Agent for inducing angiogenesis

Abstract

The present invention relates to an agent capable of inducing angiogenesis. The present disclosure also relates to the treatment of diseases such as cardiovascular diseases using the above agent.

Description

Technical Field

[0001] The present invention relates to an agent capable of inducing angiogenesis. The present disclosure also relates to the treatment of diseases such as cardiovascular diseases using the above agent.

Background Art

[0002] Cardiovascular disease (CVD) is a type of disease involving the heart or blood vessels. Examples of CVD include coronary artery disease (CAD), such as angina pectoris and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, myocarditis, aortic aneurysm, peripheral artery disease, thromboembolic disease, and venous thrombosis.

[0003] The underlying mechanisms vary depending on the disease. Dietary risk factors are estimated to be associated with 53% of CVD deaths. Atherosclerosis is involved in coronary artery disease, stroke, and peripheral artery disease. This can be caused, inter alia, by hypertension, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, an unhealthy diet, excessive alcohol consumption, and poor sleep. Hypertension is estimated to be the cause of about 13% of CVD deaths, while tobacco is the cause in 9%, diabetes in 6%, lack of exercise in 6%, and obesity in 5%. Rheumatic heart disease can be secondary to untreated streptococcal pharyngitis.

Summary of the Invention

[0004] The inventors of the present disclosure have identified a peptide capable of inducing angiogenesis. Accordingly, the peptide is a promising candidate for the treatment of various diseases or disorders associated with a decrease in angiogenesis, including cardiovascular diseases.

[0005] One aspect of the present disclosure is for use in the treatment and / or prevention of a disease or disorder associated with a decrease or abnormality of angiogenesis in a subject, a) (i) General formula: X 5 X6 SX 7 X 8 A peptide comprising or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), wherein wherein X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A; said peptide (ii) General formula: X 14 LX 15 A peptide comprising or consisting of the amino acid sequence of YGIK (SEQ ID NO: 105), wherein wherein X 14 is E or G, X 15 is S or T; said peptide (iii) VDTYDGDISVVYGL (SEQ ID NO: 34), VDTYDGDISVVYG (SEQ ID NO: 35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR (SEQ ID NO: 40), VDVPNGDISLAYGL (SEQ ID NO: 41), VDVPNGDISLAYG (SEQ ID NO: 42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR (SEQ ID NO: 45), LDGLVRAYDNISPVG (SEQ ID NO: 46), GDPNGDISVVYGLR (SEQ ID NO: 47), VDVPNGDISLAYRLR (SEQ ID NO: 48), VDVPEGDISLAYRLR (SEQ ID NO: 49), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52), CLAEIDSC (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK (circular) (SEQ ID NO: 131), Circular CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI (SEQ ID NO: 133), KPLAEIDSIELSYG (SEQ ID NO: 134), KPLAEIDSIELSY (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138) and comprising or consisting of an amino acid sequence selected from the group consisting of; a peptide selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c); A medicament comprising is provided.

[0006] In one aspect, the present invention is a method for treating or preventing a disease or disorder in a subject, wherein the disease or disorder is i. a cardiovascular disease, ii. damage from external factors, iii. an immune system disease, iv. a nervous system disease, and v. a musculoskeletal or connective tissue disease selected from the group consisting of, The method relates to a method comprising administering to a subject in need thereof a therapeutically effective amount of the agent described herein.

[0007] In one aspect, the present invention relates to i. a cardiovascular disease, ii. an injury by external factors, iii. an immune system disease, iv. a nervous system disease, and v. a musculoskeletal system or connective tissue disease relates to the use of the agent described herein for the manufacture of an agent for the treatment or prevention of a disease or disorder selected from the group consisting of.

[0008] In one aspect, the present invention relates to an agent described herein for use in improving angiogenesis in a subject after surgery.

[0009] In one aspect, the present invention relates to a method for inducing angiogenesis, the method comprising administering to a subject an agent described herein.

[0010] In one aspect, the present invention relates to an implant agent comprising the peptide described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21A

Figure 21B

Figure 21C

Figure 21D

Figure 22

Figure 23

Figure 24A

Figure 24B

Figure 24C

Figure 24D

Figure 24E

Figure 25

Figure 26

Figure 27

Figure 28

Figure 29

Figure 30

Figure 31

DETAILED DESCRIPTION OF THE INVENTION

[0012] Definitions As used herein, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

[0013] The term "some embodiments" can include one or more embodiments.

[0014] When used throughout the specification, or when used in the claims and / or the specification in conjunction with the term "comprising", the use of the word "a" or "an" may mean "one", which is also consistent with the meanings of "one or more", "at least one", and "one or more than one".

[0015] As used herein, "prevent" or "prevention" includes delaying the onset of a disease, disorder, or condition, preventing its onset, and reducing the risk of its onset.

[0016] Agent The agent of the present invention can be a peptide; a polynucleotide encoding the peptide; a vector containing the polynucleotide; or a cell containing the polynucleotide or the vector.

[0017] Peptide In one embodiment, the agent is a peptide or a pharmaceutically acceptable salt thereof.

[0018] As used herein, the term "amino acid" includes the 20 standard amino acids encoded by genes and their corresponding "D" stereoisomers (compared to the natural "L" form), ω-amino acids, as well as other naturally occurring amino acids, non-conventional amino acids (e.g., α,α-disubstituted amino acids, N-alkyl amino acids, etc.), and chemically derivatized amino acids (see below).

[0019] When an amino acid, e.g., "alanine" or "Ala" or "A" is specifically listed, unless otherwise specified, the term refers to both L-alanine and D-alanine. Other non-conventional amino acids may be suitable components of the peptides of the present disclosure as long as the desired functional properties are retained by the peptide. For the peptides shown, each encoded amino acid residue is represented, as appropriate, by the one-letter notation corresponding to the conventional name of the normal amino acid.

[0020] In one embodiment, the peptide is non-natural, for example, a peptide containing non-proteinogenic amino acid residues.

[0021] In one embodiment, the agent comprises or consists of a tandem repeat containing two or more repeating units. In one embodiment, the repeating unit comprises or consists of any one or more of the amino acid sequences described herein.

[0022] In one embodiment, the peptide is cyclic. The cyclic structure can be achieved by any suitable synthetic method. Thus, heterodetic bonds include, but are not limited to, formation by disulfide bridges, cysteine bridges, alkylene bridges, or sulfide bridges. In one embodiment, the peptide can form at least one intramolecular cysteine bridge.

[0023] In one embodiment, the agent has the general formula: X 5 X 6 SX 7 X 8 and comprises or consists of a peptide containing or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), wherein X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A.

[0024] In one embodiment, the peptide has the general formula: VDX 2 X 3 X 4 GX 5 X 6 SX 7 X 8 and comprises or consists of the amino acid sequence of YGLR (SEQ ID NO: 2), wherein X 2 is T or V, X 3 is Y or P, X 4 is D or N, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A.

[0025] In one embodiment, the peptide has the general formula: VDTYX 4 GX 5 X 6 SX 7 X 8 contains or consists of the amino acid sequence of YGLR (SEQ ID NO: 3), wherein, X 4 is D or N, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A.

[0026] In one embodiment, the peptide has the general formula: VDTYDGZ 7 Z 8 SZ 10 Z 11 contains or consists of the amino acid sequence of YGLR (SEQ ID NO: 4), wherein, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A.

[0027] In one embodiment, the peptide has the general formula: VDTYDGZ 7 Z 8 comprises or consists of the amino acid sequence of SVVYGLR (SEQ ID NO: 5), wherein X 5 is D or G, X 6 is I or G.

[0028] In one embodiment, the agent comprises or consists of a peptide having the general formula: X 14 LX 15 comprises or consists of a peptide having the amino acid sequence of YGIK (SEQ ID NO: 105), wherein X 14 is E or G, X 15 is S or T.

[0029] In one embodiment, the peptide has the general formula: KX 9 LAX 10 X 11 X 12 X 13 IX 14 LX 15 comprises or consists of the amino acid sequence of YGIK (SEQ ID NO: 106), wherein X 9 is C, P, or G, X 10 is E or G, X 11 is C, D, or I, X 12 is D, I, S, or G, X 13 is S, D, or G, X 14 is E or G, X 15 is S or T.

[0030] In one embodiment, the peptide has the general formula: KX 9 LAX 10 X 11X 12 X 13 IX 14 comprises or consists of the amino acid sequence of LSYGIK (SEQ ID NO: 107), wherein, X 9 is C, P, or G, X 10 is E or G, X 11 is C, I, or absent, X 12 is D, G, or absent, X 13 is S, G, or absent, X 14 is E or G.

[0031] In one embodiment, the peptide has the general formula: KX 9 LAX 10 IX 14 comprises or consists of the amino acid sequence of LSYGIK (SEQ ID NO: 108), wherein, X 9 is C, P, or G, X 10 is E or G, X 14 is E or G.

[0032] In one embodiment, the peptide comprises or consists of the amino acid sequence IELSYGIK (SEQ ID NO: 109).

