VEGF Regulatory Peptides

Abstract

The present invention provides a peptide or pharmaceutical salt thereof comprising a sequence having a length of 14-50 and having at least 85% sequence identity to SEQ ID NO:1, wherein "m", "n", "p" and "q" represent integers and are selected from 0 and 1, the C-terminus corresponds to -C(O)R4, the N-terminus corresponds to -NHR5, and the peptide optionally comprises a linker biradical "L" of formula (I) linking the alpha carbon atom of the amino acid located at position "i" in the peptide sequence of SEQ ID NO:1 to the alpha carbon atom of the amino acid located at position "i+4" or "i+7". The present invention also provides fusion proteins and pharmaceutical compositions comprising the peptides of the invention and their use in therapy, particularly in the treatment of diseases resulting from increased or decreased VEGF levels.

Description

[Technical field]

[0001] The present invention relates to the field of peptides and therapy. In particular, the present invention provides peptides capable of regulating VEGF protein. Thus, they are useful for regulating processes in which VEGF plays an important role, such as angiogenesis. The present invention also provides fusion proteins and pharmaceutical compositions comprising the peptides of the present invention. [Background technology]

[0002] Angiogenesis plays a crucial role in a wide range of fundamental physiological processes in normal individuals, including embryogenesis, somatic growth, and differentiation of the nervous system. In the female reproductive system, angiogenesis occurs in the ovarian follicle during development, in the corpus luteum after ovulation, and in the placenta to establish and maintain pregnancy. Angiogenesis also occurs as part of the body's repair processes, such as wound and fracture healing. Thus, promoting angiogenesis can be useful in situations where the establishment or expansion of vascularization is desirable. However, angiogenesis is also an important factor in many pathological processes, perhaps most notably tumor growth and metastasis, since tumors require the constant stimulation of new capillaries to grow. Other pathological processes that are affected by angiogenesis include conditions associated with blood vessel proliferation, particularly in capillaries, such as diabetic retinopathy, macular degeneration, arthropathy, psoriasis, rheumatoid arthritis, pulmonary hypertension, chronic obstructive pulmonary disease, liver disease, kidney disease, etc. (Non-Patent Document 1).

[0003] Recent studies have demonstrated that a family of endothelial cell-specific growth factors, the vascular endothelial growth factors (VEGFs), together with their cognate receptors, are primarily responsible for stimulating the growth and differentiation of endothelial cells. These factors are members of the PDGF family and appear to act primarily through endothelial receptor tyrosine kinases (RTKs).

[0004] Sprouting angiogenesis, an important mode of angiogenesis during both embryonic development and adulthood, forms new blood vessels by outgrowth of endothelial cells from pre-existing vessels. Endothelial cells are normally quiescent, so stimulatory cytokines such as VEGF are required to initiate angiogenesis. VEGF is itself considered the master regulator of angiogenesis, causing endothelial cells to detach from the parent vessel and migrate into the adjacent stroma. VEGF is a direct transcriptional target of both HIF-1α and HIF-2α, so hypoxia is the primary regulator of VEGF expression. Arnt mutant vasculopathy is accompanied by reduced VEGF expression, and reduced VEGF expression is responsible for many of the vascular abnormalities observed, as exogenous VEGF rescues these disorders.

[0005] Vascular occlusive diseases remain the most important cause of mortality and morbidity in industrialized societies. End-stage treatments such as myocardial infarction, peripheral arterial disease (PAD) and stroke are usually limited to palliative interventions such as angioplasty, or amputation in severe cases of PAD. The ability to induce and regulate angiogenesis and vascular remodeling in a directed manner would represent a major advance in the treatment of ischemic vascular diseases.

[0006] Meanwhile, a further example of uncontrolled angiogenesis with dramatic health effects is the uncontrolled vascular growth that is the central pathological component of many human blinding disorders, including diabetic retinopathy, age-related macular degeneration (AMD), glaucoma, and retinopathy of prematurity (ROP). The neuronal cell death and vision loss observed in these diseases are caused by abnormal leaky blood vessels, often accompanied by pathological neovascularization. Taken together, these diseases are the most common cause of vision loss, suggesting that highly effective antiangiogenic therapies would have a profound impact on the prevalence of blindness in industrialized societies. Indeed, neovascular eye diseases are the most obvious example of the therapeutic utility of inhibiting angiogenesis, as VEGF inhibitors have been successfully used in the clinic and shown efficacy in treating wet (neovascular) AMD.

[0007] In light of the above, much effort has been focused on finding molecules that have the ability to modulate angiogenesis either in a positive manner (ie, stimulation of VEGF) or in a negative manner (ie, inhibition of VEGF).

[0008] Hypoxia-inducible factors (HIFs) are transcription factors involved in the transcriptional activation of several genes, including angiogenic factors (e.g., VEGF and FLT1), glucose transporters (Glut-1 and Glut-3), and glycolytic enzymes involved in the production of ATP in the absence of O2 (for reviews, see Non-Patent Document 2, Non-Patent Document 3, Non-Patent Document 4). The HIF transcription factor heterodimer is composed of two subunits, HIF-α and HIF-β. HIF-β is constitutively expressed, whereas HIF-α expression is regulated by oxygen levels. Thus, in the presence of normoxia (i.e., normal oxygen), HIF-1α is hydroxylated at two critical proline residues (402 and 564 in GenBank accession number NP_001521) by members of the prolyl hydroxylase protein (PHD) family (PHD-1, PHD-2, and PHD-3). Hydroxylated-HIF-1α can then bind to the von Hippel-Lindau (VHL) tumor suppressor protein, which recruits the E3 ubiquitin ligase complex and directs HIF-α protein to proteasomal degradation. However, at low oxygen tension (i.e., hypoxic conditions), prolyl hydroxylases cannot hydroxylate HIF-α because oxygen is the rate-limiting cofactor for PHD enzymes. As a result, VHL interaction does not occur, and the E3 ubiquitin ligase complex cannot direct HIF-1α to proteasomal degradation, resulting in stabilization of HIF. Stabilized HIF-1α can then form a heterodimer with HIF-1β, which interacts with the basic helix-loop-helix domain of hypoxia response factor (FIRE) in target genes. In addition, hydroxylation of the asparagine residue (position 803) in the C-terminal transactivation domain (TAD) of HIF-α by factor-1 inhibitor (FIH-1) negatively regulates the transcriptional activity of HIF by preventing interaction with p300 and CBP transactivators. WO 2006 / 023966 discloses peptides derived from HIF-α, including a linear peptide of 15 amino acids corresponding to SEQ ID NO:36 of the present disclosure, which are proposed to have VEGF-reducing activity and anti-cancer properties, but WO 2006 / 023966 does not contain any experimental data to support these alleged properties.On the other hand, US Pat. No. 5,399,623 and US Pat. No. 5,499,633 describe cyclic peptides that are said to modulate the interaction of HIF with the p300 and CBP transactivators. [Prior art documents] [Patent documents]

[0009] [Patent Document 1] International Publication No. 2006038208 [Patent Document 2] International Publication No. 2010034028 [Patent Document 3] U.S. Patent Application Publication No. 2019225650 [Non-patent literature]

[0010] [Non-Patent Document 1] Carmeliet P., 2003 [Non-Patent Document 2] Semenza GL. 2003; Nat. Rev. Cancer 3: 721-732 [Non-Patent Document 3] Paul SA, Simons JW, Mabjeesh NJ. 2004; J. Cell Physiol. 200: 20-30 [Non-Patent Document 4] Wang Guang l et al 1995, PNAS, 92(12): 5510-5514 Summary of the Invention [Problem to be solved by the invention]

[0011] Unfortunately, VEGF-based therapies are not sufficiently effective to adequately regulate angiogenesis, and therefore there remains a need for VEGF inhibitory therapies that are effective in regulating angiogenesis. [Means for solving the problem]

[0012] The present inventors have discovered peptides that efficiently regulate VEGF expression under hypoxic conditions.

[0013] Thus, in a first aspect, the present invention provides a nucleic acid sequence having a length of between 14 amino acids and 50 amino acids and represented by SEQ ID NO:1: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q (where: "m", "n", "p" and "q" represent integers and are selected from 0 and 1; The C-terminus corresponds to -C(O)R4, A peptide or a pharmaceutical salt thereof, comprising a sequence having at least 85% sequence identity to a peptide having an N-terminus corresponding to -NHR5, The peptide optionally comprises a peptide of formula (I) linking the alpha carbon atom of an amino acid located at position "i" with the alpha carbon atom of an amino acid located at position "i+4" or "i+7" in the peptide sequence of SEQ ID NO:1: -[(R1) a -(R2)-(R3) b ] c - (I) (In the formula, "a" and "b" are the same or different and are 0 or 1; "c" is composed of 1 to 10, R1 and R3 are (C1 to C 10 )Alkyl;Halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 )Alkyl;(C2-C 10 ) alkenyl; halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12(C2 to C 10 ) alkenyl; (C2-C 10 ) alkynyl; and halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) Alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; Ring systems include halogen, -OH, -NO2, (C1-C 10 ) Alkyl, (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O-; R4 is -OH and -NR 17 R 18 is a radical selected from the group consisting of R5 is -H and (C1 to C 20 ) alkyl, R6, R7, R8, R9, R 10, R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is -H and (C1 to C 10 ) alkyl; The amino acids linked by the linker have the formula (II): [ka] (In the formula, R 19 (C1~C 10 ) Alkyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 ) Alkyl, (C2-C 10 ) Alkenyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkenyl, (C2-C 10 ) Alkynyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl, as well as known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; Each of the members forming the known ring systems is a monoradical selected from the group consisting of known ring systems selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S-, and -O-.

[0014] As shown below, the peptide of the first aspect of the invention efficiently regulates the expression of VEGF under hypoxic conditions compared to normoxic conditions. In particular, it is shown that when the peptide of the first aspect of the invention is linear (i.e. does not contain a linker biradical "L"), an increase in VEGF levels is obtained. More specifically, as shown in Example 1, SEQ ID NO: 13 (18 amino acids) was shown to increase VEGF expression under hypoxic conditions (Table 2). The inventors further characterized shorter versions, such as SEQ ID NO: 36 (15 amino acids) and SEQ ID NO: 37 (14 amino acids), and found that the reduced size could render the linear peptide inactive or retain the upregulation of VEGF expression (Table 3). Thus, contrary to the proposal in WO 2005 / 023366, the inventors have shown that SEQ ID NO: 36 does not affect the regulation of VEGF expression.

[0015] Surprisingly, the inventors have found that the behaviour of the peptides according to the first aspect of the invention is significantly altered when a linker biradical is included, causing a dramatic, in some cases approximately 50% reduction in VEGF expression. In particular, as shown in Example 1, crosslinked peptides under the first aspect of the invention such as SEQ ID NO: 14 to SEQ ID NO: 21 induced a reduction in VEGF expression in human retinal pigment epithelial (i.e. ARPE-19) cells in vitro under hypoxia-inducing conditions relative to non-treated cells. See Table 2. Moreover, it was further shown that such an effect was also obtained for SEQ ID NO: 16 in two other cell lines, namely a breast cancer cell line and an immortalized keratinocyte cell line. See Table 4.

[0016] In addition, the inventors further demonstrated that the effect of VEGF reduction resulted in reduced angiogenesis in vivo, as shown in the breast cancer xenograft mouse model in Example 2. Indeed, the peptide of SEQ ID NO: 17 resulted in a statistically significant reduction in CD31 expression (a marker of endothelial cells of blood vessels) in treated tumors compared to controls, as determined by immunohistochemistry (ICH).

[0017] Thus, the inventors have found that peptides comprising the sequence of SEQ ID NO: 1 can modulate VEGF expression and thus angiogenesis with or without the inclusion of a linker biradical "L" in the sequence of SEQ ID NO: 1. The absence of a linker results in a peptide that can enhance VEGF expression and thus "enhance" angiogenesis, and the presence of a linker results in a peptide that decreases VEGF expression and thus "decreases" angiogenesis.

[0018] This is the first time that it has been reported that the presence of a linker biradical in the above peptides may modulate the regulatory effect of the peptides on VEGF expression.

