Transmembrane peptide antagonists of plexin-A1 and their therapeutic uses

Abstract

The present application relates to peptides derived from the transmembrane domain of Plexin-A1 that inhibit the heterodimerization of Neuropilin-1 / Plexin-A1. These peptides neutralize the inhibitory effect of Sema3A on cell migration and angiogenesis and may be useful in the treatment of diseases associated with Sema3A and / or Neuropilin-1 / Plexin-A1 activity, such as demyelinating diseases and diseases associated with abnormal angiogenesis, such as cancer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of EP Patent Application No. 21306229, filed September 8, 2021, which is incorporated herein by reference.

[0002] The present disclosure relates to the treatment of diseases and conditions related to activity of the neuropilin / plexin-A1 receptor, such as neurodegenerative diseases. [Background technology]

[0003] Multiple sclerosis (MS) is the most common chronic neurological disorder in young adults, affecting approximately one million people in the United States. MS is an autoimmune disease in which the patient's own immune cells attack and destroy the myelin sheath that protects neurons in the brain. Remyelination of these neurons by oligodendrocytes is a spontaneous phenomenon that becomes ineffective as the disease progresses, subsequently causing irreversible neuronal damage and progressive disability. Compounds currently approved for the treatment of MS are designed to limit the destructive immune attack.

[0004] Multiple sclerosis experts agree that drugs that stimulate the regeneration of the myelin sheath produced by oligodendrocytes represent an innovative approach that could benefit MS patients by protecting neurons to prevent further damage and ultimately restore neuronal function.

[0005] Among the many factors regulating the early steps of myelination, members of the semaphorin family have been shown to regulate the migration of oligodendrocyte precursor cells and inhibit their maturation. Among them, the role of sema3A as an inhibitory regulator of myelination has been recognized, but the importance of the receptors involved is still unclear.

[0006] WO2007 / 000672 describes transmembrane peptides with antagonistic activity of the semaphorin / neuropilin complex. Plexin-A1 is, among others, one of the sources of peptides, without any particular therapeutic interest associated with it.

[0007] Biname et al. (EMBO Mol Med (2019) 11: e10378) showed that plexin-A1, a signaling receptor for the oligodendrocyte inhibitor Semaphorin 3A, is overexpressed in MS patients. The authors describe a peptide antagonist antagonizing plexin-A1 (called MTP-PlexA1) that can attenuate the Sema3A inhibitory effect on oligodendrocyte migration and differentiation in vitro. MTP-PlexA1 is a synthetic peptide that mimics the transmembrane domain of plexin-A1 (TLPAIVGIGGGGGLLLLVIVAVLIAYKRK, SEQ ID NO: 1). Administration of the peptide also showed a protective effect, resulting in a reduction in the severity of demyelination in the context of experimental autoimmune encephalitis (EAE).

[0008] However, there remains a need for the identification of new antagonistic peptides. Summary of the Invention

[0009] The present disclosure provides new peptides that block the plexin-A1 receptor involved in the inhibitory signaling pathway Sema3A-Neuropilin1-Plexin-A1. The peptides inhibit the interaction between Neuropilin-1 and Plexin-A1 and the inhibitory effect of Sema3A on cell migration. These peptides are able to increase remyelination by inhibiting one of the pathways involved in blocking different stages of remyelination and have a protective effect on experimental animal models of multiple sclerosis (EAE-PLP and EAE-MOG) models, thereby indicating their therapeutic potential for the treatment of demyelinating diseases such as multiple sclerosis. Furthermore, the inventors provide evidence of the ability of the peptides to inhibit angiogenesis, thereby expanding the potential use of blocking peptides in other diseases involving abnormal angiogenesis, such as tumor growth and metastasis, hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis.

[0010] The inventors have identified rules for designing antagonistic peptides. In the peptide, the motif GxxxG is responsible for the activity. It has been found that the first glycine can be replaced by a serine. Furthermore, another important aspect for the design of the peptide is the anchoring of the motif G / SxxxG in the membrane and the distance between the membrane surface and the motif G / SxxxG. In fact, the position of the motif G / SxxxG is key. More specifically, if the peptide has an N-terminal membrane anchor, 5 amino acids should be inserted between the N-terminal membrane anchor motif and the motif G / SxxxG. If the peptide has a C-terminal membrane anchor, 13 amino acids should be inserted between the motif G / SxxxG and the C-terminal membrane anchor motif with a positively charged amino acid, and preferably 11 amino acids should be inserted between the motif G / SxxxG and the C-terminal membrane anchor motif with a negatively charged amino acid. Once these rules have been determined, the inventors have surprisingly observed that the peptide can be shortened to the motif G / SxxxG opposite the membrane anchor motif. This aspect allows the design of shorter peptides.

[0011] The present disclosure provides a peptide, preferably a peptide of 50, 45, or 40 amino acids or less, - a first domain of sequence G / SXXXG, -Sequence directly linked to the C-terminus of the motif: -(X) 11 -(CterpolyD / E) (i.e., G / SXXXG-(X) 11 -(CterpolyD / E), (NterGp)-(X)- directly linked at the N-terminus of the motif (i.e., (NterGp)-(X)-G / SXXXG), or -(X) directly linked at the C-terminus of the motif. 13 -(CterGp) (i.e., G / SXXXG-(X) 13 -(CterGp), and -X is any amino acid (D- or L-), but not more than two of the X's are charged amino acids; A peptide comprising, consisting essentially of, or consisting of, CterpolyD / E being a group of 4-10 amino acids (D- or L-) containing at least 2 negatively charged amino acids, NterGp being a group of 3-5 amino acids (D- or L-) containing at least 2 charged amino acids, and CterGp being a group of 3-5 amino acids (D- or L-) containing at least 3 positively charged amino acids. or a retro or retro-inverso sequence thereof, or a pharma- ceutically acceptable salt thereof, The peptide does not comprise or consist of the sequence TLPAIVGIGGGGGLLLLVIVAVLIAYKRK (SEQ ID NO:1).

[0012] In one embodiment, the peptide has a length of 30 or less amino acids. In one embodiment, the peptide has a length of 28 or less amino acids. In one embodiment, the peptide has a length of 26 or less amino acids. In one embodiment, the peptide has a length of 25 or less amino acids. In one embodiment, the peptide has a length of 20 or less amino acids.

[0013] The present disclosure relates to - Motif G / SXXXG, -(X) linked directly to the C-terminus of the motif 11 -(CterpolyD / E) (i.e., G / SXXXG-(X) 11 -(CterpolyD / E), (NterGp)-(X)- directly linked at the N-terminus of the motif (i.e., (NterGp)-(X)-G / SXXXG), or -(X) directly linked at the C-terminus of the motif. 13 -(CterGp) (i.e., G / SXXXG-(X) 13 -(CterGp), and -X is any amino acid (D- or L-), but not more than two of the X's are charged amino acids; A peptide comprising, consisting essentially of, or consisting of, NterGp being a group of 3-5 amino acids (D- or L-) containing at least 2 charged amino acids, CterGp being a group of 3-5 amino acids (D- or L-) containing at least 3 positively charged amino acids, and CterpolyD / E being a group of 4-10 amino acids (D- or L-) containing at least 2 negatively charged amino acids. or a retro or retro-inverso analog thereof, or a pharma- ceutically acceptable salt thereof, the peptide inhibits the inhibitory effect of Sema3A on migration and / or inhibits the interaction between Neuropilin-1 and Plexin A1 as measured by the methods detailed herein; The peptide does not have the sequence of MTP-PlexA1 (TLPAIVGIGGGGGLLLLVIVAVLIAYKRK, SEQ ID NO:1).

[0014] More specifically, the inventors have identified a new class of antagonistic peptides with advantageous properties in the context of transmembrane peptides. These peptides exhibit improved solubility and stability compared to MTP-PlexA1. They exhibit plasma half-lives longer than 24 hours and biodistribution that is favorable to reach target organs such as the brain and spinal cord.

[0015] In this advantageous embodiment, the peptide comprises G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 2), V / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 3), I / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 4), A / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 5), P / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 6), I / LP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 7), and TI / LP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO:8), In the formula, CterpolyD / E is a group of 4 to 10 amino acids including at least 2 negatively charged amino acids; This sequence may contain 1, 2, or 3 substitutions of one amino acid at any position except the residues in bold and additions of 1 to 6 amino acids at the N- or C-terminus.

[0016] Optionally, CterpolyD / E is -X"1-X"2-(Z) nwherein X"1 is a small amino acid (e.g., G or A), X"2 is an aromatic amino acid (e.g., Y or W), Z is a negatively charged residue (e.g., D or E), and n is an integer between 2 and 10, preferably between 4 and 6, or -X"1-X"1bis-X"2-(E) n wherein X″1 and X″1bis are long aliphatic amino acids such as I or L, X″2 is an aromatic amino acid (for example, Y or W), and n is an integer of 2 to 10, preferably 4 to 6.

[0017] Optionally, the peptide has the amino acid sequence: G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVEVA / LI-Y-(D / E) n (SEQ ID NO:9), This sequence may further include one, two, or three substitutions of one amino acid at any position except for the bolded residues and additions of one to six amino acids at the N-terminus and / or C-terminus, where n is an integer from 2 to 10, preferably 4 to 6.

[0018] Optionally, the peptide comprises: AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10), TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11), G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12), TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13), TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14), and TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15), This sequence may further include one, two, or three substitutions of one amino acid at any position except the bolded residues and additions of one to six amino acids at the N-terminus and / or C-terminus.

[0019] More specifically, the peptide is AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO:21), TLPAITGLVGGVGLLLEVIVEVAYEEE (SEQ ID NO: 97), TLPAITGLVGGVGLLLEVIVEVAYEE (SEQ ID NO: 98), TLPAITGLVGGVGLLLEVIVEVAYDDDDD (SEQ ID NO: 99), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101), d E d E d E d E d E d Y d A d V d E d V d I d V d E d L d L d LG d VGG d V d LG d T d I dA d P d L d T (SEQ ID NO: 106), TLPAITGLVGGVGLLLEVIVEVAYDD (SEQ ID NO: 107), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), d TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111), TLPAITGLVGGVGLLLEVIV d EVAYEEEEE (SEQ ID NO: 112), or TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113), This sequence may further include one, two, or three substitutions of one amino acid at any position except the bolded residues and additions of one to six amino acids at the N- or C-terminus.

[0020] In one embodiment, the peptide is AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO:21), TLPAITGLVGGVGLLLEVIVEVAYEE (SEQ ID NO: 98), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101), d E d Ed E d E d E d Y d A d V d E d V d I d V d E d L d L d LG d VGG d V d LG d T d I d A d P d L d T (SEQ ID NO: 106), TLPAITGLVGGVGLLLEVIVEVAYDD (SEQ ID NO: 107), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), d TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111), TLPAITGLVGGVGLLLEVIV d EVAYEEEEE (SEQ ID NO: 112), or TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113), This sequence may further include one, two, or three substitutions of one amino acid at any position except the bolded residues and additions of one to six amino acids at the N- or C-terminus.

[0021] In one embodiment, the peptide is AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO:21), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), or TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113), This sequence may further include one, two, or three substitutions of one amino acid at any position except the bolded residues and additions of one to six amino acids at the N- or C-terminus.

[0022] In another embodiment, the peptide exhibits an N-terminal membrane anchor motif (i.e., NterGp), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGG (SEQ ID NO: 22), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / V (SEQ ID NO: 23), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / V (SEQ ID NO: 24), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / E (SEQ ID NO: 25), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / EL (SEQ ID NO: 26); (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELL (SEQ ID NO: 27), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / E (SEQ ID NO: 28); (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EV (SEQ ID NO: 29), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVI (SEQ ID NO: 30), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIV (SEQ ID NO: 31), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / E (SEQ ID NO: 32), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV (SEQ ID NO: 33), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVL (SEQ ID NO: 34), and (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI (SEQ ID NO: 35), wherein NterGp is ​​a group of 3 to 5 amino acids including at least 2 charged amino acids; This sequence may contain 1, 2, or 3 substitutions of one amino acid at any position except the residues in bold and additions of 1 to 6 amino acids at the N- or C-terminus.

[0023] Optionally, NterGp has a sequence of four amino acids X1-X2-X3-X4, where X1 and X3 are two charged amino acids, optionally one positively charged and the other negatively charged, X2 is a small amino acid (e.g., G or A), and X4 is an aromatic amino acid (e.g., Y or W), more preferably NterGp is ​​KGDW (SEQ ID NO: 116).

[0024] In another embodiment, where the peptide comprises a C-terminal membrane anchor motif having a positively charged amino acid (i.e., CterGp), the peptide comprises A / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 36), I / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 37), V / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 38), and G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO:39), where CterGp is ​​a group of 3 to 5 amino acids including at least 3 positively charged amino acids; This sequence may contain one, two, or three substitutions of one amino acid at any position except the residues in bold.

[0025] Optionally, CterGp has a sequence of five amino acids X'1-X'2-X'3-X'4-X'5, where X'1 is a small amino acid (e.g., G or A), X'2 is an aromatic amino acid (e.g., Y or W), and X'3, X'4, and X'5 are basic amino acids, more preferably CterGp is ​​a sequence selected from AYKRK (SEQ ID NO:76), AYKKR (SEQ ID NO:77), AYKRR (SEQ ID NO:78), AYRRK (SEQ ID NO:79), and AYRKK (SEQ ID NO:80).

[0026] Optionally, the peptide comprises: KGDWLPAIT-G / S-LVGGVGLL (SEQ ID NO: 40) KGDWLPAIV-G / S-IGGGVVLL (SEQ ID NO: 41) KGDWIPALV-G / S-GGGGGGLL (SEQ ID NO: 42) KGDWLPALV-G / S-IGGGVGLL (SEQ ID NO: 43) KGDWIPALV-G / S-LGGGGGLL (SEQ ID NO: 44) KGDWLIAIV-G / S-IGGG (SEQ ID NO: 45) KGDWLPVIV-G / S-IGGG (SEQ ID NO: 46) KGDWLPAIV-G / S-IGGGGGLL (SEQ ID NO: 47) KGDWLPAIV-G / S-IGGGGGL (SEQ ID NO: 48) KGDWLPAIV-G / S-IGGGGG (SEQ ID NO: 49) KGDWLPAIV-G / S-IGGGG (SEQ ID NO: 50) KGDWLPAIV-G / S-IGGG (SEQ ID NO:51) AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10) TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11) G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12) TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13) TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14) TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15), This sequence may contain 1, 2, or 3 substitutions of one amino acid at any position except the residues in bold and additions of 1 to 6 amino acids at the N- or C-terminus.

[0027] In a very particular embodiment, the peptide comprises KGDWLPAITGLVGGVGLL (SEQ ID NO:52) KGDWLPAIVSIGGGVVLL (SEQ ID NO:53) KGDWIPALVGGGGGGGLL (SEQ ID NO:54) KGDWLPALVSIGGGVGLL (SEQ ID NO:55) KGDWIPALVGLGGGGGLL (SEQ ID NO:56) KGDWLIAIVGIGGG (SEQ ID NO:57) KGDWLPVIVGIGGG (SEQ ID NO:58) KGDWLPAIVGIGGGGGGLL (SEQ ID NO:59) KGDWLPAIVGIGGGGGL (SEQ ID NO: 60) KGDWLPAIVGIGGGGG (SEQ ID NO:61) KGDWLPAIVGIGGGG (SEQ ID NO:62) KGDWLPAIVGIGGG (SEQ ID NO: 63) AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16) TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17) GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18) TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19) TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20) TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21) TLPAITGLVGGVGLLLEVIVEVAYEEE (SEQ ID NO: 97), TLPAITGLVGGVGLLLEVIVEVAYEE (SEQ ID NO: 98), TLPAITGLVGGVGLLLEVIVEVAYDDDDD (SEQ ID NO: 99), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101), d E d E d E d E d E d Y d A d V d E d V d I d V d E d L d L d LG d VGG d V d LG d T d I d A d P d L d T (SEQ ID NO: 106), TLPAITGLVGGVGLLLEVIVEVAYDD (SEQ ID NO: 107), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), d TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111), TLPAITGLVGGVGLLLEVIV d EVAYEEEEE (SEQ ID NO: 112), or TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113), This sequence may contain 1, 2, or 3 substitutions of one amino acid at any position except the residues in bold and additions of 1 to 6 amino acids at the N- or C-terminus.

[0028] In one embodiment, the peptide comprises, consists essentially of, or consists of the amino acid sequence TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), or TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113).

[0029] The present disclosure also relates to a method for inhibiting the interaction of neuropilin-1 and plexin-A1 on a cell, comprising contacting the cell with an effective amount of any of the peptides defined herein.

[0030] The present disclosure also relates to the use of any of the peptides defined herein for inhibiting the interaction between neuropilin-1 and plexin-A1 on a cell.