[0033] In one embodiment, the peptide comprises or consists of VDTYDGGISVVYGLR (SEQ ID NO: 6). In one embodiment, the peptide comprises or consists of AEIDSIELSYGIK (SEQ ID NO: 110). In one embodiment, the peptide comprises or consists of VDTYDGDISVVYGLR (SEQ ID NO: 7). In one embodiment, the peptide comprises or consists of DTYDGDISVVYGLR (SEQ ID NO: 8). In one embodiment, the peptide comprises or consists of TYDGDISVVYGLRS (SEQ ID NO: 9). In one embodiment, the peptide comprises or consists of TYDGDISVVYGLR (SEQ ID NO: 10). In one embodiment, the peptide comprises or consists of YDGDISVVYGLRS (SEQ ID NO: 11). In one embodiment, the peptide comprises or consists of YDGDISVVYGLR (SEQ ID NO: 12). In one embodiment, the peptide comprises or consists of DGDISVVYGLRS (SEQ ID NO: 13). In one embodiment, the peptide comprises or consists of DGDISVVYGLR (SEQ ID NO: 14). In one embodiment, the peptide comprises or consists of GDISVVYGLRS (SEQ ID NO: 15). In one embodiment, the peptide comprises or consists of GDISVVYGLR (SEQ ID NO: 16). In one embodiment, the peptide comprises or consists of DISVVYGLRS (SEQ ID NO: 17). In one embodiment, the peptide comprises or consists of DISVVYGLR (SEQ ID NO: 18). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYGLR (SEQ ID NO: 19). In one embodiment, the peptide comprises or consists of DVPNGDISLAYGLRS (SEQ ID NO: 20). In one embodiment, the peptide comprises or consists of DVPNGDISLAYGLR (SEQ ID NO: 21). In one embodiment, the peptide comprises or consists of VPNGDISLAYGLRS (SEQ ID NO: 22). In one embodiment, the peptide comprises or consists of VPNGDISLAYGLR (SEQ ID NO: 23). In one embodiment, the peptide comprises or consists of PNGDISLAYGLRS (SEQ ID NO: 24).In one embodiment, the peptide comprises or consists of PNGDISLAYGLR (SEQ ID NO: 25). In one embodiment, the peptide comprises or consists of NGDISLAYGLRS (SEQ ID NO: 26). In one embodiment, the peptide comprises or consists of NGDISLAYGLR (SEQ ID NO: 27). In one embodiment, the peptide comprises or consists of GDISLAYGLRS (SEQ ID NO: 28). In one embodiment, the peptide comprises or consists of GDISLAYGLR (SEQ ID NO: 29). In one embodiment, the peptide comprises or consists of DISLAYGLRS (SEQ ID NO: 30). In one embodiment, the peptide comprises or consists of DISLAYGLR (SEQ ID NO: 31). In one embodiment, the peptide comprises or consists of VDTYDGDGSVVYGLR (SEQ ID NO: 32). In one embodiment, the peptide comprises or consists of VDVPEGDISLAYGLR (SEQ ID NO: 33). In one embodiment, the peptide comprises or consists of KPLAEIDSIELSYGIK (SEQ ID NO: 111). In one embodiment, the peptide comprises or consists of KCLAECDSIELSYGIK (cyclic) (SEQ ID NO: 112). In one embodiment, the peptide comprises or consists of KPLAEDISIELSYGIK (SEQ ID NO: 113). In one embodiment, the peptide comprises or consists of KPLAEISDIELSYGIK (SEQ ID NO: 114). In one embodiment, the peptide comprises or consists of KPLAEIGDIELSYGIK (SEQ ID NO: 115). In one embodiment, the peptide comprises or consists of KPLAEGDIELSYGIK (SEQ ID NO: 116). In one embodiment, the peptide comprises or consists of KPLAEIELSYGIK (SEQ ID NO: 117). In one embodiment, the peptide comprises or consists of KPLAEIDSIELTYGIK (SEQ ID NO: 118). In one embodiment, the peptide comprises or consists of KPLAEIDGIELSYGIK (SEQ ID NO: 119). In one embodiment, the peptide comprises or consists of KPLAEIDGIELTYGIK (SEQ ID NO: 120).In one embodiment, the peptide comprises or consists of KPLAEIGSIELSYGIK (SEQ ID NO: 121). In one embodiment, the peptide comprises or consists of KGLAEIDSIELSYGIK (SEQ ID NO: 122). In one embodiment, the peptide comprises or consists of KPLAGIDSIGLSYGIK (SEQ ID NO: 123). In one embodiment, the peptide comprises or consists of cyclic KCLAEIDSCELSYGIK (SEQ ID NO: 124). In one embodiment, the peptide comprises or consists of LAEIDSIELSYGIK (SEQ ID NO: 125). In one embodiment, the peptide comprises or consists of EIDSIELSYGIK (SEQ ID NO: 126). In one embodiment, the peptide comprises or consists of IDSIELSYGIK (SEQ ID NO: 127). In one embodiment, the peptide comprises or consists of DSIELSYGIK (SEQ ID NO: 128). In one embodiment, the peptide comprises or consists of SIELSYGIK (SEQ ID NO: 129). In one embodiment, the peptide comprises or consists of IELSYGIK (SEQ ID NO: 109). In one embodiment, the peptide comprises or consists of VDTYDGDISVVYGL (SEQ ID NO: 34). In one embodiment, the peptide comprises or consists of VDTYDGDISVVYG (SEQ ID NO: 35). In one embodiment, the peptide comprises or consists of VDTYDGDISVVY (SEQ ID NO: 36). In one embodiment, the peptide comprises or consists of VDTYDGDISVV (SEQ ID NO: 37). In one embodiment, the peptide comprises or consists of VDTYDGDISV (SEQ ID NO: 38). In one embodiment, the peptide comprises or consists of VDTYDGDIS (SEQ ID NO: 39). In one embodiment, the peptide comprises or consists of VDTYDGRGDSVVYGLR (SEQ ID NO: 40). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYGL (SEQ ID NO: 41). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYG (SEQ ID NO: 42).In one embodiment, the peptide comprises or consists of VDVPNGDISLA (SEQ ID NO: 43). In one embodiment, the peptide comprises or consists of VDVPNGDIS (SEQ ID NO: 44). In one embodiment, the peptide comprises or consists of GDPNDGRGDSVVYGLR (SEQ ID NO: 45). In one embodiment, the peptide comprises or consists of LDGLVRAYDNISPVG (SEQ ID NO: 46). In one embodiment, the peptide comprises or consists of GDPNGDISVVYGLR (SEQ ID NO: 47). In one embodiment, the peptide comprises or consists of VDVPNGDISLAYRLR (SEQ ID NO: 48). In one embodiment, the peptide comprises or consists of VDVPEGDISLAYRLR (SEQ ID NO: 49). In one embodiment, the peptide comprises or consists of V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50). In one embodiment, the peptide comprises or consists of VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51). In one embodiment, the peptide comprises or consists of VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52). In one embodiment, the peptide comprises or consists of CLAEIDSC (cyclic) (SEQ ID NO: 130). In one embodiment, the peptide comprises or consists of CFKPLAEIDSIECSYGIK (cyclic) (SEQ ID NO: 131). In one embodiment, the peptide comprises or consists of cyclic CFKPLAEIDSIEC (SEQ ID NO: 132). In one embodiment, the peptide comprises or consists of KPLAEIDSIELSYGI (SEQ ID NO: 133). In one embodiment, the peptide comprises or consists of KPLAEIDSIELSYG (SEQ ID NO: 134). In one embodiment, the peptide comprises or consists of KPLAEIDSIELSY (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136). In one embodiment, the peptide comprises or consists of KPLAEIDSIEL (SEQ ID NO: 137). In one embodiment, the peptide comprises or consists of KPLAEIDSIE (SEQ ID NO: 138).

[0034] Salts and Prodrugs The agents described herein can be in the form of pharmaceutically acceptable salts or prodrugs of the agent. In one embodiment, the agents described herein are pharmaceutically acceptable addition salts or hydrates of the agent, such as, but not limited to, K + , Na + , and non-salts, such as, H + and can be formulated as such.

[0035] Modifications In one embodiment, the agent is a chemical derivative of a peptide. Chemical derivatives of one or more amino acids can be achieved by reaction with a functional side group. Such derivatives include, for example, molecules in which the free amino group is derivatized to form an amine hydrochloride salt, p-toluenesulfonyl group, carboxybenzoxy group, t-butyloxycarbonyl group, chloroacetyl group, or formyl group. The free carboxyl group can be derivatized to form salts, methyl, and ethyl esters or other types of esters, and hydrazides. The free hydroxyl group can be derivatized to form O-acyl derivatives or O-alkyl derivatives. Also included as chemical derivatives are peptides containing naturally occurring amino acid derivatives of the 20 standard amino acids. For example: proline can be replaced with 4-hydroxyproline; lysine can be replaced with 5-hydroxylysine; histidine can be replaced with 3-methylhistidine; serine can be replaced with homoserine, lysine can be replaced with ornithine. Derivatives include peptides containing one or more additions or deletions as long as the required activity is maintained. Other included modifications are as follows: amidation, amino-terminal acylation (e.g., acetylation or thioglycolic acid amidation), terminal carboxyamidation (e.g., by ammonia or methylamine), and similar terminal modifications.

[0036] In one embodiment, the agent is further modified by, for example, glycosylation, PEGylation, amidation, esterification, acylation, acetylation, and / or alkylation.

[0037] In some embodiments, the agent may be further conjugated to a moiety selected from the group consisting of polyethylene glycol (PEG), monosaccharides, fluorophores, chromophores, radioactive compounds, and cell-penetrating peptides. In one embodiment, the fluorophore is lucifer yellow, biotin, 5,6-carboxytetramethylrhodamine (TAMRA), indodicarbocyanine (C5), Alexa Fluor® 488, Alexa Fluor® 532, Alexa Fluor® 647, ATTO 488, ATTO 532, 6-carboxyfluorescein (6-FAM), Alexa Fluor® 350, DY-415, ATTO 425, ATTO 465, Bodipy® FL, fluorescein isothiocyanate, Oregon Green® 488, Oregon Green® 514, Rhodamine Green™, 5'-tetrachlorofluorescein, ATTO 520, 6-carboxy-4',5'-dichloro-2',7'-dimethoxyfluorescein, Yakima Yellow™ dye, Bodipy® 530 / 550, hexachlorofluorescein, Alexa Fluor® 555, DY-549, Bodipy® TMR-X, cyanine phosphoramidite (cyanine 3, cyanine 3.5, cyanine 5, cyanine 5.5, cyanine 7.5), ATTO 550, Rhodamine Red (trademark), ATTO 565, Carboxy-X-Rhodamine, Texas Red (Sulforhodamine 101 acid chloride), LightCycler® Red 610, ATTO 594, DY-480-XL, DY-610, ATTO 610, LightCycler® Red 640, Bodipy 630 / 650, ATTO 633, Bodipy 650 / 665, ATTO 647N, DY-649, LightCycler® Red 670, ATTO 680, LightCycler® Red 705, DY-682, ATTO 700, ATTO 740, DY-782, IRD 700, IRD 800, CAL Fluor® Gold 540nm, CAL Fluor® Gold 522nm, CAL Fluor® Gold 544nm, CAL Fluor® Orange 560nm, CAL Fluor® Orange 538nm, CAL Fluor® Orange 559nm, CAL Fluor® Red 590nm, CAL Fluor® Red 569nm, CAL Fluor® Red 591nm, CAL Fluor® Red 610nm, CAL Fluor® Red 590nm, CAL Fluor® Red 610nm, CAL Fluor® Red 635nm, Quasar® 570nm, Quasar® 548nm, Quasar® 566nm (Cy3), Quasar® 670nm, Quasar® 647nm, Quasar® 670nm, Quasar® 705nm, Quasar® 690nm, Quasar® 705nm (Cy5.5) It is selected from the group consisting of Pulsar (registered trademark) 650 pigment and SuperRox (registered trademark) pigment. In one embodiment, the agent further comprises a detectable moiety, for example, a moiety detectable by imaging techniques such as SPECT, PET, MRI, optical imaging, or ultrasonic imaging. In one embodiment, the detectable moiety is, for example, 99 mTc, 111 In, 67 Ga, 68 Ga, 72 As, 89 Zr, 123 I, and 201 Tl, and comprises or consists of a radioisotope selected from the group consisting of.

[0038] In one embodiment, the peptide comprises or consists of a fusion. For example, the peptide can comprise a fusion of two amino acid sequences as disclosed herein.

[0039] The term "fusion" of a peptide refers to an amino acid sequence fused to another peptide. For example, the peptide can be fused to a polypeptide such as glutathione - S - transferase (GST) or protein A to facilitate purification of the peptide. Examples of such fusions are known to those skilled in the art. Similarly, the peptide can be fused to an oligohistidine tag such as His6 or to an epitope recognized by an antibody such as the well - known Myc epitope tag. Fusions with any variant or derivative of the peptide are also included within the scope of the present disclosure. Alternatively, the moiety to be fused can be a lipophilic molecule or a peptide domain capable of promoting cellular uptake of the polypeptide, as known to those skilled in the art.

[0040] Peptide length In one embodiment, the peptide has a length of 85 amino acids or less, for example, 80 amino acids or less, for example, 75 amino acids or less, for example, 70 amino acids or less, for example, 65 amino acids or less, for example, 60 amino acids or less, for example, 55 amino acids or less, for example, 50 amino acids or less, for example, 55 amino acids or less, for example, 40 amino acids or less, for example, 35 amino acids or less, for example, 30 amino acids or less, for example, 28 amino acids or less, for example, 26 amino acids or less, for example, 24 amino acids or less, for example, 22 amino acids or less, for example, 20 amino acids or less, for example, 19 amino acids or less, for example, 18 amino acids or less, for example, 17 amino acids or less, for example, 16 amino acids or less, for example, 15 amino acids or less, for example, 14 amino acids or less, for example, 13 amino acids or less, for example, 12 amino acids or less, for example, 11 amino acids or less, for example, 10 amino acids or less.

[0041] In one embodiment, the peptide contains at least 2 additional amino acids conjugated to the N-terminus or C-terminus of the peptide, for example, at least 3, for example, at least 4, for example, at least 5, for example, at least 6, for example, at least 7, for example, at least 8, for example, at least 9, for example, at least 10, for example, at least 15, or for example, at least 20 amino acids.