[0019] In a second aspect, the present invention provides a peptide having a length of 15 amino acids to 50 amino acids and represented by SEQ ID NO: 22: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v (where: "r", "s", "t" and "v" represent integers and are selected from 0 and 1; The C-terminus corresponds to -C(O)R4, A peptide or a pharmaceutical salt thereof, comprising a sequence having at least 85% sequence identity to a peptide having an N-terminus corresponding to -NHR5, The peptide has the formula (I) which links the alpha carbon atom of the amino acid located at position "i" of the peptide sequence of formula (I) to the alpha carbon atom of the amino acid located at position "i+4" or "i+7" in the peptide sequence of SEQ ID NO: 22: -[(R1) a -(R2)-(R3)b ] c - (I) (In the formula, "a" and "b" are the same or different and are 0 or 1; "c" is composed of 1 to 10, R1 and R3 are (C1 to C 10 )Alkyl;Halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 )Alkyl;(C2-C 10 ) alkenyl; halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkenyl; (C2-C 10 ) alkynyl; and halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) Alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; Ring systems include halogen, -OH, -NO2, (C1-C 10 ) Alkyl, (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O-; R4 is -OH and -NR 17 R 18 is a radical selected from the group consisting of R5 is -H and (C1 to C 20 ) alkyl, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is -H and (C1 to C 10 ) alkyl; The amino acids linked by the linker have the formula (II): [ka] (In the formula, R 19 (C1~C 10 ) Alkyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 ) Alkyl, (C2-C 10 ) Alkenyl, halogen, (C1-C 10)Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkenyl, (C2-C 10 ) Alkynyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl, as well as known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; Each of the members forming the known ring systems is a monoradical selected from the group consisting of known ring systems selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S-, and -O-.

[0020] As shown below, peptides of the second aspect of the invention incorporating linker biradicals may also modulate angiogenesis. In particular, it has been found that peptides of the second aspect of the invention are capable of increasing VEGF expression under hypoxic conditions relative to levels obtained under normoxic conditions.

[0021] Thus, the peptides of the second aspect of the invention may be useful for restoring VEGF levels in situations where there is a decline in growth factors, and as a consequence, these peptides of the second aspect of the invention may be applied in the prevention or treatment of diseases resulting from dysregulation of angiogenesis due to reduced VEGF levels.

[0022] In a third aspect, the present invention provides a fusion protein comprising a peptide as defined in the first or second aspect of the invention and, optionally, a cell membrane penetrating peptide.

[0023] In a fourth aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention, or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, together with an acceptable pharmaceutical excipient and / or carrier.

[0024] As described above, the peptide of the present invention can regulate the expression of VEGF. This indicates the usefulness of the peptide of the present invention in the treatment of diseases related to VEGF dysregulation. VEGF has been widely reported to play a central role in the angiogenesis process. Therefore, the peptide of the present invention can also regulate the angiogenesis process as a regulator of VEGF expression. Increased expression of VEGF stimulates angiogenesis, and decreased expression of VEGF downregulates the angiogenesis process.

[0025] Thus, in a fifth aspect, the present invention provides a peptide or a pharmaceutical salt thereof as defined in the first or second aspect of the invention, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, for use in therapy.

[0026] In a sixth aspect, the present invention provides a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, for use in the treatment or prevention of a disease caused by dysregulation of VEGF expression levels. This aspect may alternatively be constructed as a method for preventing or treating a disease caused by dysregulation of VEGF expression levels, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention. This aspect may alternatively be constructed as the use of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease caused by dysregulation of VEGF expression levels.

[0027] In a seventh aspect, the present invention provides a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, for use in the treatment or prevention of a disease resulting from dysregulation of angiogenesis, in particular by modulating the VEGF expression level. This aspect may alternatively be expressed as a method for the treatment or prevention of a disease resulting from dysregulation of angiogenesis, in particular by modulating the VEGF expression level, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention. This aspect may alternatively be formulated as the use of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease resulting from dysregulation of angiogenesis, in particular by modulating the VEGF expression level. [Brief description of the drawings]

[0028] [Figure 1] FIG. 1 shows immunohistochemistry (IHC) staining with anti-CD31 antibody of breast tumor tissue from untreated mice (vehicle) and after treatment with SEQ ID NO: 17 by subcutaneous (SC) administration. [Diagram 2] FIG. 1 shows the calculated relative CD31 staining intensity of breast tumour tissue from untreated mice (vehicle) and following treatment with SEQ ID NO: 17 by subcutaneous (SC) administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] All terms used in the specification of this application are to be understood in their ordinary meaning known in the art unless otherwise specified. Other more specific definitions of certain terms used in this application are set forth below, but are intended to be uniformly applied throughout the specification and claims, and unless otherwise expressly set forth, the definitions are to be given broader definitions.

[0030] For purposes of the present invention, any given range includes both the lower and upper endpoints of the range.

[0031] The present invention provides a peptide comprising a sequence having an identity to the extent of at least 85% with SEQ ID NO:1 or SEQ ID NO:22, as described above.

[0032] In the present invention, the term "identity" refers to the percentage of identical residues in two sequences when the sequences are optimally aligned. In optimal alignment, if a position in the first sequence is occupied by the same amino acid residue as the corresponding position in the second sequence, the sequences show identity at that position. The level of identity (or "percent sequence identity") between two sequences is measured as the ratio of the number of identical positions shared by the sequences to the size of the sequences (i.e., percent sequence identity = (number of identical positions / total number of positions) x 100).

[0033] Numerous mathematical algorithms for rapidly obtaining optimal alignments between two or more sequences and calculating identity are known and are incorporated into many available software programs. Examples of such programs include, inter alia, the MATCH-BOX, MULTAIN, GCG, FASTA and ROBUST programs for amino acid sequence analysis. Preferred software analysis programs include the ALIGN, CLUSTAL W and BLAST programs (e.g., BLAST 2.1, BL2SEQ and later versions).

[0034] For amino acid sequence analysis, a weight matrix such as a BLOSUM matrix (e.g., BLOSUM45 matrix, BLOSUM50 matrix, BLOSUM62 matrix, and BLOSUM80 matrix), a Gonnet matrix, or a PAM matrix (e.g., PAM30 matrix, PAM70 matrix, PAM120 matrix, PAM160 matrix, PAM250 matrix, and PAM350 matrix) is used to determine identity.

[0035] The BLAST program provides an analysis of at least two amino acid sequences by either aligning a selected sequence against multiple sequences in a database (e.g., GenSeq) or by aligning between two selected sequences using BL2SEQ. The BLAST program is preferably modified by a low complexity filtering program, such as the DUST program or the SEG program, which is preferably integrated into the BLAST program operation. When using a gap existence cost (or gap score), the gap existence cost is preferably set to about -5 to -15. Similar gap parameters can be used with other programs as needed. The BLAST program and its basic principles are further described, for example, in Altschul et al., "Basic local alignment search tool", 1990, J. Mol. Biol, v. 215, pages 403-410.

[0036] For multiple sequence analysis, the CLUSTAL W program can be used. The CLUSTAL W program is preferably run using the "dynamic" (vs. "fast") settings. Amino acid sequences are scored using a variable set of BLOSUM matrices depending on the level of identity between the sequences. The CLUSTAL W program and basic principles of operation are further described, for example, in Higgins et al., "CLUSTAL V: improved software for multiple sequence alignment", 1992, CABIOS, 8(2), pages 189-191.

[0037] In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is a peptide having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 1. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is a peptide having 100% identity to any of the sequences of SEQ ID NO: 1. In one embodiment, in any combination with any of the embodiments set out above or below, the two amino acid residues connected by a linker are not taken into account when determining the identical positions by alignment to ascertain the degree of identity. In one embodiment of the first aspect of the invention, the peptide or salt thereof consists of the sequence of SEQ ID NO: 1 as defined above, and optionally includes an "L" biradical of formula (I).

[0038] In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is a peptide having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to SEQ ID NO: 22. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is a peptide having 100% identity to any of the sequences of SEQ ID NO: 22. In one embodiment, in any combination with any of the embodiments set out above or below, two amino acid residues linked by a linker are not taken into account when determining identical positions by alignment to ascertain the degree of identity.

[0039] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., within the scope of sound medical judgment, and commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are known in the art. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods used in the art, such as ion exchange. Other pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, clopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, Salts derived from suitable bases include alkali metals, alkaline earth metals, and ammonium salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.Further pharma-ceutically acceptable salts include those formed, where appropriate, with non-toxic ammonium, quaternary ammonium and amine cations, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

[0040] (C1~C 10 The term alkyl refers to a saturated straight or branched alkyl chain having 1 to 10 carbon atoms. Illustrative non-limiting examples are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.

[0041] (C1~C 20 ) The term alkyl refers to saturated straight or branched alkyl chains having 1 to 20 carbon atoms.

[0042] (C2~C 10 The term alkenyl refers to a saturated straight or branched alkyl chain containing from 2 to 10 carbon atoms and further containing one or more double bonds. Illustrative non-limiting examples are ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

[0043] (C2~C 10 The term alkynyl refers to a saturated straight or branched alkyl chain containing 2 to 20 carbon atoms and further containing one or more triple bonds. Examples include ethynyl, 1-propynyl, 2-butynyl, 1,3-butadienyl, 4-pentynyl, and 1-hexynyl, among others.

[0044] The term "halogen" refers to a group in the periodic table of five chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I) and astatine (At).

[0045] (C1~C 10The term haloalkyl means a (C1-C2) alkyl group consisting of one or more, preferably 1 to 6, halogen atoms which may be the same or different. 10 ) refers to groups resulting from the replacement of one or more hydrogen atoms of an alkyl group. Examples include trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, and nonafluorobutyl, among others.

[0046] The term "known" ring system, as used herein, refers to ring systems that are chemically feasible and known in the art, and is intended to exclude ring systems that are not chemically feasible.

[0047] According to the present invention, when a ring system is formed by "independent" rings, it is meant that the ring system is formed by two, three or four rings, which are connected via a bond from an atom of one ring to an atom of the other ring. The term "independent" also encompasses the embodiment in which the ring system has only one ring. Illustrative non-limiting examples of known ring systems consisting of one ring are derived from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, phenyl and cycloheptenyl.

[0048] According to the present invention, when a ring system has "fully fused" rings, it is meant that the ring system is formed by two, three or four rings, where two or more atoms are common to two adjacent rings. Illustrative non-limiting examples are 1,2,3,4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, anthryl or phenanthryl.

[0049] According to the present invention, when a ring system is "partially fused", it is meant that the ring system is formed by three or four rings, at least two of which are fully fused (i.e., two or more atoms are common to two adjacent rings), and the remaining ring(s) are connected via a bond from an atom of one ring to an atom of the fused ring.

[0050] Unless otherwise stated, one or more of the amino acids forming the peptide of the invention may have an L-configuration or a D-configuration. In one embodiment of the first or second aspect of the invention, in any combination with any of the embodiments presented above or below, at least one of the amino acids forming the peptide is a D-amino acid. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments presented above or below, one of the amino acids forming the peptide is a D-amino acid. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments presented above or below, at least one of the amino acids linked by the linker is a D-amino acid. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments presented above or below, one of the amino acids linked by the linker is a D-amino acid and the other is an L-amino acid. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments presented above or below, the amino acids linked by the linker are such that the amino acid closest to the N-terminus is a D-amino acid and the amino acid closest to the C-terminus is an L-amino acid.

[0051] The amino acids used in the construction of the peptides of the invention can be prepared by organic synthesis or obtained by other routes such as, for example, degradation of natural sources or isolation from natural sources.

[0052] In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments presented above or below, the peptide is one in which m and n are the same, preferably 1. In an alternative embodiment, the peptide is one in which m and n are different, i.e. m is 0 and n is 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments presented above or below, the peptide is one in which p and q are the same, preferably 1. In an alternative embodiment, the peptide is one in which p and q are different, i.e. p is 1 and q is 0. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments presented above or below, m, n, p and q are the same, in particular 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments presented above or below, m, n and q are the same. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments presented above or below, m, n and q represent 0 and p represents 1. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, m, n and p are the same. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, m, n and p represent 1 and q represents 0.

[0053] In another embodiment of the first aspect of the invention, in any combination with any of the embodiments presented above or below, the peptide is a linear peptide. In the present invention, the term "linear peptide" means that it does not contain an "L" biradical. In another embodiment, in any combination with any of the embodiments presented above or below, the linear peptide is one in which m, n, p and q are the same. In another embodiment, in any combination with any of the embodiments presented above or below, the linear peptide is one in which m, n, p and q are the same and represent 1.

[0054] In one embodiment of the second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide is such that r and s are the same. In another embodiment of the second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide is such that t and v are the same. In another embodiment of the second aspect of the invention, in any combination with any of the embodiments set out above or below, r and s represent 1 and t and v represent 0. In another embodiment of the second aspect of the invention, in any combination with any of the embodiments set out above or below, r and s represent 0 and t and v represent 1.

