encoding the corresponding linear sequence of the cyclic peptide as defined herein.

In one aspect, the present invention concerns a vector comprising said polynucleotide.

In one aspect, the present invention concerns a host cell comprising said polynucleotide or said 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.

Medical use

In one aspect, the present disclosure relates to a peptide, a composition, a polynucleotide, vector, or a 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.

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

In one aspect, the present disclosure relates to use of the peptide, the composition, the polynucleotide, the vector, or the host cell as defined herein for the manufacture of a medicament for the treatment and/or prevention of an excitotoxicity-related disease and/or neuropathic pain in a subject.

Excitotoxicity-related diseases

In one aspect, the present disclosure relates to a peptide, a composition, a polynucleotide, vector, or a host cell as defined herein for use in prevention and/or treatment of an excitotoxicity-related disease in a subject. In some embodiments, the present disclosure relates to a cyclic peptide as defined herein for use in prevention and/or treatment of an excitotoxicity-related disease in a subject.

The ternary complex between the N-methyl-D-aspartate receptor (NMDAR), Postsynaptic density protein-95 (PSD-95) and neuronal nitric oxide synthase (nNOS) plays an important role in the excitotoxicity mechanism of cell death. As the peptides of the present disclosure are capable of inhibiting binding of GluN2B to PSD-95, and thus prevent/interrupt formation of excess NO causing excitotoxicity, the peptides may be useful in the treatment of excitotoxicity-related diseases.

A large number of indications such as ischemia, trauma, epilepsy and chronic neurodegenerative disorders have been linked to 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 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.

Neuropathic pain

In one aspect, the present disclosure relates to a peptide, a composition, a polynucleotide, a vector, or a host cell as defined herein for use in prevention and/or treatment of neuropathic pain in a subject. In some embodiments, the present disclosure relates to a cyclic peptide as defined herein for use in prevention and/or treatment of neuropathic pain in a subject.

Neuropathic pain is a category of pain that includes several forms of chronic pain and which results from dysfunction of nervous rather than somatic tissue. Neuropathic pain, that is pain deriving from dysfunction of the central or peripheral nervous system, may also be a consequence of damage to peripheral nerves or to regions of the central nervous system, may result from disease, or may be idiopathic. Symptoms of neuropathic pain include sensations of burning, tingling, electricity, pins and needles, paresthesia, dysesthesia, stiffness, numbness in the extremities, feelings of bodily distortion, allodynia (pain evoked by stimulation that is normally innocuous), hyperalgesia (abnormal sensitivity to pain), hyperpathia (an exaggerated pain response persisting long after the pain stimuli cease), phantom pain, and spontaneous pain.

PSD-95 has been demonstrated 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). As the peptides of the present disclosure inhibit PSD-95, the peptides may be useful in the treatment of neuopathic pain.

Administration

According to the present disclosure, a peptide, or a composition comprising a peptide as defined herein, is administered to individuals in need of treatment in pharmaceutically effective doses or a therapeutically effective amount. The dosage requirements will vary with the particular drug composition employed the route of administration and the particular subject being treated, which depend on the severity and the sort of the disorder as well as on the weight and general state of the subject. It will also be recognized by one skilled in the art that the optimal quantity and spacing of individual dosages of a 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 that such optima can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. , the number of doses of a compound given per day for a defined number of days, can be ascertained using conventional course of treatment determination tests.

Pharmaceutical composition

Whilst it is possible for the peptides of the present disclosure to be administered as the raw peptide, it is preferred to present them in the form of a pharmaceutical formulation. Accordingly, the present disclosure further provides a pharmaceutical formulation, which comprises a peptide of the present disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier therefore. Thus, in one aspect, the present disclosure concerns a composition, such as a pharmaceutical composition, comprising the peptide as defined herein. The pharmaceutical formulations may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

Items

1. A peptide comprising the amino acid sequence IETTFX1X2X3RIETSFX4C (SEQ ID NO: 1) wherein:

Xi is independently selected from the group consisting of: A, F, H, I, L, N, Q, S, T, V, Wand Y;

X₃ is independently selected from the group consisting of: N, C, F, G, H, L, R, Wand Y;

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

XDIETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein:

XD is a D-amino acid, or glycine;

X2 is independently selected from the group consisting of: G, A, D, E, F,

H, K, L, N, Q, R, S, W, and Y;

3. The peptide according to item 2, wherein

XD is a D-phenylalanine;

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; X4 is independently selected from the group consisting of: T, F, G, H, and W; 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 the functional variant thereof. 4. The peptide according to any of the preceding items, wherein the peptide is cyclized.

5. The peptide according to any of the preceding items, wherein the peptide is back bone cyclized.

6. The peptide according to any of the preceding items, wherein the peptide comprises a chloro-acetylated N-terminal residue.

7. The peptide according to any of the preceding items, wherein the chloroacetylated N-terminal residue forms a link with the side chain of a C-terminal cysteine.

8. The peptide according to any one of the preceding items, wherein Xi is A.

9. The peptide according to any one of items 1 to 7, wherein Xi is F.

10. The peptide according to any one of items 1 to 7, wherein Xi is H.

11 . The peptide according to any one of items 1 to 7, wherein Xi is I.

12. The peptide according to any one of items 1 to 7, wherein Xi is L.

13. The peptide according to any one of items 1 to 7, wherein Xi is N.

14. The peptide according to any one of items 1 to 7, wherein Xi is Q.

15. The peptide according to any one of items 1 to 7, wherein Xi is S.

16. The peptide according to any one of items 1 to 7, wherein Xi is T.

17. The peptide according to any one of items 1 to 7, wherein Xi is V.

18. The peptide according to any one of items 1 to 7, wherein Xi is W. 19. The peptide according to any one of items 1 to 7, wherein Xi is Y.

20. The peptide according to any one of items 1 to 19, wherein X2 is G.

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

22. The peptide according to any one of items 1 to 19, wherein X2 is D.

23. The peptide according to any one of items 1 to 19, wherein X2 is E.

24. The peptide according to any one of items 1 to 19, wherein X2 is F.

25. The peptide according to any one of items 1 to 19, wherein X2 is H.

26. The peptide according to any one of items 1 to 19, wherein X2 is K.

27. The peptide according to any one of items 1 to 19, wherein X2 is L.

28. The peptide according to any one of items 1 to 19, wherein X2 is N.

29. The peptide according to any one of items 1 to 19, wherein X2 is Q.

30. The peptide according to any one of items 1 to 19, wherein X2 is R.

31. The peptide according to any one of items 1 to 19, wherein X2 is S.

32. The peptide according to any one of items 1 to 19, wherein X2 is W.

33. The peptide according to any one of items 1 to 19, wherein X2 is Y.

34. The peptide according to any one of items 1 to 33, wherein X3 is N.

35. The peptide according to any one of items 1 to 33, wherein X3 is C.

36. The peptide according to any one of items 1 to 33, wherein X3 is F. 37. The peptide according to any one of items 1 to 33, wherein X3 is G.

38. The peptide according to any one of items 1 to 33, wherein X3 is H.

39. The peptide according to any one of items 1 to 33, wherein X3 is L.

40. The peptide according to any one of items 1 to 33, wherein X3 is R.

41. The peptide according to any one of items 1 to 33, wherein X3 is W.

42. The peptide according to any one of items 1 to 33, wherein X3 is Y.

43. The peptide according to any one of items 1 to 42, wherein X4 is T.

44. The peptide according to any one of items 1 to 42, wherein X4 is F.

45. The peptide according to any one of items 1 to 42, wherein X4 is G.

46. The peptide according to any one of items 1 to 42, wherein X4 is H.

47. The peptide according to any one of items 1 to 42, wherein X4 is I.

48. The peptide according to any one of items 1 to 42, wherein X4 is L.

49. The peptide according to any one of items 1 to 42, wherein X4 is N.

50. The peptide according to any one of items 1 to 42, wherein X4 is S.

51. The peptide according to any one of items 1 to 42, wherein X4 is V.

52. The peptide according to any one of items 1 to 42, wherein X4 is W.

53. The peptide according to any one of items 1 to 42, wherein X4 is Y. The 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:

XDIETTFAGNRIETSFTC (SEQ ID NO: 3); X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5); XDIETTFHGNRIETSFTC (SEQ ID NO: 6); XDIETTFIGNRIETSFTC (SEQ ID NO: 7); XDIETTFLGNRIETSFTC (SEQ ID NO: 8); XDIETTFNGNRIETSFTC (SEQ ID NO: 9); XDIETTFQGNRIETSFTC (SEQ ID NO: 10); XDIETTFSGNRIETSFTC (SEQ ID NO: 11); XDIETTFTGNRIETSFTC (SEQ ID NO: 12); XDIETTFVGNRIETSFTC (SEQ ID NO: 13); X_DI ETTFWGN RI ETSFTC (SEQ ID NO: 14); XDIETTFVGNRIETSFTC (SEQ ID NO: 15); XDIETTFAANRI ETSFTC (SEQ ID NO: 16); XDIETTFADNRI ETSFTC (SEQ ID NO: 17); XDIETTFAENRI ETSFTC (SEQ ID NO: 18); XDIETTFAFNRI ETSFTC (SEQ ID NO: 19); XDIETTFAHNRI ETSFTC (SEQ ID NO: 20);