[0042] In one embodiment, the peptide has a length of 5 to 30 amino acids, for example, 5 to 20 amino acids, for example, 8 to 20 amino acids, for example, 8 to 18 amino acids, for example, 10 to 16 amino acids.

[0043] In one embodiment, when X 14 is T, the peptide contains 25 or fewer amino acid residues.

[0044] In yet another embodiment, the agent is a fragment of the peptide described herein, and the fragment includes lengths of 15 amino acids or less, such as 14 amino acids or less, such as 13 amino acids or less, such as 12 amino acids or less, such as 11 amino acids or less, such as 10 amino acids or less, such as 9 amino acids or less, such as 8 amino acids or less, such as 7 amino acids or less, such as 6 amino acids or less, such as 5 amino acids or less.

[0045] Amino acid sequences of at least 5 consecutive amino acids, such as amino acid sequences of at least 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive amino acids are also included in "fragment". The fragment can be of a length of 15 amino acids or less, such as 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 amino acids in length.

[0046] Variant In one embodiment, the agent is a variant of the peptide as described herein, where the variant includes or consists of a sequence in which any one amino acid is modified to another proteinogenic or non-proteinogenic amino acid, provided that 5 or fewer amino acids are so modified.

[0047] The term "variant" refers to a peptide that does not share 100% amino acid sequence identity with the parent peptide, i.e., one or more amino acids must be mutated. "Mutation" refers to changing an amino acid at a specific position in the parent peptide. For example, the amino acid at a specific position may be deleted, modified, or substituted, or may be a site of insertion / addition of one or more amino acids. It will be understood by those skilled in the art that the substitution can be conservative or non-conservative.

[0048] In one embodiment, the peptide variant comprises, or consists of, a sequence in which 5 or fewer amino acids are modified to another proteinogenic or non-proteinogenic amino acid, for example, 4 or fewer amino acids, for example, 3 or fewer amino acids, for example, 2 or fewer amino acids, for example, 1 or fewer amino acids are modified. In one embodiment, one or more amino acids are conservatively substituted. "Conservatively substituted" refers to the substitution of an amino acid with another amino acid having similar properties (such as size, hydrophobicity, etc.) such that the function of the peptide does not change significantly. Thus, "conservative substitutions" are intended to include combinations such as Gly, Ala; Val, Ile, Leu; Asp, Glu; Asn, Gln; Ser, Thr; Lys, Arg; and Phe, Tyr.

[0049] In one embodiment, the peptide has one additional amino acid. In one embodiment, the peptide comprises, or consists of, one or more additional amino acids inserted at the N-terminus and / or C-terminus, and / or within the sequence. In one embodiment, at least 2 additional amino acids, for example, at least 3, for example, at least 4, for example, at least 5, for example, at least 6, for example, at least 7, for example, at least 8, for example, at least 9, for example, at least 10, for example, at least 15, or for example, at least 20 additional amino acids are inserted.

[0050] In one embodiment, the agent increases angiogenesis in a subject. In one embodiment, the agent is an angiogenesis inducer. In one embodiment, the agent can improve myocyte survival in cardiovascular diseases. In one embodiment, the agent can improve neuronal survival in cerebrovascular diseases.

[0051] Polynucleotides, Vectors, and Cells In an embodiment, the agent is a polynucleotide encoding a peptide as described herein upon expression. In an embodiment, the agent is a vector comprising a polynucleotide as described herein. In an embodiment, the agent is a cell comprising a polynucleotide or vector as described herein.

[0052] Compositions and Coatings In one embodiment, the agent is present in a composition. In one embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition is a cosmetic composition. In one embodiment, the composition is a coating.

[0053] Coatings for various implants are known in the art. Uses in humans include central venous catheters, coronary stents, ventricular assist devices, extracorporeal blood circuits, blood collection devices, and artificial blood vessels. Such coatings can be in gel or non-gel form. As used herein, "coatings containing the agent" include agents adsorbed on the surface, agents bound to the surface, and agents embedded in the polymer surface.

[0054] Transplants In one aspect, the present invention relates to a transplant comprising the agent described herein. In one embodiment, the transplant is coated with a composition containing the agent. Thus, the agent may be, for example, adsorbed on the surface of the transplant, bound to the surface, or embedded in the polymer surface.

[0055] In one embodiment, the implant is a biomaterial such as bone.

[0056] In one embodiment, the implant is a medical device such as a stent.

[0057] Medical Uses The agents disclosed herein have been shown to induce angiogenesis. This property can be used to treat various diseases or disorders. Such diseases or disorders are typically associated with abnormal levels of angiogenesis, for example, decreased angiogenesis compared to healthy tissue.

[0058] One embodiment of the present disclosure provides an agent as disclosed herein for use in increasing angiogenesis in a subject.

[0059] One embodiment of the present disclosure provides an agent as disclosed herein for use as an angiogenesis inducer.

[0060] For example, it may be desirable to increase angiogenesis in the myocardium by increasing angiogenesis in the affected tissue. Various cardiovascular diseases are associated with ischemia, for example, a decrease in oxygen supply to the affected tissue. Accordingly, one embodiment of the present disclosure provides an agent as disclosed herein for use in improving myocyte survival in cardiovascular diseases.

[0061] Certain cerebrovascular diseases are associated with a decrease in oxygen flow to the affected tissue. Increasing angiogenesis to the affected tissue can be beneficial, for example, to improve the oxygen supply. One embodiment of the present disclosure provides an agent as disclosed herein for use in improving neuronal survival in cerebrovascular diseases.

[0062] One embodiment of the present disclosure provides an agent as disclosed herein for use in the treatment of diseases or disorders associated with decreased or abnormal angiogenesis.

[0063] One embodiment of the present disclosure provides a method for inducing angiogenesis, the method comprising administering an agent of the present disclosure to a subject.

[0064] A number of diseases or disorders are associated with reduced or abnormal angiogenesis or can be beneficially improved by increasing angiogenesis in the affected tissue. One embodiment of the present disclosure provides an agent as disclosed herein for use in treating or preventing a disease or disorder in a subject, wherein the disease or disorder is i. a cardiovascular disease, ii. an injury due to external factors, iii. an immune system disease, iv. a nervous system disease, and v. a musculoskeletal or connective tissue disease selected from the group consisting of.

[0065] Cardiovascular diseases refer to diseases of the organ system that deliver nutrients (e.g., amino acids, electrolytes, and lymph) to the body's cells and from the body's cells, gases, hormones, blood cells, etc. to help the body fight the disease, to stabilize body temperature and pH, and to maintain homeostasis. Injury due to external factors means physical or physiological injury to the body caused by the interaction of the body with energy (mechanical energy, thermal energy, electrical energy, chemical energy, or radiant energy, or energy resulting from extreme pressure) in an amount or rate of transfer that exceeds physical or physiological tolerance. The injury can also be due to a lack of essential elements such as oxygen. Included are poisoning by substances and toxic effects of substances such as injury to an implanted device or injury caused by an implanted device. Injury usually shows rapid onset in response to a distinct event (e.g., a motor vehicle accident, a collision with the ground after a fall, drinking a strongly alkaline liquid, drug overdose, a burn received during a surgical procedure). These events are often referred to as external factors of injury. However, the harmful energy may also be derived from the injured person and / or the surrounding environment (e.g., a person running on a hot day experiences heat fatigue), and the injury may be caused by the injured person (i.e., intentional self-harm). Injury includes symptoms that become apparent immediately after occurrence (which may or may not persist) and symptoms that become apparent only later.

[0066] In one embodiment, a disease or disorder associated with reduced or abnormal angiogenesis is a i. cardiovascular disease, ii. injury from external factors, iii. immune system disease, iv. cardiovascular symptoms, signs, or clinical findings, v. myocardial or ventricular disease, and vi. endocrine, nutritional, or metabolic diseases and is a complication associated with a disease or disorder selected from the group consisting of.

[0067] One embodiment of the present disclosure is vii. cardiovascular disease, viii. injury from external factors, ix. immune system disease, x. cardiovascular symptoms, signs, or clinical findings, xi. myocardial or ventricular disease, and xii. endocrine, nutritional, or metabolic diseases and provides a medicament as disclosed herein for use in treating or preventing a complication associated with a disease or disorder selected from the group consisting of.

[0068] In one embodiment of the present disclosure, the cardiovascular disease is i. ischemic heart disease, ii. cerebrovascular disease, iii. coronary artery disease, iv. diseases of arteries, arterioles, or capillaries, v. cardiovascular symptoms, signs, or clinical findings, vi. myocardial or ventricular disease, and vii. endocrine, nutritional, or metabolic diseases selected from the group consisting of.

[0069] Cerebrovascular disease is a group of brain dysfunction related to diseases of the blood vessels supplying blood to the brain. This includes "stroke", which includes the following disease units: intracerebral hemorrhage, subarachnoid hemorrhage, cerebral ischemic stroke, and stroke of unknown ischemic or hemorrhagic nature.

[0070] Clinical findings of the circulatory system include those obtained using examinations, clinical tests, and imaging techniques. Diseases take various forms and can appear in various systems of the body. Such specific symptoms can be a reason for treatment or medical consultation, and may or may not lead to identification or management of an underlying disease. This includes conditions and symptoms that are not well-defined, for which no case review has been done to reach a final diagnosis, and are described as "otherwise unexplained", "undiagnosed", or "transient". The conditions, signs, or symptoms included are as follows: cases where, despite investigating all facts related to the case, no clearer diagnosis could be made; signs or symptoms present at the first medical consultation that were transient and for which the cause could not be identified; provisional diagnoses of patients who did not return for subsequent observation or treatment; cases referred elsewhere for observation or treatment before a diagnosis was made; cases where no more detailed diagnosis was made for any other reason; specific symptoms for which additional information has been provided, but the additional information does not by itself represent a medically significant problem.

[0071] Diseases of the myocardium or ventricles include a disease of a type of involuntary striated muscle found in the walls of the heart and histological support structures (specifically referring to the atrial and ventricular cavities, as well as the myocardium itself).

[0072] In one embodiment of the present disclosure, ischemic heart disease is i. Acute ischemic heart disease, for example, myocardial infarction, for example, acute myocardial infarction and acute ischemic heart disease of unknown detail (acute coronary syndrome), ii. Chronic ischemic heart disease, for example, other specific chronic ischemic heart diseases (cardiovascular atherosclerosis), iii. Angina pectoris, for example, unstable angina pectoris, and iv. Occlusive arteriosclerosis selected from the group consisting of.

[0073] Chronic heart disease is recognized as being caused by atherosclerosis of the coronary arteries. This is characterized by angina pectoris and unstable angina pectoris.

[0074] In one embodiment, the myocardial infarction is a ST-elevation myocardial infarction (STEMI) or a non-ST-elevation myocardial infarction (NSTEMI). In one embodiment, STEMI or NSTEMI subsequently exhibits certain existing complications, for example, within 28 days.

[0075] In one embodiment, the cardiovascular disease is arteriosclerosis. In one embodiment, the cardiovascular disease is systemic sclerosis or is associated with systemic sclerosis.

[0076] In one embodiment, the cerebrovascular disease is i. Cerebral ischemia, for example, a cerebral ischemic attack (stroke), for example, cerebral infarction, and ii. Asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis) selected from the group consisting of.

[0077] Acute local neurological dysfunction caused by local infarction in a single or multiple sites of the brain. Evidence of acute infarction can be obtained by either a) a symptom duration exceeding 24 hours, or b) neuroimaging or other techniques in the clinically relevant area of the brain.

[0078] In one embodiment, the cerebral ischemic attack is related to the patient history of a transient ischemic attack (TIA) or cerebral infarction without sequelae. It is a transient episode of local neurological dysfunction caused by local cerebral ischemia, without findings of acute infarction in the clinically relevant area of the brain, or transient monocular visual loss due to retinal ischemia. The symptoms must completely disappear within 24 hours.