[0055] In another embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the linker biradical of formula (I) is between the alpha carbon atom of the amino acid located at position "i" and the alpha carbon atom of the amino acid located at position "i+7" in the peptide sequence of SEQ ID NO:1.

[0056] In another embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the peptide comprises SEQ ID NO: 2: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 3: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 4: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 5: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-(Lys)q, SEQ ID NO: 6: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 7: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 8: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 9: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 10: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, SEQ ID NO: 11: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, and SEQ ID NO: 12: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, is selected from the group consisting of Here, the bold and underlined amino acids, having the same (both L- or D-amino acids) or different configurations, refer to the position (i, i+7) of the linker biradical "L", with the C-terminus corresponding to -C(O)R4 and the N-terminus corresponding to -NHR5.

[0057] In another embodiment of the second aspect of the invention in any combination with any of the embodiments set out above or below, the linker biradical of formula (I) is between the alpha carbon atom of the amino acid located at position "i" and the alpha carbon atom of the amino acid located at position "i+7" in the peptide sequence of SEQ ID NO:22.

[0058] In another embodiment of the second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide comprises SEQ ID NO: 23: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v, SEQ ID NO: 24: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)-(Pro)v, SEQ ID NO: 25: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v, SEQ ID NO: 26: Arg-Ser-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln, SEQ ID NO: 27: Arg-Ser-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln, and SEQ ID NO: 28: Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-Leu-Pro, is selected from the group consisting of Here, the bold and underlined amino acids, having the same (both L- or D-amino acids) or different configurations, refer to the position (i, i+7) of the linker biradical "L", with the C-terminus corresponding to -C(O)R4 and the N-terminus corresponding to -NHR5.

[0059] In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, where a=1. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, where b=1. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, where c=1. In another embodiment of the first aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, where a=b=c=1.

[0060] In another embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof is 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 In another embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, which is a biradical independently selected from the group consisting of R1 and R3, which are the same or different, and which are selected from the group consisting of (C1-C 10 ) alkyl, including the "L" linker.

[0061] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof has R2 -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) Alkynyl, -NR 15 -NR 16-, -N=N-, -SS- and one known ring system having 3 to 6 members, which ring is saturated, partially unsaturated or aromatic; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; Ring systems include halogen, -OH, -NO2, (C1-C 10 ) Alkyl, (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O-, optionally substituted with one or more radicals independently selected from the group consisting of known ring systems.

[0062] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof is 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 In another embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises an "L" linker, wherein R2 is a biradical selected from the group consisting of (C2-C 10 ) alkenyl,

[0063] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises R1 and R3, which are the same or different, and (C1 to C 10 ) alkyl, R2 is (C2-C 10 ) alkenyl,

[0064] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises R1 and R3, which are the same or different, and (C1 to C 10) alkyl, R2 is (C2-C 10 ) alkenyl, and a=b=c=1.

[0065] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises R 19 (C1~C 10 ) Alkyl, (C1-C 10 )Haloalkyl, (C2-C 10 ) alkenyl and (C2-C 10 In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof is selected from the group consisting of R 19 (C1~C 10 ) alkyl monoradicals, preferably (C1-C4) alkyl monoradicals such as methyl, ethyl, propyl, isopropyl or butyl; or (C1-C 10 ) haloalkyl, preferably halomethyl, e.g., (C1-C4) haloalkyl monoradicals such as fluoromethyl. In a preferred embodiment, R 19 In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises R1, R3 and R 19 are the same or different, (C1 to C 10 ) alkyl, R2 is (C2-C 10 ) alkenyl.

[0066] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, L is a linear or branched C3-C alkyl group, optionally interrupted one or more times by one or more groups independently selected from: -O-, -S-, -SO-, NH-, -CO-, -NMe-, -NHCO-, -CONH-, an arylene group, a heteroarylene group, a linear or branched C1-C6 alkylene group and a cyclic alkylene group, and a 5- to 10-membered heterocyclic group having up to four heteroatoms selected from the group consisting of N, O and S, optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -COOH, -NH2, -NO2, C1-C6 alkyl and C1-C6 alkenyl. 30 It is a biradical containing a hydrocarbon.

[0067] In certain embodiments, L is of formula (Ia): -(CH2) y -P-(CH2) a -(Q) b -(CH2) c -(V) d -(CH2) z - (Ia) (In the formula, P, Q and V are each independently selected from the group consisting of O, S, NH, CONH, C(O)O, C1-C6 alkylene, arylene groups such as phenylene, and heteroarylene groups such as triazolene, optionally substituted with halogen; y and z are each independently an integer value selected from 1 to 10; a and c are each independently an integer value selected from 0 to 10; b and d each independently represent an integer value selected from 0 to 3.

[0068] In a preferred embodiment, the linker (L) of the ligand is -(CH2) y -CH=CH-(CH2) z - (Ib) wherein preferably y and z are the same or different and are integer values ​​selected from 1 to 10, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. Preferably, y and z are independently integer values ​​selected from 3 to 6, more preferably independently integer values ​​selected from 3 and 6; [ka] (In the formula, preferably, P and V are each independently selected from the group consisting of O and S; preferably, y and z are 1; preferably, a is 1 or selected from 6 to 10; preferably, b is 0 or 1; and preferably, c is 0 or 1; Some particular embodiments of formula (Ic) are -(CH2) y -P-(CH2) a -V-(CH2) z - (Id1) wherein preferably P and V are each independently selected from the group consisting of O and S; and preferably y and z are 1; a is selected from 6 to 10, preferably a is 8; and in some preferred embodiments, the ligand of formula (Id1) is selected from (Id1.1) and (Id1.2): -(CH2) n -O-(CH2) n -O-(CH2) n - (Id1.1) -(CH2) n -S-(CH2) n -S-(CH2) n - (Id1.2) ), [ka] wherein preferably P and V are each independently selected from the group consisting of O and S, and preferably y, a, c and z are 1; in some preferred embodiments, the ligand of formula (IIId2) is selected from the group consisting of (Id2.1) and (Id2.2): [ka] is selected from [ka] and in formulae (Id1.1), (Id1.2), (Id2.1), (Id2.2), (Ie) and (If), each n is an integer value independently selected from 1 to 10, including 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In some preferred embodiments, each n is an integer value independently selected from 3 to 6. For ligands of formula (Ie) or (If), each n is preferably an integer value independently selected from 3 to 6. In other preferred embodiments, each n is independently selected from 1 or 2. For ligands of formula (Id), each n is preferably 1. In a preferred embodiment, the linker (L) has the formula defined above: -(CH2) y -CH=CH-(CH2) z - (Ib) and R 19 As defined above, (C1 to C 10 ) alkyl monoradical, R 19 is preferably a methyl group.

[0069] In one embodiment of the first aspect of the invention in any combination with any of the embodiments set out above or below, the peptide is: R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m" and "n" are the same and "p" and "q" are the same, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m" and "n" are the same and "p" and "q" are different, or alternatively R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C10 ) alkenyl, where "m", "n", "p" and "q" are the same, in particular the same, and represent 1, or alternatively R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m", "n" and "q" are the same and "q" is different, particularly where m=n=q=0 and q=1.

[0070] In one embodiment of the second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide is: R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "r" and "s" are the same and "t" and "v" are the same, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "r" and "s" are the same and represent 1, and "t" and "v" are the same and represent 0, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "r" and "s" are the same and represent 0, and "t" and "v" are the same and represent 1.

[0071] In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is one in which R4 is -OH (i.e., the C-terminus is -C(O)OH). In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the peptide or salt thereof is one in which R4 is -NR 17 R 18 and R 17 and R 18are equivalent. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the N-terminus corresponds to -NH2. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the C-terminus and N-terminus of the peptide of the invention are -C(O)OH and -NH2, respectively. In another embodiment of the first or second aspect of the invention, in any combination with any of the embodiments set out above or below, the C-terminus and N-terminus of the peptide of the invention are -C(O)NH2 and -NH2, respectively.

[0072] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the C-terminus and N-terminus of the peptide of the invention are -C(O)R4 and -NH2, respectively, where R4 is -NHR 18 means R 18 (C1~C 10 ) alkyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 ) alkyl.

[0073] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the C-terminus and N-terminus of the peptide of the invention are -C(O)R4 and -NH2, respectively, where R4 is -NR 17 R 18 means R 17 and R 18 (C1~C 10 ) alkyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12(C1 to C 10 ) alkyl.

[0074] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the C-terminus and N-terminus of the peptide of the invention are -C(O)OH and NHR5, respectively, where R5 is (C1-C 20 ) alkyl, halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 ) alkyl.

[0075] In another embodiment of the first and second aspects of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof comprises R1, R3 and R 19 are the same or different, (C1 to C 10 ) alkyl, R2 is (C2-C 10 In another embodiment of the first and second aspects of the invention in any combination with any of the embodiments set out above or below, the peptide or salt thereof is 19 are the same or different, (C1 to C 10 ) alkyl, R2 is (C2-C 10 ) alkenyl, the C-terminus being selected from -C(O)OH and -CONH2, and the N-terminus being -NH2.

[0076] In another embodiment of the first aspect of the invention, the peptide has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity to a sequence selected from the group consisting of the sequences SEQ ID NO: 13 to SEQ ID NO: 21:

[0077] SEQ ID NO:13 Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys Here, the N-terminus corresponds to -NH2 and the C-terminus corresponds to -C(O)NH2.

[0078] Other linear peptide sequences derived from SEQ ID NO:1 are SEQ ID NO:36 and SEQ ID NO:37 shown herein below: SEQ ID NO:36: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg SEQ ID NO:37: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val

[0079] Notably, SEQ ID NO:37 differs from SEQ ID NO:36 by lacking the terminal arginine.

[0080] SEQ ID NO:14 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 3 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0081] SEQ ID NO:15 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 5 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0082] SEQ ID NO:16 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 6 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0083] SEQ ID NO:17 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)OH, the amino acid at position 6 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0084] Notably, SEQ ID NO:16 and SEQ ID NO:17 differ only in the C-terminal functional group, which corresponds to -C(O)NH2 in SEQ ID NO:16 and to -C(O)OH in SEQ ID NO:17.

[0085] SEQ ID NO:18 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 8 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0086] SEQ ID NO:19 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 5 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0087] SEQ ID NO:20 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 7 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0088] SEQ ID NO:21 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 8 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0089] In another embodiment of the first aspect of the invention, the peptide comprises or consists of any of the sequences SEQ ID NO:13 to SEQ ID NO:21, such as SEQ ID NO:14 to SEQ ID NO:21, preferably selected from the group comprising or consisting of any of the sequences SEQ ID NO:14, SEQ ID NO:16 and SEQ ID NO:17, and any of the sequences SEQ ID NO:19 to SEQ ID NO:21. In another embodiment of the second aspect of the invention, the peptide has at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to any of the sequences selected from the group consisting of SEQ ID NO:29 to SEQ ID NO:31:

[0090] SEQ ID NO:29 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 8 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0091] SEQ ID NO:30 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 10 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0092] SEQ ID NO:31 [ka] Here, the N-terminus corresponds to -NH2, the C-terminus corresponds to -C(O)NH2, the amino acid at position 3 is a D-amino acid, and the remaining amino acids are L-amino acids.

[0093] In another embodiment of the second aspect of the invention in any combination with any of the embodiments presented above, the peptide is selected from the group consisting of SEQ ID NO:29 to SEQ ID NO:31.