[0031] The present disclosure also relates to the use of any of the peptides defined herein for the manufacture of a medicament for inhibiting the interaction between neuropilin-1 and plexin-A1 on a cell.

[0032] The present disclosure also relates to a peptide as defined herein for use in inhibiting the interaction between neuropilin-1 and plexin-A1 on a cell.

[0033] The present disclosure also relates to a method for inhibiting the anti-migratory and anti-differentiation effects of Sema3A in glial cells (e.g., oligodendrocytes), comprising contacting the glial cells with an effective amount of any of the peptides defined herein.

[0034] The present disclosure also relates to the use of any of the peptides defined herein for inhibiting the anti-migratory and anti-differentiation effects of Sema3A in glial cells (eg, oligodendrocytes).

[0035] The present disclosure also relates to the use of any of the peptides defined herein for the manufacture of a medicament for inhibiting the anti-migratory and anti-differentiation effects of Sema3A in neuroglial cells (eg, oligodendrocytes).

[0036] The present disclosure also relates to a peptide as defined herein for use in inhibiting the anti-migratory and anti-differentiation effects of Sema3A in glial cells (eg, oligodendrocytes).

[0037] The present disclosure also relates to a peptide as defined herein for use in stimulating remyelination in a subject, such as a subject suffering from a demyelinating disease.

[0038] The present disclosure also relates to a pharmaceutical composition comprising any of the peptides defined herein for use as a medicament.

[0039] The present disclosure further relates to the treatment of multiple sclerosis, transverse myelitis, neuromyelitis optica (Devic's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Krabbe disease, Barot disease, Charcot-Marie-Tooth disease (CMT), HIV encephalitis, HTLV-I associated myelopathy (HAM), Binswanger disease (subcortical leukoencephalopathy and subcortical arteriosclerotic encephalopathy (SAE)), globoid cell leukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis, polyradiculopathy (Guillain-Barre syndrome), The present invention relates to a pharmaceutical composition comprising any of the peptides defined herein for the treatment of demyelinating diseases, including those caused by anti-cancer drugs, such as inflammatory bowel syndrome (GBS) and chronic inflammatory demyelinating polyradiculopathy, anti-cancer drugs, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia or irradiation, in particular demyelinating autoimmune or inflammatory diseases, or for the treatment of diseases or disorders associated with abnormal angiogenesis that may require treatment to reduce angiogenesis (e.g. hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis), and / or for the treatment of cancer. It relates to the use of a pharmaceutical composition comprising any of the peptides defined herein for the manufacture of a medicament for the treatment of demyelinating diseases, including those defined herein, in particular demyelinating autoimmune diseases, or for the treatment of diseases or disorders associated with abnormal angiogenesis, and / or for the treatment of cancer. Finally, it relates to a method for treating a demyelinating disease, including a disease as defined herein, in particular a demyelinating autoimmune disease, a disease or disorder associated with abnormal angiogenesis, or cancer, in a subject in need thereof, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of any of the peptides defined herein.

[0040] In various aspects and embodiments, the present disclosure provides the following items 1-68: 1. A peptide comprising: a first domain of sequence X37-X5-X6-X7-G; (i) a second domain of formula I: -(X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36)-(CterpolyD / E) directly linked at the carboxy terminus of the first domain; (ii) a second domain of formula II: -(X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25)-(CterGp) directly linked at the carboxy terminus of the first domain; or (iii) a second domain of formula III: (NterGp)-(X8-X9-X10-X11-X12)- linked directly at the amino terminus of the first domain; During the ceremony, X37 is Gly, L-Ser, or D-Ser; X5, X6, and X7 are independently any amino acid; X8, X9, X10, X11, and X12 are independently any amino acid; X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are independently any amino acid, and no more than two amino acids among X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are charged amino acids; X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, and X36 are independently any amino acid, and up to two of X26, X27, X28, X29, X30, X31, X32, X33, X34, and X35 are charged amino acids; CterpolyD / E is a group of 4 to 10 amino acids including at least 2 negatively charged amino acids; NterGp is ​​a group of 3 to 5 amino acids including at least 2 charged amino acids; CterGp is ​​a group of 3-5 amino acids including at least 3 positively charged amino acids; or its retro or retro-inverso form, or a pharma- ceutically acceptable salt thereof; A peptide, wherein the peptide does not comprise or consist of the sequence TLPAIVGIGGGGGLLLLVIVAVLIAYKRK (SEQ ID NO:1). 2. The peptide according to item 1, wherein X5, X6, and X7 are aliphatic uncharged amino acids. 3. The peptide according to item 2, wherein X5, X6, and X7 are each independently Gly, D or L-Ala, D or L-Val, D or L-Leu, and D or L-Ile. 4. The peptide according to item 3, wherein X5 is D-Leu, L-Leu, D-Ile, or L-Ile, X6 is Gly, D-Val, or L-Val, and / or X7 is Gly. 5. The peptide according to item 4, wherein X5 is L-Leu and / or X6 is L-Val. 6. The peptide according to any one of items 1 to 5, wherein X6 is Gly, D-Val, or L-Val. 7. The peptide according to any one of items 1 to 6, wherein X37 is Gly. 8. The peptide according to any one of items 1 to 7, wherein X26 is an aliphatic uncharged amino acid, X27 is an aliphatic uncharged amino acid, X28 is an aliphatic uncharged amino acid, X29 is an aliphatic uncharged amino acid, X30 is an aliphatic uncharged amino acid, X31 is a negatively charged amino acid, X32 is an aliphatic uncharged amino acid, X33 is an aliphatic uncharged amino acid, X34 is an aliphatic uncharged amino acid, X35 is a negatively charged amino acid and / or X36 is an aliphatic uncharged amino acid. 9. X26 is Gly, D-Val, or L-Val, X27 is Gly, D-Val, or L-Val, X28 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X29 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X30 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X31 is D- or L-Glu, and X32 is D- or L-Ile. 9. The peptide according to item 8, wherein X33 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X34 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X35 is D- or L-Glu, and / or X36 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile. 10. The peptide according to item 9, wherein X26 is L-Val, X27 is Gly, X28 is L-Leu, X29 is L-Leu, X30 is L-Leu, X31 is L-Glu, X32 is L-Val, X33 is L-Ile, X34 is L-Val, X35 is L-Glu and / or X36 is L-Val. 11. The peptide according to any one of items 1 to 10, wherein X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36 is VGLLLEVIVEV (SEQ ID NO: 91), GGELLLVIVE (SEQ ID NO: 92), VVLLLEVIVEV (SEQ ID NO: 93), VGLLVEVIVEV (SEQ ID NO: 117), or VGLVLEVIVEV (SEQ ID NO: 118). 12. CterpolyD / E comprises the sequence -X"1-X"2-Z or -X"3-X"3bis-X"2-Z; During the ceremony, X″1 is a small amino acid, X″2 is an aromatic amino acid, X"3 and X"3bis are independently a long aliphatic amino acid; 12. The peptide according to any one of items 1 to 11, wherein Z is 2 to 10 D / L-Asp and / or D / L-Glu residues. 13. The peptide according to item 12, wherein X"1 is D- or L-Ala. 14. The peptide according to item 12 or 13, wherein X"3 and X"3bis are independently D- or L-Leu, or D- or L-Ile. 15. The peptide according to item 14, wherein X"3 is D- or L-Leu and X"3bis is D- or L-Ile. 16. The peptide according to any one of items 12 to 15, wherein Z is 3 to 6 D / L-Asp and / or D / L-Glu residues. 17. The peptide according to any one of items 12 to 16, wherein Z is 3 to 5 L-Glu residues. 18. The peptide according to any one of items 1 to 17, wherein the peptide comprises a second domain of formula I or II and further comprises a third domain of 1 to 10 amino acids attached at the amino terminus of the first domain. 19. The peptide according to item 18, wherein the third domain comprises 1 to 6 amino acids. 20. The third domain is a third domain of formula IV: X38-X39-X40-X41-X42-X43; X38 is D-Thr or L-Thr or is absent; X39 is D- or L-Leu, D- or L-Ile, or is absent; X40 is Pro, D- or L-Ile, or is absent; X41 is D- or L-Ala, D- or L-Val, or is absent; X42 is D- or L-Leu, D- or L-Ile, or is absent, and 20. The peptide according to item 19, wherein X43 is D- or L-Val, D-Thr or L-Thr. 21. A peptide according to any one of items 1 to 20, comprising not more than 35 amino acids. 22. A peptide according to any one of items 1 to 21, comprising not more than 30 amino acids. 23. The following sequence: AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO:21), TLPAITGLVGGVGLLLEVIVEVAYEEE (SEQ ID NO: 97), TLPAITGLVGGVGLLLEVIVEVAYEE (SEQ ID NO: 98), TLPAITGLVGGVGLLLEVIVEVAYDDDDD (SEQ ID NO: 99), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101), TLPAITGLVGGVGLLLEVIVEVVYEEEEE (SEQ ID NO: 105), d E d E d E d E d E d Y d A d V d E d V d I d V d E d L d L d LG d VGG d V dLG d T d I d A d P d L d T (SEQ ID NO: 106), TLPAITGLVGGVGLLLEVIVEVAYDD (SEQ ID NO: 107), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), d TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111), TLPAITGLVGGVGLLLEVIV d EVAYEEEEE (SEQ ID NO: 112), or 23. The peptide according to any one of items 1 to 22, comprising one of the following: TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113). 24. The following sequence: TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), or 24. The peptide according to item 23, comprising one of the following: TLPAITGLVGGVGLLVEVIVEVAYEEEEE (sequence number 113). 25. The peptide according to any one of items 1 to 7, wherein X8 is an aliphatic residue, X9 is Pro, or D- or L-Ile, X10 is an aliphatic residue, X11 is an aliphatic residue, and / or X12 is an aliphatic residue. 26. The peptide according to item 25, wherein X8 is D- or L-Leu, or D- or L-Ile, X9 is Pro, X10 is D- or L-Ala, or D- or L-Val, X11 is D- or L-Leu, or D- or L-Ile, and / or X12 is D- or L-Thr, or D- or L-Val. 27. The peptide according to item 26, wherein X8-X9-X10-X11-X12 is LPAIT (SEQ ID NO: 82), LPAIV (SEQ ID NO: 83), IPALV (SEQ ID NO: 84), LPALV (SEQ ID NO: 85), LIAIV (SEQ ID NO: 86), or LPVIV (SEQ ID NO: 87). 28. The peptide according to any one of items 1 to 7 and 25 to 27, wherein NterGp comprises one positively charged amino acid and one negatively charged amino acid. 29. The peptide according to item 28, wherein NterGp has a sequence of four amino acids of formula V: X1-X2-X3-X4, where X1 is a positively charged residue, X3 is a negatively charged residue, X2 is a small amino acid, and X4 is an aromatic amino acid. 30. The peptide according to item 29, wherein X1 is D- or L-Lys, X2 is Gly, X3 is D- or L-Asp, and / or X4 is D- or L-Trp. 31. The peptide according to item 30, wherein NterGp is ​​KGDW (sequence number 116). 32. The peptide according to any one of items 1 to 7 and 25 to 31, wherein the second domain is a second domain of formula III and the peptide further comprises a third domain of 1 to 10 amino acids attached at the carboxy terminus of the first domain. 33. The peptide according to item 32, wherein the third domain is a third domain of formula VI: X26-X27-X28-X29-X30-X31-X32-X33-X34-X35, wherein X26, X27, X28, X29, X30, X31, X32, X33, X34, and X35 are as defined in any one of items 1 and 8 to 11. 34. The following sequence: KGDWLPAITGLVGGVGLL (SEQ ID NO:52), KGDWLPAIVSIGGGVVLL (SEQ ID NO:53), KGDWIPALVGGGGGGGLL (SEQ ID NO:54), KGDWLPALVSIGGGVGLL (SEQ ID NO:55), KGDWIPALVGLGGGGGLL (SEQ ID NO:56), KGDWLIAIVGIGGG (SEQ ID NO:57), KGDWLPVIVGIGGG (SEQ ID NO:58), KGDWLPAIVGIGGGGGLL (SEQ ID NO:59), KGDWLPAIVGIGGGGGL (SEQ ID NO: 60), KGDWLPAIVGIGGGGG (SEQ ID NO:61), 34. The peptide according to any one of items 1 to 7 and 25 to 33, comprising one of the following: KGDWLPAIVGIGGGG (SEQ ID NO: 62), or 35. The peptide according to any one of items 1 to 7, wherein X13 is an aliphatic and / or small residue, X14 is an aliphatic and / or small residue, X15 is an aliphatic residue or a negatively charged residue, X16 is an aliphatic residue, X17 is an aliphatic residue, X18 is an aliphatic residue or a negatively charged residue, X19 is an aliphatic residue, X20 is an aliphatic residue, X21 is an aliphatic residue, X22 is a small residue or a negatively charged residue, X23 is an aliphatic residue, X24 is an aliphatic residue, and / or X25 is an aliphatic residue. 36. X13 is GIy or D- or L-Val, X14 is GIy or D- or L-Val, X15 is D- or L-Ile or D- or L-Leu, X16 is D- or L-Ile or D- or L-Leu, X17 is D- or L-Ile or D- or L-Leu, X18 is D- or L-Ile or D- or L-Leu, and X19 is D 36. The peptide according to item 35, wherein X20 is D- or L-Ile, or D- or L-Leu, X21 is D- or L-Val, X22 is D- or L-Ala, X23 is D- or L-Val, X24 is D- or L-Ile, or D- or L-Leu, and / or X25 is D- or L-Ile, or D- or L-Leu. 37. The peptide according to item 35, wherein X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25 is GGLLLLVIVAVLI (sequence number 88). 38. A peptide according to any one of items 1 to 7 and 35 to 37, wherein CterGp comprises a mixture of Lys and Arg residues. 39. The peptide according to item 38, wherein CterGp comprises one of the following sequences: AYKRK (SEQ ID NO: 76), AYKKR (SEQ ID NO: 77), AYKRR (SEQ ID NO: 78), AYRRK (SEQ ID NO: 79), or AYRKK (SEQ ID NO: 80). 40. A pharmaceutical composition comprising the peptide according to any one of items 1 to 39, its retro or retro-inverso form, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier. 41. A peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40, for use as a medicament. 42. A peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40, for use in treating a demyelinating disease in a subject. 43. The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or composition for use according to item 42, wherein the demyelinating disease is a demyelinating autoimmune disease. 44. Demyelinating diseases include multiple sclerosis, transverse myelitis, neuromyelitis optica (Devic's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Krabbe disease, Barot disease, Charcot-Marie-Tooth disease (CMT), HIV encephalitis, HTLV-I associated myelopathy (HAM), Binswanger disease (subcortical leukoencephalopathy and subcortical arteriosclerotic encephalopathy (SAE)), globoid cell leukodystrophy, and metachromatic encephalopathy. 44. The peptide, its retro or retro-inverso form, its pharmacologic acceptable salt, or composition for use according to item 42 or 43, wherein the disease is a demyelinating disease caused by anti-cancer drugs, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia, or irradiation, wherein the disease is progressive leukodystrophy, Pelizaeus-Merzbacher disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis, polyradiculopathy, or a demyelinating disease caused by antineoplastic agents, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia, or irradiation. 45. The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or the composition for use according to item 44, wherein the polyradiculopathy is Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculopathy. 46. ​​The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or composition for use according to item 44, wherein the demyelinating disease is multiple sclerosis. 47. A peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40, for use in the treatment of a disease or disorder associated with abnormal angiogenesis. 48. The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or the composition for use according to item 47, wherein the disease or disorder associated with abnormal angiogenesis is cancer, hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis. 49. The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or the composition for use according to any one of items 42 to 48, wherein the peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or the composition is for use in combination with one or more additional therapeutic agents. 50. The peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or the composition for use according to item 49, wherein the one or more additional therapeutic agents comprises fingolimod. 51. Use of a peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40, for the manufacture of a medicament for the treatment of a demyelinating disease in a subject. 52. The use according to item 51, wherein the demyelinating disease is a demyelinating autoimmune disease. 53. Demyelinating diseases include multiple sclerosis, transverse myelitis, neuromyelitis optica (Devic's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Krabbe disease, Baro disease, Charcot-Marie-Tooth disease (CMT), HIV encephalitis, HTLV-I associated myelopathy (HAM), Binswanger's disease (subcortical leukoencephalopathy and subcortical arteriosclerosis). 53. The use according to item 51 or 52, wherein the disease is a demyelinating disease caused by anti-cancer drugs, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia or irradiation, such as cerebrovascular accidents, ... 54. The use according to item 53, wherein the polyradiculopathy is Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculopathy. 55. The use according to item 53, wherein the demyelinating disease is multiple sclerosis. 56. Use of a peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40, for the manufacture of a medicament for the treatment of a disease or disorder associated with abnormal angiogenesis. 57. The use according to item 56, wherein the disease or disorder associated with abnormal angiogenesis is cancer, hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis. 58. The use according to any one of items 51 to 57, wherein the medicament is for use in combination with one or more additional therapeutic agents. 59. The use according to item 58, wherein the one or more additional therapeutic agents comprises fingolimod. 60. A method for treating a demyelinating disease in a subject in need thereof, comprising administering to the subject an effective amount of a peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40. 61. The method according to item 60, wherein the demyelinating disease is a demyelinating autoimmune disease. 62. Demyelinating diseases include multiple sclerosis, transverse myelitis, neuromyelitis optica (Devic's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Krabbe disease, Baro disease, Charcot-Marie-Tooth disease (CMT), HIV encephalitis, HTLV-I associated myelopathy (HAM), Binswanger's disease (subcortical leukoencephalopathy and subcortical arteriosclerosis). 62. The method according to item 60 or 61, wherein the cause of the disease is selected from the group consisting of cerebrovascular accidents (CEA), globoid cell leukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis, polyradiculopathy, and demyelinating diseases caused by anti-cancer drugs, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia, or irradiation. 63. The method according to item 62, wherein the polyradiculopathy is Guillain-Barré syndrome (GBS) or chronic inflammatory demyelinating polyradiculopathy. 64. The method according to item 62, wherein the demyelinating disease is multiple sclerosis. 65. A method for treating a disease or disorder associated with abnormal angiogenesis in a subject in need thereof, comprising administering to the subject an effective amount of a peptide according to any one of items 1 to 39, a retro or retro-inverso form thereof, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to item 40. 66. The method according to item 65, wherein the disease or disorder associated with abnormal angiogenesis is cancer, hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis. 67. The method according to any one of items 60 to 66, wherein the peptide, its retro or retro-inverso form, its pharma- ceutically acceptable salt, or composition is for use in combination with one or more additional therapeutic agents. 68. The method of item 67, wherein the one or more additional therapeutic agents comprises fingolimod. [Brief description of the drawings]