[0079] In one embodiment, the cerebral ischemic attack is related to the patient history of traumatic brain injury or the sequelae of cerebrovascular disease.

[0080] In one embodiment, the cerebrovascular disease is i. Nontraumatic subarachnoid hemorrhage, ii. Nontraumatic intracerebral hemorrhage, iii. Other and intracranial hemorrhage of unknown details, iv. Cerebral infarction, v. Occlusion and stenosis of the anterior cerebral artery that did not lead to cerebral infarction, vi. Occlusion and stenosis of cerebral arteries that did not lead to cerebral infarction, vii. Other cerebrovascular diseases, viii. Cerebrovascular disorders associated with other diseases (cerebrovascular disorders classified elsewhere), and ix. Sequelae of cerebrovascular diseases selected from the group consisting of.

[0081] In one embodiment, the disease of the artery, arteriole, or capillary is i. Atherosclerosis, ii. Aortic aneurysm and aortic dissection, iii. Other aneurysms, iv. Other peripheral vascular diseases, v. Arterial embolism and thrombosis, vi. Atheroembolism, vii. Septic arterial embolism, viii. Other disorders of arteries and arterioles, ix. Diseases of capillaries, and x. Disorders of arteries, arterioles, or capillaries associated with another disease (disorders of arteries, arterioles, or capillaries in diseases classified elsewhere) selected from the group consisting of.

[0082] In one embodiment, the disease of the artery, arteriole, or capillary is chronic arterial occlusion, for example, atherosclerotic thrombotic chronic arterial occlusion or arteriosclerosis.

[0083] In one embodiment, the symptoms, signs, or clinical findings of the circulatory system are symptoms or signs occurring in the circulatory system, for example, abnormal blood pressure measurements for which no diagnosis has been made, for example, cardiac arrest.

[0084] In one embodiment, the disease of the myocardium or ventricle is cardiomyopathy, for example, dilated cardiomyopathy. These are myocardial disorders in which the myocardium is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease, and congenital heart disease sufficient to cause the observed myocardial abnormalities.

[0085] In one embodiment, the disease of the immune system is an organ-nonspecific systemic autoimmune disease, such as vasculitis, such as thromboangiitis obliterans (Buerger's disease).

[0086] In one embodiment, the disease of the nervous system is i. Movement disorders, such as Parkinsonism, such as Parkinson's disease, ii. Multiple sclerosis or other white matter abnormalities, such as multiple sclerosis, and iii. Disorders accompanied by neurocognitive impairment as a major feature, such as Alzheimer's disease selected from the group consisting of.

[0087] In one embodiment, the disease of the musculoskeletal system or connective tissue is a condition related to the spine, such as a herniated disc.

[0088] In one embodiment, the disease of the circulatory system, the disease of the immune system, the disease of the nervous system, or the disease of the musculoskeletal system or connective tissue is diabetes or is related to diabetes. In one embodiment, the diabetes is selected from type 1 diabetes and type 2 diabetes. In one embodiment, the subject has diabetes.

[0089] In one embodiment, the subject is a mammal. In one embodiment, the mammal is a human.

[0090] One embodiment of the present disclosure is a method for treating or preventing a disease or disorder in a subject, wherein the disease or disorder is i. A disease of the circulatory system, ii. Injury by external factors, iii. A disease of the immune system, iv. A disease of the nervous system, and v. A disease of the musculoskeletal system or connective tissue selected from the group consisting of, the method comprising administering to a subject in need thereof a therapeutically effective amount of the agent described herein, provides the method.

[0091] One embodiment of the present disclosure is i. Diseases of the circulatory system, ii. Injury from external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue The use of the agent described herein in the manufacture of an agent for the treatment or prevention of a disease or disorder selected from the group consisting of.

[0092] One aspect of the present disclosure provides an agent as disclosed herein for use in increasing angiogenesis in a subject.

[0093] One aspect of the present disclosure provides an agent as disclosed herein for use as an angiogenesis inducer.

[0094] One aspect of the present disclosure provides an agent as disclosed herein for use in the treatment of a disease or disorder associated with a decrease or abnormality of angiogenesis.

[0095] One aspect of the present disclosure provides a method for inducing angiogenesis, the method comprising administering an agent of the present disclosure to a subject.

[0096] One aspect of the present disclosure provides an agent as disclosed herein for use in the treatment or prevention of a disease or disorder in a subject, wherein the disease or disorder is i. Diseases of the circulatory system, ii. Injury from external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue selected from the group consisting of.

[0097] One aspect of the present disclosure is i. Diseases of the circulatory system, ii. Injury from external factors, iii. Diseases of the immune system, iv. Symptoms, signs, or clinical findings of the circulatory system, v. Diseases of the myocardium or ventricles, and vi. Endocrine, nutritional, or metabolic diseases To provide a drug as disclosed herein for use in treating or preventing complications associated with a disease or disorder selected from the group consisting of.

[0098] Surgery, grafts, and transplants One embodiment of the present disclosure provides a drug of the present disclosure for use in improving post-surgical angiogenesis. In one embodiment, the surgery is cardiovascular surgery. In one embodiment, the cardiovascular surgery is vascular grafting. In one embodiment, the graft is a biomaterial. In one embodiment, the biomaterial is bone. In one embodiment, the graft is a medical device. In one embodiment, the medical device is a stent.

[0099] One embodiment of the present disclosure provides a disclosed drug for use in increasing angiogenesis in a subject who has received or will receive a transplant. In one embodiment, the transplant is an organ transplant, tissue transplant, or cell transplant. In one embodiment, the cell graft is bone marrow cells. In one embodiment, the organ graft is the heart or cardiovascular tissue.

[0100] Item 1. a) (i) General formula: X 5 X 6 SX 7 X 8 A peptide comprising or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), wherein, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A, said peptide; (ii) General formula: X 14 LX15 A peptide comprising or consisting of the amino acid sequence of YGIK (SEQ ID NO: 105), wherein, X 14 is E or G, X 15 is S or T, said peptide; (iii) VDTYDGDISVVYGL (SEQ ID NO: 34), VDTYDGDISVVYG (SEQ ID NO: 35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR (SEQ ID NO: 40), VDVPNGDISLAYGL (SEQ ID NO: 41), VDVPNGDISLAYG (SEQ ID NO: 42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR (SEQ ID NO: 45), LDGLVRAYDNISPVG (SEQ ID NO: 46), GDPNGDISVVYGLR (SEQ ID NO: 47), VDVPNGDISLAYRLR (SEQ ID NO: 48), VDVPEGDISLAYRLR (SEQ ID NO: 49), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52), CLAEIDSC (cyclic) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK (cyclic) (SEQ ID NO: 131), Cyclic CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI (SEQ ID NO: 133), KPLAEIDSIELSYG (SEQ ID NO: 134), KPLAEIDSIELSY (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138), or a peptide comprising or consisting of an amino acid sequence selected from the group consisting of; a peptide selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c); A medicament comprising the same.

[0101] 2. The peptide has the general formula: VDX 2 X 3 X 4 GX 5 X 6 SX 7 X 8 YGLR (SEQ ID NO: 2), and wherein, X 2 is T or V, X 3 is Y or P, X 4 is D or N, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A, the medicament according to item 1.

[0102] 3. The peptide has the general formula: VDTYX 4 GX 5 X 6 SX 7 X 8comprising the amino acid sequence of YGLR (SEQ ID NO: 3), wherein, X 4 is D or N, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A, the agent according to any one of the preceding items.

[0103] 4. The peptide has the general formula: VDTYDGZ 7 Z 8 SZ 10 Z 11 comprising the amino acid sequence of YGLR (SEQ ID NO: 4), wherein, X 5 is D or G, X 6 is I or G, X 7 is V or L, X 8 is V or A, the agent according to any one of the preceding items.

[0104] 5. The peptide has the general formula: VDTYDGZ 7 Z 8 comprising the amino acid sequence of SVVYGLR (SEQ ID NO: 5), wherein, X 5 is D or G, X 6 is I or G, the agent according to any one of the preceding items.

[0105] 6. The peptide has the general formula: KX 9 LAX 10 X 11 X 12 X 13 IX 14 LX 15 comprising the amino acid sequence of YGIK (SEQ ID NO: 106), wherein, X 9 is C, P, or G, X 10 is E or G, X 11 is C, D, or I, X 12 is D, I, S, or G, X 13 is S, D, or G, X 14 is E or G, X 15 is S or T, the agent according to item 1.

[0106] 7. The peptide has the general formula: KX 9 LAX 10 X 11 X 12 X 13 IX 14 contains the amino acid sequence of LSYGIK (SEQ ID NO: 107), wherein, X 9 is C, P, or G, X 10 is E or G, X 11 is C, I, or absent, X 12 is D, G, or absent, X 13 is S, G, or absent, X 14 is E or G, the agent according to item 1.

[0107] 8. The peptide has the general formula: KX 9 LAX 10 IX 14 contains the amino acid sequence of LSYGIK (SEQ ID NO: 108), wherein, X 9 is C, P, or G, X 10 is E or G, X 14 is E or G, the agent according to item 1.

[0108] 9. The agent according to item 1, wherein the peptide contains the amino acid sequence IELSYGIK (SEQ ID NO: 109).

[0109] 10. X 14 When is T, the agent according to item 1, under the condition that the peptide contains 25 or fewer amino acid residues.

[0110] 11. The peptide is VDTYDGGISVVYGLR (SEQ ID NO: 6), VDTYDGDISVVYGLR (SEQ ID NO: 7), DTYDGDISVVYGLR (SEQ ID NO: 8), TYDGDISVVYGLRS (SEQ ID NO: 9), TYDGDISVVYGLR (SEQ ID NO: 10), YDGDISVVYGLRS (SEQ ID NO: 11), YDGDISVVYGLR (SEQ ID NO: 12), DGDISVVYGLRS (SEQ ID NO: 13), DGDISVVYGLR (SEQ ID NO: 14), GDISVVYGLRS (SEQ ID NO: 15), GDISVVYGLR (SEQ ID NO: 16), DISVVYGLRS (SEQ ID NO: 17), DISVVYGLR (SEQ ID NO: 18), VDVPNGDISLAYGLR (SEQ ID NO: 19), DVPNGDISLAYGLRS (SEQ ID NO: 20), DVPNGDISLAYGLR (SEQ ID NO: 21), VPNGDISLAYGLRS (SEQ ID NO: 22), VPNGDISLAYGLR (SEQ ID NO: 23), PNGDISLAYGLRS (SEQ ID NO: 24), PNGDISLAYGLR (SEQ ID NO: 25), NGDISLAYGLRS (SEQ ID NO: 26), NGDISLAYGLR (SEQ ID NO: 27), GDISLAYGLRS (Array No. 28), GDISLAYGLR (Array No. 29), DISLAYGLRS (Array No. 30), DISLAYGLR (Array No. 31), VDTYDGDGSVVYGLR (Array No. 32), VDVPEGDISLAYGLR (Array No. 33), AEIDSIELSYGIK (Array No. 110), KPLAEIDSIELSYGIK (Array No. 111), KCLAECDSIELSYGIK (Circular) (Array No. 112), KPLAEDISIELSYGIK (Array No. 113), KPLAEISDIELSYGIK (Array No. 114), KPLAEIGDIELSYGIK (Array No. 115), KPLAEGDIELSYGIK (Array No. 116), KPLAEIELSYGIK (Array No. 117), KPLAEIDSIELTYGIK (Array No. 118), KPLAEIDGIELSYGIK (Array No. 119), KPLAEIDGIELTYGIK (Array No. 120), KPLAEIGSIELSYGIK (Array No. 121), KGLAEIDSIELSYGIK (Array No. 122), KPLAGIDSIGLSYGIK (Array No. 123), Circular KCLAEIDSCELSYGIK (Array No. 124), LAEIDSIELSYGIK (Array No. 125), EIDSIELSYGIK (Array No. 126), IDSIELSYGIK (Array No. 127), DSIELSYGIK (Array No. 128), SIELSYGIK (Array No. 129), and The agent according to item 1, comprising or consisting of an amino acid sequence selected from the group consisting of IELSYGIK (SEQ ID NO: 109).