[0094] The process for preparing a peptide according to the first aspect of the invention comprises: (1.a) coupling by condensation of the corresponding amino acids of the peptide with compounds of formula (III) and (IV) corresponding to the amino acids designated "i" and "i+4" or "i+7". Compounds (III) and (IV) are then subjected to a subsequent cyclization step to generate the "L" biradical: [ka] (In the formula, R 19 is as defined above, Z1 and Z2 are the same or different, (C2 to C 10 ) alkenyl; and (1.b) a cyclization step comprising ring-closing metathesis of Z1 and Z2 carried out in solution using a Grubbs (first or second generation) catalyst (see Kim Young-Woo et al., "Synthesis of all-hydrocarbon stapled a-helical peptides by ring-closing olefin metathesis", Nature Protocols, 2011, 6(6), p. 761-771; Scott JM et al., "Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides", J. Am. Chem. Soc., 1996, v.118 (40), pp 9606-9614); or alternatively, (2a) Coupling by condensation of the required amino acids, including compounds of formula (V) and formula (VI) corresponding to the amino acids designated "i" and "i+4" or "i+7". Compounds (V) and (VI) are then subjected to a subsequent cyclization step to generate the "L" biradical: [ka] (In the formula, R 19 is as defined above, Z3 and Z4 are the same or different, halogen -SH, -NHR 20 , -OH, (C2-C 10 )Alkyl-SH, (C1-C 10 ) Alkyl-OH, (C1-C 10 )Alkyl-NHR 21 , C(=O)OH, (C1~C 10 )C(=O)OH, C(=O)NHR 22 , (C1~C 10 )Alkyl-C(=O)NHR 23 , OR 24 , C(=O)-halogen, C(=O)-OR 25 , S(=O)-Halogen, S(=O)-OR 26 , S(=O)2R 27 where R 20 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 and R 27 is hydrogen, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 ) alkynyl, a known ring system containing 3 to 14 carbon atoms, said system containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; The ring system is halogen, -OH, -NH2, -SH, C(=O)-halogen (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O- is a monoradical selected from the group consisting of known ring systems, optionally substituted with one or more radicals independently selected from the group consisting of; (2b) a cyclization step comprising a coupling reaction between a Z3 radical and a Z4 radical; or alternatively, (3a) Coupling by condensation of the corresponding amino acids of the peptide with compounds of formula (VII) and (VIII) corresponding to the amino acids designated "i" and "i+4" or "i+7". Compounds (VII) and (VIII) are then subjected to a subsequent cyclization step to generate the "L" biradical: [ka] (In the formula, R 19 is as defined above, and one of Z5 and Z6 is (C2 to C 10 ) alkynyl, and the other is (C 10 ) alkylN3; and (3.b) A cyclization step involving condensation of Z5 and Z6 radicals via known protocols such as the Cu(I)-mediated Huisgen 1,3-dipolar cycloaddition reaction (also known as the "click" reaction) to generate 1,4-substituted 1,2,3-triazole bridges (see Kolb HC et al., "The growing impact of click chemistry on drug discovery", 2003, Drug Discov Today, 8(24):1128-1137).

[0095] The process for preparing a peptide according to the second aspect of the invention involves coupling by condensation the carboxylic acid group or C-terminus of one amino acid with the amino group or N-terminus of another amino acid, and repeating this coupling reaction as many times as required to obtain the desired peptide.

[0096] Compounds of formula (III), (IV), (V), (VI), (VII) and (VIII) are commercially available and are coupled by condensation to portions of already formed peptide sequences. These compounds may carry beads for suitable solid phase synthesis of peptides, as well as carboxy, amino or side chain protecting groups. Illustrative non-limiting examples of compounds are 2-(2'-propenyl)alanine, 2-(3'-butenyl)glycine, 2-(4'-pentenyl)alanine, 2-(6'-heptenyl)alanine, 2-(7'-octenyl)alanine, allyl-glycine, 5-azido-norvaline and α-propargyl-alanine, among others.

[0097] The "coupling" step can be carried out in solid phase according to the protocol "deprotection-wash-coupling-wash" by condensation of the carboxylic acid group of one amino acid with the amino group of another amino acid residue using the amino acids as defined above and α-α di-substituted amino acids of formulae (III) to (VIII).

[0098] The general principle of solid phase peptide synthesis is repeated cycles of deprotection-wash-coupling-wash. The free N-terminal amine of the peptide attached to the solid phase is coupled to a single N-protected amino acid unit. This unit is then deprotected to expose a new N-terminal amine to which further amino acids can be attached. Amino acids have reactive moieties at the N-terminus and C-terminus, which facilitate amino acid coupling during synthesis. Many amino acids also have reactive side chain functionalities that can interact with free termini or other side chain groups during synthesis and peptide elongation, adversely affecting yield and purity. To minimize side chain reactivity and facilitate proper amino acid synthesis, chemical groups have been developed that bind to specific amino acid functionalities and prevent non-specific reactions of the functional groups or protect the functional groups. These protecting groups are found in great numbers in nature and can be divided into three groups: N-terminal protecting groups, C-terminal protecting groups (mainly used in solution phase synthesis) and side chain protecting groups.

[0099] For the coupling of peptides, the carboxyl group is usually activated. This is important to speed up the reaction. There are two main types of activating groups: carbodiimides and triazoles. However, the use of pentafluorophenyl esters (FDPP, PFPOH) and BOP-Cl are useful for the cyclization of peptides.

[0100] The individual purified amino acids are reacted with these protecting groups prior to synthesis, and then selectively removed at specific steps in the peptide synthesis.

[0101] Exemplary resins that can be used in the present invention include: (1) alkenyl resins (e.g., REM resins, vinylsulfone polymer-bound resins, vinyl-polystyrene resins); (2) amine-functionalized resins (e.g., amidine resins, polymer-bound N-(4-benzyloxybenzyl)hydroxylamine, (aminomethyl)polystyrene, polymer-bound (R)-(+)-a-methylbenzylamine, 2-chlorotrityl Knorr resin, 2-N-Fmoc-amino-dibenzocyclohepta-1,4-diene polymer-bound resin, 4-[4-(1-Fmoc-aminoethyl)-2-methoxy-5-nitrophenoxy]butyramidomethyl-polystyrene resin, polymer-bound 4-benzyloxybenzylamine, polymer-bound 4-carboxybenzenesulfonamide, polymer-bound bis(tert-butoxycarbonyl)thiopseudourea, dimethylaminomethyl-polystyrene resin, and the like). (3) benzhydrylamine (BHA) resins (e.g., polymer-bound 2-chlorobenzhydryl chloride, polymer-bound HMPB-benzhydrylamine, polymer-bound 4-methylbenzhydrol, polymer-bound benzhydryl chloride, polymer-bound benzhydrylamine); (4) Br-functionalized resins (e.g., polymer-bound 4-(benzyloxy)benzyl bromide, 4-bromopolystyrene, brominated PPOA resin, brominated Wang resin, polymer-bound bromoacetal, bromopolystyrene, HypoGel™). 200 Br, polystyrene A-Br for peptide synthesis, polymer-bound selenium bromide, TentaGel HL-Br, TentaGel MB-Br, TentaGel S-Br; (5) chloromethyl resins (e.g., polymer-bound 5-[4-(chloromethyl)phenyl]pentyl]styrene, polymer-bound 4-(benzyloxy)benzyl chloride, polymer-bound 4-methoxybenzhydryl chloride);(6) CHO-functionalized resins (e.g., (4-formyl-3-methoxyphenoxymethyl)polystyrene, (4-formyl-3-methoxyphenoxymethyl)polystyrene, polymer-bound 3-benzyloxybenzaldehyde, polymer-bound 4-benzyloxy-2,6-dimethoxybenzaldehyde, formyl polystyrene, HypoGel™ 200 CHO, indole resin, polystyrene A-CH(OEt)2, TentaGel HL-CH(OEt)2); (7) Cl-functionalized resins (e.g., polymer-bound benzoyl chloride, (chloromethyl)polystyrene, Merrifield resin); (8) CO2H-functionalized resins (e.g., carboxyethyl polystyrene, HypoGel™ 200 COOH, polystyrene AM-COOH, TentaGel HL-COOH, TentaGel MB-COOH, TentaGel S-COOH; (9) Hypo-Gel resins (e.g., HypoGel™ 200 FMP, HypoGel™ 200 PHB, HypoGel™ 200 Trt-OH, HypoGel™ 200 HMB); (10) I-functionalized resins (e.g., polymer-bound 4-iodophenol, iodopolystyrene); Janda-Jel™ (JandaJel; <au>-Rink amide, JandaJel-NH2, JandaJel-Cl, JandaJel-4-mercaptophenol, JandaJel-OH, JandaJel-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, JandaJel-1,3,4,6,7,8-hexahydro-2H-pyrimido-[1,2-a]pyrimidine, JandaJel-morpholine, JandaJel-polypyridine, JandaJel-triphenylphosphine, JandaJel-W ang); (11) MBHA resins (3[4'-(hydroxymethyl)phenoxy]propionic acid-4-methylbenzhydrylamine resin, 4-(hydroxymethyl)phenoxyacetic acid polymer bound to MBHA resin, polymer-bound HMBA-4-methylbenzhydrylamine, polymer-bound 4-methylbenzhydrylamine hydrochloride Capacity (amine)); (12) NH2-functionalized resins ((aminomethyl)polystyrene, (aminomethyl)polystyrene, HypoGel™) 200 NH2, polystyrene AM-NH2, 2-aminoethylated polystyrene microspheres, 2-bromoethylated polystyrol microspheres, 2-hydroxyethylated polystyrol microspheres, TentaGel HL-NH2, Tentagel M Br, Tentagel M NH2, Tentagel M OH, TentaGel MB-NH2, TentaGel S-NH2, TentaGel S-NH2; (13) OH-functionalized resins (e.g., polymer-bound 4-hydroxymethylbenzoic acid, hydroxymethyl resin, OH-functionalized Wang resin); (14) oxime resins (e.g., polymer-bound 4-chlorobenzophenone oxime, polymer-bound benzophenone oxime, polymer-bound 4-methoxybenzophenone oxime); (15) PEG resins (e.g., polymer-bound ethylene glycol);(16) Boc- / Blz peptide synthesis resin (e.g., Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]-Cys(Acm)-b-Ala-O-PAM resin, Boc-Lys(Fmoc)-Lys[Boc-Lys(Fmoc)]-b-Ala-O-Pam resin, Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]}-b-Ala-O-PAM resin, Boc-Lys(Fmoc)-Lys[Boc-Lys(Fmoc)]-Lys[Boc-Lys(Fmoc)-Lys{Boc-Lys(Fmoc)]}-b-Ala-O-PAM resin, Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]}-Cys(Acm)-b-Ala-O-PAM resin, preloaded type PAM resin); (17) Fmoc- / t-Bu peptide synthesis resin (e.g., Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]-b-Ala-O-Wang resin, Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]-Lys{Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]}-b-Ala-O-Wang resin, preloaded type TentaGel™ S trityl resin, preloaded type TentaGel™ resin, preloaded type trityl resin, preloaded type Wang resin, amino alcohol preloaded type trityl resin); (19) Thiol-functionalized resin (e.g., HypoGel™ 200 S-Trt, polystyrene AM-S-trityl, TentaGel HL-S-trityl, TentaGel MB-S-trityl, TentaGel S-S-trityl);and (20) Wang resin (e.g., Fmoc-Ala-Wang resin, Fmoc-Arg(Pbf)-Wang resin, Fmoc-Arg(Pmc)-Wang resin, Fmoc-Asn(Trt)-Wang resin, Fmoc-Asp(OtBu)-Wang resin, Fmoc-Cys(Acm)-Wang resin, Fmoc-Cys(StBu)-Wang resin, Fmoc-Cys(Trt)Wang resin, Fmoc-Gln(Trt)-Wang resin, Fmoc-Glu(OtBu)-Wang resin, Fmoc-Gly-Wang resin, Fmoc-His(Trt)-Wang resin, Fmoc-I Examples of suitable Wang resins include, but are not limited to, Fmoc-Leu-Wang resin, Fmoc-Lys(Boc)-Wang resin, Fmoc-Met-Wang resin, Fmoc-D-Met-Wang resin, Fmoc-Phe-Wang resin, Fmoc-Pro-Wang resin, Fmoc-Ser(tBu)-Wang resin, Fmoc-Ser(Trt)-Wang resin, Fmoc-Thr(tBu)-Wang resin, Fmoc-Trp(Boc)Wang resin, Fmoc-Trp-Wang resin, Fmoc-Tyr(tBu)-Wang resin, and Fmoc-Val-Wang resin.

[0102] "Protecting group" (PG) refers to a grouping of atoms attached to a reactive group in a molecule to block, reduce or prevent that reactivity.

[0103] Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylphenylcarbamate (Tm ... Tylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t -Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, albamate, Kyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonyl methyl carbamate, Tyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, phenothiazinyl-(10)-carbonyl derivatives, N'-p-toluenesulfonylaminocarbonyl derivatives, N'-phenylaminothiocarbonyl derivatives, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl Silcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxycarbonylvinylcarbamate, o-(N,N-dimethylcarboxamido)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isobornylcarbamate, isobutylcarbamate, isononylcarbamate, Cotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-Tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzyl carbamate, 2,4,6-trimethylbenzyl carbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, ( N'-Dithiobenzyloxycarbonylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, o-(benzoyloxymethyl)benzamide, 4,5-diphenyl-3-oxazolin-2-one, N-furan N-Dithiasuccinimide (Dts), N-2,3-Diphenylmaleimide, N-2,5-Dimethylpyrrole, N-1,1,4,4-Tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine Aminopropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-Dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1 -cyclohexenyl)amines, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentacarbonylchromium- or tungsten)carbonyl]amines, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthiophosphinamides (Mpt), diphenylthiophosphinamides (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides , o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, 3-nitropyridine sulfenamide (Npys), p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-meth 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylsulfonamide.