[0041] [Figure 1] Membrane targeting peptides block NRP1-Plexin A1 receptor dimerization. The interfering activity of the membrane targeting peptides promotes a reduction in the interaction between Nrp1 and Plexin A1 as measured by a proximity ligation assay. [Figure 1A] Quantification of NRP1-PlexinA1 interaction per Oli-neu cell treated with different doses of GUNGNIR or MIMMING as measured by proximity ligation assay (data presented as mean ± SEM, Kruskal-Wallis test, ***P<0.0001 **P<0.01). [Figure 1B] Quantification of NRP1-PlexinA1 interaction per Oli-neu cell treated with different doses of GUNGNIR or MIMMING as measured by proximity ligation assay (data presented as mean ± SEM, Kruskal-Wallis test, ***P<0.0001 **P<0.01). [Diagram 2] Membrane-targeting peptides negate the negative effects of Sema3A on the migration of the oligodendrocyte cell line Oli-neu. [Figure 2A] Peptides with different synthetic sequences (n=3 except for SKOLL and HATI where n=1) with the GXXXG motif of rescue migration. [Figure 2B] Peptides with G / SXXXG motifs but not GXXXS or SXXXA motifs (n=3 except for SKIRNIR, where n=1) rescued migration of Oli-neu cells treated with Sema3A. [Figure 2C] Although peptides with deletions next to the GXXXG motif rescued migration to the N-ter or C-ter of Sema3A-treated Oli-neu cells, deletion of one G in the motif abolished peptide activity (n=1). [Figure 2D] N-ter truncations between (NterGp) and the GXXXG motif impair peptide efficiency (n=3 except for BROKK and EITRI where n=1). [Figure 2E] Among other peptide sequences with (CterpolyD / E), rescue transfer of RATI, GUNGNIR and MIMMING (n=3). [Figure 2F] GUNGNIR IC50 calculation at 1,2nM (n=3). [Figure 2G] Comparison of MTP-PlexA1 (SEQ ID NO: 1) with its retro-analogue (ODIN). Data are presented as mean ± SEM, n=3 independent experiments, ANOVA and Bonferroni's multiple comparison test **P<0.01, ***P<0.0001 versus vehicle condition. [Diagram 3] Analysis of biodistribution of membrane-targeting peptides. Percentage of GUNGNIR-Cy5 bioluminescence in different organs 4 h after intraperitoneal injection of the indicated doses (μg / kg). [Figure 4] GUNGNIR reduces the severity of EAE. [Figure 4A]GUNGNIR at 10 mg / kg reduces EAE clinical scores following PLP immunization. [Figure 4B] GUNGNIR at 10 mg / kg reduces EAE clinical scores after MOG immunization. Data are presented as mean ± SEM, n=7 (FIG. 4A) and n=10 (FIG. 4B), nonlinear regression (bell-shaped) plots are used for statistical significance P<0.0001 (FIG. 4A) P=0.0002 (FIG. 4B). [Figure 5A] Membrane-targeted peptides inhibit angiogenesis. Tubule formation was measured by counting the tubular intersections of HUVECs. A decrease in the number of tubular intersections indicates the inhibition of angiogenesis by MTPs. [Figure 5B] 1 shows the results of an MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyltetrazolium bromide) toxicity assay on HUVEC cells. [Figure 6] Gait analysis results after 6 days of remyelination showing two parameters that were found to be different between the vehicle and 100 μg / kg GUNGNIR groups. [Figure 6A] Propel 6 days Right hind leg. [Figure 6B] Min dA / dT 6 days Left hind leg. [Figure 7] Results of gait analysis after 11 days of remyelination showing five parameters that were found to be different between vehicle and 10 or 100 μg / kg GUNGNIR groups. [Figure 7A] Min dA / dT 11 days Right front paw. [Figure 7B] Stance factor 11 days left front leg. [Figure 7C] Propel 11 days Right hind leg. [Figure 7D] Stance 11 days Right hind leg. [Figure 7E] Paws fluctuate with left hind paw at peak stance for 11 days [Figure 8A]Results of histology experiments showing staining for the major myelin protein PLP (FIG. 8A) and Luxol Fast Blue (LFB) staining of myelin phospholipids (FIG. 8B) in brain tissue from mice undergoing cuprizone-induced demyelination. [Figure 8B] Results of histology experiments showing staining for the major myelin protein PLP (FIG. 8A) and Luxol Fast Blue (LFB) staining of myelin phospholipids (FIG. 8B) in brain tissue from mice undergoing cuprizone-induced demyelination. [Figure 9] Body weight results in mice subjected to cuprizone-induced demyelination. [Figure 9A] Body weight before the start of GUNGNIR treatment (i.e., day 21). [Figure 9B] Body weight at the start of the experiment. [Figure 9C] Body weight at the end of the experiment. [Figure 9D] Weight loss on day 21 in the 6-day remyelination group. [Figure 9E] Weight loss on day 21 in the 11-day remyelination group. [Figure 9F] Weight loss at week 5 in the 6-day remyelination group. [Figure 9G] Weight loss at week 5 in the 11-day remyelination group. [Figure 10] Body weight monitoring over the course of the experiment in different groups of EAE-PLP mice. [Figure 11] Clinical scores of disease severity in different groups of EAE-PLP mice. [Figure 11A] Clinical scores over the course of the experiment. [Figure 11B] Clinical scores on days 22, 26, 28, 38, and 39, respectively. [Figure 11C] Clinical scores on days 22, 26, 28, 38, and 39, respectively. [Figure 11D] Clinical scores on days 22, 26, 28, 38, and 39, respectively. [Figure 11E]Clinical scores on days 22, 26, 28, 38, and 39, respectively. [Figure 11F] Clinical scores on days 22, 26, 28, 38, and 39, respectively. [Figure 12] Body weight monitoring over the course of the experiment in different groups of EAE-MOG mice. [Figure 13] Clinical scores of disease severity in different groups of EAE-MOG mice. [Figure 13A] Clinical scores over the course of the experiment. [Figure 13B] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13C] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13D] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13E] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13F] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13G] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13H] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13I] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13J]Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13K] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13L] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13M] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13N] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. [Figure 13O] Clinical scores on days 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, and 30, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0042] Any and all examples provided herein, or the use of exemplary language (such as, for example, or the like) are intended merely to better illustrate the invention and do not limit the scope of the claims unless otherwise stated.

[0043] As used herein, the term "about" has its ordinary meaning. The term "about" is used to indicate that a value includes the inherent variation for error of the device or method being used to determine the value, or includes values ​​that approximate a recited value, e.g., within 10% or 5% of a recited value (or range of values).

[0044] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0045] Any and all combinations and subcombinations of the embodiments and features disclosed herein are encompassed by the present invention.

[0046] The present disclosure provides new antagonistic peptides capable of inhibiting the inhibitory effect of Sema3A on Neuropilin-1 / Plexin-A1 interaction and / or translocation, and relates to pharmaceutical compositions comprising such antagonistic peptides and their use as drugs.

[0047] definition Plexin-A1 is a protein encoded by the PLXNA1 gene. It is listed in several databases, namely UniProt ID number Q9UIW2; HGNG ID number 9099. The reference sequences are disclosed in Genbank under NM_032242.3 for the mRNA and NP_115618.3 for the protein.

[0048] Neuropilin-1 is a protein encoded by the NRP1 gene. It is listed in several databases, namely UniProt ID number O14786; HGNG ID number 8004. The reference sequences are disclosed in Genbank under NM_001330068.1 for the mRNA and NP_001316997.1 for the protein.

[0049] "consists of," "consists essentially of," or "substantially comprises": The description herein of any aspect or embodiment of the disclosure using terms such as reference to an element(s) is intended to give support for similar aspects or embodiments of the invention that "consist of," "consist essentially of," or "substantially comprise" the particular element(s), unless otherwise indicated or clearly contradicted by context. For example, a peptide or protein described herein as comprising a particular sequence should be understood to also describe a peptide or protein consisting of that sequence, unless otherwise indicated or clearly contradicted by context. By "essentially consisting of" it is intended that the peptide or protein consists of the sequence, but may also include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 substitutions, additions, deletions, or mixtures thereof, in particular 1, 2, 3, 4 or 5 substitutions, additions, deletions, or mixtures thereof, more particularly 1, 2 or 3 substitutions, additions, deletions, or mixtures thereof. In particular, by "essentially consisting of" it is intended that the peptide may include 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 additional amino acids at the N-terminus and / or C-terminus, in particular 1, 2, 3, 4 or 5 additional amino acids, more particularly 1, 2 or 3 additional amino acids, and / or 1, 2 or 3 substitutions, deletions, additions, or mixtures thereof. In certain embodiments, the sequence has no more than two or three substitutions. Preferably, the number of substitutions, additions, deletions, or mixtures thereof depends on the length of the sequence. For example, the percentage of substitutions, deletions, additions, or mixtures thereof may be no more than 30%, preferably no more than 25%, more preferably no more than 8 or 10%.

[0050] As used herein, the term "substitution" refers to the replacement of a single amino acid with another amino acid in a peptide sequence. As used herein, the term "deletion" refers to the removal of a single amino acid in a peptide sequence. As used herein, the terms "insertion" or "addition" are equivalent and refer to the addition of a single amino acid in a peptide sequence.

[0051] By "substitution, addition, deletion" is intended the substitution, addition, or deletion of one amino acid. Then, when referring to "one, two, three, four, five, six, seven, eight, nine, or ten substitutions, additions, deletions, or mixtures thereof", "one, two, three, four, or five substitutions, additions, deletions, or mixtures thereof", or "one, two, or three substitutions, deletions, additions, or mixtures thereof", it means respectively "one, two, three, four, five, six, seven, eight, nine, or ten modifications of amino acids selected from substitutions, additions, deletions, and mixtures thereof", "one, two, three, four, or five modifications of amino acids selected from substitutions, additions, deletions, or mixtures thereof", or "one, two, or three modifications of amino acids selected from substitutions, deletions, additions, or mixtures thereof". "One, two, three, four, or five substitutions, additions, deletions, or mixtures thereof" also means "one to five substitutions, additions, deletions, or mixtures thereof." "One, two, or three substitutions, additions, deletions, or mixtures thereof" also means "one to three substitutions, additions, deletions, or mixtures thereof."

[0052] In the peptide sequences disclosed herein, amino acids are represented by their one-letter or three-letter codes according to the following nomenclature: A: Ala, alanine; C: Cys, cysteine; D: Asp, aspartic acid; E: Glu, glutamic acid; F: Phe, phenylalanine; G: Gly, glycine; H: His, histidine; I: Ile, isoleucine; K: Lys, lysine; L: Leu, leucine; M: Met, methionine; N: Asn, asparagine; P: Pro, proline; Q: Gln, glutamine; R: Arg, arginine; S: Ser, serine; T: Thr, threonine; V: Val, valine; W: Trp, tryptophan, and Y: Tyr, tyrosine.

[0053] A conservative substitution is the replacement of a given amino acid residue with another residue having a side chain ("R group") with similar chemical properties (e.g., charge, bulk, and / or hydrophobicity). In general, conservative amino acid substitutions do not substantially change the functional properties of a protein. Conservative substitutions and the corresponding rules are well described in the state of the art. For example, conservative substitutions can be defined by substitutions within the group of amino acids reflected in the following table: [Table 1] [Table 2] [Table 3]

[0054] The peptides described herein can include both L- and D-isomers of the naturally occurring amino acids as well as other amino acids (e.g., naturally occurring amino acids, non-naturally occurring amino acids, amino acids not encoded by nucleic acid sequences, etc.) used in peptide chemistry to prepare synthetic analogs of peptides. Examples of naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, etc. Other amino acids include, for example, non-genetically encoded forms of amino acids, as well as conservative substitutions for L-amino acids. Naturally occurring non-genetically encoded amino acids include, for example, beta-alanine, 3-amino-propionic acid, 2,3-diaminopropionic acid, alpha-aminoisobutyric acid (Aib), 4-amino-butyric acid, N-methylglycine (sarcosine), hydroxyproline, ornithine (e.g., L-ornithine), citrulline, t-butylalanine, t-butylglycine, N-methylisoleucine, phenylglycine, cyclohexylalanine, norleucine (Nle), norvaline, 2-naphthylalanine, pyridylalanine, 3-benzothienylalanine, 4-chlorophenylalanine, 2-fluorophenylalanine, 5-chlorophenylalanine, 5-fluoro ... Examples of amino acids include phenylalanine, 3-fluorophenylalanine, 4-fluorophenylalanine, penicillamine, 1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid, beta-2-thienylalanine, methionine sulfoxide, L-homoarginine (Hoarg), N-acetyl-lysine, 2-aminobutyric acid, 2-aminobutyric acid, 2,4,-diaminobutyric acid (D- or L-), p-aminophenylalanine, N-methylvaline, homocysteine, homoserine (HoSer), cysteic acid, epsilon-aminohexanoic acid, delta-aminovaleric acid, or 2,3-diaminobutyric acid (D- or L-), etc. These amino acids are well known in the art of biochemistry / peptide chemistry.

[0055] The peptides described herein can include any L-amino acid, any D-amino acid, or a mixture of L- and D-amino acids, hi one embodiment, the peptides include only L-amino acids.

[0056] In addition to the substitutions described above, synthetic amino acids which provide similar side chain functionalities can also be introduced into the peptide. For example, aromatic amino acids can be D- or L-naphthylalanine, D- or L-phenylglycine, D- or L-2-thienylalanine, D- or L-1-, 2-, 3-, or 4-pyrenylalanine, D- or L-3-thienylalanine, D- or L-(2-pyridinyl)-alanine, D- or L-(3-pyridinyl)-alanine, D- or L-(2-pyrazinyl)-alanine, D- or L-p-cyano-phenylalanine, D- or L-(4-isopropyl)-phenylglycine, D- or L-(triphenylphosphine)-alan ... and D- or L-(fluoromethyl)-phenylglycine, D- or L-(trifluoromethyl)-phenylalanine, D- or L-p-fluorophenylalanine, D- or L-p-biphenylalanine, D- or L-p-methoxybiphenylalanine, D- or L-2-indole(alkyl)alanine, and D- or L-alkylalanine, wherein the alkyl groups are selected from the group consisting of substituted or unsubstituted methyl, ethyl, propyl, hexyl, butyl, pentyl, isopropyl, iso-butyl, and iso-pentyl.

[0057] Analogs of lysine that contain a primary amine in the side chain include ornithine, homolysine, 2,3-diaminopropionic acid (Dap), and 2,4-diaminobutyric acid (Dab).

[0058] Examples of histidine analogues include those described in Ikeda et al., Protein Eng. (2003) 16(9):699-706 (e.g., β-(1,2,3-triazol-4-yl)-DL-alanine), Stefanucci et al., Int. J. Mol. Sci. 2011, 12(5), 2853-2890 (aza-histidine, homo-histidine, β 2 -Homo-histidine, β 3 -homo-histidine, nor-histidine), N-imidazolylalanine, methylhistidine, dimethylhistidine, C-triazolylalanine, histidine methyl ester, histidinol, and histidinamide.