[0111] 12. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGGISVVYGLR (SEQ ID NO: 6).

[0112] 13. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGDISVVYGLR (SEQ ID NO: 7).

[0113] 14. The agent according to item 1, wherein the peptide comprises or consists of the amino acid sequence AEIDSIELSYGIK (SEQ ID NO: 110).

[0114] 15. The agent according to any one of the preceding items, wherein the peptide comprises 85 or fewer amino acids, for example, 80 or fewer, for example, 75 or fewer, for example, 70 or fewer, for example, 65 or fewer, for example, 60 or fewer, for example, 55 or fewer, for example, 50 or fewer, for example, 55 or fewer, for example, 40 or fewer amino acids, for example, 35 or fewer, for example, 30 or fewer, for example, 28 or fewer, for example, 26 or fewer, for example, 24 or fewer, for example, 22 or fewer, for example, 20 or fewer, for example, 19 or fewer, for example, 18 or fewer, for example, 17 or fewer, for example, 16 or fewer, for example, 15 or fewer, for example, 14 or fewer, for example, 13 or fewer, for example, 12 or fewer, for example, 11 or fewer, for example, 10 or fewer amino acids.

[0115] 16. The agent according to any one of the preceding items, wherein the peptide comprises at least 2 additional amino acids conjugated to the N-terminus or C-terminus of the peptide, for example, at least 3, for example, at least 4, for example, at least 5, for example, at least 6, for example, at least 7, for example, at least 8, for example, at least 9, for example, at least 10, for example, at least 15, or for example, at least 20 amino acids.

[0116] 17. The agent according to any one of the preceding items, wherein the agent is non-natural.

[0117] 18. The agent according to any one of the preceding items, wherein the agent is partially conjugated.

[0118] 19. The agent according to item 15, wherein the moiety is selected from the group consisting of polyethylene glycol (PEG), monosaccharide, fluorophore, chromophore, radioactive compound, and cell-penetrating peptide.

[0119] 20. The agent according to any one of the preceding items, wherein the agent is further modified by glycosylation, PEGylation, amidation, esterification, acylation, acetylation, and / or alkylation, etc.

[0120] 21. The agent according to any one of the preceding items, wherein the agent contains or consists of a tandem repeat containing two or more repeating units.

[0121] 22. The agent according to item 21, wherein the repeating unit contains or consists of any one or more amino acid sequences of the sequences described in the preceding item.

[0122] 23. The agent according to any one of the preceding items, wherein the agent is fused to another polypeptide.

[0123] 24. The agent according to item 20, wherein the polypeptide is selected from the group consisting of glutathione-S-transferase (GST) and protein A.

[0124] 25. The agent according to any one of the preceding items, wherein the agent is fused to a tag.

[0125] 26. The agent according to item 25, wherein the tag is an oligohistidine tag.

[0126] 27. The agent according to any one of the preceding items, wherein the agent is cyclic.

[0127] 28. The agent according to any one of the preceding items, wherein the peptide is capable of forming at least one intramolecular disulfide bridge.

[0128] 29. The agent according to any one of the preceding items, wherein the agent is a variant of the peptide, and the variant comprises, or consists of, a sequence in which any one amino acid is modified to another proteinogenic or non-proteinogenic amino acid, provided that no more than 5 amino acids are so modified.

[0129] 30. The agent according to item 29, wherein the variant comprises, or consists of, a sequence in which no more than 5 amino acids, such as no more than 4 amino acids, such as no more than 3 amino acids, such as no more than 2 amino acids, such as no more than 1 amino acid, are modified to another proteinogenic or non-proteinogenic amino acid.

[0130] 31. The agent according to any one of the preceding items, wherein one or more amino acids are conservatively substituted.

[0131] 32. The agent according to any one of the preceding items, wherein the peptide comprises, or consists of, one or more additional amino acids inserted at the N-terminus and / or C-terminus and / or within the sequence.

[0132] 33. The agent according to any one of the preceding items, wherein the peptide has one additional amino acid.

[0133] 34. The agent according to any one of the preceding items, wherein the agent further comprises a detectable moiety.

[0134] 35. The agent according to item 34, wherein the detectable moiety comprises, or consists of, a radioisotope.

[0135] 36. The radioisotope is 99 mTc, 111 In, 67 Ga, 68 Ga,72 As, 89 Zr, 123 I, and 201 Tl, and the agent according to item 35, which is selected from the group consisting of.

[0136] 37. The agent according to item 34, wherein the detectable portion is detectable by imaging techniques such as SPECT, PET, MRI, optical imaging, or ultrasonic imaging.

[0137] 38. A composition comprising the agent according to any one of the preceding items.

[0138] 39. The composition according to item 38, wherein the composition is a pharmaceutical composition.

[0139] 40. The composition according to item 38, wherein the composition is a cosmetic composition.

[0140] 41. The composition according to any one of the preceding items, wherein the composition is a coating.

[0141] 42. A graft comprising the agent according to any one of the preceding items.

[0142] 43. The graft according to item 42, wherein the graft is coated with a composition comprising the agent according to any one of the preceding items.

[0143] 44. The graft according to item 42, wherein the graft is a biomaterial.

[0144] 45. The graft according to item 44, wherein the biomaterial is bone.

[0145] 46. The graft according to item 42, wherein the graft is a medical device.

[0146] 47. The graft according to item 46, wherein the medical device is a stent.

[0147] 48. The agent according to any one of the preceding items, which is used to increase angiogenesis in a subject.

[0148] 49. The agent according to any one of the preceding items, which is used as an angiogenesis inducer.

[0149] 50. The agent according to any one of the preceding items, which is used to improve muscle cell survival in cardiovascular diseases.

[0150] 51. The agent according to any one of the preceding items, which is used to improve nerve cell survival in cerebrovascular diseases.

[0151] 52. The agent according to any one of the preceding items, which is used for the treatment of diseases or disorders associated with a decrease or abnormality in angiogenesis.

[0152] 53. A method for inducing angiogenesis, which comprises administering the agent according to any one of the preceding items to a subject.

[0153] 54. It is used for the treatment or prevention of diseases or disorders in a subject, and the diseases or disorders are i. Diseases of the circulatory system, ii. Injury by external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue The agent according to any one of the preceding items, which is selected from the group consisting of

[0154] 55. i. Diseases of the circulatory system, ii. Injury by external factors, iii. Diseases of the immune system, iv. Symptoms, signs, or clinical findings of the circulatory system, v. Diseases of the myocardium or ventricles, and vi. Endocrine, nutritional, or metabolic diseases A medicament for use in the treatment or prevention of a complication associated with a disease or disorder selected from the group consisting of, for use according to any one of the preceding items.

[0155] 56. The cardiovascular disease is i. Ischemic heart disease, ii. Cerebrovascular disease, iii. Coronary artery disease, iv. Diseases of arteries, arterioles, or capillaries, v. Cardiovascular symptoms, signs, or clinical findings, vi. Diseases of the myocardium or ventricles, and vii. Endocrine, nutritional, or metabolic diseases A medicament for use according to any one of the preceding items, selected from the group consisting of.

[0156] 57. The ischemic heart disease is i. Acute ischemic heart disease, such as myocardial infarction, such as acute myocardial infarction and acute ischemic heart disease of unknown details (acute coronary syndrome), ii. Chronic ischemic heart disease, such as other specific chronic ischemic heart diseases (cardiovascular atherosclerosis), iii. Angina pectoris, such as unstable angina pectoris, and iv. Occlusive arteriosclerosis A medicament for use according to any one of the preceding items, selected from the group consisting of.

[0157] 58. The myocardial infarction is ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI), a medicament for use according to any one of the preceding items.

[0158] 59. The STEMI or NSTEMI shows, for example, within 28 days thereafter, certain existing complications, a medicament for use according to any one of the preceding items.

[0159] 60. The cardiovascular disease is cardiovascular atherosclerosis, a medicament for use according to any one of the preceding items.

[0160] 61. A medicament for use according to any one of the preceding items, wherein the disease of the circulatory system is systemic sclerosis or is related to systemic sclerosis.

[0161] 62. The cerebrovascular disease is i. Cerebral ischemia, for example, a cerebral ischemic attack (stroke), for example, cerebral infarction, and ii. Asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis) A medicament for use according to any one of the preceding items, selected from the group consisting of.

[0162] 63. A medicament for use according to any one of the preceding items, wherein the cerebral ischemic attack is related to the medical history of a patient with transient ischemic attack (TIA) or cerebral infarction without sequelae.

[0163] 64. A medicament for use according to any one of the preceding items, wherein the cerebral ischemic attack is related to the medical history of a patient with traumatic brain injury or the medical history of sequelae of cerebrovascular disease.

[0164] 65. The cerebrovascular disease is x. Nontraumatic subarachnoid hemorrhage, xi. Nontraumatic intracerebral hemorrhage, xii. Other and intracranial hemorrhage of unknown details, xiii. Cerebral infarction, xiv. Occlusion and stenosis of the anterior cerebral artery that did not lead to cerebral infarction, xv. Occlusion and stenosis of cerebral arteries that did not lead to cerebral infarction, xvi. Other cerebrovascular diseases, xvii. Cerebrovascular disorders related to other diseases (cerebrovascular disorders classified elsewhere), and xviii. Sequelae of cerebrovascular disease A medicament for use according to any one of the preceding items, selected from the group consisting of.

[0165] 66. The disease of the artery, arteriole, or capillary is i. Atherosclerosis, ii. Aortic aneurysm and aortic dissection, iii. Other aneurysms, iv. Other peripheral vascular diseases, v. Arterial embolism and thrombosis, vi. Atheroembolism, vii. Septic arterial embolism, viii. Other disorders of arteries and arterioles, ix. Diseases of capillaries, and x. Disorders of arteries, arterioles, or capillaries associated with another disease (arterial, arteriolar, or capillary disorders in diseases classified elsewhere) A drug for use according to any one of the preceding items, selected from the group consisting of

[0166] 67. The drug for use according to any one of the preceding items, wherein the disease of the artery, arteriole, or capillary is chronic arterial occlusion, such as atherosclerotic thrombotic chronic arterial occlusion or arteriosclerosis.

[0167] 68. The drug for use according to any one of the preceding items, wherein the cardiovascular symptom, sign, or clinical finding is a symptom or sign occurring in the cardiovascular system, such as an abnormal blood pressure measurement value for which no diagnosis has been made, such as cardiac arrest.

[0168] 69. The drug for use according to any one of the preceding items, wherein the disease of the myocardium or ventricle is cardiomyopathy, such as dilated cardiomyopathy.

[0169] 70. The drug for use according to any one of the preceding items, wherein the disease of the immune system is an organ-nonspecific systemic autoimmune disease, such as vasculitis, such as thromboangiitis obliterans (Buerger's disease).

[0170] 71. The disease of the nervous system is i. Movement disorders, such as Parkinson's syndrome, such as Parkinson's disease, ii. Multiple sclerosis or other white matter abnormalities, such as multiple sclerosis, and iii. Disorders accompanied by neurocognitive impairment as a major feature, such as Alzheimer's disease A medicament for use according to any one of the preceding items, selected from the group consisting of.