[0104] Examples of suitable protected carboxylic acids further include, but are not limited to, silyl, alkyl, alkenyl, aryl and arylalkyl protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, t-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl), and 2- and 4-picolyl.

[0105] In a third aspect, the present invention provides a fusion protein comprising a peptide as defined in the first or second aspect of the invention.

[0106] In the present invention, the term "fusion protein" refers to a protein which joins the peptide of the present invention to one or more peptides which originally belong to another, separate protein(s).

[0107] In one embodiment of the first, second or third aspect of the invention in any combination with any of the embodiments presented above or below, the peptide or fusion protein is conjugated to a moiety such as a label, a drug, a cell membrane penetrating peptide or polyethylene glycol (PEG). Routine synthetic protocols for conjugating moieties to the peptide or fusion protein of the invention are known.

[0108] In another embodiment of the first, second or third aspect of the invention in any combination with any of the embodiments set out above or below, the peptide or fusion protein is conjugated to a label. In another embodiment of the first, second or third aspect of the invention in any combination with any of the embodiments set out above or below, the label is conjugated to the N-terminus or C-terminus of the peptide or fusion protein.

[0109] A "label" as used herein is a molecule or compound that can be detected by various methods, including fluorescence, electrical conductivity, radioactivity, size, etc. A label may be inherently capable of emitting a signal, such as a fluorescent label that emits light of a particular wavelength following excitation of another lower characteristic wavelength of light. Alternatively, a label may not be inherently capable of emitting a signal, but may be capable of being bound by another compound that does emit a signal. An example of this latter situation is a label such as biotin that does not itself emit a signal, but can be detected when bound to a labeled avidin or streptavidin molecule. Another example of this latter type of label is a ligand that specifically binds to a particular receptor. A detectably labeled receptor can be bound to a unit specific marker labeled with a ligand, allowing such a marker to be visualized.

[0110] Labels that can be used in accordance with the present invention include, but are not limited to, electron spin resonance molecules, fluorescent molecules, chemiluminescent molecules, radioisotopes, enzyme substrates, enzymes, biotin molecules, avidin molecules, charge transfer molecules, semiconductor nanocrystals, semiconductor nanoparticles, colloidal gold nanocrystals, ligands, microbeads, magnetic beads, paramagnetic molecules, quantum dots, chromogenic substrates, affinity molecules, proteins, peptides, nucleic acids, carbohydrates, haptens, antigens, antibodies, antibody fragments, and lipids.

[0111] Radioisotopes can be detected using film or charge-coupled devices (CCDs), ligands can be detected by binding of receptors bearing fluorescent, chemiluminescent or enzyme tags, and microbeads can be detected using electron or atomic force microscopy.

[0112] Conjugation of the label to the peptide can be carried out according to routine protocols known to those skilled in the art.

[0113] In another embodiment, the peptide of the first or second aspect of the invention or the fusion protein of the third aspect of the invention, in any combination with any of the embodiments presented above or below, is conjugated to a drug. In one embodiment, the drug is conjugated to the N-terminus of the peptide or protein.

[0114] In another embodiment, the peptide of the first or second aspect of the invention or the fusion protein of the third aspect of the invention, in any combination with any of the embodiments set out above or below, is conjugated to PEG, in one embodiment PEG is conjugated to the N-terminus of the peptide or protein.

[0115] The term "PEG" is used herein synonymously for polyethylene glycol and its derivatives, such as those with one methoxylated end, e.g., methoxy-polyethylene glycol / polyethylene glycol monomethyl ether. It is known to those skilled in the art that any of these compounds can be used to modify drugs, and that the end groups at one end of the PEG chain may be different, with the hydroxyl group being modified with a methoxy group. Furthermore, it is known to those skilled in the art that in order to specifically couple PEG to a peptide, the other end of the PEG must be modified with a specific "activating group". A summary of such activating groups is given in Zalipsky, Bioconjugate Chem. 1995, 6, 150-165. The molecular weight of the PEG used for conjugation can be appropriately changed depending on the degree of sustained efficacy required for the resulting PEG-conjugated peptide. The molecular weight of one PEG molecule is 5 kDa to 40 kDa, e.g., 10 kDa to 30 kDa or 20 kDa to 30 kDa. The PEG molecule used for conjugation can have a linear, branched or star-shaped morphology.

[0116] In another embodiment of the first or second aspect of the invention in any combination with any of the embodiments set out above or below, the peptide is conjugated to a cell membrane penetrating peptide.

[0117] In the present invention, the term "cell membrane penetrating peptide" ("CPP") refers to short peptides that facilitate cellular uptake of various molecular cargoes (from nano-sized particles to small chemical molecules and large fragments of DNA). The "cargo" is associated to the peptide via its C(t) or N(t) terminus, either by covalent chemical linkage or non-covalent interactions. The function of CPPs is to deliver cargo into cells, a process that generally occurs by endocytosis. Current use is limited due to the lack of cell specificity in cargo delivery via CPPs and an incomplete understanding of their uptake mode. CPPs typically have an amino acid composition that either contains a high relative abundance of positively charged amino acids such as lysine or arginine, or sequences that contain alternating patterns of polar / charged and non-polar hydrophobic amino acids. These two types of structures are referred to as polycationic or amphipathic, respectively. The third group of CPPs are hydrophobic peptides that contain only non-polar residues with low net charge, or have hydrophobic amino acid groups essential for cellular uptake. Conjugation of CPPs with the peptides provided in the present invention can be carried out according to known routine protocols such as solid-phase synthesis or solution selective capping (see Copolovici DM et al., "Cell-Penetrating Peptides: Design, Synthesis, and Applications", 2014, ACS Nano, 2014, 8 (3), pp 1972-1994). In another embodiment of the first aspect of the present invention in any combination with any of the embodiments presented above or below, the cell membrane penetrating peptide is a polycationic CPP, polyArg or alternatively penetratine.

[0118] In a fourth aspect, the present invention provides a pharmaceutical composition.

[0119] The phrase "therapeutically effective amount" as used herein refers to an amount of compound (i.e., peptide or a pharma- ceutically acceptable salt thereof) that is sufficient to enter the bloodstream when administered and prevent or alleviate to some extent one or more symptoms of the disease being addressed. The particular dose of peptide administered in accordance with the present invention will, of course, depend on the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.

[0120] The term "pharmaceutical acceptable" refers to excipients or carriers suitable for use in pharmaceutical techniques to prepare compositions for medical use.

[0121] The expression "excipient and / or carrier" refers to an acceptable material, composition or vehicle. Each component must be pharma- ceutically acceptable in the sense of being compatible with the other components of the composition. Each component must also be suitable for use in contact with tissues or organs of humans and non-human animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications, and must be commensurate with an appropriate benefit / risk ratio. Examples of suitable acceptable excipients are solvents, dispersion media, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like. Use of any conventional excipient vehicle is contemplated within the scope of the present invention, except insofar as it is incompatible with the substance or its derivatives, for example, by producing any undesirable biological effects or otherwise interacting adversely with any other component(s) of the pharmaceutical composition.

[0122] The formulations of the pharmaceutical compositions described herein can be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparation methods include the step of combining the active ingredient (peptide) with an excipient and / or one or more other accessory ingredients, and then, as necessary and / or desired, shaping and / or packaging the product into the desired single or multiple dosage unit.

[0123] Pharmaceutical compositions of the invention may be prepared, packaged, and / or sold in bulk as a single unit dose and / or a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.

[0124] The relative amounts of the active ingredient (i.e., a peptide as defined in any of the previous aspects and embodiments), acceptable excipients and / or any additional ingredients in the compositions of the invention will vary depending on the identity, size and / or condition of the subject being treated, as well as the route by which the composition is administered.

[0125] Acceptable additives used in the preparation of these compositions include, but are not limited to, inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Such additives may be optionally included in the formulations of the present invention. Additives such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents and perfuming agents may also be present in the compositions according to the judgment of the formulator.

[0126] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.

[0127] Exemplary granulating and / or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethylcellulose, cross-linked sodium carboxymethylcellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethylcellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof.

[0128] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, disodium EDTA, glyceryl stearate ... ethylene glycol stearate, glyceryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymers and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylenesorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers (e.g. polyoxyethylene lauryl ether (Brij 30), Poly(vinyl-pyrrolidone), Diethylene glycol monolaurate, Triethanolamine oleate, Sodium oleate, Potassium oleate, Ethyl oleate, Oleic acid, Ethyl laurate, Sodium lauryl sulfate, PluronicF 68, poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and the like, and / or combinations thereof.

[0129] Exemplary binders include, but are not limited to, starches (e.g., corn starch and starch paste); gelatin; sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g., gum arabic, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husk, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, microcrystalline cellulose, cellulose acetate, polyvinylpyrrolidone), magnesium aluminum silicate (Veegum) and larch arabinogalactan; alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water; alcohol; and combinations thereof.

[0130] Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butylparaben, methylparaben, ethylparaben, propylparaben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.In certain embodiments, the preservative is an antioxidant.In other embodiments, the preservative is a chelating agent.

[0131] Exemplary buffering agents include, but are not limited to, citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and combinations thereof.

[0132] Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

[0133] Exemplary oils include almond, apricot kernel, avocado, babassu, bergamot, black currant seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, palm, cod liver, coffee, corn, cottonseed, emu, eucalyptus, evening primrose, fish, linseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, lily of the valley, macadamia. Examples of suitable oils include, but are not limited to, annatto, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, camellia, vetiver, walnut, and wheat germ oil. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

[0134] Liquid dosage forms for parenteral administration include, but are not limited to, pharma- ceutically acceptable liposome emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents, such as polyethoxylated castor oil (e.g., CREMOPHOR™), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

[0135] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Sterile injectable preparations can be sterile injectable solutions, suspensions or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as a solution in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Alternatively, the preparation can be in the form of liposomes.

[0136] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water, or other sterile injectable medium prior to use.

[0137] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.In this case, the absorption rate of the drug varies depending on its dissolution rate, which may vary depending on crystal size and crystalline form.Alternatively, delayed absorption of parenterally administered drug forms can be achieved by dissolving or suspending the drug in an oil vehicle.

[0138] The peptides of the present invention may be in microencapsulated form with one or more of the additives described above. In one embodiment, the peptides of the present invention are formulated in liposomes.

[0139] It will be understood that the peptides and pharmaceutical compositions of the present invention can be used in combination therapy. The specific combination of therapies (therapeutics or treatments) used in the combination regimen will take into account the compatibility of the desired therapies and / or treatments, and the desired therapeutic effect to be achieved. It will be understood that the therapies used may be those that achieve the same desired effect or those that achieve different effects (e.g., control of any adverse effects).

[0140] The pharmaceutical compositions of the present invention can be administered alone or in combination with one or more other therapeutic agents. "In combination with" is not intended to mean that the agents must be administered simultaneously and / or formulated to be delivered together, although these delivery methods are within the scope of the present invention. The compositions can be administered simultaneously with, prior to, or after one or more other desired therapeutic or medical procedures. In general, each agent is administered at a dose and / or time schedule determined for that agent. Additionally, the present invention encompasses delivery of peptides or pharmaceutical compositions in combination with agents that can improve the bioavailability of the peptides or pharmaceutical compositions, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in the body.

[0141] The particular combination of therapies used in a combination regimen will take into account compatibility of the desired therapeutics and / or treatments and / or the desired therapeutic effect to be achieved. It will be understood that the therapies used may achieve the desired effect on the same disorder (e.g., the peptide of the present invention may be administered simultaneously with another bioactive agent used to treat the same disorder) and / or may achieve a different effect (e.g., control of any adverse effects). It will be further understood that the bioactive agents utilized in the combination may be administered together in a single composition or separately in different compositions.

[0142] The term "in combination with" also encompasses the possibility of conjugating (by chemical-physical interaction) the peptide of the invention with any of the further agents mentioned above and below, which may in particular be therapeutic agents or agents that improve the profile (such as bioavailability) of the peptide.

[0143] In a sixth and seventh aspect, the present invention provides a peptide according to the first and second aspects of the invention, a fusion protein according to the third aspect or a pharmaceutical composition according to the fourth aspect of the invention, respectively, for use in the prevention or treatment of a disease caused by dysregulation of VEGF expression and angiogenesis. This aspect may alternatively be constructed as a method for preventing or treating a disease caused by dysregulation of VEGF expression or angiogenesis, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention or a pharmaceutical composition as defined in the fourth aspect of the invention. This aspect may alternatively be constructed as the use of a peptide as defined in the first or second aspect of the invention or a pharmaceutical salt thereof, or a fusion protein as defined in the third aspect of the invention or a pharmaceutical composition as defined in the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease caused by dysregulation of VEGF expression or angiogenesis. The term "VEGF expression level" refers to either the level of VEGF protein or mRNA. In one embodiment of the present invention, the peptide of the present invention promotes the regulation of VEGF mRNA. In another embodiment of the invention, the peptides of the invention promote the regulation of VEGF protein.There are commercially available kits for determining the amount of VEGF at the protein or mRNA level.