XDIETTFAKNRI ETSFTC (SEQ ID NO: 21); XDIETTFALNRI ETSFTC (SEQ ID NO: 22); XDIETTFANNRI ETSFTC (SEQ ID NO: 23); XDIETTFAQNRI ETSFTC (SEQ ID NO: 24); XDIETTFARNRI ETSFTC (SEQ ID NO: 25); XDIETTFASNRI ETSFTC (SEQ ID NO: 26); X_DI ETTFAWN RI ETSFTC (SEQ ID NO: 27); XDIETTFAYNRI ETSFTC (SEQ ID NO: 28); XDIETTFAGCRI ETSFTC (SEQ ID NO: 29); XDIETTFAGFRI ETSFTC (SEQ ID NO: 30); X_DI ETTFAGGRI ETSFTC (SEQ ID NO: 31);

XDIETTFAGHRIETSFTC (SEQ ID NO: 32); XDIETTFAGLRI ETSFTC (SEQ ID NO: 33); XDIETTFAGRRI ETSFTC (SEQ ID NO: 34); X_DI ETTFAGYRI ETSFTC (SEQ I D NO: 35);

XDIETTFAGNRIETSFFC (SEQ ID NO: 36);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38);

XDIETTFAGNRIETSFIC (SEQ ID NO: 39);

XDIETTFAGNRIETSFLC (SEQ ID NO: 40);

XDIETTFAGNRIETSFNC (SEQ ID NO: 41);

XDIETTFAGNRIETSFSC (SEQ ID NO: 42);

XDIETTFAGNRIETSFVC (SEQ ID NO: 43);

XDIETTFAGNRIETSFWC (SEQ ID NO: 44);

XDIETTFAGNRIETSFYC (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 the functional variant thereof. 5. The 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:

XDIETTFAGNRIETSFTC (SEQ ID NO: 3);

XDIETTFAGWRIETSFTC (SEQ ID NO: 4);

XDIETTFFGNRIETSFTC (SEQ ID NO: 5);

XDIETTFHGNRIETSFTC (SEQ ID NO: 6);

XDIETTFNGNRIETSFTC (SEQ ID NO: 9);

XDIETTFQGNRIETSFTC (SEQ ID NO: 10);

XDIETTFSGNRIETSFTC (SEQ ID NO: 11);

XDIETTFVGNRIETSFTC (SEQ ID NO: 13);

XDIETTFYGNRIETSFTC (SEQ ID NO: 15);

XDIETTFAHNRIETSFTC (SEQ ID NO: 20);

XDIETTFANNRIETSFTC (SEQ ID NO: 23);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38); 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 the functional variant thereof. 56. The peptide according to any one of the preceding items, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFTC (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 the functional variant thereof.

57. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGWRIETSFTC (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 the functional variant thereof.

58. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFFGNRIETSFTC (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 the functional variant thereof.

59. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFHGNRIETSFTC (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 the functional variant thereof.

60. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFIGNRIETSFTC (SEQ ID NO: 7) 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 the functional variant thereof.

61. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFLGNRIETSFTC (SEQ ID NO: 8) 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 the functional variant thereof. 62. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFNGNRIETSFTC (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 the functional variant thereof.

63. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFQGNRIETSFTC (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 the functional variant thereof.

64. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFSGNRIETSFTC (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 the functional variant thereof.

65. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFTGNRIETSFTC (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 the functional variant thereof.

66. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFVGNRIETSFTC (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 the functional variant thereof.

67. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFWGNRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFYGNRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAANRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFADNRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAENRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAFNRIETSFTC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAHNRIETSFTC (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 the functional variant thereof.

74. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAKNRIETSFTC (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 the functional variant thereof.

75. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFALNRIETSFTC (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 the functional variant thereof.

76. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFANNRIETSFTC (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 the functional variant thereof.

77. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAQNRIETSFTC (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 the functional variant thereof.

78. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFARNRIETSFTC (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 the functional variant thereof. 79. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFASNRIETSFTC (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 the functional variant thereof.

80. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAWNRIETSFTC (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 the functional variant thereof.

81. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAYNRIETSFTC (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 the functional variant thereof.

82. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGCRIETSFTC (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 the functional variant thereof.

83. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGFRIETSFTC (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 the functional variant thereof.

84. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGGRIETSFTC (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 the functional variant thereof. 85. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGHRIETSFTC (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 the functional variant thereof.

86. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGLRIETSFTC (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 the functional variant thereof.

87. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGRRIETSFTC (SEQ ID NO: 34) 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 the functional variant thereof.

88. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGYRIETSFTC (SEQ ID NO: 35) 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 the functional variant thereof.

89. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFFC (SEQ ID NO: 36) 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 the functional variant thereof.

90. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFGC (SEQ ID NO: 37) 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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFHC (SEQ ID NO: 38) 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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFIC (SEQ ID NO: 39) 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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFLC (SEQ ID NO: 40) 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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFNC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFSC (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 the functional variant thereof. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDIETTFAGNRIETSFVC (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 the functional variant thereof.

97. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDI ETTFAGNRI ETSFWC (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 the functional variant thereof.

98. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence XDI ETTFAGNRI ETSFYC (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 the functional variant thereof.

99. The peptide according to any one of the preceding items, wherein XD is selected from the group consisting of: D-phenylalanine and glycine, preferably D-phenylalanine.

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: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFIGNRIETSFTC (SEQ ID NO: 50); flETTFLGNRIETSFTC (SEQ ID NO: 51); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFTGNRIETSFTC (SEQ ID NO: 55); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFWGNRIETSFTC (SEQ ID NO: 57); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAANRIETSFTC (SEQ ID NO: 59); flETTFADNRIETSFTC (SEQ ID NO: 60); flETTFAENRIETSFTC (SEQ ID NO: 61); flETTFAFNRIETSFTC (SEQ ID NO: 62); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFAKNRIETSFTC (SEQ ID NO: 64); flETTFALNRIETSFTC (SEQ ID NO: 65); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAQNRIETSFTC (SEQ ID NO: 67); flETTFARNRIETSFTC (SEQ ID NO: 68); flETTFASNRIETSFTC (SEQ ID NO: 69); flETTFAWNRIETSFTC (SEQ ID NO: 70); flETTFAYNRIETSFTC (SEQ ID NO: 71); flETTFAGCRIETSFTC (SEQ ID NO: 72); flETTFAGFRIETSFTC (SEQ ID NO: 73); flETTFAGGRIETSFTC (SEQ ID NO: 74); flETTFAGHRIETSFTC (SEQ ID NO: 75); flETTFAGLRIETSFTC (SEQ ID NO: 76); flETTFAGRRIETSFTC (SEQ ID NO: 77); flETTFAGYRIETSFTC (SEQ ID NO: 78); flETTFAGNRIETSFFC (SEQ ID NO: 79); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); flETTFAGNRIETSFIC (SEQ ID NO: 82); flETTFAGNRIETSFLC (SEQ ID NO: 83); flETTFAGNRIETSFNC (SEQ ID NO: 84); flETTFAGNRIETSFSC (SEQ ID NO: 85); flETTFAGNRIETSFVC (SEQ ID NO: 86); flETTFAGNRIETSFWC (SEQ ID NO: 87); flETTFAGNRIETSFYC (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 the functional variant thereof. 01 . The peptide according to any one of items 1 to 55, wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (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 the functional variant thereof. 02. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFTC (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 the functional variant thereof. 03. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGWRIETSFTC (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 the functional variant thereof. 104. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFFGNRIETSFTC (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 the functional variant thereof.

105. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFHGNRIETSFTC (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 the functional variant thereof.

106. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFIGNRIETSFTC (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 the functional variant thereof.

107. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFLGNRIETSFTC (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 the functional variant thereof.

108. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFNGNRIETSFTC (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 the functional variant thereof. 109. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFQGNRIETSFTC (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 the functional variant thereof.

110. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFSGNRIETSFTC (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 the functional variant thereof.

111. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFTGNRIETSFTC (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 the functional variant thereof.

112. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFVGNRIETSFTC (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 the functional variant thereof.

113. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFWGNRIETSFTC (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 the functional variant thereof. 114. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFYGNRIETSFTC (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 the functional variant thereof.

115. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAANRIETSFTC (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 the functional variant thereof.

116. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFADNRIETSFTC (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 the functional variant thereof.

117. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAENRIETSFTC (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 the functional variant thereof.

118. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAFNRIETSFTC (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 the functional variant thereof. 119. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAHNRIETSFTC (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 the functional variant thereof.

120. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAKNRIETSFTC (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 the functional variant thereof.

121 . The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFALNRIETSFTC (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 the functional variant thereof.

122. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFANNRIETSFTC (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 the functional variant thereof.

123. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAQNRIETSFTC (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 the functional variant thereof. 124. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFARNRIETSFTC (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 the functional variant thereof.

125. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFASNRIETSFTC (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 the functional variant thereof.

126. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAWNRIETSFTC (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 the functional variant thereof.

127. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAYNRIETSFTC (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 the functional variant thereof.

128. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGCRIETSFTC (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 the functional variant thereof. 129. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGFRIETSFTC (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 the functional variant thereof.

130. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGGRIETSFTC (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 the functional variant thereof.

131 . The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGHRIETSFTC (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 the functional variant thereof.

132. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGLRIETSFTC (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 the functional variant thereof.

133. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGRRIETSFTC (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 the functional variant thereof. 134. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGYRIETSFTC (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 the functional variant thereof.

135. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFFC (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 the functional variant thereof.

136. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFGC (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 the functional variant thereof.

137. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFHC (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 the functional variant thereof.

138. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFIC (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 the functional variant thereof. 139. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFLC (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 the functional variant thereof.

140. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFNC (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 the functional variant thereof.

141 . The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFSC (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 the functional variant thereof.

142. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFVC (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 the functional variant thereof.

143. The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFWC (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 the functional variant thereof. . The peptide according to any one of items 1 to 54, wherein the peptide comprises or consists of the amino acid sequence flETTFAGNRIETSFYC (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 the functional variant thereof. . The 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:

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124);

[flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127);

[flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129);

[flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144); [flETTFAYNRIETSFTC] (SEQ ID NO: 145);

[flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148);

[flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159);

[flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

[flETTFAGNRIETSFYC] (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 thereof the peptide or the functional variant thereof. 6. The 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:

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124);

[flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127);

[flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129); [flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144);

[flETTFAYNRIETSFTC] (SEQ ID NO: 145);

[flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148);

[flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159);

[flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

[flETTFAGNRIETSFYC] (SEQ ID NO: 162), or a pharmaceutically acceptable salt thereof. 147. The peptide according to any 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.

148. The peptide according to any 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.

149. The peptide according to any of the preceding items, wherein the peptide comprises in the range of 17 to 50 amino acid residues, such as in the range of 19 to 45 amino acid residues, such as in the range of 17 to 40 amino acid residues, such as in the range of 17 to 35 amino acid residues, such as in the range of 17 to 30 amino acid residues, such as in the range of 17 to 25 amino acid residues, such as in the range of 17 to 23 amino acid residues, such as in the range of 17 to 20 amino acid residues, such as in the range of 17 to 18 amino acid residues.

150. The peptide according to anyone of the preceding items, wherein the peptide is conjugated to a cell-penetrating peptide (CPP).

151 . The peptide according to anyone 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.

152. The peptide according to any one of the preceding items, wherein the peptide is capable of binding to PSD-95.

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

154. The peptide according to any one of the preceding items, wherein the peptide has a Ki value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, such as less than 2 pM, such as less than 1 pM, such as less than 0.9 pM, such as less than 0.8 pM, such as less than 0.7 pM, such as less than 0.6 pM, such as less than 0.5 pM, such as less than 0.4 pM, such as less than 0.35 pM, such as less than 0.3 pM, preferably less than 0.3 pM.

155. The peptide according to any one of the preceding items, wherein the peptide has a IC50 value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 of less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, preferably less than 3 pM. 156. The peptide according to any one of the preceding items, wherein the peptide is further conjugated to a moiety.

157. The peptide according to item 156, wherein the moiety is selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides.

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

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

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

161. A composition comprising the peptide according to any of the preceding items.

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

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

164. A vector comprising a polynucleotide as defined in item 163.

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

166. The host cell according to item 165, wherein the host cell is a bacterial cell. . The host cell according to item 165, wherein the host cell is a mammalian cell. . The host cell according to item 165, wherein the host cell is a human cell. . 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 as a medicament. . 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 prevention and/or treatment of an excitotoxicity- related disease in a subject. . The peptide, the composition, the polynucleotide, the vector, or the host cell for use according to item 170, wherein the excitotoxicity-related disease is stroke, such as ischemic stroke. . The peptide, the composition, the polynucleotide, the vector, or the host cell for use according to item 170, wherein the excitotoxicity-related disease is ischemic or traumatic injury of the CNS, such as spinal cord injury and traumatic brain injury. . The peptide, the composition, the polynucleotide, the vector, or the host cell for use according to item 170, wherein the excitotoxicity-related disease is epilepsy. . The peptide, the composition, the polynucleotide, the vector, or the host cell for use according to item 170, wherein the excitotoxicity-related disease is a neurodegenerative disease of the CNS. . The peptide, the composition, the polynucleotide, the vector, or the host cell for use according to 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.

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 prevention and/or treatment of neuropathic pain in a subject.

177. A method of preventing and/or treating an excitotoxicity-related disease and/or neuropathic pain, said method comprising administering a therapeutically effective amount of the peptide according to any one of items 1 to 160, the composition according to any one of items 161 to 162, the polynucleotide according to item 163, the vector according to item 164, or the host cell according to any one of items 165 to 168, to a subject in need thereof.

178. Use of the peptide according to any one of items 1 to 160, the composition according to any one of items 161 to 162, the polynucleotide according to item 163, the vector according to item 164, or the host cell according to any one of items 165 to 168, for the manufacture of a medicament for the treatment and/or prevention of an excitotoxicity-related disease and/or neuropathic pain in a subject.

179. A method for manufacturing the peptide according to any of items 1 to 160, said method comprising the steps of: a) preparing a peptide using solid-phase peptide synthesis (SPPS); and b) cyclization of said peptide via thioether cyclization.

180. The method according to item 179, further comprising a step following step b), wherein a fluorophore is conjugated to the peptide. Examples

Example 1: Material and Methods

Flexizyme tRNA aminoacylation

Flexizyme and ⁱⁿⁱtRNAcAu were prepared in buffer (HEPES-KOH pH 7.6) to final concentrations of approximately 41.6 pM. The mixture was heated to 95 °C for 2 min followed by cooling at RT for 5 min. Next, MgCh (0.75 M) was added and the solution was left at RT for 5 min. N-CIAc-D-Phe-CME (5 mM) was added and the reaction was incubated on ice for 2 h. Aminoacylated tRNA was precipitated in acidic buffer (0.23 M NaOAc pH 5.2) by addition of 2 x volume of ethanol. After centrifugation (12,000 rpm, 15 min) the pellet was washed with 70% ethanol, 0.1 M NaOAc pH 5.2 and centrifuged (12,000 rpm, 5 min).

Transcription

The DNA libraries were transcribed overnight at 37 °C in a mixture of 10 x T7 buffer, dithiothreitol (DTT, 10 mM), MgCh (30 mM), NTPs (7.5 mM), T7 RNA polymerase (0.05 x volume, ThermoFisher, Catalog# 10753931) and RNasinRPIus ribonuclease inhibitor (0.015 x volume, Promega, Catalog# N2615). To the mRNA mixture 1 x volume of 0.6 M NaCI 50 mM ethylene diamine tetraacetic acid (EDTA) was added and mRNA was then purified with phenol/chloroform extraction. First, 1 x volume of phenol:chloroform:isoamyl alcohol (25:24:1) was added and the mix was centrifuged (13,000 rpm, 10 min). Addition of 1 x volume of chloroform-isoamyl alcohol (24:1) to the aqueous phase was followed by centrifugation (13,000 rpm, 10 min) and mRNA was precipitated with 0.8 x volume isopropanol. After centrifugation (13,000 rpm, 5 min) the pellet was resuspended in 0.3 M NaCI and precipitated again with 0.8 x volume isopropanol and centrifuged (13,000 rpm, 5 min). Last, pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min).

Puromycin ligation

Puromycin ligation was performed by preparing a solution of pur-linker (1.5 pM), mRNA library (1 pM), ATP (1 mM, New England Biolabs, Catalog# NEB-P0756S), 10 x T4 RNA ligase buffer (0.1 x volume, New England Biolabs, Catalog# B0216L) and T4 ssRNA ligase 1 (0.1 x volume, New England Biolabs, Catalog# NEB-M0204S). The reaction was allowed at RT for 30 min and pur-mRNA was then purified following phenol-chloroform extraction. First, 1 x volume of 0.6 M NaCI 10 mM EDTA was added followed by 1 x volume of phenol:chloroform:isoamyl alcohol (25:24:1). The mix was centrifuged (13,000 rpm, 10 min) and 1 x volume of chloroform-isoamyl alcohol (24:1) was added to the aqueous phase. After centrifugation (13,000 rpm, 10 min), 2 x volume of ethanol was added and mix was centrifuged (13,000 rpm, 15 min). Pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min).