[0171] 72. A medicament for use according to any one of the preceding items, wherein the disease of the musculoskeletal system or connective tissue is a condition related to the spine, for example, intervertebral disc herniation.

[0172] 73. A medicament for use according to any one of the preceding items, wherein the disease of the cardiovascular system, the disease of the immune system, the disease of the nervous system, or the disease of the musculoskeletal system or connective tissue is diabetes or is related to diabetes.

[0173] 74. A medicament for use according to any one of the preceding items, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

[0174] 75. A medicament for use according to any one of the preceding items, wherein the subject is suffering from diabetes.

[0175] 76. A medicament for use according to any one of the preceding items, wherein the subject is a mammal. 77. A medicament for use according to item 76, wherein the mammal is a human.

[0176] 78. A method for treating or preventing a disease or disorder in a subject, wherein the disease or disorder is

[0177] i. A disease of the cardiovascular system, ii. Injury by external factors, iii. A disease of the immune system, iv. A disease of the nervous system, and v. A disease of the musculoskeletal system or connective tissue selected from the group consisting of, the method comprising administering to a subject in need thereof a therapeutically effective amount of a medicament according to any one of the preceding items.

[0178] 79. i. A disease of the cardiovascular system, ii. Damage from external factors, iii. Diseases of the immune system, iv. Diseases of the nervous system, and v. Diseases of the musculoskeletal system or connective tissue Use of the agent according to any one of the preceding items in the manufacture of a medicament for the treatment or prevention of a disease or disorder selected from the group consisting of.

[0179] 80. The agent according to any one of the preceding items for use in improving angiogenesis in a subject after surgery.

[0180] 81. The agent for use according to any one of the preceding items, wherein the surgery is a cardiovascular surgery.

[0181] 82. The agent for use according to any one of the preceding items, wherein the cardiovascular surgery is a vascular graft.

[0182] 83. The agent according to any one of the preceding items for use in increasing angiogenesis in a subject having a graft.

[0183] 84. The agent for use according to any one of the preceding items, wherein the graft is a biomaterial.

[0184] 85. The agent for use according to any one of the preceding items, wherein the biomaterial is bone.

[0185] 86. The agent for use according to any one of the preceding items, wherein the graft is a medical device.

[0186] 87. The agent for use according to any one of the preceding items, wherein the medical device is a stent.

[0187] 88. The agent according to any one of the preceding items for use in increasing angiogenesis in a subject who is to receive or has received a transplant.

[0188] 90. A medicament for use according to any one of the preceding items, wherein the transplantation is an organ transplantation, a tissue transplantation, or a cell transplantation.

[0189] 91. A medicament for use according to any one of the preceding items, wherein the cell transplantation is a bone marrow cell transplantation.

[0190] 92. A medicament for use according to any one of the preceding items, wherein the organ transplantation is a heart transplantation or a cardiovascular tissue transplantation.

Examples

[0191] Example 1: The polypeptide of the present disclosure stimulates the proliferation of endothelial cells and vascular smooth muscle cells Method Cell proliferation was evaluated using the BrdU Cell Proliferation Elisa Kit (Abcam, UK). After incubation overnight at 37 °C in the corresponding complete medium, in the NRP-1 knockdown comparison experiment, siRNA / siRNA-NC was directly transfected into HUVEC and HCASMC on a 96-well plate, and for stimulation with the test polypeptide, HUVEC and HCASMC were further starved for 24 hours and 48 hours under low serum conditions before treatment. 32 hours after transfection or polypeptide stimulation, the cells were cultured with BrdU reagent for an additional 16 hours to measure cell proliferation. The subsequent steps were performed as per the manufacturer's instructions, and the data was read by Wallac 1420 Victor 2 (Perkin Elmer, USA).

[0192] For the stimulation of endothelial cell proliferation, human umbilical vein endothelial cells were first treated with scrambled non-coding siRNA (NC) or siRNA of NRP-1, and then they were treated with FOL26 at concentrations of 10 nM, 100 nM, and 1000 nM, and DNA synthesis was analyzed by measuring BrdU incorporation.

[0193] Results The results are shown in Figure 1 for FOL26 and in Figure 11 for FOL56. Both test polypeptides induced a significant increase in the proliferation of HUVEC and HCASMC.

[0194] The stimulation of endothelial cell proliferation by FOL26 is NRP-1 dependent (Figure 8).

[0195] Conclusion The polypeptides of the present disclosure stimulate the proliferation of endothelial cells and vascular smooth muscle cells.

[0196] Example 2: The polypeptides of the present disclosure induce tube formation of HUVEC Method Cells were transfected on 6-well plates for 48 hours as described above or subjected to starvation with 0.5% medium supplement for 24 hours and dissociated with Accutase (Gibco, USA) to obtain a cell suspension. Geltrex low growth factor basement membrane matrix (Invitrogen, USA CA) was thawed overnight at 4 °C and then added to 96-well plates (50 μl / well). The coated 96-well plates were placed in an incubator for more than 30 minutes for further use, and the cell suspension was seeded therein at a density of 1.5×104 cells / well. For the NRP-1 silencing experiment, the cells were cultured in complete medium. For the polypeptide treatment experiment, the cells were stimulated with complete medium supplemented with different concentrations of the polypeptide. For the NRP-1 rescue experiment, the cells transfected with siRNA were cultured with complete medium and NRP-1 stimulation. After 24 hours of incubation, images were recorded with an inverted microscope (Nikon, Eclipse TE2000-U, Japan), and the total length of the vascular master segments in each image was quantified using the Angiogenesis Analyzer, an ImageJ plugin software program (in pixel units). Data were analyzed using 8-14 photos per condition.

[0197] Human umbilical vein endothelial cells were initially treated with scrambled non-coding siRNA (NC) or siRNA of NRP-1, and then treated with FOL26 at concentrations of 10 nM, 100 nM, and 1000 nM. Endothelial tube formation and the total number of master segments were measured using ImageJ. The gene expression of PECAM-1 (CD31) was analyzed.

[0198] Results The results for FOL26 are shown in Figure 2 and for FOL56 are shown in Figure 12. The test polypeptide significantly increased tube formation in HUVEC. This polypeptide also increased the expression of PECAM-1. Figure 10 shows that FOL26 increased tube formation in an NRP-1-dependent manner compared to the control.

[0199] Conclusions The polypeptide of the present disclosure induces tube formation in HUVEC.

[0200] Example 4: The polypeptide of the present disclosure prevents apoptosis in HUVEC and HCASMC Methods Human umbilical vein endothelial cells (HUVEC) and human coronary artery smooth muscle cells (HCASMC) were purchased from Thermo Fisher. The cells were grown in Medium 200 containing 2% low serum growth medium additive with antibiotics-antimycotics (1%, Invitrogen, CA, USA) and in Medium 231 containing 5% smooth muscle cell growth medium additive (Invitrogen, USA CA), respectively. The test polypeptide and sFasL (PeproTech, NJ, USA) were dissolved in the corresponding complete medium.

[0201] The Caspase-Glo 3 / 7 Assay (Promega, USA) was performed to evaluate cell apoptosis. HUVEC and HCASMC were seeded at 3 - 5×10 cells per well 3They were seeded into 96-well plates at a density of

[0202] Results The results for FOL26 are shown in Figure 3 and those for FOL56 in both HUVEC and HCASMC are shown in Figure 13. Both polypeptides reduced apoptosis induced by sFasL in cell lines.

[0203] Conclusion The polypeptides of the present disclosure prevent apoptosis of HUVEC and HCASMC.

[0204] Example 5: Effect of the polypeptides of the present disclosure on gene expression in HUVEC and HCASMC Method Cells on the 6-well plate were washed with cold DPBS (Gibco, USA) and homogenized in TRIzol reagent (Invitrogen, CA, USA). Total RNA was extracted using the PureLink RNA Mini Kit (Invitrogen, CA, USA), and then nucleic acids were quantified using the NanoDrop 2000c (Thermo Fisher Scientific, USA). To measure the mRNA expression of the target gene, real-time qPCR was performed on the LightCycler 480 system (Roche, Mannheim, Germany) using the KAPA SYBR FAST One-Step qRT-PCR Master Mix Kit (KAPA Biosystems, USA). All primers were purchased from the miScript Primer Assay (Qiagen, Valencia, CA), and the GAPDH mRNA expression of each sample was used for normalization. Cells on the 6-well plate were washed with cold DPBS, lysed on ice using a mixture of lysis buffer and protease inhibitor, and then centrifuged at 15000g for 20 minutes at 4°C. The supernatant was assayed to measure the protein concentration using the BCA Protein Assay Kit (Thermo Fisher Scientific, USA). Protein samples were loaded onto an SDS-PAGE gel, separated by electrophoresis, and then transferred to a PVDF membrane (Millipore, USA). The membrane was blocked with 5% non-fat milk. Primary antibody (Abcam, UK) and secondary antibody were assayed and incubated with the membrane overnight at 4°C and for 1 hour at room temperature, respectively.

[0205] Results The results for FOL26 are shown in Figures 4 - 7, and the results for FOL56 are shown in Figures 14 - 17. Table 1 shows various important biological mediators in the tissue regeneration process. [Table 1]

[0206] Conclusion The polypeptide of the present disclosure induces an environment that induces tissue regeneration through TNF and IL-6 expression, which may promote fibroblast migration and proliferation, collagen secretion, and angiogenesis, and induces correct tissue regeneration by inducing cell remodeling through MMP expression.

[0207] Example 6: Effects of FOL-026 Peptide on Endothelial Cell Function and Gene Expression Methods The effects of the FOL-026 peptide on the proliferation of human umbilical vein endothelial cells (HUVEC) (Figure 18a) and apoptosis induced by hypoxia (Figure 18c) were measured by BrdU incorporation (n = 8 - 9 per group) and active caspase-3 / 7 (n = 7 - 10 per group), respectively. The ROS levels (Figure 18b) activated by 50 ug / ml of oxidized low-density lipoprotein (oxLDL) for 2 hours in cells pre-incubated with the FOL-026 peptide were evaluated using H2O2 measurement (n = 4 - 8 per group). Representative images of endothelial cell migration into in vitro scratch wounds are shown (Figure 19a). The wound closure rate (Figure 19b) in HUVEC stimulated with increasing concentrations of the FOL-026 peptide was quantified using ImageJ software (n = 8 - 9 per group). Scale bar = 150 um. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicate experiments. By one-way analysis of variance and Dunnett's post hoc test * P < 0.05, ** P < 0.01, **** P < 0.0001.

[0208] Results The results shown in Figure 18a indicate that the proliferation of human umbilical vein endothelial cells increases with the addition of the FOL-026 peptide. Also, FOL-026 can reduce the apoptosis effect of HUVEC induced by hypoxia and reduce the amount of ROS levels induced by oxLDL (Figures 18c and 18b).

[0209] Figures 19a and 19b show that the addition of FOL-026 promotes wound closure by HUVEC.

[0210] Conclusion The FOL-026 peptide has a stimulatory effect on endothelial cell proliferation.

[0211] Example 7: Effect of FOL-026 Peptide on Angiogenesis In Vitro and In Vivo Method Representative images of tube formation in HUVECs treated with the FOL-026 peptide are shown in Fig. 20a. Quantitative measurements of total length (Fig. 20b), master segment total length (Fig. 20c), total branch length (Fig. 20d), and segment total length (Fig. 20e) were performed to evaluate angiogenesis in vitro (n = 7 per group for Fig. 29b - e). Quantification of vascular density was evaluated by CD31+ positive area (Fig. 21a, n = 13 per group). Western blot analysis of phosphorylated AKT (pAKT-T308), AKT, phosphorylated ERK1 / 2 (p-ERK1 / 2), and ERK1 / 2 in endothelial cells stimulated with the FOL-26 peptide for 48 h (Fig. 21b). Quantification of phosphorylation intensity normalized to the total expression level of each (Fig. 21c - d, n = 3 per group).