[0144] In the context of the present invention, dysregulation of angiogenesis is due to changes in VEGF expression levels. Thus, there are diseases in which dysregulation of angiogenesis is due to increased VEGF expression. In such situations, peptides of the first aspect of the invention comprising the biradical "L" may be useful, as they are able to reduce VEGF expression (see data presented below). Thus, in one embodiment of the sixth and seventh aspects of the invention, a peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above, and is used for the treatment or prevention of diseases resulting from elevated VEGF levels. Illustrative non-limiting examples of diseases resulting from elevated VEGF levels are in particular diabetic retinopathy, age-related macular degeneration (AMD), blinding disorders such as glaucoma, psoriasis, chronic obstructive pulmonary disease and cancer (Cameliet P. 2003).

[0145] Preferred embodiments of the sixth and seventh aspects of the invention relate to a peptide of the first and second aspects of the invention, a fusion protein of the third aspect or a pharmaceutical composition of the fourth aspect of the invention for use in the prevention or treatment of cancer, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above. Related embodiments of the sixth and seventh aspects of the invention relate to a method for treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide of the first and second aspects of the invention, a fusion protein of the third aspect or a pharmaceutical composition of the fourth aspect of the invention, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above. Further related embodiments of the sixth and seventh aspects of the invention relate to the use of a peptide of the first and second aspects of the invention, a fusion protein of the third aspect or a pharmaceutical composition of the fourth aspect of the invention in the manufacture of a medicament for the prevention or treatment of cancer, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above.

[0146] The term "cancer" as used herein includes carcinoma, lymphoma, blastoma, sarcoma, myeloma (e.g., multiple myeloma) and leukemia (e.g., acute myeloid leukemia). More specific examples of such cancers include breast cancer, squamous cell carcinoma, small cell lung cancer, non-small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, peritoneal cancer, hepatocellular carcinoma, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, colon cancer, colorectal cancer, endometrial or uterine cancer, salivary gland cancer, kidney cancer, liver cancer, prostate cancer, renal cancer, vulvar cancer, thyroid cancer, liver cancer, gastric cancer, melanoma, and various types of head and neck cancer.

[0147] In a more specific embodiment, the peptide of the first and second aspects of the invention, the fusion protein of the third aspect or the pharmaceutical composition of the fourth aspect of the invention, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above, is used for the treatment or prevention of cancer in combination with one or more anti-cancer agents.

[0148] The term anti-cancer agent may include, but is not limited to, chemotherapeutic agents, growth inhibitory agents, cytotoxic agents, anti-hormonal agents, agents used in radiotherapy, anti-angiogenic agents, apoptotic agents, anti-tubulin agents, etc., and any combination thereof. The above anti-cancer agents may be administered before, simultaneously with, or after the cyclic peptides, fusion proteins, or pharmaceutical compositions described herein. Two or more drugs may form part of the same composition, or may be provided as separate compositions that are administered at the same time or at different times.

[0149] In other particular embodiments, the peptide of the first and second aspects of the invention, the fusion protein of the third aspect or the pharmaceutical composition of the fourth aspect of the invention, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above, is used for the treatment or prevention of blinding disorders such as diabetic retinopathy, age-related macular degeneration (AMD) or glaucoma in combination with one or more standard of care treatments, such as anti-VEGF therapy or photodynamic therapy (PDT).

[0150] In a further particular embodiment, the peptide of the first and second aspects of the invention, the fusion protein of the third aspect or the pharmaceutical composition of the fourth aspect of the invention, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above, is used for the treatment or prevention of psoriasis in combination with one or more standard of care drugs, such as corticosteroids or other immune system modulating agents.

[0151] In a further particular embodiment, the peptide of the first and second aspects of the invention, the fusion protein of the third aspect or the pharmaceutical composition of the fourth aspect of the invention, wherein the peptide is according to the first aspect and comprises a linker biradical "L" as defined in any of the embodiments presented above, is used for the treatment or prevention of chronic obstructive pulmonary disease in combination with one or more standard of care drugs such as bronchodilators or corticosteroids.

[0152] In other situations, the dysregulation of angiogenesis is due to a decrease in VEGF expression. Thus, in an alternative embodiment of the sixth and seventh aspects of the invention, the peptide is either a linear peptide as provided under the first aspect of the invention or one as provided under the second aspect of the invention, for use in the treatment or prevention of a disease resulting from reduced VEGF levels. In a further embodiment of the sixth and seventh aspects of the invention, the invention provides a method for treating or preventing a disease resulting from reduced VEGF levels, comprising administering to a subject in need thereof a therapeutically effective amount of a peptide according to the first and second aspects of the invention, a fusion protein according to the third aspect or a pharmaceutical composition according to the fourth aspect of the invention, wherein the peptide is either a linear peptide as provided under the first aspect of the invention or one as provided under the second aspect of the invention. In a further related embodiment, the invention relates to the use of a peptide according to the first and second aspects of the invention, a fusion protein according to the third aspect or a pharmaceutical composition according to the fourth aspect of the invention, in the manufacture of a medicament for the treatment or prevention of a disease resulting from reduced VEGF levels, wherein the peptide is either a linear peptide as provided under the first aspect of the invention or one as provided under the second aspect of the invention, in a subject in need thereof.

[0153] Either the linear peptides provided under the first aspect of the invention or those provided under the second aspect of the invention increase low VEGF levels and stimulate VEGF production (data also presented below). Illustrative non-limiting examples of diseases associated with reduced angiogenesis and VEGF expression levels are pulmonary fibrosis, ischemic tissue injury, gastric ulcers, nephropathy, bone loss, motor neuron degeneration, chronic wounds, skin vascular fragility, among others (Manish B. et al., 2010).

[0154] Throughout the specification and claims, the word "comprise" and variations of this word are not intended to exclude other technical features, additives, components or steps. Furthermore, the word "comprise" also encompasses the term "consisting of." Additional objects, advantages and features of the present invention will become apparent to those skilled in the art upon examination of the specification or may be learned by practice of the present invention. The following examples are offered by way of illustration and are not intended to limit the present invention. Moreover, the present invention encompasses all possible combinations of the specific preferred embodiments described herein. EXAMPLES

[0155] Example 1: Regulation of VEGF by peptides of the invention under hypoxic-induced conditions in human retinal pigment epithelium (RPE), human keratinocytes and human breast cancer cell lines 1. Materials and Methods Basic synthesis procedure Materials were purchased as follows: Fmoc-protected α-amino acids (---); Rink amide MBHA resin (Tianjin Nankai HECHENG S&T Co., Ltd); HBTU ((2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), GL Biochem); N-methylmorpholine (Sinopharm Chemical Reagent Co., Ltd.); succinic anhydride (Aladdin); acetonitrile (Xingke Chemical); ninhydrin (Sinopharm Chemical Reagent Co., Ltd.); piperidine (Vertellus); dimethylformamide, DMF (Zhejiang jiangshan chemical co., Ltd); trifluoroacetic acid, TFA (trifluoroacetic acid, Solvay), TIS (thioanisole, Solvay).

[0156] Briefly, linear polypeptides were manually synthesized using Fmoc-based SPPS (solid phase peptide synthesis) on Rink amide MBHA resin as support.

[0157] The following protocol was used: 1. The Fmoc protecting group was removed with 20% piperidine in DMF. 2. The resin was washed five times with DMF. 3. The subsequent Fmoc-protected amino acid was coupled using Fmoc-AA (3 eq.), HBTU (3 eq.) and N-methylmorpholine (6 eq.) for 45 min. 4. The resin was washed 5 times with DMF. Coupling was confirmed by the ninhydrin test. 5. Repeat from step 1. 6. The N-terminus was capped by reaction with succinic anhydride (10 eq.) and N-methylmorpholine (10 eq.).

[0158] The peptide was cleaved from the resin, deprotected by exposure to solution F (95% TFA, 2.5% water, 2.5% TIS) and lyophilized.

[0159] Lyophilized peptides were purified by reversed-phase HPLC using a C18 column (see compound characterization for details). Peptides were identified by LC-MS-ESI. Full mass spectral data for all compounds are shown in Table 1 below.

[0160] Materials were purchased as follows: Fmoc-protected α-amino acids (including the olefinic amino acids Fmoc-[(S)-2-(4-pentenyl)alanine]OH, Fmoc-[(R)-2-(4-pentenyl)alanine]OH, Fmoc-[(S)-2-(7-octenyl)alanine]OH, Fmoc-[(R)-2-(4-pentenyl)alanine]OH), 2-(6-chloro-1-H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (TBTU), resin, dimethylformamide (DMF), N,N-diisopropylethylamine (DIEA), trifluoroacetic acid (TFA), 1,2-dichloroethane (DCE), Grubbs Ru(IV) catalyst, and piperidine were purchased from various suppliers.

[0161] Briefly, linear polypeptides were synthesized on an automated synthesizer using Fmoc solid-phase peptide chemistry. Only the coupling with the olefinic amino acid was performed manually after removing the resin from the reactor as disclosed in the previous section.

[0162] The ring-closing metathesis reaction was carried out in solution with the first generation Grubbs catalyst after cleavage of the linear peptide from the resin as disclosed by Scott JM et al. (Scott JM et al., "Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides", 1996, J. Am. Chem. Soc., 1996, 118 (40), pp 9606-9614).

[0163] The deprotected peptide was precipitated with methyl-tert-butyl ether at 4° C. and lyophilized.

[0164] Lyophilized peptides were purified by reversed-phase HPLC using an Agilent ZORBAX 300SB-C18 5 μm column (see compound characterization for details). Peptides were identified by LC-MS-ESI. Full mass spectral data for all compounds are shown in Table 1 below.

[0165] HPLC conditions: SEQ ID NO: 13. The compound was purified by HPLC-RP (C-18 column; pump A: 100% H2O with 0.1% TFA; pump B 80%: acetonitrile with 0.1% TFA) with a linear gradient of 29% → 39% B in 20 min (RT = 10.2). Purity grade by HPLC 95.16%; SEQ ID NO: 14. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 40% → 50% B in 20 min (RT = 6.5-7.8). Purity grade by HPLC > 95%; SEQ ID NO: 15. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 36% → 46% B in 20 min (RT = 9.2 to 10.3). Purity grade by HPLC > 95%; SEQ ID NO: 16. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 50% → 60% B in 20 min (RT = 10.3 to 10.9). Purity grade by HPLC > 95%; SEQ ID NO: 17. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 35% → 55% B in 20 min (RT = 12.5 to 13.1). Purity grade by HPLC > 95%; SEQ ID NO:18. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 55% → 75% B in 20 min (RT = 8.5-9.3). Purity grade by HPLC >95%; SEQ ID NO:19. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 36% → 46% B in 20 min (RT = 9.9 to 10.4). Purity grade by HPLC >95%; SEQ ID NO: 20. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 35% → 45% B in 20 min (RT = 9.8 to 10.4). Purity grade by HPLC > 95%; SEQ ID NO:21. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 45% → 55% B in 20 min (RT = 13.2 to 14.4). Purity grade by HPLC: 95.7%; SEQ ID NO:29. Compound was purified by HPLC-RP (C-18 column; Pump A: 100% HO with 0.1% TFA; Pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 38% → 48% B in 20 min (RT = 8.9 to 9.3). Purity grade by HPLC: 95.13%; SEQ ID NO: 30. Compound was purified by HPLC-RP (C-18 column; Pump A: 100% HO with 0.1% TFA; Pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 36% → 46% B in 20 min (RT = 12.4). Purity grade by HPLC: 95.13%; SEQ ID NO: 31. Compound was purified by HPLC-RP (C-18 column; pump A: 100% HO with 0.1% TFA; pump B: 80% acetonitrile with 0.1% TFA) with a linear gradient of 28% → 48% B in 20 min (RT = 9.9 to 10.2). Purity grade by HPLC: 95.13%; SEQ ID NO: 36. Compound was purified by HPLC-RP (C-18 column; Pump B: 100% H2O with 0.1% TFA; Pump A: 100% acetonitrile with 0.1% TFA) using a linear gradient of 23% → 48% A in 25 min (RT = 11.2). Purity grade by HPLC 96.65%; SEQ ID NO: 37. The compound was purified by HPLC-RP (C-18 column; Pump B: 100% H2O with 0.1% TFA; Pump A: 100% acetonitrile with 0.1% TFA) using a linear gradient of 24% → 49% A in 25 min (RT = 9.54). Purity grade by HPLC: 96.42%;

[0166] [Table 1]

[0167] Cell lines, cell culture and hypoxic induction conditions MDA-MB-231 human breast cancer cell line, HaCat immortalized human keratinocyte cell line, and ARPE-19 human retinal pigment epithelium (RPE) cell line were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA). Human cells were routinely authenticated using genotype profiling according to ATCC guidelines. ARPE-19 cells were maintained in DMEM / F12 medium containing 10% fetal bovine serum and HEPES supplemented with antibiotics. MDA-MB-231 and HaCaT were maintained in DMEM medium containing 4.5 grams (gr) / L glucose, glutamine, and 2 mM pyruvate, supplemented with 10% fetal bovine serum and antibiotics.