PURE translation

PURE translation mixture was constituted by SolA and SolB solutions (PUREfrex, Catalog# PF201-10-EX) and 1 mM of amino acids mixture without Met. For the first RaPID round in vitro translation was performed using 25 pmol puromycin-ligated mRNA library in 25 pL of translation mixture supplemented with 1250 pmol of CIAc-d- Phe-initRNACAU. Subsequently, the translation mixture was incubated at 37 °C for 40 min. Next, 5 pL of 100 mM EDTA pH 8.0 were added to the solution for dissociation of the ribosome from mRNA-peptide conjugates and the solution was incubated at 37 °C for 30 min. For the following selection rounds, the same procedure was followed, though the amounts were adjusted to 5 pL of translation mixture.

Reverse transcription

Reverse transcription (RT) was prepared in the translation solution (25 pL) by adding RT-Premix solution (7.6 pL, 1), Mg(OAc)2 (16.4 mM), 0.006 x volume of RNasinRPIus ribonuclease inhibitor (Promega, Catalog# N2615) and 0.03 x volume of RTase superscript IV (ThermoFisher, Catalog# 15387686). The reaction was incubated at 45 °C for 1 h. RT solution was prepared for the RaPID selection by 1:1 dilution in 2 x blocking buffer (Table 1).

RaPID positive selection

Protein was immobilized to magnetic beads (Dynabeads M-280, Invitrogen, Catalog# 11206D) to give a final concentration of 200 nM when incubated with the peptide library. The bead slurry was then washed twice with selection buffer (Table 1) and then incubated with protein for 15 min at 4 °C with rotation. Next, biotin (25 mM) was added to the solution and beads were incubated for another 15 min at 4 °C with rotation.

Beads were washed (3 x) with cold selection buffer and left on ice until needed. For the first RaPID round, protein beads were directly incubated with peptide library and selection was performed at 4 °C for 30 min. Beads were washed (3 x) with cold selection buffer (Table 1) and bound peptides were eluted in elution PCR mix (Table 1) by heating beads at 95 °C for 5 min. DNA concentration was determined with qPCR. Next, Phusion polymerase (New England Biolabs, Catalog# NEB-M0530S) was added to the PCR mix and cDNA was PCR amplified. Amplified DNA was purified with phenol/chloroform extraction and ethanol precipitation. First, to the PCR reaction was added 0.1 x volume 3 M NaCI followed by addition of 1 x volume phenol:chloroform:isoamyl alcohol (25:24:1). The mix was centrifuged (13,000 rpm, 10 min) and 1 x volume of chloroform-isoamyl alcohol (24:1) was added to the aqueous phase. After centrifugation (13,000 rpm, 10 min) DNA was precipitated with 2 x volume of ethanol and centrifuged (13,000 rpm, 15 min). The pellet was washed with 70% ethanol and centrifuged (13,000 rpm, 3 min). The purified DNA was then used as library for the subsequent selection rounds.

RaPID negative selection

For the second RaPID selection rounds and onwards, as well as for RaPID mutational scan, a negative selection round was performed prior to library incubation with protein beads. Three samples of negative beads, in an equal amount to that used for positive selection, were prepared by initial washing with cold selection buffer (Table 1). Next, beads from each sample were split and biotin (25 mM) was added to one of the halves followed by 15 min incubation at 4 °C with rotation. Beads were then washed with selection buffer (3 x) and recombined. The first sample of negative beads was incubated with blocked peptide-mRNA/cDNA library for 30 min at 4 °C with rotation. The same procedure was followed twice by transferring the recovered library to the next sample of negative beads. The recovered library from the three negative selections was used as input for the subsequent positive selection. Pellets of negative beads were then resuspended in 1% TritonX-100 and pooled. Bound peptides were eluted by heating at 95 °C for 5 min and samples were analyzed with qPCR.

Quantitative PCR

To monitor the selection process quantitative PCR (qPCR) was used enabling the quantification of the amount of DNA molecules that were selected against the protein target as well as the DNA that was recovered after positive and negative selection rounds. Samples of input and output libraries (1 pL) were added in 19 pL of qPCR master mix (Table 1) followed by addition of 0.08 pL of Taq polymerase (VWR, Catalog# 733-1819). Samples were then analyzed using a MyGo Pro real-time PCR thermocycler (IT-IS Life Science Ltd.).

Solid phase peptide synthesis (SPPS)

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). 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 Fmoc-protected resin was performed in 10 mL glass reaction vessels with 300 rpm constant shaking for all steps: deprotection (2 x 2 min, RT), coupling (2 x 7 min, 50 °C) with intermediate washing steps using DMF. For coupling, 5eq of amino acids, 5 eq of HCTU and 5 eq of DI PEA were used.

Peptide cleavage

Release of peptide from the solid support and simultaneously removal of the acid-labile side chain protecting groups was performed by incubation with a trifluoroacetic acid (TFA):triethylsilane:H2O (95:2.5:2.5) mixture for 3 h at RT. The peptides were precipitated using cold diethyl ether.

Peptide purification

Peptides were purified using a preparative reverse phase high performance liquid chromatography (HPLC) system (Waters) with a reverse phase C18 column (Zorbax, 300 SB-C18, 21.2 x 250 mm). A linear gradient using a binary buffer system of H2O:MeCN:TFA (A: 95:5:0.1 ; B: 5:95:0.1) at 20 mL/min was used. Collected fractions were characterized by liquid chromatography mass spectrometry (LC-MS) with a reverse phase C18 column (Zorbax Eclipse XBD-C18, 4.6 x 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 reverse phase ultra-performance liquid chromatography (RP-UPLC) (Waters) system with a reverse phase C18 column (Acquity UPLC BEH C18, 1.7 pm, 2.1 x 50 mm) using a binary buffer system consisting of H2O:ACN:TFA (A: 95:5:0.1 ; B: 5:95:0.1) at 0.45 mL/min. Thioether cyclization

N-terminal chloroacetylation was performed on-resin using a mixture of chloroacetic acid (0.5 M), Oxyma (0.5) and DIG (0.2 M) in DMF and resin was shaked for 10 min at RT. Chloroacetylated peptides were then cleaved and the peptide crudes were dissolved in MeC kFW (1 :1) and freeze-dried. A basic buffer of MeC kFW (1 :1) was prepared by slow addition of DI PEA and pH was monitored with pH meter. Crude peptide powders were dissolved in DMSO and added dropwise to a basic mixture of MeCN:H2O. Reaction was stirred for 15-30 min and peptides were then directly injected to RP-HPLC for purification.

Fluorescent labelling 5(6)-carboxytetramethylrhodamine (5(6)-TAMRA (Anaspec, Catalog# AS-81124) labelling was performed on-resin by coupling TAMRA with a mixture of TAMRA:PyBOP:DIPEA (1.5:1.5:3) in NMP. Reaction was carried out overnight in RT.

Fluorescence polarization

FP binding experiments were performed using a Safire2 plate reader (Tecan). Samples were prepared in 50 mM HEPES, 100 mM NaCI, pH 7.4 and transferred to a flatbottom black 384-well plate (Corning Life Science, Catalog# 3573). For saturation assays, protein was prepared in 1 :1 dilutions and TAMRA-labeled peptide probe was added to a final concentration of 500 nM. Dilutions were prepared in triplicates and data were analyzed based on a one-site binding model. For inhibition assays, unlabeled peptides were prepared in 1 :1 dilution ranging from 0.24-500 pM. Unlabeled peptides competed TAMRA-probe (C = 25 nM) for binding to the His10-SUMO-PDZ2- Avi-BTN (C = 4 pM). Experiments were performed in triplicates and data was analyzed based on a sigmoidal dose response curve. All data were analyzed using GraphPad Prism 9. Ki values were calculated according to Nikolvoska-Coleska et al.²⁶

Klenow PCR

Klenow PCR was used to produce the DNA library for RaPID mutational scan. 2 pM of forward (NNKX_F86) and reverse primers (RaPID_HA_R) (Table 2) were prepared in NEBuffer 2 (New England BioLabs, GmbH, Catalog# B7002S). The mix was heated to 94 °C for two minutes, cooled down to 50 °C with a rate of 0.2 °C/sec, temperature was held for 2 min and then decreased to 37 °C with a rate of 0.2 °C/sec. Next, dNTPs (0,25 pM) and 0.01 x volume Klenow (New England BioLabs, GmbH, Catalog# M0210S) were added to the mixture that was held at 37 °C for 30 min.

HA purification HA purification was performed according to Vinogradov et al.²⁷ In brief, anti-HA magnetic beads (8 pL/ pmol of mRNA library, ThermoFisher, Catalog# 88836) were washed in selection buffer (Table 1) and subsequently incubated with peptide- mRNA/cDNA library for 1 h at 4 °C with rotation. Next, supernatant was recovered and saved for later NGS sequencing. Bound library was eluted by incubating beads with HA peptide (2 mg/mL in water) at 37 °C for 15 min. The elution step was repeated, and supernatants were pooled, blocked with 2 x blocking buffer (Table 1) and used for RaPID mutational scan.