[0059] Analogs of tryptophan include, for example, naphthylalanine, indenylalanine, 2Me-Trp (or Mrp), 5-methyl-DL-tryptophan, azatryptophan (7-azatryptophan), hydroxytryptophan (5-hydroxytryptophan), fluorotryptophan, aminotryptophan, tryptamine, and desaminotryptophan, α-methyl-tryptophan; β-(3-benzothienyl)-D-alanine; β-(3-benzothienyl)-L-alanine; 1-methyl-tryptophan; 4-methyl-tryptophan; 5-benzyloxy-tryptophan; 5-bromo-tryptophan; 5-chloro-tryptophan; 5-fluoro-tryptophan; 5-hydroxy-tryptophan; 5-hydroxy-L-tryptophan; 5 -Methoxy-tryptophan; 5-methoxy-L-tryptophan; 5-methyl-tryptophan; 6-bromo-tryptophan; 6-chloro-d-tryptophan; 6-chloro-tryptophan; 6-fluoro-tryptophan; 6-methyl-tryptophan; 7-benzyloxy-tryptophan; 7-bromo-tryptophan; 7-methyl-tryptophan; D-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 6-methoxy-1,2,3,4-tetrahydronorharman-1-carboxylic acid; L-1,2,3,4-tetrahydro-norharman-3-carboxylic acid; 5-methoxy-2-methyl-tryptophan; 2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid (Tca), and 6-chloro-L-tryptophan.

[0060] Analogs of alanine, glycine, valine, and leucine include β-alanine, aminoisobutyric acid (α or β), methylalanine, t-butylalanine, aminohexanoic acid, alpha,beta-diaminopropionic acid, propargylglycine, beta-cyclohexyl-L-alanine, beta-hydroxyleucine, aminocaproic acid, and allylglycine.

[0061] If a sequence contains X / Z, it means that the sequence contains amino acid X or amino acid Z.

[0062] As used herein, the term "sequence identity" or "identity" refers to the exact amino acid-to-amino acid correspondence of two peptides. Percent identity can be determined by direct comparison of the sequence information between the two molecules by aligning the sequences, counting the number of exact matches between the two aligned sequences, dividing by the length of the shorter sequence, and multiplying the result by 100.

[0063] Sequence identity can be determined by alignment of two peptide sequences using a global or local alignment algorithm, depending on the length of the two sequences. Sequences of similar length are preferably aligned using a global alignment algorithm (e.g., Needleman Wunsch) that optimally aligns the sequences over their entire length, while sequences of substantially different lengths are preferably aligned using a local alignment algorithm (e.g., Smith Waterman). Sequences can then be called "substantially identical" or "essentially similar" if they share at least a certain minimum percentage of sequence identity (e.g., when optimally aligned by the programs GAP or BESTFIT using default parameters). GAP uses the Needleman and Wunsch global alignment algorithm to align two sequences over their entire length (full length), maximizing the number of matches and minimizing the number of gaps. Global alignment is preferably used to determine sequence identity when two sequences have similar lengths.

[0064] The term "retro form" or "retro analog" refers to a peptide that contains an amino acid sequence in the reverse orientation relative to a reference peptide. The term "retro-inverso form" or "retro-inverso analog" refers to a peptide that contains an amino acid sequence in the reverse orientation relative to a reference peptide, and also has the chirality of the amino acids inverted from L to D. The retro and retro-inverso forms according to the present disclosure retain the biological activity of the reference peptide, for example, having the ability to inhibit the interaction between neuropilin-1 and plexin-A1.

[0065] The term "pharmaceutically acceptable salts" refers to salts of the peptides described herein that are pharmacologically acceptable and substantially non-toxic to subjects to which they are administered. More specifically, these salts retain the biological effectiveness and properties of the peptides and are formed from suitable non-toxic organic or inorganic acids or bases.

[0066] For example, these salts include acid addition salts of the peptides described herein that are sufficiently basic to form such salts, such as acetate, adipate, alginate, lower alkanesulfonate such as methanesulfonate, trifluoromethanesulfonate or ethanesulfonate, arylsulfonate such as benzenesulfonate, 2-naphthalenesulfonate, or toluenesulfonate (also known as tosylate), ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphorate, camphorsulfonate, cinnamate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanoate, ethyl acetate ... Examples of the salts of these acids include dimethylformamide, dimethylsulfate, dimethylformamide ...

[0067] Additionally, acids generally considered suitable for forming pharma- ceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC).

[0068] Also, if the peptides described herein are sufficiently acidic, the salts of the present disclosure include base salts formed with inorganic or organic bases. Such salts include alkali metal salts such as sodium, lithium, and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; metal salts such as aluminum, iron, zinc, copper, nickel, and cobalt salts; inorganic amine salts such as ammonium salts or substituted ammonium salts such as trimethylammonium salts; and salts with organic bases (e.g., organic amines), such as chloroprocaine salts, dibenzylamine salts, dicyclohexylamine salts, diethanolamine salts, ethylamine salts (diethylamine salts and triethylamine salts). amine salts), ethylenediamine salts, glucosamine salts, guanidine salts, methylamine salts (including dimethylamine and trimethylamine salts), morpholine salts, N,N'-dibenzylethylenediamine salts, N-benzyl-phenethylamine salts, N-methylglucamine salts, phenylglycine alkyl ester salts, piperazine salts, piperidine salts, procaine salts, t-butylamine salts, tetramethylammonium salts, t-octylamine salts, tris-(2-hydroxyethyl)amine salts, and tris(hydroxymethyl)aminomethane salts.

[0069] Such salts can be formed very easily by those skilled in the art using standard techniques. In fact, chemical modification of pharmaceutical peptides into salts is a technique well known to medicinal chemists (see, for example, H. Ansel et.al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457). Salts of the peptides described herein can be formed, for example, by reacting the peptide with an amount of acid or base, such as an equivalent amount, in a medium in which the salt precipitates or in an aqueous medium, followed by lyophilization.

[0070] "Increased," "increase," or "enhance" is intended to refer to a measurement that is increased by at least 10, 20, 30, 40, 50, 60, 70, 80, or 90% compared to a measurement measured in the absence of the peptide tested under the same conditions. "Decreased" or "decrease" is intended to refer to a measurement that is decreased by at least 10, 20, 30, 40, 50, 60, 70, 80, or 90% compared to a measurement measured in the absence of the peptide tested under the same conditions.

[0071] As used herein, the terms "treatment," "treat," or "treating" refer to any action intended to improve the health of a patient, such as curing, alleviating, or delaying a disease or disorder. This includes prophylactic and therapeutic treatment.

[0072] As used herein, a "pharmaceutical composition" refers to a preparation of one or more active agents, such as peptides according to the present disclosure, with any other chemical components, such as physiologically suitable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of an active agent to an organism. The compositions of the present disclosure may be in a form suitable for any conventional route of administration or use. In one embodiment, a "composition" typically contemplates a combination of an active agent (e.g., a compound or composition) with a naturally occurring or non-naturally occurring carrier, an inert (e.g., detectable agent or label) or an active agent (e.g., adjuvants, diluents, binders, stabilizers, buffers, salts, lipophilic solvents, preservatives, adjuvants, etc.), and includes a pharma- ceutically acceptable carrier. An "acceptable vehicle" or "acceptable carrier" as referred to herein is any known compound or combination of these compounds known to those skilled in the art to be useful in formulating a pharmaceutical composition.

[0073] As used herein, "effective amount" or "therapeutically effective amount" refers to the amount of an active agent, alone or in combination with one or more other active agents, required to confer a therapeutic effect on a subject, e.g., the amount of active agent required to treat a target disease or disorder or to produce a desired effect. An "effective amount" will vary depending on the agent(s), the disease and its severity, the characteristics of the subject being treated, including age, health, size, sex and weight, the duration of treatment, the nature of concurrent treatment (if any), the particular route of administration, and similar factors within the knowledge and expertise of the medical practitioner. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. In general, it is preferred that the maximum dose of the individual components or combinations thereof is used, i.e., the highest safe dose according to sound medical judgment.

[0074] As used herein, the term "agent" refers to any substance or composition that has therapeutic or prophylactic properties against a disorder or disease.

[0075] The term "treatment" refers to any action intended to improve the well-being of a patient, such as the treatment, prevention, prophylaxis, and delay of a disease or symptoms of a disease. It refers to both curative and / or prophylactic treatment of a disease. Curative treatment is defined as treatment that results in a cure or treatment that alleviates, improves, and / or eliminates, relieves, and / or stabilizes a disease or symptoms of a disease, or the suffering caused directly or indirectly by a disease. Prophylactic treatment includes both treatment that results in the prevention of a disease and treatment that reduces and / or delays the progression and / or occurrence of a disease or the risk of its occurrence. In certain embodiments, such terms refer to the improvement or eradication of a disease, disorder, infection, or symptoms associated therewith. Treatment according to the present invention does not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that a person skilled in the art would recognize as having a potential benefit or therapeutic effect. Preferably, the term "treatment" refers to the application or administration of a composition comprising one or more active agents to a subject having a disorder / disease.

[0076] As used herein, the term "disorder" or "disease" refers to an improperly functioning organ, part, structure, or system of the body resulting from genetic or developmental abnormalities, infection, toxins, nutritional deficiencies or imbalances, toxicity, or the effects of unfavorable environmental factors. Preferably, these terms refer to a health impairment or disease, e.g., a disease that disrupts normal physical or mental functioning.

[0077] As used herein, the terms "subject," "individual," or "patient" are used interchangeably to refer to animals, preferably mammals, and even more preferably humans, including adults, children, and neonates.

[0078] As used herein, the term "isolated" indicates that the recited material (e.g., compound, peptide, antibody, polypeptide, nucleic acid, etc.) is substantially separated from or enriched relative to other materials in which it naturally occurs. In particular, an "isolated" peptide is one that has been identified, separated and / or recovered from a component of its natural environment.

[0079] Antagonistic peptides The present inventors have defined rules for designing antagonistic peptides of Plexin A1 as defined above.

[0080] In the peptide, the G / SXXXG motif or domain is responsible for the activity. The possibility of replacing the first Gly residue with a Ser residue is surprising and could not be predicted since the GXXXG motif is generally considered essential. The X residues can be any amino acid. In a particular embodiment, among the three X residues, no more than two residues can be charged amino acids. Preferably, none of the three X residues are charged. In a particular embodiment, they can be selected from among the aliphatic uncharged amino acids (Gly, Ala, Val, Leu, and Ile), more particularly in the group consisting of Gly, Val, Ile, and Leu.

[0081] Furthermore, another important aspect for the design of the peptide is the anchoring of the G / SXXXG motif in the membrane and the distance between the membrane surface and the G / SXXXG motif. Indeed, the location of the motif is important and an inappropriate positioning of the motif leads to a reduction or loss of the antagonist activity of the peptide.

[0082] More specifically, if a peptide has an N-terminal membrane anchor such as NterGp, it should preferably insert 5 amino acids between the N-terminal membrane anchor motif and the G / SXXXG motif. For example, plexA1-S1, which has 6 amino acids, and BROCK or EITRI, which have 4 and 2 amino acids, respectively, could not counteract the negative effect of Sema3A on oligodendrocyte migration (Figure 2D). On the contrary, peptides BALDR, FREYR, BRAGI, NJORD, ULLR, SKOLL, HATI, plexA1-S2, FJALAR, GALAR, IVALDI, and ALVISS all have 5 amino acids between the N-terminal membrane anchor motif and the G / SXXXG motif, and therefore counteract the negative effect of Sema3A on oligodendrocyte migration (Figures 2A-2D).

[0083] If the peptide has a C-terminal membrane anchor, preferably 13 amino acids should be inserted between the G / SXXXG motif and the C-terminal membrane anchor motif with positively charged amino acids such as CterGp, and preferably 11 amino acids should be inserted between the G / SXXXG motif and the C-terminal membrane anchor motif with negatively charged amino acids such as CterpolyD / E. More specifically, in the context of peptides with a C-terminal membrane anchor motif with negatively charged amino acids such as CterpolyD / E, peptides KVASIR, GERD, THRUD, RATI, GUNGNIR, and MIMMING, which have 11 amino acids between the G / SXXXG motif and the C-terminal membrane anchor motif, were all able to counteract the negative effect of Sema3A on oligodendrocyte migration compared to peptide DRAUPNIR, which has 12 amino acids between the G / SXXXG motif and the C-terminal membrane anchor motif.

[0084] Once these rules were determined, the inventors surprisingly observed that the peptides could be shortened to the motif G / SXXXG opposite the membrane anchor motif, this aspect allowing the design of shorter peptides.

[0085] For example, compared to peptide MTP-PlexA1, which is 29 amino acids in length, peptides BALDR, FREYR, BRAGI, NJORD, ULLR, and plexA1-S2 are only 18 amino acids in length, peptide FJALAR is only 17 amino acids in length, peptide GALAR is only 16 amino acids in length, peptide IVALDI is only 15 amino acids in length, and peptides SKOLL, HATI, and ALVISS are only 14 amino acids in length. Similarly, peptides KVASIR, GERD, THRUD, which contain 5 amino acids of the C-terminal polyE, are 26, 24, and 23 amino acids in length, respectively.

[0086] Thus, the present disclosure: - the motif of sequence G / SXXXG, -(X) linked directly to the C-terminus of the motif 11 -(CterpolyD / E) (i.e., G / SXXXG-(X) 11 -(CterpolyD / E), (NterGp)-(X)- directly linked at the N-terminus of the motif (i.e., (NterGp)-(X)-G / SXXXG), or -(X) directly linked at the C-terminus of the motif. 13 -(CterGp) (i.e., G / SXXXG-(X) 13 -(CterGp), and -X is any amino acid, but not more than two of X are charged amino acids, - a pharmaceutical composition comprising a peptide comprising, consisting essentially of, or consisting of: NterGp is ​​a group of 3-5 amino acids containing at least 2 charged amino acids, CterGp is ​​a group of 3-5 amino acids containing at least 3 positively charged amino acids, and CterpolyD / E is a group of 4-10 amino acids containing at least 2 negatively charged amino acids, the peptide inhibits the inhibitory effect of sema3A on migration and / or inhibits the interaction between neuropilin-1 and plexin A1 as measured by the methods detailed herein; The peptide does not have the sequence of MTP-PlexA1 (TLPAIVGIGGGGGLLLLVIVAVLIAYKRK, SEQ ID NO:1).

[0087] The present disclosure also provides a first domain of sequence G / S-X5-X6-X7-G, - (i) a second domain of formula I:-(X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36)-(CterpolyD / E) (i.e. G / SXXXG-(X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36)-(CterpolyD / E) directly linked at the C-terminus of the first domain, - (ii) a second domain of formula II: -(X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25)-(CterGp) (i.e. G / SXXXG-(X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25)-(CterGp) directly linked at the C-terminus of the first domain, or - (iii) a second domain of formula III: (NterGp)-(X8-X9-X10-X11-X12)- (i.e. (NterGp)-(X8-X9-X10-X11-X12)-G / SXXXG) directly linked at the N-terminus of the first domain, X5, X6, and X7 are any amino acid, preferably an uncharged amino acid, more preferably an aliphatic uncharged amino acid such as Gly, Ala, Val, Leu, and Ile; X8, X9, X10, X11, and X12 are any amino acid, preferably an uncharged amino acid, more preferably an aliphatic or non-polar uncharged amino acid; X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are any amino acids, and up to two amino acids among X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are charged amino acids; X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, and X36 are any amino acids, and up to two of X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, and X36 are charged amino acids; NterGp is ​​a membrane anchor motif containing charged amino acids, preferably a membrane anchor motif containing 3 to 5 amino acids including at least 2 charged amino acids; CterGp is ​​a membrane anchor motif containing positively charged amino acids, preferably a membrane anchor motif containing 3 to 5 amino acids including at least 3 positively charged amino acids; CterpolyD / E is a membrane anchor motif containing negatively charged amino acids, and is preferably a membrane anchor motif containing 4 to 10 amino acids including at least 2 negatively charged amino acids.

[0088] The peptides are associated with the functional property of inhibiting the inhibitory effect of Sema3A on migration and / or inhibiting the Neuropilin-1 / Plexin-A1 interaction. Preferably, the peptides fulfil both properties.

[0089] The interaction between neuropilin-1 / plexin-A1 and the inhibition of this interaction by peptide can be measured by any available method. More specifically, it can be measured by proximity ligation assay, as specifically detailed in the Examples section. The interaction between neuropilin-1 / plexin-A1 is inhibited by at least 10, 20, 30, 40, or 50% compared to the interaction in the absence of peptide.