[0168] Hypoxia was effectively induced in assay cells treated with CoCl2. Fresh 0.4M CoCl2 stock solutions were prepared in water and added to the culture medium to obtain concentrations of 50 μM for MDA-MB-231, 200 μM for HaCaT, and 300 μM for ARPE-19 cells. Cells were incubated with the respective CoCl2 concentrations for 24 h to mimic hypoxic conditions.

[0169] VEGF assay The VEGF content of the cultured cell supernatants was measured by VEGF-ELISA (Abcam; ab100662; Cambridge, UK) according to the manufacturer's instructions. The detection range of the ELISA was 8.23 ​​pg / ml to 6000 pg / ml. The ELISA detects all isoforms of human VEGF-A. The assay was performed on untreated cells under normoxic and hypoxic conditions, and the ratio of the amount of VEGF in hypoxia to the amount of VEGF in normoxic conditions at 24 hours was determined and calculated to be >1 for each cell line tested. The same procedure was used in the presence of the peptides of the invention.

[0170] Real-time quantitative RT-PCR Extraction of RNA from the indicated cells was performed using the NZY Total RNA Isolation Kit (Nzytech, Lisboa, Portugal) and cDNA was prepared using the NZY First-Strand cDNA Synthesis Kit (Nzytech). Primers were designed using Primer Blast software (NCBI) and obtained from Thermo-Fisher. mRNA expression levels were assessed by qRT-PCR (QuantStudio 5 Real-Time PCR System, Applied Biosystems, Foster City, CA, USA) using SYBR green master mix (Applied Biosystems) and normalized to β-actin. The following primers were used in this study: β-actin (forward: 5'-AGA AAA TCT GGC ACC ACA CC-3' (SEQ ID NO: 32); reverse: 5'-GGG GTG TTG AAG GTC TCA AA-3' (SEQ ID NO: 33)); VGFA (forward: 5'-TAC TGC CAT CCA ATC GAG AC-3' (SEQ ID NO: 34); reverse: 5'-GCA TGG TGA TGT TGG ACT-3' (SEQ ID NO: 35)).

[0171] statistical analysis RT-PCR experiments were repeated at least twice. For VEGF assays, the mean ± SD of three determinations performed in triplicate was calculated. Statistical significance was determined using the Mann-Whitney test for comparison of means in SPPS statistical software for Microsoft Windows, release 6.0 (Professional Statistic, Chicago, IL, USA). Individual comparisons were performed using the Student's unpaired two-tailed t test. The criterion for significance was P<0.05 for all comparisons.

[0172] 2. Results The aim of this study was to determine the regulation of VEGF by peptides in hypoxia-inducing conditions in ARPE-19 cell line. VEGF protein (using ELISA kit) was calculated in hypoxia vs normoxia in untreated cells to set the activity threshold. Cells were then treated with a solution of 20 μM of the corresponding peptide of the invention dissolved in cell culture medium alone (normoxic conditions) or in the presence of CoCl2 (hypoxic conditions) and the ratio of VEGF protein amount was calculated. As reported in Table 2, VEGF protein amount was higher than that in untreated cells. hyp / VEGF norm Peptides showing a ratio were considered inducers of VEGF protein and were considered to have a lower VEGF protein than the ratio in untreated cells. hyp / VEGF norm Peptides yielding this ratio were considered reducers of VEGF protein.

[0173] [Table 2]

[0174] [Table 3]

[0175] The results show that the peptides of the present invention can significantly modulate VEGF levels.

[0176] In particular, the linear peptide of the first aspect of the invention increased VEGF levels under hypoxic conditions. Surprisingly, when the peptide of the first aspect of the invention contains a staple, its behavior towards VEGF is significantly changed, resulting in a dramatic reduction of VEGF by about 50%. Thus, the inventors have found that peptides comprising the sequence of SEQ ID NO:1 can modulate VEGF and thus angiogenesis with or without the linker biradical "L" in the sequence of SEQ ID NO:1. The absence of a linker results in a peptide that enhances VEGF expression and thus "enhances" angiogenesis, while the presence of a linker results in a peptide that reduces VEGF expression and thus "reduces" angiogenesis.

[0177] It has been found that the peptides of the second aspect of the invention are capable of increasing VEGF expression under hypoxic conditions relative to the levels obtained under normoxic conditions, and therefore may also be useful in restoring VEGF levels in situations where there has been a depletion of the growth factor.

[0178] To confirm this result, the peptide of SEQ ID NO: 16 was tested in human keratocyte and MDA-MB-231 cell lines, cell lines in which induction of hypoxic conditions induces an increase in VEGF protein expression compared to normoxia. Cells were treated with a solution of 10 μM of the peptide of the invention dissolved in cell culture medium alone (normoxic conditions) or in the presence of CoCl2 (hypoxic conditions) and the ratio of VEGF amounts was calculated. The results are reported in Table 4.

[0179] [Table 4]

[0180] The results show that the peptides of the invention reduced the VEGF ratio, consistent with the results obtained in ARPE-19 cells.

[0181] VEGF expression regulation was also determined by RP-PCR in ARPE-19 cells treated with 10 μM of peptide SEQ ID NO: 17 for 24 hours under normoxic and hypoxic conditions. The results are reported in Table 5.

[0182] [Table 5]

[0183] When cells were in hypoxic conditions, a clear increase in the level of VEGF mRNA was detected. The results show that treatment with peptide of SEQ ID NO: 17 significantly reduced the mRNA level compared to untreated cells in hypoxia, whereas only a slight reduction was detected in normoxia.

[0184] Example 2: Reduction of angiogenesis in vivo 1. Materials and Methods MDA-MB-231 cells were inoculated into the mammary fat pad of athymic mice in 100 μl of DMEM (2.5 × 10 6 cells / animal). Tumors were 100 mm 3 Once the tumors reached a volume of 1000 mg / kg, animals were divided into groups and treated twice weekly with vehicle administered sc (2% Tween-20 in 0.9% sterile NaCl, control group) or twice weekly with SEQ ID NO: 17 administered sc (treated group). At the time of sacrifice, tumors were harvested, weighed and fixed in formalin (24 h). Formalin-fixed tumors were processed for paraffin-embedded tissue blocks and sent to the Dept. Bioquímica y Biologia Molecular A, Facultad de Veterinaria, Universidad de Murcia for analysis.

[0185] Histology and immunohistochemistry Hematoxylin, eosin, diaminobenzidine tetrahydrochloride and hydrogen peroxide were from Merck (Madrid, Spain). Mouse monoclonal anti-CD31 antibody was from Novus. In immunohistochemistry, CD31 is primarily used to demonstrate the presence of endothelial cells in histological tissue sections and to assess the degree of angiogenesis in tumors.

[0186] Tumors were washed with PBS, fixed in 10% formalin and embedded in paraffin.

[0187] Hematoxylin and eosin (H&E) staining was performed on serial sections of paraffin-embedded tissues. For immunohistochemistry, paraffin sections were deparaffinized and subjected to antigen retrieval in sodium citrate buffer (pH 6.0). Endogenous peroxidase in tissues was inactivated with 5% hydrogen peroxide. Slides were blocked and incubated with primary antibodies overnight at 4°C. Slides were then incubated with secondary antibodies conjugated with peroxidase, and specific reactions were developed with 0.2% diaminobenzidine tetrahydrochloride and hydrogen peroxide. Stained slides were scanned using an SCN400F Leica scanner, and images were analyzed using ImageJ software.

[0188] 2. Results CD31 staining images (Figure 1) and calculated relative intensity of CD31 (Figure 2) show a significant reduction in blood vessels (angiogenesis) in treated tumors compared to controls.

[0189] References Altschul et al., "Basic local alignment search tool", 1990, J. Mol. Biol, v. 215, pages 403-410. Carmeliet P., "Angiogenesis in health and disease", Nature Medicine, 2003, 9, 653-660. Copolovici DM et al., "Cell-Penetrating Peptides: Design, Synthesis, and Applications", 2014, ACS Nano, 2014, 8 (3), pp 1972-1994. Higgins et al., "CLUSTAL V: improved software for multiple sequence alignment", 1992, CABIOS, 8(2), pages 189-191. Kim Young-Woo et al., "Synthesis of all-hydrocarbon stapled a-helical peptides by ring-closing olefin metathesis", Nature Protocols, 2011, 6(6), p. 761-771. Kolb HC et al., "The growing impact of click chemistry on drug discovery", 2003, Drug Discov Today, 8(24):1128-1137. Manisha B. et al., "Angiogenesis: Future of pharmacological modulation", Indian J. Pharmacol., 2010, 42(1), pages 2-8. Scott JM et al., "Application of Ring-Closing Metathesis to the Synthesis of Rigidified Amino Acids and Peptides", J. Am. Chem. Soc., 1996, v.118 (40), pp 9606-9614. Zalipsky S., "Functionalized Poly(ethylene glycols) for Preparation of Biologically Relevant Conjugates", Bioconjugate Chemistry, 1995, 6 (2), 150-165.