Table 1 : Sequences of primers used for the preparation of RaPID libraries.

CGS3an RvTr R23

TAGCTGCCGCTGCCGCTGCCGCA

(SEQ ID NO: 89)

T7g10M_CEL_F51 GAATTTAATACGACTCACTATAGGGTTAACTTTAAGAAGG (SEQ ID NO: 90) AGATATACATA

GS3an R36

TTTCCGCCCCCCGTCCTAGCTGCCGCTGCCGCTGCC

(SEQ ID NO: 91)

TTTAAGAAGGAGATATACATATGNNKGAGACTAC I I I I GC NNK1 F86

TGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG

(SEQ ID NO: 92)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTNNKACTAC I I I I GC NNK2 F86

TGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 93)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGNNKAC I I I I GC NNK3 F86

TGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG

(SEQ ID NO: 94)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTNNKI I I GC NNK4 F86

TGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG

(SEQ ID NO: 95)

CAGCTAC TTTAAGAAGGAGATATACATATGATTGAGACTACTN N KGC NNK5 F86

TGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG

(SEQ ID NO: 96)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I 1 1 1 NN NNK6 F86

KGGTAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG

(SEQ ID NO: 97)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC 1 1 1 1 GC NNK7 F86

TN N KAATCGTATTGAGACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 98)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC 1 1 1 1 GC NNK8 F86

TGGTN N KCGTATTGAGACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 99)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC 1 1 1 1 GC NNK9 F86

TGGTAATN N KATTGAGACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 100)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK10 F86

TGGTAATCGTN N KGAGACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 101)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK11 F86

TGGTAATCGTATTN N KACTTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 102)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK12 F86

TGGTAATCGTATTGAGNNKTCGTTTACTTGCGGCAGCGG (SEQ ID NO: 103)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK13 F86

TGGTAATCGTATTGAGACTN N KTTTACTTGCGGCAGCGG (SEQ ID NO: 104)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK14 F86

TGGTAATCGTATTGAGACTTCGNNKACTTGCGGCAGCGG (SEQ ID NO: 105)

CAGCTAC

TTTAAGAAGGAGATATACATATGATTGAGACTAC I I I I GC NNK15 F86

TGGTAATCGTATTGAGACTTCGTTTN N KTGCGGCAGCGG (SEQ ID NO: 106)

CAGCTAC

RaPID_HA_R TAAGAACCAGAACCAGAACCTGCATAGTCGGGCACGTC

(SEQ ID NO: 107) GTATGGGTAGCTGCCGCTGCCGCA GS3 HA R36

“ “ TTTCCGCCCCCCGTCCTAAGAACCAGAACCAGAACC

(SEQ ID NO: 108)

GS3 HA RvTr R20

“ “ “ TAAGAACCAGAACCAGAACC

(SEQ ID NO: 109)

Table 2: Composition of buffers and reagent mixtures that were used for RaPID selections.

50 mM HEPES-KOH, 100 mM NaCI, 0.05% Tween, pH Selection buffer

7.6

100 mM HEPES-KOH pH 7.6, 100 mM NaCI, 0.1%

2 x blocking buffer

Tween 20, 0.2% acetylated BSA (20 mg/ml)

3 mM dNTPs, 10 pM CGS3an_RvTr_R23, 150 mM Tris RT-premix pH 8.3

RT-premix 2mM dNTPs, 10 pM GS3_HA_RvTr_R20, 150 mM Tris

(deep mutational scan) pH 8.3

5 x Phusion GC buffer, 0.2 mM dNTPs, 0.6 pM

Elution PCR mix

T7g10M_CEL_F51 , 0.6 pM GS3an_R36, 25 pM Biotin

10 x Key buffer, 0.2 mM dNTPs, 0.5 pM qPCR master mix T7g10M_CEL_F51 , 0.5 pM GS3an_R36, 0.5 pM SYBR

Green

Example 2: RaPID selection of PDZ2/PSD-95

A DNA library encoding 4 to 15 randomized amino acids (NNK4-15, N = A/C/G/T and K = G/T) was prepared based on the theoretical diversity of each NNK library

((4*4*2)ⁿ*^NNK). For NNK4-8 all possible DNA sequences were represented in the final library. Due to the high diversity of larger libraries the remaining library space was divided across NNK9-15 based on rough ratio estimations for accommodating approximately equal diversity between libraries (Table 3).

Table 3: Fractions of individual NNK libraries that were prepared for the RaPID selection against PDZ2. Theoretical Library DNA Fraction of theoretical

Library diversity molecules diversity in RaPID library

NNK4 1.05E+06 1.05E+06 1

NNK5 3.36E+07 3.36E+07 1

NNK6 1.07E+09 1.07E+09 1

NNK7 3.44E+10 3.44E+10 1

NNK8 1.10E+12 1.10E+12 1

NNK9 3.52E+13 4.62E+11 1.31 E-02

NNK10 1.13E+15 9.23E+11 8.20E-04

NNK11 3.60E+16 1.85E+12 5.12E-05

NNK12 1.15E+18 3.69E+12 3.20E-06

NNK13 3.69E+19 7.39E+12 2.00E-07

NNK14 1.18E+21 1.48E+13 1.25E-08

NNK15 3.78E+22 2.95E+13 7.82E-10

For the generation of cyclic peptides genetic code reprogramming was performed using the enhanced flexizyme (eFx) for loading of the initiator tRNA (ⁱⁿⁱtRNAcAu) with the CME ester of /V-terminally chloroacetyled D -Phe (CIAc-d-Phe-CME) (Goto et al. 2008). The aminoacylated CIAc-d-Phe-ⁱⁿⁱtRNAcAu was then supplied to the in vitro translation system that was lacking Met, and the formyl donor. CIAc-d-Phe was then incorporated at the initiation position and thioether cyclic peptides were generated post- translationally. mRNA display protocol was followed for the puromycin-tag of mRNA sequences and the puromycin-mediated attachment of each cyclic peptide to its encoding mRNA during translation. Reverse transcription generated the complementary DNA and the resulting peptide-mRNA/cDNA conjugates were used for affinity selection, performed by incubating the library with immobilized biotinylated PDZ2 to streptavidin magnetic beads. Washing of unbound peptides was followed by heat elution of bound library and the determination of the number of the recovered DNA molecules through quantitative PCR (qPCR). Amplification of the bound cDNA by PCR allowed the resynthesis of the enriched bound cyclic peptides that were applied in the next affinity selection round.

For subsequent rounds a ‘negative selection’ was included in which peptide library was incubated with biotin-streptavidin beads prior to the selection against PDZ2. With this approach, non-specific peptide binders to biotin and streptavidin beads were discarded. qPCR analysis of the input library as well as the recovered library from negative and positive selections was used for monitoring the progress of the RaPID selection by calculating the library recovery rate. Increasing recovery rates of positive selection after the second selection round suggested enrichment of PDZ2 specific binders. As higher fraction of the positive compared to the negative selection was observed for rounds four and five, selection was stopped and libraries from both positive and negative selections were prepared for next-generation sequencing (NGS) analysis (Fig. 2).

Example 3: Next generation sequencing showed enrichment of hit peptides

Decoding of library composition indicated progressive enrichment of peptide sequences across rounds 2 to 5 primarily containing 15 randomized amino acids (Fig. 3A, Table 4). Interestingly, all the identified peptides included the ‘TTF’ PDZ binding motif which is present in the nNOS binding sequence, in some cases two ‘TTF’ or similar motifs in the same peptide. Moreover, decoding of the DNA libraries from negative selection showed that the hit peptides had lower enrichment than in the equivalent positive selections, suggesting preferential binding to PDZ2 on the streptavidin beads, over streptavidin beads alone (Fig. 3B). These promising findings led us to the chemical synthesis of the top enriched peptides by solid phase peptide synthesis (SPPS) and the validation of their binding properties to PDZ2.

Table 4: Sequences of the top enriched peptides from the RaPID PDZ2/PSD-95 selection.

Peptide Length (aa) Sequence

1 17 fTRIVTTFSYCIVTTFC (SEQ ID NO: 110)

2 17 fCVYTTFEQKIVTTFWC (SEQ ID NO: 111)

3 17 flETTFAGNRIETSFTC (SEQ ID NO: 46)

4 16 fCVYTTFEQKIVTTFC (SEQ ID NO: 112)

5 10 fTRIVTTFWC (SEQ ID NO: 113)

Example 4: Validation of PDZ2 binding of hit peptides

A fluorescence polarization (FP) assay was applied in order to characterize the binding properties of the RaPID-identified peptides. For this purpose, the C-terminal binding motif of the GluN2B receptor was synthesized as a fluorescent-labeled peptide (TAMRA-NNG-EKLSSIESDV - SEQ ID NO: 119). A saturation assay of TAMRA- GluN2B showed similar binding affinity to two tested PDZ2 constructs, a biotinylated PDZ2 and sumoylated/biotinylated PDZ2 (3.6 ± 0.3 pM and 2.0 ± 0.3 pM, respectively) that were in good correlation with the literature (Bach, A. et al. 2012) (Fig. 4).