[0090] The effect of peptide on the inhibitory effect of sema3A on migration can be measured by any available method. More specifically, it can be measured by cell migration assay, as detailed in the Example section. If the peptide can restore at least 80% of the migration of positive control, the peptide is considered to inhibit the inhibitory effect of sema3A on migration.

[0091] (NterGp), (CterGp) and (CterpolyD / E) are also referred to as membrane anchor motifs in the present disclosure. They are groups of amino acids that allow the peptide to be anchored to the surface of a membrane. A membrane anchor motif generally comprises one or several charged amino acids, for example at least two charged amino acids, for example 2-7 charged amino acids.

[0092] More specifically, NterGp can be a group of 3-5 amino acids including at least two charged amino acids. For example, NterGp can include one positively charged amino acid such as Glu or Asp and one negatively charged amino acid such as Lys or Arg, or two positively charged amino acids such as Glu or Asp, or two negatively charged amino acids such as Lys or Arg. In a very specific embodiment, NterGp includes or consists of a KGD motif. Optionally, NterGp can further include an aromatic amino acid. In a particular embodiment, NterGp has a sequence of four amino acids X1-X2-X3-X4, where X1 and X3 are two charged amino acids, preferably one positively charged and the other negatively charged, X2 is a small amino acid (e.g., G or A), and X4 is an aromatic amino acid (e.g., Y or W), and more preferably, NterGp is ​​KGDW (SEQ ID NO: 116). NterGp is ​​preferably selected to be located on the extracellular side of the membrane.

[0093] In one embodiment, X5 is an aliphatic residue, such as L or I, preferably L. In one embodiment, X6 is P or I, preferably P. In one embodiment, X7 is an aliphatic residue, such as A or V, preferably A. In one embodiment, X8 is an aliphatic residue, such as L or I, preferably I. In one embodiment, X9 is an aliphatic and / or small residue, such as T or V, preferably V. In a further embodiment, X8-X9-X10-X11-X12 is LPAIT (SEQ ID NO: 82), LPAIV (SEQ ID NO: 83), IPALV (SEQ ID NO: 84), LPALV (SEQ ID NO: 85), LIAIV (SEQ ID NO: 86), or LPVIV (SEQ ID NO: 87).

[0094] Optionally, the peptide comprises: (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGG (SEQ ID NO: 22), (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / V (SEQ ID NO: 23), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V (SEQ ID NO: 24), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E (SEQ ID NO: 25), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L (SEQ ID NO: 26), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L (SEQ ID NO: 27), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E (SEQ ID NO: 28), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V (SEQ ID NO: 29), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V-I (SEQ ID NO: 30), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V-I-V (SEQ ID NO: 31), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V-I-V-A / E (SEQ ID NO: 32), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V-I-V-A / E-V (SEQ ID NO: 33), (NterGp)-L / I-P / I-A / V-I / L-V / T-G / S-I / G / L-G / V-G-G-G / V-G / V-L / E-L-L-L / E-V-I-V-A / E-V-L (SEQ ID NO: 34), and (NterGp)-L / IP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI (SEQ ID NO: 35), In the formula, NterGp is ​​as defined above, for example, a group of 3 to 5 amino acids including at least 2 charged amino acids, This sequence may include one, two, or three substitutions (e.g., conservative substitutions) of one amino acid at any position except the bolded residues and / or the addition of one to six amino acids at the N-terminus and / or C-terminus.

[0095] In one embodiment, the peptide comprises a second domain of formula II, and the peptide comprises 5 or fewer amino acids at the N-terminus of the first domain. In one embodiment, the peptide comprises 4 or fewer amino acids at the N-terminus of the first domain. In one embodiment, the peptide comprises 3 or fewer amino acids at the N-terminus of the first domain. In one embodiment, the peptide comprises 2 or fewer amino acids at the N-terminus of the first domain. In one embodiment, the peptide comprises 1 amino acid at the N-terminus of the first domain. In one embodiment, the peptide does not comprise any amino acids at the N-terminus of the first domain.

[0096] In one embodiment, the peptide comprises a second domain of formula II and the peptide has a length of 28 amino acids or less, 27 amino acids or less, or 26 amino acids or less. In one embodiment, the peptide comprises a second domain of formula II and has a length of 23-26 amino acids.

[0097] In one embodiment, X13 is an aliphatic and / or small residue, such as G or V, preferably G. In one embodiment, X14 is an aliphatic and / or small residue, such as G or V, preferably G. In one embodiment, X15 is L or E, preferably L. In one embodiment, X16 is an aliphatic residue, preferably L. In one embodiment, X17 is an aliphatic residue, preferably L. In one embodiment, X18 is L or E, preferably L. In one embodiment, X19 is an aliphatic residue, preferably V. In one embodiment, X20 is an aliphatic residue, preferably I. In one embodiment, X21 is an aliphatic residue, preferably V. In one embodiment, X22 is A or E, preferably A. In one embodiment, X23 is an aliphatic residue, preferably V. In one embodiment, X24 is an aliphatic residue, preferably L. In one embodiment, X25 is an aliphatic residue, preferably L.

[0098] In a further embodiment, X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25 are GGLLLLVIVAVLI (sequence number 88).

[0099] More specifically, CterGp may be 3-5 amino acids including at least 3 positively charged amino acids. For example, CterGp may include KRK, KKR, RRK, or KRR. Optionally, it may further include aromatic amino acids and / or small amino acids. In a very specific embodiment, CterGp has a sequence of 5 amino acids X'1-X'2-X'3-X'4-X'5, where X'1 is a small amino acid (e.g., G or A), X'2 is an aromatic amino acid (e.g., Y or W), and X'3, X'4, and X'5 are basic amino acids, more preferably, CterGp is ​​a sequence selected from AYKRK (SEQ ID NO: 76), AYKKR (SEQ ID NO: 77), AYKRR (SEQ ID NO: 78), AYRRK (SEQ ID NO: 79), and AYRKK (SEQ ID NO: 80). CterGp is ​​preferably selected to be located on the intracellular side of the membrane.

[0100] Optionally, the peptide comprises: A / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 36), I / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 37), V / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO: 38), and G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EVLI-(CterGp) (SEQ ID NO:39), In the formula, CterGp is ​​as defined above, for example, a group of 3 to 5 amino acids including at least 3 positively charged amino acids, This sequence may contain one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the residues in bold.

[0101] More specifically, the CterpolyD / E comprises a cluster of negatively charged amino acids, in particular Glu. For example, it can be a group of 4-10 amino acids that comprises at least 2, at least 3, or at least 4 negatively charged amino acids, such as Glu, Asp, or a combination of Glu and Asp. The CterpolyD / E domain can comprise 2, 3, 4, or 5 Glu residues, 2, 3, 4, or 5 Asp residues, or a combination of 2, 3, 4, or 5 Glu and Asp residues. In certain embodiments, the CterpolyD / E comprises a -X"1-X"2-(Z) n wherein X"1 is a small amino acid (e.g., G or A), X"2 is an aromatic amino acid (e.g., Y or W), Z is D or E, and n is an integer from 2 to 10, preferably 4 to 6; or -X"1-X"1bis-X"2-(Z) nwhere X"1 and X"1bis are long aliphatic amino acids such as I or L, X"2 is an aromatic amino acid (e.g., Y or W), Z is D or E, and n is an integer between 2 and 10, preferably between 4 and 6. In a very particular embodiment, CterpolyD / E has the sequence -X"1-X"2-(E) n wherein X"1 is a small amino acid (e.g., G or A), X"2 is an aromatic amino acid (e.g., Y or W), and n is an integer from 2 to 10, preferably 4 to 6; or -X"1-X"1bis-X"2-(E) n where X"1 and X"1bis are long aliphatic amino acids such as I or L, X"2 is an aromatic amino acid (e.g., Y or W), and n is an integer between 2 and 10, preferably between 4 and 6. The CterpolyD / E is preferably selected to be located on the intracellular side of the membrane. In one embodiment, the CterpolyD / E comprises or consists of the sequence AYEEEEE (SEQ ID NO: 89) or LIYEEEEE (SEQ ID NO: 90).

[0102] The presence of the CterpolyD / E membrane anchor motif is a particularly preferred embodiment, since peptides containing such a membrane anchor motif are soluble and stable, allowing for a plasma half-life of more than 24 hours, and a biodistribution suitable for reaching target organs such as the brain and spinal cord.

[0103] In one embodiment, X26 is an aliphatic and / or small residue, e.g., G or V, preferably V. In one embodiment, X27 is an aliphatic and / or small residue, e.g., G or V, preferably G. In one embodiment, X28 is L or E, preferably L. In one embodiment, X29 is an aliphatic residue, preferably L. In one embodiment, X30 is an aliphatic residue, preferably L. In one embodiment, X31 is L or E, preferably L. In one embodiment, X32 is an aliphatic residue, preferably V. In one embodiment, X33 is an aliphatic residue, preferably I. In one embodiment, X34 is an aliphatic residue, preferably V. In one embodiment, X35 is A or E, preferably E. In one embodiment, X36 is an aliphatic residue, preferably V.

[0104] In one embodiment, X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36 are VGLLL E V I V EV (SEQ ID NO: 91), or a variant thereof, having one, two or three amino acid substitutions, such as conservative substitutions, excluding the underlined residues. In one embodiment, X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36 is V G L LL EVIVEV (SEQ ID NO: 91), or a variant thereof, having one, two, or three amino acid substitutions, such as conservative substitutions, excluding the underlined residues. In one embodiment, the variant has one or two amino acid substitutions, such as conservative substitutions. In one embodiment, the variant has one amino acid substitution, such as conservative substitution.

[0105] In one embodiment, X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36 is VGLLLEVIVEV (SEQ ID NO: 91), GGELLLVIVE (SEQ ID NO: 92), VVLLLEVIVEV (SEQ ID NO: 93), VGLLVEVIVEV (SEQ ID NO: 117), VGLVLEVIVEV (SEQ ID NO: 118).

[0106] In another embodiment, the peptide is G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 2), V / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 3), I / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 4), A / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 5), P / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 6), I / LP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO: 7), and TI / LP / IA / VI / LV / TG / SI / G / LG / VGGG / VG / VL / ELLL / EVIVA / EV-(CterpolyD / E) (SEQ ID NO:8), In the formula, CterpolyD / E is as defined above, for example, a group of 4 to 10 amino acids including at least 2 negatively charged amino acids; This sequence may include one, two, or three substitutions (e.g., conservative substitutions) of one amino acid at any position except the bolded residues and / or the addition of one to six amino acids at the N-terminus or C-terminus.

[0107] Optionally, the CterpolyD / E is according to any particular aspect or embodiment disclosed herein.

[0108] Optionally, the peptide has the amino acid sequence G / SI / G / LG / VGGG / VG / VL / ELLL / EVIVEVA / LI-Y-(E) n (SEQ ID NO: 9), or G / SLVGGG / VG / VL / ELL / VL / EVIVEVAY-(E / D) n (SEQ ID NO: 119), The sequence may further comprise one, two or three substitutions (e.g. conservative substitutions) of one amino acid at any position except the bolded residues and / or an addition of one to six amino acids at the N-terminus or C-terminus, where n is an integer from 2 to 10, preferably from 4 to 6. "A / LI" means that the peptide comprises either the amino acid A or two amino acids LI. Optionally, n is an integer selected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9 and 10, preferably 4, 5, 6, 7 and 8, e.g. 4, 5 or 6. Optionally, the peptide may comprise an addition of one to six amino acids at the N-terminus.

[0109] Optionally, the peptide comprises: AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10), TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11), G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12), TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13), TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14), and TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15), This sequence may further include one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues and one to six additional amino acids at the N- or C-terminus.

[0110] In a very particular embodiment, the peptide comprises AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10), TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11), G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12), TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13), TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14), and TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15), This sequence may further include one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues.

[0111] In a further very particular embodiment, the peptide comprises AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10), TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11), G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12), TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13), TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14), and TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15).

[0112] Optionally, the peptide comprises: AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), and TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21), This sequence may further include one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues and one to six additional amino acids at the N- or C-terminus.

[0113] In a very particular embodiment, the peptide comprises AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), and TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21), This sequence may further include one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues.

[0114] In a further very particular embodiment, the peptide comprises AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), and TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21).

[0115] Thus, the peptides of the present disclosure include: KGDWLPAIT-G / S-LVGGVGLL (SEQ ID NO: 40) KGDWLPAIV-G / S-IGGGVVLL (SEQ ID NO: 41) KGDWIPALV-G / S-GGGGGGLL (SEQ ID NO: 42) KGDWLPALV-G / S-IGGGVGLL (SEQ ID NO: 43) KGDWIPALV-G / S-LGGGGGLL (SEQ ID NO: 44) KGDWLIAIV-G / S-IGGG (SEQ ID NO: 45) KGDWLPVIV-G / S-IGGG (SEQ ID NO: 46) KGDWLPAIV-G / S-IGGGGGLL (SEQ ID NO: 47) KGDWLPAIV-G / S-IGGGGGL (SEQ ID NO: 48) KGDWLPAIV-G / S-IGGGGG (SEQ ID NO: 49) KGDWLPAIV-G / S-IGGGG (SEQ ID NO: 50) KGDWLPAIV-G / S-IGGG (SEQ ID NO:51) AIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 10) TG / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 11) G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 12) TLPAIV-G / S-IGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 13) TLPAIT-G / S-LVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 14) TLPAIV-G / S-IGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 15), This sequence may contain one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues and one to six amino acid additions at the N- or C-terminus.

[0116] In a very particular embodiment, the peptide comprises KGDWLPAITGLVGGVGLL (SEQ ID NO:52) KGDWLPAIVSIGGGVVLL (SEQ ID NO:53) KGDWIPALVGGGGGGGLL (SEQ ID NO:54) KGDWLPALVSIGGGVGLL (SEQ ID NO:55) KGDWIPALVGLGGGGGLL (SEQ ID NO:56) KGDWLIAIVGIGGG (SEQ ID NO:57) KGDWLPVIVGIGGG (SEQ ID NO:58) KGDWLPAIVGIGGGGGGLL (SEQ ID NO:59) KGDWLPAIVGIGGGGGL (SEQ ID NO: 60) KGDWLPAIVGIGGGGG (SEQ ID NO:61) KGDWLPAIVGIGGGG (SEQ ID NO:62) KGDWLPAIVGIGGG (SEQ ID NO: 63) AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16) TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17) GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18) TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19) TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20) TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO:21), This sequence may contain one, two, or three substitutions (eg, conservative substitutions) of one amino acid at any position except the bolded residues and one to six amino acid additions at the N- or C-terminus.

[0117] In particular embodiments, the peptide has a length of 35, 34, 33, 32, 31, or 30 amino acids or less, particularly 25 or 20 amino acids or less.

[0118] In certain aspects, the peptide is not found in nature. The peptide is a non-naturally occurring peptide. It can be purified, isolated, or recombinant. It can be produced by well-known peptide synthesis methods.

[0119] The N-terminus and C-terminus of the peptides disclosed herein may optionally be protected from proteolysis. In a preferred embodiment, the N-terminus may be in the form of an acetyl group and / or the C-terminus may be in the form of an amide group. In a preferred embodiment, the peptide has a free C-terminus.

[0120] Alternatively or additionally, internal modifications of the peptides that are resistant to proteolysis are also contemplated, for example, at least the -CONH-peptide bond is modified and replaced by a (CH2NH) reduced bond, (NHCO) retro-inverso bond, (CH2-O) methylene-oxy bond, (CH2-S) thiomethylene bond, (CH2CH2) carba bond, (CO-CH2) cetomethylene bond, (CHOH-CH2) hydroxyethylene bond), (NN) bond, E-arsenic bond, or -CH=CH- bond. In certain aspects, the peptide can be a retro analog (same sequence but in reverse orientation) of any peptide disclosed herein or a retro-inverso analog (same sequence but in reverse orientation, with the chirality of the amino acids inverted from L to D) of any peptide disclosed herein.

[0121] For example, peptides can be modified by acetylation, acylation, amidation, cross-linking, cyclization, disulfide bond formation, covalent cross-link formation, cysteine ​​formation, pyroglutamic acid formation, formylation, gamma-carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristylation, oxidation, phosphorylation, and the like.

[0122] Peptides according to the present disclosure may include one or more amino acids that are rare amino acids, particularly hydroxyproline, hydroxylysine, allohydroxylysine, 6-N-methyllysine, N-ethylglycine, N-methylglycine, N-ethylasparagine, allo-isoleucine, N-methylisoleucine, N-methylvaline, pyroglutamine, aminobutyric acid, or synthetic amino acids, particularly ornithine, norleucine, norvaline, and cyclohexyl-alanine.