[0212] Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicate experiments. By one-way ANOVA and Dunnett's post hoc test * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.

[0213] Results Figs. 20a - d show a clear effect of FOL-026 on tube formation. This demonstrates the effect of FOL-026 on increasing vascular density and how FOL-026 induces upregulation of angiogenesis-related genes.

[0214] Conclusion The FOL-026 peptide affects angiogenesis both in vitro and in vivo.

[0215] Example 8: Effect of NRP-1 knockdown on endothelial cell functions induced by FOL-026 peptide Method The effectiveness of 48-hour small interfering RNA transfection in HUVEC was confirmed by qRT-PCR (n = 4) (Figure 22a). The effects of stimulation by FOL-026 peptide on cell proliferation (Figure 22b) and cell apoptosis at 0.1% oxygen (Figure 22c) of HUVEC transfected with siRNA-NC or siNRP-1 were evaluated by BrdU incorporation (n = 4 - 7 per group) and active caspase-3 / 7 (n = 4 - 7 per group). Representative images of endothelial cells at 0 and 5 hours after scratch wound formation are shown in Figure 23a. The wound closure rate (Figure 23b) of siRNA-NC / siNRP-1 transfected HUVEC stimulated with increasing concentrations of FOL-026 peptide was quantified by ImageJ software (n = 9 - 12 per group). Scale bar = 150um. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicate experiments. Student's t-test for A, and Sidak's and Dunnett's multiple comparison tests following two-way ANOVA for B, C, and E * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.

[0216] Results Figures 22a - c show that the reduction of NRP-1 expression inhibits the effect of FOL-026.

[0217] Figures 23a - b show that FOL-026 has a significant effect on wound closure in siRNA-NC / siNRP-1 transfected HUVEC.

[0218] Conclusion FOL-026 stimulates wound closure in HUVEC by binding to NRP-1.

[0219] Example 9: Effect of NRP-1 knockdown on tube formation induced by FOL-026 peptide Method Tube formation by increasing doses of FOL-026 peptide treatment in the siRNA-NC or siNRP-1 groups (Figure 24a), as well as full length (Figure 24b), master segment full length (Figure 24c), branch full length (Figure 24d), and segment full length (Figure 24e) were evaluated using the Angiogenesis Analyzer plugin of ImageJ (n = 7 - 12 per group). Scale bar = 150um. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicates. By Sidak's and Dunnett's multiple comparison tests following two-way ANOVA * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.

[0220] Results and Conclusions FOL-026 peptide induces tube formation in the siRNA-NC and siNRP-1 groups.

[0221] Example 10: Effect of FOL-026 Peptide on Smooth Muscle Cell Function Method The effects of FOL-026 peptide treatment on smooth muscle cell proliferation (Figure 25a) and apoptosis induced by hypoxia (Figure 25c) were evaluated by BrdU incorporation (n = 10 per group) and active caspase-3 / 7 (n = 6 - 8 per group), respectively. H2O2 measurement of smooth muscle cells pre-incubated with FOL-26 peptide after 2-hour stimulation with 50 ug / ml of oxidized low-density lipoprotein (oxLDL) (n = 6 - 7 per group) (Figure 25b). Representative images of in vitro scratch wound assay are shown (Figure 26a). The wound healing ability of human coronary artery smooth muscle cells (HCASMC) treated with FOL-026 peptide (Figure 26b) was measured by ImageJ software (n = 10 per group). Scale bar = 150um. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicates. By one-way ANOVA and Dunnett's post hoc test * P < 0.05, ** P < 0.01,*** P < 0.001, **** P < 0.0001.

[0222] Results and conclusions FOL-026 induces smooth muscle cell proliferation, inhibits apoptosis, reduces ROS formation, and promotes wound closure.

[0223] Example 11: Effect of NRP-1 knockdown on smooth muscle cell function induced by FOL-026 peptide Methods qRT-PCR analysis of NRP-1 mRNA expression in HCASMC transfected with small interfering RNA for 48 hours (n = 4) (Figure 27a). Evaluation of BrdU incorporation (Figure 27b, n = 10 - 11) and caspase-3 / 7 activation (Figure 27c, n = 3 - 10) in siRNA-NC / siNRP-1 transfected HUVEC treated with FOL-026 peptide at the indicated concentrations. Representative images of smooth muscle cells at 0 and 5 hours after scratch wound formation are shown in Figure 28a. The wound closure rate of HCASMC in the siRNA-NC and siNRP-1 groups stimulated with increasing concentrations of FOL-026 peptide (Figure 28b) was quantified by ImageJ software (per group = 9 - 12). Scale bar = 150 um. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicate experiments. By Student's t-test (A), Sidak's and Dunnett's multiple comparison tests following two-way analysis of variance * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001.

[0224] Results and conclusions FOL-026 has a significant effect on wound closure in siRNA-NC / siNRP-1 transfected HUVEC.

[0225] Example 12: FOL-005 peptide promotes the proliferation ability and wound healing ability of endothelial cells and smooth muscle cells Methods Endothelial cell proliferation (Figure 29a) was evaluated by BrdU incorporation in human umbilical vein endothelial cells (HUVECs) stimulated with increasing concentrations of FOL-005 peptide for 48 hours (n = 7 - 10 per group).

[0226] The wound closure rate (Figure 29b) in HUVECs treated with FOL-005 at the indicated doses was quantified by ImageJ software (n = 12 - 14 per group), and representative images at 0 and 6 hours after scratch wound formation are shown (Figure 29c).

[0227] The effect of FOL-005 peptide on smooth muscle cell proliferation (Figure 30a) was measured by BrdU incorporation in human coronary artery smooth muscle cells (HCASMCs) treated with the peptide. The scratch wound assay of HCASMCs incubated with FOL-005 peptide for 5 hours (Figure 30b) was evaluated by ImageJ software (n = 10 - 12 per group), and representative images of smooth muscle cell migration into in vitro scratch injuries are shown (Figure 30c). Scale bar = 150 μm. Data are shown as mean ± SEM. Data were obtained from 3 - 4 independent replicates. p-values are shown as in the figure. p-values were calculated by one-way ANOVA and Dunnett's post hoc test.

[0228] Results The results shown in Figure 29a indicate that the proliferation of human umbilical vein endothelial cells (HUVECs) increases with the addition of FOL-005 peptide. The scratch wound assays in Figures 29b and 29c indicate that FOL-005 peptide promotes wound closure by HUVECs. The results shown in Figure 30a indicate that the proliferation of human coronary artery smooth muscle cells (HCASMCs) increases with the addition of FOL-005 peptide.

[0229] The scratch wound assays in Figures 30b and 30c indicate that FOL-005 peptide promotes HCASMC wound closure.

[0230] Conclusions The FOL-005 peptide has a clear effect on the proliferation ability and wound healing ability of endothelial cells and smooth muscle cells.

[0231] Example 13: Effect of the FOL-005 peptide on tube formation Method The tube formation of human umbilical vein endothelial cells (HUVEC) treated with the FOL-005 peptide is shown in Fig. 31a. The quantitative measurement of the full length of the master segment in Fig. 31b was used to evaluate angiogenesis in vitro (n = 7 per group). Scale bar = 150 μm. Data are shown as mean ± SEM. The data were obtained from 3 - 4 independent repeated experiments. The p-values are shown as in the figure. The p-values were calculated by one-way ANOVA and Dunnett's post hoc test (B), and Sidak's and Dunnett's multiple comparison tests following two-way ANOVA.

[0232] Results The results shown in Figs. 31a and 31b indicate that the addition of the FOL-005 peptide increases the tube formation of human umbilical vein endothelial cells (HUVEC).

[0233] Conclusion The addition of the FOL-005 peptide has a stimulatory effect on endothelial tube formation. [Table 2] TIFF2025516717000004.tif222159TIFF2025516717000005.tif226159TIFF2025516717000006.tif224159TIFF2025516717000007.tif126159

[0234] References Gottrup F., A specialized wound-healing center concept: importance of a multidisciplinary department structure and surgical treatment facilities in the treatment of chronic wounds. The American Journal of Surgery. 2004;187(5):S38-S43。 Kirker K.R., James G.A., In vitro studies evaluating the effects of biofilms on wound-healing cells: a review. APMIS. 2017;125(4):344-52。 Frykberg R.G., Banks J., Challenges in the Treatment of Chronic Wounds. Adv Wound Care (New Rochelle). 2015;4(9):560-82。

Claims

1. For use in the treatment and / or prevention of a disease or disorder associated with a decrease or abnormality in angiogenesis in a subject, a) (i) General formula: X ５ X ６ SX ７ X ８ A peptide comprising or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), wherein, X ５ is D or G, X ６ is I or G, X ７ is V or L, X ８ is the peptide that is V or A; (ii) General formula: X １４ LX １５ a peptide comprising or consisting of the amino acid sequence of YGIK (SEQ ID NO: 105), wherein, X １４ is either E or G, X １５ is the peptide that is S or T; (iii) VDTYDGDISVVYGL (SEQ ID NO: 34), VDTYDGDISVVYG (SEQ ID NO: 35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR (SEQ ID NO: 40), VDVPNGDISLAYGL (SEQ ID NO: 41), VDVPNGDISLAYG (SEQ ID NO: 42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR (SEQ ID NO: 45), LDGLVRAYDNISPVG (SEQ ID NO: 46), GDPNGDISVVYGLR (SEQ ID NO: 47), VDVPNGDISLAYRLR (SEQ ID NO: 48), VDVPEDGDISLAYRLR (SEQ ID NO: 49), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52), CLAEIDS C (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK (circular) (SEQ ID NO: 131), Circular CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYG I (SEQ ID NO: 133), KPLAEIDSIELSYG (SEQ ID NO: 134), KPLAEIDSIELS Y (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136), KPLAEIDSIEL (SEQ ID NO: 137), and KPLAEIDSIE (SEQ ID NO: 138); a peptide comprising or consisting of an amino acid sequence selected from the group consisting of a peptide selected from the group consisting of; b) a polynucleotide encoding the peptide of a) upon expression; c) a vector comprising the polynucleotide of b); or d) a cell comprising the polynucleotide of b) or the vector of c); A medicament comprising.

2. wherein the peptide has the general formula: VDX ２ X ３ X ４ GX ５ X ６ SX ７ X ８ and contains the amino acid sequence of YGLR (SEQ ID NO: 2). wherein, X ２ is T or V, X ３ is Y or P, X ４ is D or N, X ５ is D or G, X ６ is I or G, X ７ is V or L, X ８ The agent for use according to claim 1, wherein X is V or A.

3. wherein the peptide has the general formula: VDTYX ４ GX ５ X ６ SX ７ X ８ and contains the amino acid sequence of YGLR (SEQ ID NO: 3). wherein, X ４ is D or N, and X ５ is D or G, X ６ is I or G, and X ７ is V or L, X ８ A medicament for use according to any one of the preceding claims, wherein X is V or A.

4. wherein the peptide has the general formula: VDTYDGZ ７ Z ８ SZ １０ Z １１ contains the amino acid sequence of YGLR (SEQ ID NO: 4), wherein, X ５ is D or G, X ６ is I or G, X ７ is V or L, X ８ A medicament for use according to any one of the preceding claims, wherein X is V or A.

5. wherein the peptide has the general formula: VDTYDGZ ７ Z ８ contains the amino acid sequence of SVVYGLR (SEQ ID NO: 5), wherein, X ５ is D or G, and X ６ A medicament for use according to any one of the preceding claims, wherein X is I or G.