To investigate the binding properties of the RaPID enriched sequences 1 , 2, 3 and 5 (Table 4), peptides were synthesized by SPPS. Notably, 1 contained an internal cysteine, thus the two possible thioether-linked analogues cyclized either through the terminal or the internal cysteine were investigated. Cyclization of 2 through its internal cysteine was not investigated since it has been reported that cyclization with the side chain of cysteine in the second position of the peptide sequence is not favored (Iwasaki et al. 2012). Moreover, the unlabeled GluN2B peptide (6) was synthesized as control. Due to poor solubility of peptides 1 and 2, these peptides were synthesized with a Flag solubility tag, yielding to analogues 7, 8 and 9 (Table 5). To validate that the tag does not interfere with peptide binding a Flag-tagged analogue of 3 was synthesized, yielding peptide 11. Lastly, a linear analogue of 3, peptide 12, was synthesized to evaluate the importance of the peptide cyclic structure.

Table 5: Comparison of K, and IC50 values of chemically synthesized RaPID- identified peptides and analogues. Ki is presented as mean ± SD, n = 3. IC50 is presented as mean ± SD, n = 3; N.B., not-binding for ICso > 250 pM

Pept

N’ IC50 (pM) Kj (pM) Sequence

[flETTFAGNRIETSFTC] (SEQ ID NO:

3 Cyclic 2.3 ± 0.1 < 0.3 **

120)

5 Cyclic N.B. N.B. [fTRIVTTFWC] (SEQ ID NO: 113)

6 H 12.0 ± 0.7 3.1 ± 0.2 YEKLSSIESDV (SEQ ID NO: 114)

[fTRIVTTFSYAIVTTFC]-GSGS-

53.3 ± 17.3 ±

7 Cyclic DYKDDDDK (SEQ ID NO: 115 and

2.7* 0.9*

163)

[fTRIVTTFSYC]IVTTFA-GSGS-

8 Cyclic N.B. N.B. DYKDDDDK (SEQ ID NO: 116 and

164) [fCVYTTFEQKIVTTFWC]-GSGS-

58.2 ± 19.0 ±

9 Cyclic DYKDDDDK (SEQ ID NO: 117 and

2.1* 0.7*

163)

[fl ETTFAGN Rl ETSFTC]-GSGS-

10 Cyclic 3.8 ± 0.4 0.3 ± 0.1 DYKDDDDK (SEQ ID NO: 118 and

163) flETTFAGNRIETSFTC (SEQ ID NO:

11 H 13.1 ± 1.0 3.5 ± 0.3

46)

* Estimated values

** K\ cannot be calculated

The unlabeled GluN2B peptide (6) and the RaPID hit peptides (3 and 5) and analogues (7-11) were characterized for their binding to PDZ2 by an FP competition assay using TAMRA-GluN2B as probe. Peptide 3 was the most potent peptide binder to PDZ2 (IC50 = 2.3 ± 0.1 pM, Ki < 0.3 pM) with approximately ten-fold higher binding affinity compared to control, linear GluN2B peptide (6) ( = 3.1 ± 0.2 pM). Notably, the value of 3 was outside the linear range of the TMARA-GluN2B probe, thus its exact binding affinity was not determined. The linear peptide 11 showed decreased affinity compared to 3 (IC50 = 13.1 ± 1.0, = 3.5 ± 0.3 pM) and similar binding profile was observed for its Flag-tagged analogue 10 (IC50 = 3.8 ± 0.4 pM, = 0.3 ± 0.1 pM), indicating that the tag itself does not bind to PDZ2 or interfere with binding. Peptides 7 and 9 showed poorer binding to PDZ2 ( ~ 50 pM) though peptide precipitation in high concentrations that was indicated by increase of polarization, did not allow the determination of their exact binding affinity. Peptides 5 and 8 did not bind to PDZ2 (Table 5, Fig. 5).

Example 5: Structure-activity mapping shows key amino acids for PDZ2 binding

The peptide 3 showed the highest affinity to PDZ2/PSD-95 as measured by the FP assay. Thus, it was selected for a structure-activity relationship study aiming to better understand peptide binding and optimize its affinity. For this purpose, the RaPID system was applied for the generation of a library of peptide mutants in which the 15 internal residues in the peptide sequence were substituted to all 20 proteinogenic amino acids. First, a site-saturation mutagenesis DNA library (Chronopoulou & Labrou, 2011) was designed in which sequences encoding each wild type amino acid were replaced with randomized NNK codons. Additionally, a DNA sequence encoding an influenza hemagglutinin (HA) tag at the C-terminus of each peptide was incorporated allowing library purification prior to the incubation with the protein target. mRNA library was translated to peptide mutants and cDNA-linked peptides were purified based on an HA- tag affinity method. The peptide library was incubated with three PDZ2 samples immobilized in titrated amounts of bead slurry. Final protein concentrations of 40, 200 and 1000 nM were evaluated aiming on the identification of the optimal conditions in which peptide binding would reach equilibrium. Moreover, library was selected against beads for the detection of potential bead binding peptides.

After library selection qPCR analysis of the input and recovered samples showed a five-fold higher recovery rate for PDZ2 in a concentration of 1000 nM compared to the lower protein concentrations (Fig. 6). Though, similar recovery rates to these observed during RaPID selection (Fig. 3) were obtained.

The populations of all bound protein samples, as well as the input library, were decoded by NGS. Following the data analysis described by Rogers et al. 2018, the enrichment ratios (e) of peptides were calculated by counting the fractions of DNA reads (F) in the bound against the input sample (e = Fbound I Fj_nput). Next, the enrichment score (E) of each mutant was determined based on the e of each mutant (ei) against the wild type (ewr, E\ = e ewr).

A largely complete heat map representing E scores of the majority of peptide mutants was obtained with the analysis of the recovered library from the selection against 1000 nM PDZ2 (Fig. 7 and table below).

It was observed that substitutions in most positions in the peptide sequence, including the nNOS ‘TTF’ binding motif, were deleterious for binding to PDZ2. Changes in positions 6, 7, 8 and 15 appear to be better tolerated and the mutant N9Wwas particularly beneficial as indicated by the highest E score. Importantly, the peptide sequences that appeared in the bead samples did not correlate with the maps of the bound libraries.

References

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).

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).

Goto, Y. et al. Reprogramming the translation initiation for the synthesis of physiologically stable cyclic peptides. ACS Chem. Biol. 3, 120-129 (2008)

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).

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:

X2 is independently selected from the group consisting of: G, A, D, E, F,

H, K, L, N, Q, R, S, W, and Y;

2. A peptide comprising the amino acid sequence

IETTFX1X2X3RIETSFX4C (SEQ ID NO: 1) wherein:

3. The peptide according to claim 1 , wherein the peptide comprises or consists of the amino acid sequence

XDIETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein: XD is a D-amino acid, such as D-phenylalanine;

4. The peptide according to claim 2, wherein

XD is a D-phenylalanine;

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 or consists of an amino acid sequence selected from the group consisting of:

XDIETTFAGNRIETSFTC (SEQ ID NO: 3); X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5); XDIETTFHGNRIETSFTC (SEQ ID NO: 6); XDIETTFIGNRIETSFTC (SEQ ID NO: 7); XDIETTFLGNRIETSFTC (SEQ ID NO: 8); XDIETTFNGNRIETSFTC (SEQ ID NO: 9); XDIETTFQGNRIETSFTC (SEQ ID NO: 10); XDIETTFSGNRIETSFTC (SEQ ID NO: 11); XDIETTFTGNRIETSFTC (SEQ ID NO: 12); XDIETTFVGNRIETSFTC (SEQ ID NO: 13); X_DI ETTFWGN RI ETSFTC (SEQ ID NO: 14); XDIETTFVGNRIETSFTC (SEQ ID NO: 15); XDIETTFAANRI ETSFTC (SEQ ID NO: 16);

XDIETTFADNRI ETSFTC (SEQ ID NO: 17);

XDIETTFAENRI ETSFTC (SEQ ID NO: 18);

XDIETTFAFNRI ETSFTC (SEQ ID NO: 19);

XDIETTFAHNRI ETSFTC (SEQ ID NO: 20);

XDIETTFAKNRIETSFTC (SEQ ID NO: 21);

XDIETTFALNRIETSFTC (SEQ ID NO: 22);

XDIETTFANNRIETSFTC (SEQ ID NO: 23);