[0123] Optionally, the peptide can be linked to an additional moiety, optionally via a linker or spacer (e.g., diglycine), for example, to form a conjugate. Optionally, the peptide can be part of a fusion protein. The additional moiety can be a homing peptide, a stabilizer, for example, PEG (polyethylene glycol), oligo-N-methoxy-ethylglycine (NMEG), albumin, albumin-binding protein or immunoglobulin Fc domain, an affinity tag, for example, an immune tag, biotin, a lectin, or a chelator, a purification tag such as a His-tag, an optical tag, a detectable label such as a chelating lanthamide, a fluorescent dye, or a FRET / BRET acceptor / donor, a targeting moiety, a secretion signal peptide, or a combination thereof. This additional moiety can, for example, allow specific targeting of cells, for example, cancer cells or oligodendrocytes. For example, the peptides can be combined with targeting moieties attached to nanocarriers as described in Nguyen et al. (J Control Release. (2019) 298:142-153) or Gamper et al. (2019, Cancers, 11, 1609). Thus, in certain aspects, the present disclosure relates to nanocarriers (e.g., nanoparticles) attached to the peptides of the present disclosure. Nanocarriers can be, for example, artificial nanocarriers or virus-derived nanoparticles (Steinmetz et al., Org. Biomol. Chem, 2007, 5, 2891-2902; Hashizume et al., Am. J. Pathol. 2000, 156, 1363-1380; Maeda et al, J. Control. Release, 2000, 65, 271-284; Allen et al., Science 2004, 303, 1818-1822; Cho et al., J. Vis. Exp. 2011, 52, e2808; Gamper et al, 2019, Cancers, 11, 1609). Peptides can be conjugated to moieties that target the peptide to the nervous system (e.g., the central nervous system (CNS)) and / or facilitate entry of the peptide across the blood-brain barrier into the CNS.

[0124] The additional moiety can be added to either the N-terminus or C-terminus of the peptide, or can be attached to the side chains of one or more of the amino acids of the peptide (e.g., to a lysine or cysteine ​​residue). Preferably, the additional moiety is fused or conjugated at the terminus bearing the membrane anchor motif.

[0125] In another aspect of the disclosure, the peptide is covalently attached to a polymer such as a polyethylene glycol (PEG) molecule, particularly 1500 MW or 4000 MW PEG, via the C-terminus or lysine residue of the peptide to reduce urinary clearance and the therapeutic dose used, and to increase half-life in plasma. In yet another embodiment, the half-life of the peptide is increased by including the peptide in a biodegradable and biocompatible polymeric material for drug delivery systems forming microspheres. Polymers and copolymers are, for example, poly(D,L-lactide-co-glycolide) (PLGA) (as shown in US2007 / 0184015).

[0126] The present disclosure also encompasses pharma- ceutically acceptable salts of the peptides according to the present disclosure.The pharma- ceutically acceptable salts may be, for example, salts of pharma- ceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, salts of pharma- ceutically acceptable organic acids such as acetic acid, citric acid, maleic acid, malic acid, succinic acid, ascorbic acid, and tartaric acid, salts of pharma- ceutically acceptable inorganic bases such as sodium, potassium, calcium, magnesium, or ammonium salts, or salts of organic bases containing salifiable nitrogen commonly used in pharmaceutical technology.Methods for preparing such salts are well known to those skilled in the art.

[0127] In certain aspects, the present disclosure relates to nucleic acids, such as mRNA molecules, that encode a peptide according to the present disclosure.

[0128] Pharmaceutical Compositions The present disclosure relates to pharmaceutical compositions comprising the peptides disclosed herein. The peptides are the active ingredients.

[0129] The pharmaceutical composition may further comprise a pharma- ceutically acceptable vehicle.

[0130] Pharmaceutical compositions containing the peptides are formulated according to standard pharmaceutical practice known by those skilled in the art (Lippincott Williams & Wilkins, 2000 and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 1988-1999, Marcel Dekker, New York).

[0131] For example, the composition can include emulsions, microemulsions, oil-in-water emulsions, anhydrous lipids, and other types of emulsions. The composition can further include one or more additives, such as diluents, excipients, stabilizers, and preservatives.

[0132] In one aspect, the present disclosure provides a stable formulation for parenteral injection of a pharmaceutical composition according to the present disclosure comprising a peptide or a salt thereof, the peptide being dried and then reconstituted in a solvent prior to use. The peptide (or each peptide, in embodiments where the formulation comprises two or more peptides) is mixed with a non-volatile buffer and dried to a dry peptide powder. Suitable buffers include, but are not limited to, glycine buffer, citrate buffer, phosphate buffer, and mixtures thereof. In one aspect, the buffer is a glycine buffer. In another aspect, the buffer is a mixture of citrate buffer and phosphate buffer. Alternatively, the pharmaceutical composition according to the present disclosure can be stored in an aqueous state. The solution may optionally contain further additives or excipients that must be compatible with the active drug substance, and if they are not removed during the lyophilization step, they must also be compatible with the route of administration.

[0133] For oral administration, the composition can be formulated into conventional oral dosage forms such as tablets, capsules, powders, granules, and liquid preparations such as syrups, elixirs, and concentrated drops. For example, non-toxic solid carriers or diluents can be used, including pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonates, and the like. For compressed tablets, binders (agents that give the powdered ingredients cohesiveness) are also required. For example, starch, gelatin, sugars such as lactose or dextrose, and natural or synthetic gums can be used as binders. Disintegrants are also required in tablets to facilitate the breakup of the tablet. Disintegrants include starch, clay, cellulose, algins, gums, and cross-linked polymers. In addition, lubricants and glidants are also included in tablets to prevent adhesion of tablet materials to surfaces during the manufacturing process and to improve the flow properties of powdered materials during manufacturing. Colloidal silicon dioxide is most commonly used as a glidant, and compounds such as talc or stearic acid are most commonly used as lubricants.

[0134] For transdermal administration, the compositions can be formulated into ointments, creams, or gels, and appropriate penetrants or detergents, such as dimethylsulfoxide, dimethylacetamide, and dimethylformamide, can be used to enhance penetration.

[0135] For transmucosal administration, nasal sprays, pulmonary inhalation, rectal or vaginal suppositories can be used. In one embodiment, the peptide, its salt, or composition of the present disclosure can be administered by the pulmonary route, using either a dry powder or liquid formulation administered using a pulmonary drug delivery device by methods known in the art. The active compound (peptide or its salt) can be incorporated into any of the known suppository bases by methods known in the art. Examples of such bases include cocoa butter, polyethylene glycol (carbowax), polyethylene sorbitan monostearate, and mixtures of these with other compatible materials to modify the melting point or dissolution rate.

[0136] The form of the pharmaceutical composition, the route of administration, the dosage and the regimen will naturally depend on the condition to be treated, the severity of the disease, the age, weight, and sex of the patient, etc.

[0137] The pharmaceutical or therapeutic compositions of the present disclosure can be formulated for topical, oral, parenteral, intranasal, intravenous, intramuscular, intratumoral, subcutaneous, or intraocular administration, etc. For parenteral administration, the compositions can be injected intradermally, subcutaneously, intramuscularly, or intravenously.

[0138] In one embodiment, a pharmaceutical or therapeutic composition of the disclosure is formulated for administration to the nervous system, e.g., the central nervous system (CNS), of a subject, such as by intracranial injection or injection into the cerebrospinal fluid (e.g., meningeal injection).

[0139] In certain embodiments, a pharmaceutical composition according to the present disclosure comprises 0.01 ng to 10 mg of a peptide of the present disclosure per kg of body weight. In one embodiment, a pharmaceutical composition according to the present disclosure comprises 0.1 ng to 1 g of a peptide of the present disclosure per kg of body weight.

[0140] therapeutic use The antagonistic peptides of the present disclosure may be useful in the treatment of any disease or disorder that can be prevented or treated by blocking the Plexin-A1 receptor, which is involved in the inhibitory signaling pathway Sema3A-Neuropilin1-Plexin-A1.

[0141] In one embodiment, the disclosure relates to a peptide, salt or composition as described herein for use in treating a demyelinating disease, use of a peptide, salt or composition as described herein for the manufacture of a medicament for treating a demyelinating disease, and a method for treating a myelinating disease in a subject, comprising administering to the subject a therapeutically effective amount of a peptide, salt or composition as described herein. The therapeutic effect of the peptide or salt may involve inhibition of the Sema3A inhibitory effect on oligodendrocyte migration and differentiation, thereby inhibiting demyelination and / or promoting remyelination.

[0142] The demyelinating disease may be an autoimmune demyelinating disease. In one embodiment, the demyelinating disease is multiple sclerosis, transverse myelitis, neuromyelitis optica (Devic's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Baro disease, Charcot-Marie-Tooth disease (CMT), HTLV-I associated myelopathy (HAM), globoid cell leukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, progressive multifocal leukoencephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis, and Guillain-Barre syndrome (GBS) or polyradiculopathy, including chronic inflammatory demyelinating polyradiculopathy. In a further embodiment, the demyelinating disease is an autoimmune or inflammatory demyelinating disease, such as multiple sclerosis. In a further embodiment, the multiple sclerosis is relapsing-remitting multiple sclerosis, hi another embodiment, the multiple sclerosis is progressive multiple sclerosis.

[0143] Furthermore, the peptide, its salt, or composition may be used in combination with other active ingredients used for the treatment of demyelinating diseases, or the pharmaceutical composition may further comprise such other active ingredients. For example, the peptide, its salt, or composition may be used in combination with active ingredients used for the treatment of multiple sclerosis, such as teriflunomide, interferon beta-la, interferon beta-lb, glatiramer acetate, fingolimod, mitoxantrone, or corticosteroids. In one embodiment, the peptide, its salt, or composition is used in combination with fingolimod.

[0144] The antagonistic peptide or salt thereof of the present disclosure may be useful for the treatment of cancer, more specifically, PlexinA1 / NRP1 expressing cancer. In fact, it may be used to block Sema3A-dependent cancer cell migration, thereby preventing or reducing the occurrence of metastasis. In addition, as shown in the examples, the peptide may exhibit antiangiogenic effects, thereby having therapeutic effects against cancer. (Albrecht et al, Frontiers in Oncology, 2020, 10, Article 519). Disruption of NRP1 / PlexA1 heterodimerization has previously been shown to block the pro-angiogenic activity of PlexinA1 and inhibit tumor growth (Jacob et al, 2016, Oncotarget, 7, 57851-57865).

[0145] Thus, the present disclosure relates to a peptide, a salt thereof or a composition as described herein for use in the treatment of cancer (Plexin A1 / NRP1 expressing cancer), a use of a peptide, a salt thereof or a composition as described herein for the manufacture of a medicament for the treatment of cancer (Plexin A1 / NRP1 expressing cancer), and a method for the treatment of cancer (Plexin A1 / NRP1 expressing cancer) in a subject, comprising administering to the subject a therapeutically effective amount of a peptide, a salt thereof or a composition as described herein. The therapeutic effect of the peptide may involve a reduction in the occurrence of metastasis, a reduction in tumor growth, and / or a reduction in angiogenesis, in particular by reducing the migration of cancer cells.

[0146] Cancer can be selected from hematopoietic cancer or solid tumor, preferably solid tumor.Examples of cancer include but are not limited to solid tumor and hematological cancer, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumor (including carcinoid tumor, gastrinoma and islet cell carcinoma), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancy. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma), lung cancer (including small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, and lung squamous cell carcinoma), peritoneal cancer, hepatocellular carcinoma, gastric cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, neuroblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, urethral cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial cancer, or uterine cancer, salivary gland cancer, kidney or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver cancer, anal cancer, penile cancer, testicular cancer, esophageal cancer, biliary tract tumor, and head and neck cancer. Optionally, the cancer may be a cancer that overexpresses Plexin A1, such as glioblastoma or gastric cancer. In preferred aspects, the cancer is a CNS cancer, such as pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, oligodendroglioma, ependymal tumor, medulloblastoma, pineal tumor, meningeal tumor, and germ cell tumor, especially glioblastoma.

[0147] Furthermore, the peptides, salts thereof, or compositions may be used in combination with, or the pharmaceutical compositions may further comprise, other active ingredients or therapies used to treat cancer. Examples of active ingredients or therapies used to treat cancer include chemotherapy (e.g., vinca alkaloids, agents that interfere with microtubule formation (e.g., colchicine and its derivatives), antiangiogenic agents, therapeutic antibodies, EGFR targeting agents, tyrosine kinase targeting agents (e.g., tyrosine kinase inhibitors), transition metal complexes, proteasome inhibitors, antimetabolites (e.g., nucleoside analogs), alkylating agents, platinum-based agents, anthracycline antibiotics, topoisomerase inhibitors, macrolides, retinoids (e.g., all-trans retinoic acid or its derivatives), geldane, and the like. These include namycin or its derivatives (17-AAG), surgery, immune checkpoint inhibitors or immunotherapeutics (e.g., PD-1 / PD-L1 inhibitors such as anti-PD-1 / PD-L1 antibodies, CTLA-4 inhibitors such as anti-CTLA-4 antibodies, B7-1 / B7-2 inhibitors such as anti-B7-1 / B7-2 antibodies, TIM3 inhibitors such as anti-TIM3 antibodies, BTLA inhibitors such as anti-BTLA antibodies, CD47 inhibitors such as anti-CD47 antibodies, GITR inhibitors such as anti-GITR antibodies), antibodies against tumor antigens (e.g., anti-CD19, anti-CD22 antibodies), cell-based therapies (e.g., CAR T cells, CAR NK cells), and cytokines such as IL-2, IL-7, IL-21, and IL-15.

[0148] In further aspects, the disclosure relates to a peptide, salt thereof, or composition as described herein for use in treating a disease or disorder associated with abnormal angiogenesis, use of a peptide, salt thereof, or composition as described herein for the manufacture of a medicament for treating a disease or disorder associated with abnormal angiogenesis, and a method for treating a disease or disorder associated with abnormal angiogenesis in a subject, comprising administering to the subject a therapeutically effective amount of a peptide, salt thereof, or composition as described herein. The therapeutic effect of the peptide may involve inhibition of angiogenesis.

[0149] As used herein, the term "disease or disorder associated with abnormal angiogenesis" refers to a disease caused by the abnormal regulation of the process that mediates angiogenesis. In particular, the disease associated with abnormal angiogenesis refers to hemangioma, psoriasis, Kaposi's sarcoma, endometriosis, atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet age-related macular degeneration (AMD), choroidal neovascularization, ocular or retinal neovascularization, and diabetic retinopathy. In a particular embodiment, the disease or disorder associated with abnormal angiogenesis is selected from among tumor growth and metastasis, hemangioma, psoriasis, Kaposi's sarcoma, ocular neovascularization, rheumatoid arthritis, endometriosis, or atherosclerosis.

[0150] Inhibition of Plexin A1 and / or NRP1 has also been shown to inhibit immune cell infiltration, reduce inflammation, and be suitable for the treatment of inflammatory and autoimmune diseases (see, for example, EP 2 497 498 A1 and WO2016 / 033699). Thus, in another aspect, the present disclosure relates to a peptide, a salt thereof or a composition as described herein for use in treating an inflammatory or autoimmune disease or condition, a use of a peptide, a salt thereof or a composition as described herein for the manufacture of a medicament for treating an inflammatory or autoimmune disease or condition, and a method for treating an inflammatory or autoimmune disease or condition in a subject, comprising administering to the subject a therapeutically effective amount of a peptide, a salt thereof or a composition as described herein. The therapeutic effect of the peptide may involve inhibition of immune cell infiltration and / or inflammation.

[0151] In one embodiment, the inflammatory or autoimmune disease or condition is anemia (aplastic anemia, hemolytic anemia, autoimmune hemolytic anemia, idiopathic thrombocytopenia), autoimmune hepatitis, iridocyclitis, scleritis, uveitis, orchitis, idiopathic thrombocytopenic purpura, Graves' disease, Hashimoto's thyroiditis, juvenile onset diabetes mellitus, inflammatory bowel disease, Addison's disease, demyelinating encephalitis, multiple sclerosis, septic shock, arthritis, inflammatory bowel disease (IBD), skin inflammation, diabetes, uveitis, diabetic retinopathy, age-related macular degeneration (AMD), retinopathy of prematurity, amyotrophic lateral sclerosis (ALS), age-related cognitive decline / Alzheimer's disease, stroke, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, or psoriasis.

[0152] Further aspects and advantages of the present invention are disclosed in the following experimental section, which should be considered as illustrative and not limiting the scope of this application. Several references are cited herein, and each of these cited references is incorporated herein by reference. EXAMPLES

[0153] Example 1: Proximity ligation assay To demonstrate the ability of membrane targeting peptides (MTPs) to disrupt heterodimerization of neuropilin-1 and plexin-A1, cells were seeded overnight on Lab-Tek Permanox slides and then treated with the appropriate peptides for 1 h. After fixation with 1% PFA for 10 min, slices were permeabilized with PBS / 0.1% Triton® X-100. Primary antibodies (NRP1 from Evitria, 1:500, and plexin-A1 from Abcam, ab23391, 1:200) were incubated overnight at 4°C in PBS. A proximity ligation assay, which allows the visualization of receptor dimers (neuropilin-1 / plexin-A1), was then performed using the "detect orange" kit (Sigma) according to the manufacturer's recommendations. Quantification of the interaction (fluorescent dots on the cell surface) was performed using ImageJ software.