[0190] Item(Clause) For completeness, various aspects of the invention are described in the following numbered paragraphs. Item 1. A sequence having a length of 14 to 50 and SEQ ID NO:1: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q (where: "m", "n", "p" and "q" represent integers and are selected from 0 and 1; The C-terminus corresponds to -C(O)R4, A peptide or a pharmaceutical salt thereof, comprising a sequence having at least 85% sequence identity to a peptide having an N-terminus corresponding to -NHR5, The peptide optionally comprises a peptide of formula (I) linking the alpha carbon atom of an amino acid located at position "i" with the alpha carbon atom of an amino acid located at position "i+4" or "i+7" in the peptide sequence of SEQ ID NO:1: -[(R1) a -(R2)-(R3) b ] c - (I) (In the formula, "a" and "b" are the same or different and are 0 or 1; "c" is composed of 1 to 10, R1 and R3 are (C1 to C 10 )Alkyl;Halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 )Alkyl;(C2-C 10 ) alkenyl; halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkenyl; (C2-C 10 ) alkynyl; and halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) Alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; Ring systems include halogen, -OH, -NO2, (C1-C 10 ) Alkyl, (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O-; R4 is -OH and -NR 17 R 18 is a radical selected from the group consisting of R5 is -H and (C1 to C 20 ) alkyl, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 is -H and (C1 to C 10 ) alkyl; The amino acids linked by the linker have the formula (II): [ka] (In the formula, R 19 (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, as well as known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; Each of the members forming the known ring systems is a monoradical selected from the group consisting of known ring systems selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S-, and -O-. Item 2. A peptide according to item 1, consisting of the sequence of SEQ ID NO:1, optionally including a linker biradical "L" of formula (I) as defined in item 1. Item 3. A peptide according to any one of the preceding items, comprising a linker biradical "L" of formula (I) between the alpha carbon atom of the amino acid located at position "i" and the alpha carbon atom of the amino acid located at position "i+7" in the peptide sequence of SEQ ID NO:1. Item 4. SEQ ID NO: 2: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 3: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 4: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q, SEQ ID NO: 5: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-(Lys)q, SEQ ID NO: 6: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 7: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 8: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 9: Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 10: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, SEQ ID NO: 11: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, and SEQ ID NO: 12: Leu-Asp-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-Arg-Lys, is selected from the group consisting of A peptide according to any one of the preceding paragraphs, wherein the bolded and underlined amino acids, having the same (both L- or D-amino acids) or different configurations, indicate the position of the linker biradical "L", the C-terminus corresponds to -C(O)R4 and the N-terminus corresponds to -NHR5. Item 5. A peptide according to any one of the preceding items, wherein "a", "b" and "c" are 1. Item 6. R1 and R3 are (C1 to C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 ) alkynyl. Item 7. R2 is (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 ) alkynyl. Item 8.R 19 (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 ) alkynyl. Item 9. R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m" and "n" are the same and "p" and "q" are the same, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m" and "n" are the same and "p" and "q" are different, or alternatively R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "m", "n", "p" and "q" are the same, in particular 1; or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, "m", "n" and "q" are the same and "p" is different, in particular m=n=q=0 and p=1. Item 10. A peptide according to any one of the preceding items, wherein the C-terminus corresponds to -C(O)OH or -C(O)NH2 and the N-terminus corresponds to -NH2. Item 11. A peptide according to any one of the preceding items, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a peptide selected from the group consisting of the sequences of SEQ ID NO:13 to SEQ ID NO:21. Item 12. A peptide according to any one of the preceding items, conjugated to a label, a drug, a cell membrane-penetrating peptide or polyethylene glycol (PEG). Item 13. A fusion protein comprising a peptide as defined in any one of the preceding items. Item 14. A pharmaceutical composition comprising a therapeutically effective amount of a peptide or a pharmaceutical salt thereof as defined in any one of items 1 to 12, or a fusion protein as defined in item 13, together with an acceptable pharmaceutical additive and / or carrier. Item 15. A peptide or a pharmaceutical salt thereof as defined in any one of items 1 to 12, or a fusion protein as defined in item 13, or a pharmaceutical composition as defined in item 14, for use in therapy. Item 16. A peptide or a pharmaceutical salt thereof as defined in any one of items 1 to 12, or a fusion protein as defined in item 13, or a pharmaceutical composition as defined in item 14, for use in the treatment or prevention of a disease caused by dysregulation of VEGF expression, in particular caused by increased or decreased VEGF expression. Item 17. A peptide or a pharmaceutical salt thereof as defined in any one of items 1 to 12, or a fusion protein as defined in item 13, or a pharmaceutical composition as defined in item 14, for use in the treatment or prevention of a disease associated with dysregulation of angiogenesis based on VEGF expression. Item 18. A sequence having a length of 15 to 50 and SEQ ID NO: 22: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v (where: "r", "s", "t" and "v" represent integers and are selected from 0 and 1; The C-terminus corresponds to -C(O)R4, A peptide or a pharmaceutical salt thereof, comprising a sequence having at least 85% sequence identity to a peptide having an N-terminus corresponding to -NHR5, Optionally, the peptide has the formula (I) linking the alpha carbon atom of an amino acid located at position "i" to the alpha carbon atom of an amino acid located at position "i+4" or "i+7" in the peptide sequence of SEQ ID NO:21: -[(R1) a -(R2)-(R3) b ] c - (I) (In the formula, "a" and "b" are the same or different and are 0 or 1; "c" is composed of 1 to 10, R1 and R3 are (C1 to C 10 )Alkyl;Halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C1 to C 10 )Alkyl;(C2-C 10 ) alkenyl; halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkenyl; (C2-C 10 ) alkynyl; and halogen, (C1-C 10 )Alkyl, -OR6, -NR7R8, -SR9, -SOR 10 , -SO2R 11 and -CO2R 12 (C2 to C 10 ) alkynyl; R2 is -O-, C(=O), C(=O)NR 13 , C(=O)O, S(=O), S(=O)2, NR 14 , (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) Alkynyl, -NR 15 -NR 16 -, -N=N-, -SS-, and known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; each of the members forming the known ring system is selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S- and -O-; Ring systems include halogen, -OH, -NO2, (C1-C 10 ) Alkyl, (C1-C 10 ) haloalkyl and (C1-C 10 ) alkyl-O-; R4 is -OH and -NR 17 R 18 is a radical selected from the group consisting of R5 is -H and (C1 to C 20 ) alkyl, R6, R7, R8, R9, R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 and R 18 -H and (C1-C 10 ) alkyl; The amino acids linked by the linker have the formula (II): [ka] (In the formula, R 19 (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, and known ring systems containing 3 to 14 members, said systems containing 1 to 3 rings; each of the rings is saturated, partially unsaturated or aromatic; The rings are separate or partially or completely fused; Each of the members forming the known ring systems is a monoradical selected from the group consisting of known ring systems selected from the group consisting of -CH-, -CH2-, -NH-, -N-, -SH-, -S-, and -O-. Item 19. A peptide according to item 18, consisting of the sequence of SEQ ID NO: 21 and optionally comprising a linker biradical "L" of formula (I) as defined in item 18. Item 20. A peptide according to the previous items 18 or 19, comprising a linker biradical "L" of formula (I) between the alpha carbon atom of the amino acid located at position "i" and the alpha carbon atom of the amino acid located at position "i+7" in the peptide sequence of SEQ ID NO:21. Item 21. SEQ ID NO: 23: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v, SEQ ID NO: 24: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)-(Pro)v, SEQ ID NO: 25: (Arg)r-(Ser)s-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-(Leu)t-(Pro)v, SEQ ID NO: 26: Arg-Ser-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln, SEQ ID NO: 27: Arg-Ser-Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln, and SEQ ID NO: 28: Arg-Arg-Ser-Lys-Glu-Ser-Glu-Val-Phe-Tyr-Glu-Leu-Ala-His-Gln-Leu-Pro, is selected from the group consisting of A peptide according to any one of paragraphs 18-20 above, wherein the bold and underlined amino acids, having the same (both L- or D-amino acids) or different configuration, indicate the position of the linker biradical "L", the C-terminus corresponds to -C(O)R4 and the N-terminus corresponds to -NHR5. Item 22. A peptide according to any one of the preceding items 18 to 21, wherein "a", "b" and "c" are 1. Item 23. R1 and R3 are (C1 to C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 23. A peptide according to any one of the preceding items 18 to 22, wherein the biradical is independently selected from the group consisting of: Item 24. R2 is (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 24. A peptide according to any one of the preceding items 18 to 23, wherein the biradical is selected from the group consisting of alkynyl. Item 25.R 19 (C1~C 10 ) Alkyl, (C2-C 10 ) alkenyl and (C2-C 10 25. A peptide according to any one of the preceding items 18 to 24, wherein the monoradical is selected from the group consisting of alkynyl. Item 26. R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "r" and "s" are the same and "t" and "v" are the same, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 ) alkenyl, where "r" and "s" are the same and represent 1, and "t" and "v" are the same and represent 0, or alternatively, R1, R3 and R 19 (C1~C 10 ) alkyl, and R2 is (C2-C 10 26. A peptide according to any one of the preceding items 18 to 25, wherein "r" and "s" are the same and represent 0, and "t" and "v" are the same and represent 1. Item 27. A peptide according to any one of the preceding items 18 to 26, in which the C-terminus corresponds to -C(O)OH or -C(O)NH2, in particular -C(O)NH2, and the N-terminus corresponds to -NH2. Item 28. A peptide according to any one of the preceding items 18 to 27, having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to a peptide selected from the group consisting of the sequences of SEQ ID NO:29 to SEQ ID NO:31. Item 29. A peptide according to any one of items 18 to 28 above, which is conjugated to a label, a drug, a cell membrane-permeable peptide or PEG. Item 30. A fusion protein comprising a peptide according to any one of items 18 to 29 above. Item 31. A pharmaceutical composition comprising a therapeutically effective amount of a peptide or a pharmaceutical salt thereof defined in any one of items 18 to 29, or a fusion protein defined in item 30, together with an acceptable pharmaceutical additive and / or carrier. Item 32. A peptide or a pharmaceutical salt thereof as defined in any one of items 18 to 29, or a fusion protein as defined in item 30, or a pharmaceutical composition as defined in item 31, for use in therapy. Item 33. A peptide or a pharmaceutical salt thereof as defined in any one of items 18 to 29, or a fusion protein as defined in item 30, or a pharmaceutical composition as defined in item 31, for use in the treatment or prevention of a disease caused by dysregulation of VEGF expression. Item 34. The peptide or pharmaceutical salt thereof defined in any one of Items 18 to 29, or the fusion protein defined in Item 30, or the pharmaceutical composition defined in Item 31, for use in the treatment or prevention of a disease associated with dysregulation of angiogenesis based on the expression level of VEGF.< / au>

Claims

1. Having lengths of 14 to 50, Sequence ID 1: (Leu)m-(Asp)n-Lys-Ala-Ser-Val-Met-Arg-Leu-Thr-Ile-Ser-Tyr-Leu-Arg-Val-(Arg)p-(Lys)q (Here, "m", "n", "p", and "q" represent integers, selected from 0 and 1. The C-terminus is -C(O)R ４ This corresponds to, The N-terminus is -NHR ５ This corresponds to, R4 is a radical selected from the group consisting of -OH and -NR17 R18. R5 is a radical selected from the group consisting of -H and (C1 to C20) alkyl groups. A peptide or pharmaceutical salt thereof comprising the amino acid sequence of a modified R17 and R18 (radicals independently selected from the group consisting of -H and (C1 to C10) alkyl groups), The peptide is formed by linking the α-carbon atom of the amino acid located at position "i" in the peptide sequence of Sequence ID No. 1 with the α-carbon atom of the amino acid located at position "i+7", formula (Ib): -(CH 2 )y-CH=CH-(CH 2 )z- (Ib) The formula includes a linker pyroradical "L" (wherein y and z are the same or different, selected from 1 to 10, preferably independently selected from 3 to 6, and more preferably independently selected from 3 and 6), The modified version of Sequence ID No. 1 has amino acids linked by the linker that are of formula (II): 【Chemistry 1】 (In the formula, R １９ It differs from Sequence ID No. 1 in that it is replaced by an amino acid of methyl or a halomethyl such as fluoromethyl. The aforementioned peptide SEQ ID NO: 6: Lys-Ala-*Ser*-Val-Met-Arg-Leu-Thr-Ile-*Ser*-Tyr-Leu-Arg-Val-Arg, SEQ ID NO: 8: Lys-Ala-Ser-Val-Met-*Arg*-Leu-Thr-Ile-Ser-Tyr-Leu-*Arg*-Val-Arg, SEQ ID NO: 10: Leu-Asp-Lys-Ala-*Ser*-Val-Met-Arg-Leu-Thr-Ile-*Ser*-Tyr-Leu-Arg-Val-Arg-Lys, SEQ ID NO: 11: Leu-Asp-Lys-Ala-Ser-Val-*Met*-Arg-Leu-Thr-Ile-Ser-Tyr-*Leu*-Arg-Val-Arg-Lys, and SEQ ID NO: 12: Leu-Asp-Lys-Ala-Ser-Val-Met-*Arg*-Leu-Thr-Ile-Ser-Tyr-Leu-*Arg*-Val-Arg-Lys Selected from the group consisting of, Here, the amino acids enclosed in asterisks refer to the position of the linker bioradical "L," with the C-terminus corresponding to -C(O)R 4 and the N-terminus corresponding to -NHR 5, and are peptides or their pharmaceutical salts.

2. The C-terminus is -C(O)OH or -C(O)NH ２ This corresponds to, and the N-terminus is -NH ２ The peptide according to claim 1, which corresponds to the peptide described in claim 1.

3. The peptide according to claim 1 or 2, comprising or consisting of a sequence selected from the group consisting of sequences 14, 16, 17, 19, and 21, preferably comprising or consisting solely of sequence 16 or sequence 17.

4. The peptide according to any one of claims 1 to 3, which is conjugated with a label, a drug, a cell membrane permeable peptide, or polyethylene glycol.

5. A fusion protein comprising the peptide described in any one of claims 1 to 4.

6. A pharmaceutical composition comprising a therapeutically effective amount of the peptide or pharmaceutical salt thereof according to any one of claims 1 to 4, or the fusion protein according to claim 5, together with an acceptable pharmaceutical additive and / or carrier.

7. Used in therapy: A composition comprising the peptide or pharmaceutical salt thereof according to any one of claims 1 to 4, or a composition comprising the fusion protein according to claim 5; or The pharmaceutical composition according to claim 6.

8. Used to treat or prevent diseases caused by elevated VEGF levels: A composition comprising the peptide or pharmaceutical salt thereof according to any one of claims 1 to 4, or a composition comprising the fusion protein according to claim 5; or The pharmaceutical composition according to claim 6.

9. The composition or pharmaceutical composition according to claim 8, wherein the disease is selected from the group consisting of diabetic retinopathy, age-related macular degeneration (AMD), or blindness disorders such as glaucoma; psoriasis; chronic obstructive pulmonary disease; and cancer.

10. A composition or pharmaceutical composition according to any one of claims 7 to 9, in combination with one or more other therapeutic agents, or active substances that can improve their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in the body.

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