XDIETTFAQNRIETSFTC (SEQ ID NO: 24);

XDIETTFARNRIETSFTC (SEQ ID NO: 25);

XDIETTFASNRIETSFTC (SEQ ID NO: 26);

XDIETTFAWNRI ETSFTC (SEQ ID NO: 27);

XDIETTFAYNRIETSFTC (SEQ ID NO: 28);

XDIETTFAGCRIETSFTC (SEQ ID NO: 29);

XDIETTFAGFRIETSFTC (SEQ ID NO: 30);

XDIETTFAGGRI ETSFTC (SEQ ID NO: 31);

XDIETTFAGHRIETSFTC (SEQ ID NO: 32);

XDIETTFAGLRI ETSFTC (SEQ ID NO: 33);

XDIETTFAGRRIETSFTC (SEQ ID NO: 34);

X_DI ETTFAGYRI ETSFTC (SEQ I D NO: 35);

XDIETTFAGNRIETSFFC (SEQ ID NO: 36);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38);

XDIETTFAGNRIETSFIC (SEQ ID NO: 39);

XDIETTFAGNRIETSFLC (SEQ ID NO: 40);

XDIETTFAGNRIETSFNC (SEQ ID NO: 41);

XDIETTFAGNRIETSFSC (SEQ ID NO: 42);

XDIETTFAGNRIETSFVC (SEQ ID NO: 43);

XDIETTFAGNRIETSFWC (SEQ ID NO: 44);

XDIETTFAGNRIETSFYC (SEQ ID NO: 45); wherein XD is a D-amino acid, such as D-phenylalanine; 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 the functional variant thereof.

6. The peptide according to claim 1 , wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of: XDIETTFAGNRIETSFTC (SEQ ID NO: 3);

X_DI ETTFAGWRI ETSFTC (SEQ ID NO: 4); XDIETTFFGNRIETSFTC (SEQ ID NO: 5); XDIETTFHGNRIETSFTC (SEQ ID NO: 6); XDIETTFIGNRIETSFTC (SEQ ID NO: 7); XDIETTFLGNRIETSFTC (SEQ ID NO: 8); XDIETTFNGNRIETSFTC (SEQ ID NO: 9); XDIETTFQGNRIETSFTC (SEQ ID NO: 10);

XDIETTFSGNRIETSFTC (SEQ ID NO: 11); XDIETTFTGNRIETSFTC (SEQ ID NO: 12); XDIETTFVGNRIETSFTC (SEQ ID NO: 13); X_DI ETTFWGN RI ETSFTC (SEQ ID NO: 14); XDIETTFYGNRIETSFTC (SEQ ID NO: 15); XDIETTFAANRI ETSFTC (SEQ ID NO: 16); XDIETTFADNRI ETSFTC (SEQ ID NO: 17);

XDIETTFAENRI ETSFTC (SEQ ID NO: 18); XDIETTFAFNRI ETSFTC (SEQ ID NO: 19); XDIETTFAHNRI ETSFTC (SEQ ID NO: 20); XDIETTFAKNRI ETSFTC (SEQ ID NO: 21);

XDIETTFALNRI ETSFTC (SEQ ID NO: 22); XDIETTFANNRI ETSFTC (SEQ ID NO: 23); XDIETTFAQNRIETSFTC (SEQ ID NO: 24); XDIETTFARNRIETSFTC (SEQ ID NO: 25); XDIETTFASNRIETSFTC (SEQ ID NO: 26); X_DI ETTFAWN RI ETSFTC (SEQ ID NO: 27); XDIETTFAYNRIETSFTC (SEQ ID NO: 28); XDIETTFAGCRI ETSFTC (SEQ ID NO: 29); XDIETTFAGFRI ETSFTC (SEQ ID NO: 30); X_DI ETTFAGGRI ETSFTC (SEQ ID NO: 31); XDIETTFAGHRIETSFTC (SEQ ID NO: 32); XDIETTFAGLRI ETSFTC (SEQ ID NO: 33); XDIETTFAGRRI ETSFTC (SEQ ID NO: 34);

XDIETTFAGYRI ETSFTC (SEQ ID NO: 35); XDIETTFAGNRIETSFFC (SEQ ID NO: 36);

XDIETTFAGNRIETSFGC (SEQ ID NO: 37);

XDIETTFAGNRIETSFHC (SEQ ID NO: 38);

XDIETTFAGNRIETSFIC (SEQ ID NO: 39);

XDIETTFAGNRIETSFLC (SEQ ID NO: 40);

XDIETTFAGNRIETSFNC (SEQ ID NO: 41);

XDIETTFAGNRIETSFSC (SEQ ID NO: 42);

XDIETTFAGNRIETSFVC (SEQ ID NO: 43);

XDIETTFAGNRIETSFWC (SEQ ID NO: 44);

XDIETTFAGNRIETSFVC (SEQ ID NO: 45); wherein XD is a D-amino acid, such as D-phenylalanine; or a pharmaceutically acceptable salt thereof.

7. The peptide according to any 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 of the preceding claims, wherein the peptide is cyclized.

10. The peptide according to any of the preceding claims, wherein the peptide is back bone cyclized.

11. The peptide according to any of the preceding claims, wherein the peptide comprises a chloro-acetylated N-terminal residue.

12. The peptide according to any of the preceding claims, wherein the chloroacetylated N-terminal residue forms a link with the side chain of a C-terminal cysteine.

13. The peptide according to claim 1 , wherein the peptide is cyclic and comprises or consists of the amino acid sequence

XDIETTFX1X2X3RIETSFX4C (SEQ ID NO: 2) wherein:

XD is a D-amino acid;

14. The peptide according to claim 13, wherein XD is D-phenylalanine.

15. The peptide according to claim 13, wherein

XD is a D-phenylalanine;

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 has a Ki value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 less than 0.3 pM.

18. The peptide according to any one of the preceding claims, wherein the peptide has a IC50 value for inhibiting binding of GluN2B to PDZ2 domain of

19. The peptide according to claim 1 , wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFIGNRIETSFTC (SEQ ID NO: 50); flETTFLGNRIETSFTC (SEQ ID NO: 51); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFTGNRIETSFTC (SEQ ID NO: 55); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFWGNRIETSFTC (SEQ ID NO: 57); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAANRIETSFTC (SEQ ID NO: 59); flETTFADNRIETSFTC (SEQ ID NO: 60); flETTFAENRIETSFTC (SEQ ID NO: 61); flETTFAFNRIETSFTC (SEQ ID NO: 62); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFAKNRIETSFTC (SEQ ID NO: 64); flETTFALNRIETSFTC (SEQ ID NO: 65); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAQNRIETSFTC (SEQ ID NO: 67); flETTFARNRIETSFTC (SEQ ID NO: 68); flETTFASNRIETSFTC (SEQ ID NO: 69); flETTFAWNRIETSFTC (SEQ ID NO: 70); flETTFAYNRIETSFTC (SEQ ID NO: 71); flETTFAGCRIETSFTC (SEQ ID NO: 72); flETTFAGFRIETSFTC (SEQ ID NO: 73); flETTFAGGRIETSFTC (SEQ ID NO: 74); flETTFAGHRIETSFTC (SEQ ID NO: 75); flETTFAGLRIETSFTC (SEQ ID NO: 76); flETTFAGRRIETSFTC (SEQ ID NO: 77); flETTFAGYRIETSFTC (SEQ ID NO: 78); flETTFAGNRIETSFFC (SEQ ID NO: 79); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); flETTFAGNRIETSFIC (SEQ ID NO: 82); flETTFAGNRIETSFLC (SEQ ID NO: 83); flETTFAGNRIETSFNC (SEQ ID NO: 84); flETTFAGNRIETSFSC (SEQ ID NO: 85); flETTFAGNRIETSFVC (SEQ ID NO: 86); flETTFAGNRIETSFWC (SEQ ID NO: 87); flETTFAGNRIETSFYC (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 the functional variant thereof.