[0154] The results show that GUNGNIR caused a -60% reduction in the number of NRP1 / Plexin A1 interactions, MIMMING caused a similar -51% reduction, while the control inactive peptide SURTR had no effect on the number of NRP1 / Plexin A1 dimers (Table 1). [Table 4]

[0155] As can be seen in Figures 1A and 1B, both GUNGNIR and MIMMING showed dose-dependent effects on the number of NRP1 / Plexin A1 interactions, with IC 50 were 74 pM and 17 nM, respectively.

[0156] While demonstrating the ability of MTP to disrupt NRP1 / Plexin A1 dimers, these results indicate that MTP exhibits sequence-dependent blocking of NRP1 / Plexin A1 receptor dimerization.

[0157] Example 2: Cell Migration Assay To demonstrate that MTP rescues the negative effect of Sema3A on the migration of the oligodendrocyte cell line Oli-neu, a cell migration assay was performed using an xCELLigence RTCA DP Instrument (ACEA Biosciences Inc.) and Transwell CIM-Plate 16 (8 μm pore size filter ACEA Biosciences, Inc.). Cells were preincubated with vehicle alone or MTP for 1 h. 1 × 10 5 Cells were seeded in the upper chamber with 150 μl of medium. The lower wells contained 160 μl of medium supplemented with 2% fetal bovine serum for chemical attraction and 20 ng / ml of Sema3A (recombinant mouse semaphorin 3A Fc chimeric protein carrier-free ref: 5926-S3 / CF; RnD systems) for repulsion. Analysis was performed after 8 hours of migration according to the manufacturer's instructions. Data are expressed as a percentage of migration of the positive control, i.e. Oli-neu with 2% serum and without Sema3A.

[0158] The results show that MTPs with different sequences rescue the control migration, thereby counteracting the Sema3A inhibitory effect (Figure 2A). Peptides with a G / SXXXG motif rescued migration in contrast to peptides in which the G / SXXXG motif was replaced by GXXXS or SXXXA (n=3, except for SKIRNIR, where n=1, Figure 2B). Peptides with deletions next to the GXXXG motif on the N- or C-terminal side rescued migration, but deletion of one G of the motif abolished peptide activity (Figure 2C). N-terminal truncation between (NterGp) and the GXXXG motif impairs peptide efficiency (n=3, except for BROKK and EITRI, where n=1, Figure 2D). Among other peptide sequences with (CterpolyD / E), RATI, GUNGNIR, and MIMMING rescued migration (n=3, Figure 2E). Thus, in this functional assay, GUNGNIR showed an IC of 1.2 nM. 50 (FIG. 2F). Finally, similar activity was observed for MTP-PlexA1 (SEQ ID NO: 1) and its retro analog ODIN (SEQ ID NO: 81) (FIG. 2G), providing evidence that the retro analogs of the peptides described herein exhibit similar biological activity as their corresponding retro analogs of the peptides.

[0159] Overall, these results indicate that MTP exhibits sequence-dependent rescue of the Sema3A inhibitory effect on oligodendrocyte migration, which depends on the minimal G / SXXXG motif (Figure 2A-C) and favorable distance from (N-terGp) (Figure 2D) and (C-terGp) (Figure 2E).

[0160] Example 3: Solubility Studies The solubility of MTP was tested in either phosphate buffered saline (PBS) or a mixture of PBS and lithium dodecyl sulfate (LDS), and the results are reported in Table 1. [Table 5]

[0161] Failure to detect the concentration by absorbance measurement indicates that the peptide without CterpolyD / E is not soluble in 100% PBS and requires additional vehicle such as LDS, whereas the peptide with CterpolyD / E is soluble in 100% PBS. This was more specifically exemplified by MTP-PlexA1 and DRAUPNIR, which contain the same sequence except for the C-terminal domain (MTP-PlexA1:TLPAIVGIGGGGGLLLLVIVAVLIAY KRK (SEQ ID NO:1), DRAUPNIR:TLPAIVGIGGGGGLLLEVIVEVLIAY EEEEE (Sequence number 72).

[0162] Example 4: Biodistribution Studies To address the bioavailability of MTP in vivo, three CD1 8-week-old female mice were subjected to intraperitoneal injection of GUNGNIR-cy5 at doses of 1, 10, 100, and 1000 μg / kg in a dose-response experiment. Fluorescence was detected in gas-anesthetized animals thanks to a Bioimager (Nightowl LB-983, Berthold) as previously described (Destouches et al. 2011, Cancer Res., 71(9):3296-305; Page et al. 2011, Ann Rheum Dis.; 70(5):837-43). After the mice were sacrificed at 4 hours, fluorescence was measured for each organ. Acquisitions were made during a 10-second period for analysis, and the surface and intensity of fluorescence were measured using the Nightowl program. As shown in Figure 3, GUGNIR shows a large biodistribution profile that includes the elimination organs (liver and kidney) in a dose-dependent manner. The brain and spinal cord contents were similar to those measured in peripheral organs (heart, lungs), indicating efficient crossing of the blood-brain barrier. Therefore, GUNGNIR can reach the central nervous system and may be suitable for the treatment of neurological disorders such as neurodegenerative diseases.

[0163] Example 5: Induction and evaluation of active experimental autoimmune encephalomyelitis (EAE) To evaluate the therapeutic potential of GUNGNIR, in vivo administration in mice suffering from induced demyelination was performed. Mice were purchased from Janvier (8-9 weeks old when immunization was performed). All mice were fed in a controlled environment (25°C) with free access to food and water and housed in a 12h / 12h day / night cycle. Mice were housed in pairs (equal number of each treatment per cage) and cages were changed weekly. All operations were performed in the morning. SJL / JRj female mice were used for the EAE protocol with PLP immunization and C57BL / 6 female mice were used for EAE MOG immunization. After one week of acclimatization, mice were immunized with a kit developed by Hooke laboratories (EK-2120 or EK-2110) during a brief anesthesia with isoflurane. EAE PLP: PLP in CFA (complete Freund's adjuvant) 139-151 An emulsion of the fragment (HSLGKWLGHPDKF, SEQ ID NO: 74) was administered as four subcutaneous injections of 50 μl according to the manufacturer's protocol. Mice received 0.4 μg of pertussis toxin intraperitoneally on the day of immunization. EAE MOG: MOG in CFA (complete Freund's adjuvant) 35-55 An emulsion of the fragment (MEVGWYRSPFSRVVHLYRNGK, SEQ ID NO: 75) was administered as two 100 μl subcutaneous injections according to the manufacturer's protocol. Mice received 0.4 μg pertussis toxin intraperitoneally on the day of immunization and a second dose on day 1.

[0164] Peptide treatment was started 1 day after immunization (EAE PLP) or 3 days after immunization (EAE MOG) depending on the intraperitoneal administration of 100 μl of PBS or GUNGNIR diluted in PBS (10 μg / kg) 3 times a week (Monday / Wednesday / Friday). Clinical scores were evaluated daily from day 6 after immunization and systematically performed before peptide injection. EAE was clinically evaluated daily in a blinded manner according to the following criteria: 0, no disease; 1, tail hypotension; 2, righting reflex and partial hind limb paresthesia; 3, complete hind limb paralysis; 4, hind limb paralysis with partial forelimb paralysis; and 5, moribund or dead.

[0165] The analysis showed a significant reduction in clinical scores when animals received 10 μg / kg GUNGNIR in PLP (mimicking relapsing-remitting multiple sclerosis) (Figure 4A). Similarly, a significant reduction in clinical scores in mice receiving GUNGNIR was observed in the EAE MOG model (mimicking progressive multiple sclerosis) (Figure 4B).

[0166] Overall, these results indicate that GUNGNIR reduces the severity of EAE in the PLP and MOG models.

[0167] Example 6: Angiogenesis Assay To address the clinical potential of MTP targeting Plexin-A1 in angiogenesis-related pathologies (including cancer and other diseases that lead to abnormal blood vessel formation), an angiogenesis assay was performed to measure the ability of the peptide to block angiogenesis. Human umbilical vein endothelial cells (HUVECs) were cultured at 37°C under 5% CO2 in endothelial cell culture medium (PromoCell, Heidelberg, Germany) supplemented with endothelial cell growth supplement (ECGS, 4 μL / mL), fetal calf serum (FCS, 20 μL / mL, Thermo Fisher Scientific), human epidermal growth factor (hEGF, 0.1 ng / mL), and human basic fibroblast growth factor (hbFGF, 1 ng / mL, Thermo Fisher Scientific). For the assay, plates (15μ slide angiogenesis, Ibidi plates, Biovalley, Nanterre, France) were coated with Matrigel (Merck-Millipore, Billerica, MA, USA) for 1 h at 37 °C. Subsequently, 5000 HUVECs in culture medium (50 μL) with peptide treatment were added to each well for 3 h (37 °C, 5% CO2). Cells in each well were imaged by DIC microscope (Leitz DM RB, Leica, Nanterre, France) and the number of closed tubes was counted for 3–5 wells per condition.

[0168] The results show that GUNGNIR and RATI have the ability to inhibit angiogenesis, whereas the inactive control peptide HODR showed no effect in this assay (Table 2). Several analogs of GUNGNIR were also shown to inhibit angiogenesis (Figure 5A). [Table 6]

[0169] Example 7: MTT Assay The toxicity of MTP was evaluated using the MTT assay. HUVEC cells were used for this assay at a concentration of 20,000 cells in 100 μL per well (in a 96-well plate). After 24 h of incubation at 37° C., peptides or their vehicle (PBS) were added at 10 -7 M. After 4 hours of incubation at 37° C., the medium was removed and replaced with MTT (stock concentration of 5 mg / mL) diluted 1 / 20 with Gey's Balanced Salt Solution (GBSS). After 4 hours of incubation at 37° C., the cells were lysed with 100 μL of isopropanol per well and the plates were analyzed spectrophotometrically at a wavelength of 570 nm.

[0170] The results are reported in FIG. 5B.

[0171] Example 8: Remyelination Assay Experimental design and conditions We next evaluated whether GUNGNIR could induce CNS remyelination and motor function recovery after demyelination induced by the copper chelator cuprizone in a mouse model. Oral intoxication with cuprizone induces oligodendrocyte apoptosis within a few days, closely followed by activation of innate immune cells in the brain, i.e., astrocytes and microglia, ultimately leading to demyelination of different white and grey matter brain regions.

[0172] The following treatment groups were included in the study: (a) Control (n=5) (b) Cuprizone for 5 weeks (to indicate demyelination, n = 10). (c) Cuprizone for 5 weeks followed by vehicle treatment for 6 consecutive days (n=10). (d) Cuprizone for 5 weeks followed by treatment with GUNGNIR (10 μg / kg) for 6 consecutive days (n=10). (e) Cuprizone for 5 weeks followed by treatment with GUNGNIR (100 μg / kg) for 6 consecutive days (n=10). (f) Cuprizone for 5 weeks followed by vehicle treatment for 11 consecutive days (n=10). (g) Cuprizone for 5 weeks followed by treatment with GUNGNIR (10 μg / kg) for 11 consecutive days (n=10). (h) Cuprizone for 5 weeks followed by treatment with GUNGNIR (100 μg / kg) for 11 consecutive days (n=10).

[0173] Acute demyelination was induced by intoxication of approximately 8-week-old (19-21 g) male mice with a diet containing 0.25% cuprizone [bis(cyclohexanone) oxaldihydrazone; Sigma-Aldrich Inc., St Louis, MO, USA] mixed into ground standard rodent chow for 5 consecutive weeks. Treatment with vehicle or GUNGNIR compounds (10 and 100 μg / kg) was performed by intraperitoneal (ip) injection treatment 3 times / week from 3 weeks after cuprizone administration (i.e., at the beginning of week 4) until the end of the experiment (i.e., after 6 or 11 days of remyelination).

[0174] Assessment of myelination was performed by immunohistochemistry and histochemistry. The myelin marker proteolipid protein (PLP), the major myelin protein in the central nervous system, was visualized by immunohistochemistry using the following antibody: Bio-Rad catalog number MCA839G, RRID: AB_2237198, 1:5000. Intact and damaged myelin was further visualized using Luxol Fast Blue (LFB) / Periodic Acid-Shiff (PAS) histochemical staining.

[0175] High-speed abdominal planar videography was used to assess motor function (gait analysis). Gait analysis was performed once before the end of the experiment in all experimental mice using a DigiGait™ imaging system with DigiGait™ 15.0 analysis software (Mouse Specifics, Inc.; Quincy MA) as previously described (Zhan et al., 2019).

[0176] Differences between individual experimental groups were statistically tested with appropriate multiple comparisons. In the gait analysis groups, d-e (i.e., 6-day remyelination) and f-h (i.e., 11-day remyelination) were separately tested for normal data distribution by using the Kolmogorov-Smirnov test. Then, for parametric data, a regular one-way ANOVA followed by Dunnett's multiple comparison test was performed, whereas for non-parametric data, a Kruskal-Wallis test followed by Dunn's multiple comparison test was performed. In all cases, multiple comparisons were performed by comparing the vehicle with the low- and high-dose groups.

[0177] For histological LFB / PAS-related data, non-parametric Kruskal-Wallis test followed by Dunns' multiple comparison test was performed separately for 6-day and 11-day remyelination. For immunohistological anti-PLP-related data, parametric ordinary one-way ANOVA followed by Dunnett's multiple comparison test was performed separately for 6-day and 11-day remyelination. All results are presented as mean ± SEM.

[0178] Weights between groups were tested using either ordinary one-way analysis of variance followed by Dunnett's multiple comparison test or the non-parametric Kruskal-Wallis test followed by Dunn's multiple comparison test.

[0179] result A. Gait analysis Up to 41 different gait metrics were assessed separately for each paw (i.e., left front paw, right front paw, left hind paw, right hind paw) by DigiGait™ imaging software. As summarized in Figure 6A-B, 6 days after remyelination, 1 gait parameter was significantly different between the vehicle and 10 μg / kg groups, and 1 gait parameter was significantly different between the vehicle and 100 μg / kg groups. As summarized in Figure 7A-E, 11 days after remyelination, 1 gait parameter was significantly different between the vehicle and 10 μg / kg groups, and 4 gait parameters were significantly different between the vehicle and 100 μg / kg groups.

[0180] B. Histology As shown in FIG. 8A, high anti-PLP staining intensity was found in control mice, with a significant decrease in 5-week cuprizone-treated mice (5 weeks). Staining intensity increased during the 6 and 11-day remyelination periods. At day 11, anti-PLP staining intensity was trendwise higher in 100 μg / kg compared to the vehicle group (p=0.071). The same staining pattern was observed in LFB-treated sections. As shown in FIG. 8B, high LFB staining intensity was found in control mice, with a significant decrease in 5-week cuprizone-intoxicated mice (5 weeks). Again, staining intensity recovered, but to a slower extent. Of note, LFB staining intensity at day 11 was significantly higher in 100 μg / kg compared to the vehicle group (40±5.8 in 100 μg / kg-treated mice compared to 22±3.3 in vehicle).

[0181] C. Weight Body weight was evaluated at different time points of the experiment. As shown in Figure 9A, there was no significant difference in the body weight of mice between the Cuprizone-treated groups before the start of Cuprizone treatment (i.e., day 21). One-way ANOVA followed by Dunnett's multiple comparison test (comparing the 6-day group and the 11-day group separately with each other). Comparatively, as shown in Figures 9B and 9C, no differences were observed at the beginning and end of the experiment for the individual groups treated with GUNGNIR. As shown in Figures 9D-G, the percentage loss of body weight at weeks 3 and 5 was significantly less in some of the GUNGNIR-treated groups compared to the vehicle-treated group.

[0182] Example 9: Combination therapy in a relapsing-remitting experimental autoimmune encephalomyelitis (EAE-PLP) model Experimental design and conditions The effects of GUNGNIR, Fingolimod, and the combination of Fingolimod and GUNGNIR were studied in a relapsing-remitting experimental autoimmune encephalomyelitis (EAE-PLP) mouse model. Treatment was administered intraperitoneally (IP) for GUNGNIR at 10 μg / kg in PBS three times a week, and for Fingolimod at 1 mg / kg IP daily from D12 (peak). Results were compared to a control group treated with vehicle (PBS, then PBS with 25% ethanol from D12) three times a week. Treatment was started on D2 after induction (D1) for GUNGNIR, and on D12 after induction for Fingolimod. Treatment was administered for 5 weeks. Scores were assessed daily from D7, and body weight was also evaluated.