20. The peptide according to claim 1 , wherein the peptide comprises or consists of an amino acid sequence selected from the group consisting of: flETTFAGNRIETSFTC (SEQ ID NO: 46); flETTFAGWRIETSFTC (SEQ ID NO: 47); flETTFFGNRIETSFTC (SEQ ID NO: 48); flETTFHGNRIETSFTC (SEQ ID NO: 49); flETTFIGNRIETSFTC (SEQ ID NO: 50); flETTFLGNRIETSFTC (SEQ ID NO: 51); flETTFNGNRIETSFTC (SEQ ID NO: 52); flETTFQGNRIETSFTC (SEQ ID NO: 53); flETTFSGNRIETSFTC (SEQ ID NO: 54); flETTFTGNRIETSFTC (SEQ ID NO: 55); flETTFVGNRIETSFTC (SEQ ID NO: 56); flETTFWGNRIETSFTC (SEQ ID NO: 57); flETTFYGNRIETSFTC (SEQ ID NO: 58); flETTFAANRIETSFTC (SEQ ID NO: 59); flETTFADNRIETSFTC (SEQ ID NO: 60); flETTFAENRIETSFTC (SEQ ID NO: 61); flETTFAFNRIETSFTC (SEQ ID NO: 62); flETTFAHNRIETSFTC (SEQ ID NO: 63); flETTFAKNRIETSFTC (SEQ ID NO: 64); flETTFALNRIETSFTC (SEQ ID NO: 65); flETTFANNRIETSFTC (SEQ ID NO: 66); flETTFAQNRIETSFTC (SEQ ID NO: 67); flETTFARNRIETSFTC (SEQ ID NO: 68); flETTFASNRIETSFTC (SEQ ID NO: 69); flETTFAWNRIETSFTC (SEQ ID NO: 70); flETTFAYNRIETSFTC (SEQ ID NO: 71); flETTFAGCRIETSFTC (SEQ ID NO: 72); flETTFAGFRIETSFTC (SEQ ID NO: 73); flETTFAGGRIETSFTC (SEQ ID NO: 74); flETTFAGHRIETSFTC (SEQ ID NO: 75); flETTFAGLRIETSFTC (SEQ ID NO: 76); flETTFAGRRIETSFTC (SEQ ID NO: 77); flETTFAGYRIETSFTC (SEQ ID NO: 78); flETTFAGNRIETSFFC (SEQ ID NO: 79); flETTFAGNRIETSFGC (SEQ ID NO: 80); flETTFAGNRIETSFHC (SEQ ID NO: 81); flETTFAGNRIETSFIC (SEQ ID NO: 82); flETTFAGNRIETSFLC (SEQ ID NO: 83); flETTFAGNRIETSFNC (SEQ ID NO: 84); flETTFAGNRIETSFSC (SEQ ID NO: 85); flETTFAGNRIETSFVC (SEQ ID NO: 86); flETTFAGNRIETSFWC (SEQ ID NO: 87); flETTFAGNRIETSFYC (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:

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124); [flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127);

[flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129);

[flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144);

[flETTFAYNRIETSFTC] (SEQ ID NO: 145);

[flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148);

[flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159); [flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

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:

[flETTFAGNRIETSFTC] (SEQ ID NO: 120);

[flETTFAGWRIETSFTC] (SEQ ID NO: 121);

[flETTFFGNRIETSFTC] (SEQ ID NO: 122);

[flETTFHGNRIETSFTC] (SEQ ID NO: 123);

[flETTFIGNRIETSFTC] (SEQ ID NO: 124);

[flETTFLGNRIETSFTC] (SEQ ID NO: 125);

[flETTFNGNRIETSFTC] (SEQ ID NO: 126);

[flETTFQGNRIETSFTC] (SEQ ID NO: 127);

[flETTFSGNRIETSFTC] (SEQ ID NO: 128);

[flETTFTGNRIETSFTC] (SEQ ID NO: 129);

[flETTFVGNRIETSFTC] (SEQ ID NO: 130);

[flETTFWGNRIETSFTC] (SEQ ID NO: 131);

[flETTFYGNRIETSFTC] (SEQ ID NO: 132);

[flETTFAANRIETSFTC] (SEQ ID NO: 133);

[flETTFADNRIETSFTC] (SEQ ID NO: 134);

[flETTFAENRIETSFTC] (SEQ ID NO: 135);

[flETTFAFNRIETSFTC] (SEQ ID NO: 136);

[flETTFAHNRIETSFTC] (SEQ ID NO: 137);

[flETTFAKNRIETSFTC] (SEQ ID NO: 138);

[flETTFALNRIETSFTC] (SEQ ID NO: 139);

[flETTFANNRIETSFTC] (SEQ ID NO: 140);

[flETTFAQNRIETSFTC] (SEQ ID NO: 141);

[flETTFARNRIETSFTC] (SEQ ID NO: 142);

[flETTFASNRIETSFTC] (SEQ ID NO: 143);

[flETTFAWNRIETSFTC] (SEQ ID NO: 144);

[flETTFAYNRIETSFTC] (SEQ ID NO: 145); [flETTFAGCRIETSFTC] (SEQ ID NO: 146);

[flETTFAGFRIETSFTC] (SEQ ID NO: 147);

[flETTFAGGRIETSFTC] (SEQ ID NO: 148);

[flETTFAGHRIETSFTC] (SEQ ID NO: 149);

[flETTFAGLRIETSFTC] (SEQ ID NO: 150);

[flETTFAGRRIETSFTC] (SEQ ID NO: 151);

[flETTFAGYRIETSFTC] (SEQ ID NO: 152);

[flETTFAGNRIETSFFC] (SEQ ID NO: 153);

[flETTFAGNRIETSFGC] (SEQ ID NO: 154);

[flETTFAGNRIETSFHC] (SEQ ID NO: 155);

[flETTFAGNRIETSFIC] (SEQ ID NO: 156);

[flETTFAGNRIETSFLC] (SEQ ID NO: 157);

[flETTFAGNRIETSFNC] (SEQ ID NO: 158);

[flETTFAGNRIETSFSC] (SEQ ID NO: 159);

[flETTFAGNRIETSFVC] (SEQ ID NO: 160);

[flETTFAGNRIETSFWC] (SEQ ID NO: 161); and

23. The peptide according to any 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 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 of the preceding claims, wherein the peptide comprises in the range of 17 to 50 amino acid residues, such as in the range of 19 to 45 amino acid residues, such as in the range of 17 to 40 amino acid residues, such as in the range of 17 to 35 amino acid residues, such as in the range of 17 to 30 amino acid residues, such as in the range of 17 to 25 amino acid residues, such as in the range of 17 to 23 amino acid residues, such as in the range of 17 to 20 amino acid residues, such as in the range of 17 to 18 amino acid residues.

26. The peptide according to anyone of the preceding claims, wherein the peptide is conjugated to a cell-penetrating peptide (CPP).

27. The peptide according to anyone 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 binding of GluN2B to the PDZ2 domain of PSD-95.

30. The peptide according to any one of the preceding claims, wherein the peptide has a Ki value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, such as less than 2 pM, such as less than 1 pM, such as less than 0.9 pM, such as less than 0.8 pM, such as less than 0.7 pM, such as less than 0.6 pM, such as less than 0.5 pM, such as less than 0.4 pM, such as less than 0.35 pM, such as less than 0.3 pM, preferably less than 0.3 pM.

31. The peptide according to any one of the preceding claims, wherein the peptide has a IC50 value for inhibiting binding of GluN2B to PDZ2 domain of PSD-95 of less than 100 pM, such as less than 75 pM, such as less than 50 pM, such as less than 25 pM, such as less than 20 pM, such as less than 15 pM, such as less than 10 pM, such as less than 5 pM, such as less than 4 pM, such as less than 3 pM, preferably less than 3 pM.

32. The peptide according to any one of the preceding claims, wherein the peptide is further conjugated to a moiety.

33. The peptide according to claim 32, wherein the moiety is selected from the group consisting of PEG, monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides.

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 of the preceding claims.

36. A polynucleotide encoding the peptide as defined in any one of claims 1 to

34.

37. A vector comprising a polynucleotide as defined in claim 36.

38. A host cell comprising the polynucleotide according to claim 36 or the vector according to claim 37.

39. A peptide according to any one of claims 1 to 19, a composition according to claim 16, a polynucleotide according to claim 20, a vector according to claim 21 , or a host cell according to claim 22 for use as a medicament.

40. A peptide according to any one of claims 1 to 34, a composition according to claim 35, a polynucleotide according to claim 36, a vector according to claim 37, or a host cell according to claim 38, for use in prevention and/or treatment of an excitotoxicity-related disease 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 in a subject and/or for use in prevention and/or treatment of neuropathic pain in a subject.

41. A peptide according to any one of claims 1 to 34, a composition according to claim 35, a polynucleotide according to claim 36, a vector according to claim 37, or a host cell according to claim 38, for use in prevention and/or treatment of neuropathic pain in a subject.

42. A method of preventing and/or treating an excitotoxicity-related disease and/or neuropathic pain, said method comprising administering a therapeutically effective amount of the peptide according to any one of claims 1 to 34, a composition according to claim 35, a polynucleotide according to claim 36, a vector according to claim 37, or a host cell according to claim 38, to a subject in need thereof.

43. Use of the according to any one of 1 to 34, a composition according to claim 35, a polynucleotide according to claim 36, a vector according to claim 37, or a host cell according to claim 38, for the manufacture of a medicament for the treatment and/or prevention of an excitotoxicity-related disease and/or neuropathic pain in a subject.

44. A method for manufacturing the peptide according to any of claims 1 to 34, said method comprising the steps of: c) preparing a peptide using solid-phase peptide synthesis (SPPS); and d) cyclization of said peptide via thioether cyclization.