[0183] Mice were anesthetized with 3% isoflurane induced with Hooke Kit™ [ser140]-PLP139-151 / CFA Emulsion PTX (Cat. No. EK-2120) according to the manufacturer's instructions. Briefly, mice were subcutaneously injected with 0.05 ml of PLP emulsion (meaning a total of 0.2 ml per mouse) in the left and right hips and left and right shoulders, respectively. Then, a solution of pertussis toxin (PTX) was injected intraperitoneally at 30 ng per mouse according to the concentration of the pertussis batch.

[0184] result During the experimental period, all mice showed a weight loss that did not reach the ethical cutoff point (-20%). All groups show a similar course of the disease, thus allowing a comparison (Figure 10). None of the treatments affected the peak intensity, which was similar in all experimental groups (Figure 11A). However, the three treatment groups showed a significant recovery compared to the control group (Figure 11A). The amplitude of the effect was similar for all treatments, but the GUNGNIR + Fingolimod treatment (combination) showed a better efficacy over time (Figure 11A). From D24, while fingolimod or GUGNIR alone showed intermediate scoring, the combination of GUNGNIR + Fingolimod showed an almost complete protective effect with a score not reaching 1 (Figure 11A). Analysis of the individual scores confirmed that the combination of GUNGNIR + Fingolimod provided the most efficient therapeutic effect and had less variability, as seen for the standalone condition (Figures 11B-F).

[0185] Example 10: Combination therapy in a progressive experimental autoimmune encephalomyelitis (EAE-MOG) model Experimental design and conditions The effects of GUNGNIR, Fingolimod, and the combination of Fingolimod and GUNGNIR were studied in a progressive experimental autoimmune encephalomyelitis (EAE-MOG) mouse model. Treatment was administered intraperitoneally (IP) for GUNGNIR at 10 μg / kg in PBS three times a week, and for Fingolimod at 1 mg / kg IP daily from D14. Results were compared to a control group treated with vehicle (PBS, then PBS with 25% ethanol from D14) three times a week. Treatment was started on D3 after induction (D1) for GUNGNIR, and on D14 after induction for Fingolimod. Treatment was administered for 5 weeks. Scores were assessed daily from D7, and body weight was also evaluated.

[0186] Mice were anesthetized with 3% isoflurane induced with Hooke's Kit™ MOG35-55 / CFA Emulsion PTX (Cat. No. EK-2110) according to the manufacturer's instructions. Briefly, mice were injected subcutaneously with 0.1 ml of MOG emulsion on the upper back and 0.1 ml of emulsion on the lower back. Two hours later, a solution of pertussis toxin (PTX) was injected intraperitoneally at 80 ng per mouse. A second IP injection of the same amount of PTX was given 24 hours later.

[0187] result During the experimental period, all mice showed a weight loss that did not reach the ethical limit (-20%). All groups showed a similar course of the disease, allowing comparison (Figure 12).

[0188] In this experiment, the control group reached the peak of the disease at D17. All animals in the control group showed persistence of the disease over the remaining 13 days of the protocol (Figure 13A). Surprisingly, all treated animals showed a reduction in disease severity from D15. The therapeutic effect was stronger for the combination of GUNGNIR + Fingolimod with a score of less than 1 from D22 until the last day of the study. Fingolimod or GUGNIR alone showed intermediate scoring. Analysis of the individual scores confirmed that the combination of GUNGNIR + Fingolimod showed the best therapeutic effect (Figures 13B-O). Interestingly, this group also showed smaller inter-individual variability.

[0189] Peptide sequence BALDR KGDWLPAITGLVGGVGLL (SEQ ID NO:52) FREYR KGDWLPAIVSIGGGVVLL (SEQ ID NO:53) BRAGI KGDWIPALVGGGGGGGLL (SEQ ID NO:54) NJORD KGDWLPALVSIGGGVGLL (SEQ ID NO:55) ULLR KGDWIPALVGLGGGGGLL (SEQ ID NO:56) SKOLL KGDWLIAIVGIGGG (SEQ ID NO:57) HATI KGDWLPVIVGIGGG (SEQ ID NO: 58) plexA1-S2 KGDWLPAIVGIGGGGGLL (SEQ ID NO: 59) FJALAR KGDWLPAIVGIGGGGGL (SEQ ID NO: 60) GALAR KGDWLPAIVGIGGGGG (SEQ ID NO: 61) IVALDI KGDWLPAIVGIGGGG (SEQ ID NO:62) ALVISS KGDWLPAIVGIGGG (SEQ ID NO: 63) KVASIR AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16) GERD TGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 17) THRUD GLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 18) RATI TLPAIVGIGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19) GUNGNIR TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20) MIMMING TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21) SURTR TLPVIGVIVLVGSAVLELIAEGVYEEEEE (SEQ ID NO: 64), a scramble of MIMMING HODR TLPAIGVITLVGLGVLELVAEGVYEEEEE (SEQ ID NO: 65), a scramble of GUNGNIR GULLVEIG KGDWLPAIVSIGGAVVLL (SEQ ID NO: 66) SKIRNIR KGDWLPAIVGIGGSVVLL (SEQ ID NO: 67) RATATOSK KGDWLPAIVGIGG (SEQ ID NO: 68) plexA1-S1 KGDWTLPAIVGIGGGGGLL (SEQ ID NO: 69) BROKK KGDWPAIVGIGGGGGLL (SEQ ID NO: 70) EITRI KGDWIVGIGGGGGLL (SEQ ID NO: 71) DRAUPNIR TLPAIVGIGGGGGLLLEVIVEVLIAYEEEEE (SEQ ID NO: 72) MJOLLNIR TLPAITGLVGGVGLLVEVAVEIAYEEEEE (SEQ ID NO: 73) G1a TLPAITGVVVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 94) G1b TLPAITGLVVGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 95) G2a TLPAITGLVGGVGLLLEVIVEVAYEEEE (SEQ ID NO: 96) G2b TLPAITGLVGGVGLLLEVIVEVAYEEE (SEQ ID NO: 97) G2c TLPAITGLVGGVGLLLEVIVEVAYEE (SEQ ID NO: 98) G2d TLPAITGLVGGVGLLLEVIVEVAYDDDDD (SEQ ID NO: 99) G3a TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100) G3b TLPAITGLVGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101) G3c TLPAITGLVGGVGLLLVVIVEVAYEEEEE (SEQ ID NO: 102) G3d TLPAITGLVGGVGLLLEVVVEVAYEEEEE (SEQ ID NO: 103) G3e TLPAITGLVGGVGLLLEVIVVVAYEEEEE (SEQ ID NO: 104) G3f TLPAITGLVGGVGLLLEVIVEVVYEEEEE (SEQ ID NO: 105) Pep1 d E d E d E d E d E d Y d A d V d E d V d I d V d E d L d Ld LG d VGG d V d LG d T d I d A d P d L d T (SEQ ID NO: 106) Pep2 TLPAITGLVGGVGLLLEVIVEVAYDD (SEQ ID NO: 107) Pep3 TLPAITGLVGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108) Pep4 TGLVGGVGLLLEVIVEVAYEEEE (SEQ ID NO: 109) Pep5 TGLVGGVGLLLEVIVEVAYEEE (SEQ ID NO: 110) Pep6 d TLPAITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111) Pep7 TLPAITGLVGGVGLLLEVIV d EVAYEEEEE (SEQ ID NO: 112) Pep8 TLPAITGLVGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113) Pep9 TLPAITGLVGGVGLLLEVAVEVAYEEEEE (SEQ ID NO: 114) Pep10 TLPAITGLVGGVGLLLEVIVEIAYEEEEE (SEQ ID NO: 115)

Claims

1. A peptide, a first domain of sequence X37-X5-X6-X7-G; and (i) a second domain of Formula I: -(X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36)-(CterpolyD / E) directly attached at the carboxy terminus of said first domain; (ii) a second domain of formula II: -(X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25)-(CterGp) directly attached at the carboxy terminus of the first domain; or (iii) a second domain of formula III: (NterGp)-(X8-X9-X10-X11-X12)- directly attached at the amino terminus of the first domain; During the ceremony, X37 is Gly, L-Ser, or D-Ser; X5, X6, and X7 are independently any amino acid; X8, X9, X10, X11, and X12 are independently any amino acid; X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are independently any amino acid, and no more than two amino acids among X13, X14, X15, X16, X17, X18, X19, X20, X21, X22, X23, X24, and X25 are charged amino acids; X26, X27, X28, X29, X30, X31, X32, X33, X34, X35, and X36 are independently any amino acid, and no more than two amino acids among X26, X27, X28, X29, X30, X31, X32, X33, X34, and X35 are charged amino acids; CterpolyD / E is a group of 4 to 10 amino acids containing at least two negatively charged amino acids; NterGp is a group of 3 to 5 amino acids including at least 2 charged amino acids; CterGp is a group of 3-5 amino acids including at least 3 positively charged amino acids, or its retro or retro-inverso form, or a pharmaceutically acceptable salt thereof; A peptide, wherein said peptide does not comprise or consist of the sequence TLPAIVGIGGGGGGLLLLLVIVAVLIAYKRK (SEQ ID NO: 1).

2. 2. The peptide of claim 1, wherein X5, X6, and X7 are aliphatic uncharged amino acids.

3. 3. The peptide of claim 2, wherein X5, X6, and X7 are each independently Gly, D or L-Ala, D or L-Val, D or L-Leu, and D or L-Ile.

4. 4. The peptide of claim 3, wherein X5 is D-Leu, L-Leu, D-Ile, or L-Ile, X6 is Gly, D-Val, or L-Val, and / or X7 is Gly.

5. 5. The peptide of claim 4, wherein X5 is L-Leu and / or X6 is L-Val.

6. 4. The peptide of claim 3, wherein X6 is Gly, D-Val, or L-Val.

7. The peptide described in claim 3, wherein X7 is Gly.

8. 2. The peptide of claim 1, wherein X26 is an aliphatic uncharged amino acid, X27 is an aliphatic uncharged amino acid, X28 is an aliphatic uncharged amino acid, X29 is an aliphatic uncharged amino acid, X30 is an aliphatic uncharged amino acid, X31 is a negatively charged amino acid, X32 is an aliphatic uncharged amino acid, X33 is an aliphatic uncharged amino acid, X34 is an aliphatic uncharged amino acid, X35 is a negatively charged amino acid, and / or X36 is an aliphatic uncharged amino acid.

9. X26 is Gly, D-Val, or L-Val, X27 is Gly, D-Val, or L-Val, X28 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X29 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X30 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X31 is D- or L-Glu, and X32 is D- or L- 9. The peptide of claim 8, wherein X33 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X34 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile, X35 is D- or L-Glu, and / or X36 is D- or L-Ala, D- or L-Val, D- or L-Leu, or D- or L-Ile.

10. 10. The peptide of claim 9, wherein X26 is L-Val, X27 is Gly, X28 is L-Leu, X29 is L-Leu, X30 is L-Leu, X31 is L-Glu, X32 is L-Val, X33 is L-Ile, X34 is L-Val, X35 is L-Glu, and / or X36 is L-Val.

11. 10. The peptide of claim 9, wherein X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36 is VGLLLEVIVEV (SEQ ID NO: 91), GGELLLVIVE (SEQ ID NO: 92), VVLLLEVIVEV (SEQ ID NO: 93), VGLLVEVIVEV (SEQ ID NO: 117), or VGLVLEVIVEV (SEQ ID NO: 118).

12. CterpolyD / E comprises the sequence -X"1-X"2-Z or -X"3-X"3bis-X"2-Z; During the ceremony, X"1 is a small amino acid, X″2 is an aromatic amino acid; X"3 and X"3bis are independently a long aliphatic amino acid; 2. The peptide of claim 1, wherein Z is 2 to 10 D / L-Asp and / or D / L-Glu residues.

13. 13. The peptide of claim 12, wherein X"1 is D- or L-Ala; X"3 and X"3bis are independently D- or L-Leu, or D- or L-Ile; and / or Z is 3 to 6 D / L-Asp and / or D / L-Glu residues.

14. 14. The peptide of claim 13, wherein Z is 3 to 5 L-Glu residues.

15. 2. The peptide of claim 1, wherein the peptide comprises a second domain of Formula I or II and further comprises a third domain of 1 to 10 amino acids attached at the amino terminus of the first domain.

16. 16. The peptide of claim 15, wherein the third domain comprises 1 to 6 amino acids.

17. The third domain is a third domain of formula IV: X38-X39-X40-X41-X42-X43, wherein: X38 is D-Thr or L-Thr or absent; X39 is D- or L-Leu, D- or L-Ile, or absent; X40 is Pro, D- or L-Ile, or is absent; X41 is D- or L-Ala, D- or L-Val, or is absent; X42 is D- or L-Leu, D- or L-Ile, or absent; and 17. The peptide of claim 16, wherein X43 is D- or L-Val, D-Thr or L-Thr.

18. 2. The peptide of claim 1, comprising 35 or fewer amino acids.

19. The following array: AITGLVGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 16), TGLVGGVGGLLLEVIVEVAYEEEEE (SEQ ID NO: 17), GLVGGVGGLLLEVIVEVAYEEEEE (SEQ ID NO: 18), TLPAIVGIGGGGGGELLLVIVEVLIYEEEEE (SEQ ID NO: 19), TLPAITGLVGGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAIVSIGGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 21), TLPAITGLVGGGVGLLLEVIVEVAYEEE (SEQ ID NO: 97), TLPAITGLVGGGVGLLLEVIVEVAYEE (SEQ ID NO: 98), TLPAITGLVGGGVGLLLEVIVEVAYDDDDD (SEQ ID NO: 99), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGGVGLVLEVIVEVAYEEEEE (SEQ ID NO: 101), TLPAITGLVGGGVGLLLEVIVEVVYEEEEE (SEQ ID NO: 105), ｄ E ｄ E ｄ E ｄ E ｄ E ｄ Y ｄ A ｄ V ｄ E ｄ V ｄ I ｄ V ｄ E ｄ L ｄ L ｄ LG ｄ VGG ｄ V ｄ LG ｄ T ｄ I ｄ A ｄ P ｄ L ｄ T (sequence number 106), TLPAITGLVGGGVGLLLEVIVEVAYDD (SEQ ID NO: 107), TLPAITGLVGGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), ｄ TLPAITGLVGGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 111), TLPAITGLVGGVGLLLEVIV ｄ EVAYEEEEE (SEQ ID NO: 112), or TLPAITGLVGGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113).

20. The following array: TLPAITGLVGGGVGLLLEVIVEVAYEEEEE (SEQ ID NO: 20), TLPAITGLVGGVVLLLEVIVEVAYEEEEE (SEQ ID NO: 100), TLPAITGLVGGGVGLLLEVIVEVAYDEDED (SEQ ID NO: 108), or 20. The peptide of claim 19, comprising one of the following: TLPAITGLVGGGVGLLVEVIVEVAYEEEEE (SEQ ID NO: 113).

21. A pharmaceutical composition comprising the peptide of any one of claims 1 to 20, its retro or retro-inverso form, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

22. 22. The pharmaceutical composition of claim 21 for use as a medicament.

23. 22. The pharmaceutical composition of claim 21 for use in treating a demyelinating disease in a subject.

24. 24. The pharmaceutical composition for use according to claim 23, wherein the demyelinating disease is a demyelinating autoimmune disease.

25. The demyelinating diseases include multiple sclerosis, transverse myelitis, neuromyelitis optica (Devik's disease), acute hemorrhagic leukoencephalitis, acute disseminated encephalomyelitis (ADEM), Schilder's diffuse cerebral sclerosis, adrenoleukodystrophy, Alexander disease, Canavan disease, Krabbe disease, Barrot disease, Charcot-Marie-Tooth disease (CMT), HIV encephalitis, HTLV-I associated myelopathy (HAM), Binswanger's disease (subcortical leukoencephalopathy and subcortical arteriosclerotic encephalopathy (SAE)), globoid cell leukodystrophy, metachromatic leukodystrophy, Pelizaeus-Merzbacher disease, progressive multifocal leukoencephalopathy, and leukodystrophy.

25. The pharmaceutical composition for use according to claim 24, wherein the disease is a demyelinating disease caused by encephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis, polyradiculopathy, or antineoplastic agents, carbon monoxide, vitamin B12 deficiency, mercury poisoning, amblyopia due to alcohol or tobacco, hypoxia, or irradiation.

26. 26. The pharmaceutical composition for use according to claim 25, wherein the demyelinating disease is multiple sclerosis.

27. 24. The pharmaceutical composition for use according to claim 23, wherein the pharmaceutical composition is for use in combination with one or more additional therapeutic agents.

28. 28. The pharmaceutical composition for use according to claim 27, wherein the one or more additional therapeutic agents comprises fingolimod.

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