6. wherein the peptide has the general formula: KX ９ LAX １０ X １１ X １２ X １３ IX １４ LX １５ and contains the amino acid sequence of YGI K (SEQ ID NO: 106), wherein, X ９ is C, P, or G, and X １０ is E or G, and X １１ is C, D, or I, and X １２ is D, I, S, or G, and X １３ is S, D, or G, and X １４ is E or G, and X １５ The agent for use according to claim 1, wherein X is S or T.

7. wherein the peptide has the general formula: KX ９ LAX １０ X １１ X １２ X １３ IX １４ and contains the amino acid sequence of LSYGI K (SEQ ID NO: 107), wherein, X ９ is C, P, or G, and X １０ is E or G, and X １１ where C, I, or non - existent, X １２ is D, G, or non-existent, X １３ is S, G, or non-existent, X １４ The agent for use according to claim 1, wherein X is E or G.

8. wherein the peptide has the general formula: KX ９ LAX １０ IX １４ includes the amino acid sequence of LSYGIK (SEQ ID NO: 108), wherein, X ９ is C, P, or G, and X １０ is E or G, and X １４ The agent for use according to claim 1, wherein X is E or G.

9. The medicament for use according to claim 1, wherein the peptide comprises the amino acid sequence IELSYGIK (SEQ ID NO: 109).

10. X １４ A medicament for use according to claim 1, under the condition that when X is T, the peptide contains 25 or fewer amino acid residues.

11. The peptide is VDTYDGGISVVYGLR (SEQ ID NO: 6), VDTYDGDISVVYGLR (SEQ ID NO: 7), DTYDGDISVVYGLR (SEQ ID NO: 8), TYDGDISVVYGLRS (SEQ ID NO: 9), TYDGDISVVYGLR (SEQ ID NO: 10), YDGDISVVYGLRS (SEQ ID NO: 11), YDGDISVVYGLR (SEQ ID NO: 12), DGDISVVYGLRS (SEQ ID NO: 13), DGDISVVYGLR (SEQ ID NO: 14), GDISVVYGLRS (SEQ ID NO: 15), GDISVVYGLR (SEQ ID NO: 16), DISVVYGLRS (SEQ ID NO: 17), DISVVYGLR (SEQ ID NO: 18), VDVPNGDISLAYGLR (SEQ ID NO: 19), DVPNGDISLAYGLRS (SEQ ID NO: 20), DVPNGDISLAYGLR (SEQ ID NO: 21), VPNGDISLAYGLRS (SEQ ID NO: 22), VPNGDISLAYGLR (SEQ ID NO: 23), PNGDISLAYGLRS (SEQ ID NO: 24), PNGDISLAYGLR (SEQ ID NO: 25), NGDISLAYGLRS (SEQ ID NO: 26), NGDISLAYGLR (SEQ ID NO: 27), GDISLAYGLRS (SEQ ID NO: 28), GDISLAYGLR (SEQ ID NO: 29), DISLAYGLRS (SEQ ID NO: 30), DISLAYGLR (SEQ ID NO: 31), VDTYDGDGSVVYGLR (SEQ ID NO: 32), VDVPEGDISLAYGLR (SEQ ID NO: 33), AEIDSIELSYGIK (SEQ ID NO: 110), KPLAEIDSIELSYGIK (SEQ ID NO: 111), KCLAECDSELSYGIK (circular) (SEQ ID NO: 112), KPLAEDISIELSYGIK (SEQ ID NO: 113), KPLAEISDIELSYGIK (SEQ ID NO: 114), KPLAEIGDIELSYGIK (SEQ ID NO: 115), KPLAEGDIELSYGIK (SEQ ID NO: 116), KPLAEIELSYGIK (SEQ ID NO: 117), KPLAEIDSIELTYGIK (SEQ ID NO: 118), KPLAEIDGIEELSYGIK (SEQ ID NO: 119), KPLAEIDGIEELTYGIK (SEQ ID NO: 120), KPLAEIGSIELSYGIK (SEQ ID NO: 121), KGLAEIDSIELSYGIK (SEQ ID NO: 122), KPLAGIDSIGLSYGIK (SEQ ID NO: 123), The cyclic KCLAIDSCELLSYGIK (SEQ ID NO: 124), LAIDSIELLSYGIK (SEQ ID NO: 125), EIDSIELLSYGIK (SEQ ID NO: 126), IDSIELLSYGIK (SEQ ID NO: 127), DSIELLSYGIK (SEQ ID NO: 128), SIELLSYGIK (SEQ ID NO: 129), and A drug for use according to claim 1, comprising or consisting of an amino acid sequence selected from the group consisting of IELLSYGIK (SEQ ID NO: 109).

12. A drug for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGGISVVYGLR (SEQ ID NO: 6).

13. A drug for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence VDTYDGDISVVYGLR (SEQ ID NO: 7).

14. A drug for use according to claim 1, wherein the peptide comprises or consists of the amino acid sequence AEIDSIELLSYGIK (SEQ ID NO: 110).

15. A drug for use according to any one of the preceding claims, wherein the peptide comprises 85 or fewer amino acids, for example 80 or fewer, for example 75 or fewer, for example 70 or fewer, for example 65 or fewer, for example 60 or fewer, for example 55 or fewer, for example 50 or fewer, for example 55 or fewer, for example 40 or fewer amino acids, for example 35 or fewer, for example 30 or fewer, for example 28 or fewer, for example 26 or fewer, for example 24 or fewer, for example 22 or fewer, for example 20 or fewer, for example 19 or fewer, for example 18 or fewer, for example 17 or fewer, for example 16 or fewer, for example 15 or fewer, for example 14 or fewer, for example 13 or fewer, for example 12 or fewer, for example 11 or fewer, for example 10 or fewer amino acids.

16. A drug for use according to any one of the preceding claims, wherein the peptide comprises at least 2 additional amino acids conjugated to the N-terminus or C-terminus of the peptide, for example at least 3, for example at least 4, for example at least 5, for example at least 6, for example at least 7, for example at least 8, for example at least 9, for example at least 10, for example at least 15, or for example at least 20 amino acids.

17. An agent for use according to any one of the preceding claims, wherein the agent is non-natural.

18. An agent for use according to any one of the preceding claims, wherein the agent is conjugated in part.

19. The agent for use according to claim 15, wherein the moiety is selected from the group consisting of polyethylene glycol (PEG), monosaccharide, fluorophore, chromophore, radioactive compound, and cell-penetrating peptide.

20. An agent for use according to any one of the preceding claims, wherein the agent is further modified by glycosylation, PEGylation, amidation, esterification, acylation, acetylation, and / or alkylation, etc.

21. An agent for use according to any one of the preceding claims, wherein the agent contains or consists of a tandem repeat containing two or more repeating units.

22. The agent for use according to claim 21, wherein the repeating unit contains or consists of any one or more amino acid sequences among the sequences described in the preceding claims.

23. An agent for use according to any one of the preceding claims, wherein the agent is fused to another polypeptide.

24. The agent for use according to claim 23, wherein the polypeptide is selected from the group consisting of glutathione-S-transferase (GST) and protein A.

25. An agent for use according to any one of the preceding claims, wherein the agent is fused to a tag.

26. The agent for use according to claim 25, wherein the tag is an oligohistidine tag.

27. An agent for use according to any one of the preceding claims, wherein the agent is cyclic.

28. An agent for use according to any one of the preceding claims, wherein the peptide can form at least one intramolecular disulfide bridge.

29. An agent for use according to any one of the preceding claims, wherein the agent is a variant of the peptide, and the variant contains or consists of a sequence in which any one amino acid is modified to another proteinogenic or non-proteinogenic amino acid, provided that five or fewer amino acids are so modified.

30. The agent for use according to claim 29, wherein the variant comprises, or consists of, a sequence in which 5 or fewer amino acids are modified to another proteinogenic or non-proteinogenic amino acid, for example 4 or fewer amino acids, for example 3 or fewer amino acids, for example 2 or fewer amino acids, for example 1 or fewer amino acids are modified.

31. The agent for use according to any one of the preceding claims, wherein 1 or more amino acids are conservatively substituted.

32. The agent for use according to any one of the preceding claims, wherein the peptide comprises, or consists of, 1 or more additional amino acids inserted at the N-terminus and / or C-terminus and / or within the sequence.

33. The agent for use according to any one of the preceding claims, wherein the peptide has 1 additional amino acid.

34. The agent for use according to any of the preceding claims, wherein the agent further comprises a detectable moiety.

35. The agent for use according to any one of the preceding claims, wherein the agent is present in a composition.

36. The agent for use according to claim 35, wherein the composition is a pharmaceutical composition.

37. The agent for use according to claim 35, wherein the composition is a cosmetic composition.

38. The agent for use according to any one of the preceding claims, wherein the composition is a coating.

39. The agent for use according to any one of claims 35 to 38, wherein the composition is a coating of a graft.

40. The agent for use according to claim 39, wherein the graft is a biomaterial.

41. The agent for use according to claim 40, wherein the biomaterial is bone.

42. The agent for use according to claim 39, wherein the graft is a medical device.

43. The agent for use according to claim 42, wherein the medical device is a stent.

44. The agent for use according to any one of the preceding claims, wherein the agent increases angiogenesis in the subject.

45. The agent for use according to any one of the preceding claims, wherein the agent is an angiogenesis inducer.

46. The agent for use according to any one of the preceding claims, wherein the agent is capable of improving myocyte survival in cardiovascular diseases.

47. A medicament for use according to any one of the preceding claims, wherein the medicament can improve neuronal survival in cerebrovascular diseases.

48. The disease or disorder is i. a cardiovascular disease, ii. an injury caused by external factors, iii. an immune system disease, iv. a nervous system disease, and v. a disease of the musculoskeletal system or connective tissue A medicament for use according to any one of the preceding claims, selected from the group consisting of.

49. The cardiovascular disease is i. an ischemic heart disease, ii. a cerebrovascular disease, iii. a coronary artery disease, iv. a disease of arteries, arterioles, or capillaries, v. a cardiovascular symptom, sign, or clinical finding, vi. a disease of the myocardium or ventricles, and vii. an endocrine, nutritional, or metabolic disease A medicament for use according to claim 48, selected from the group consisting of.

50. The ischemic heart disease is i. an acute ischemic heart disease, such as a myocardial infarction, such as an acute myocardial infarction and an acute ischemic heart disease of unknown details (acute coronary syndrome), ii. a chronic ischemic heart disease, such as other specific chronic ischemic heart diseases (cardiovascular arteriosclerosis), iii. angina pectoris, such as unstable angina pectoris, and iv. obstructive arteriosclerosis A medicament for use according to claim 49, selected from the group consisting of.

51. The medicament for use according to claim 50, wherein the myocardial infarction is ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI).

52. The medicament for use according to claim 51, wherein the STEMI or NSTEMI exhibits specific existing complications, for example, within 28 days thereafter.

53. The medicament for use according to claim 48, wherein the cardiovascular disease is arteriosclerosis.

54. The medicament for use according to claim 48, wherein the cardiovascular disease is systemic sclerosis or is associated with systemic sclerosis.

55. The cerebrovascular disease is i. cerebral ischemia, such as a cerebral ischemic attack (stroke), such as a cerebral infarction, and ii. asymptomatic stenosis of intracranial or extracranial arteries (cerebral arteriosclerosis) A medicament for use according to claim 49, selected from the group consisting of.

56. The medicament for use according to claim 55, wherein the cerebral ischemic attack is related to a patient history of transient ischemic attack (TIA) or cerebral infarction without sequelae.

57. A medicament for use according to any one of claims 55 or 56, wherein the cerebral ischemic attack is associated with the medical history of a patient with traumatic brain injury or the medical history of a patient with sequelae of cerebrovascular disease.

58. The cerebrovascular disease is i. non-traumatic subarachnoid hemorrhage, ii. non-traumatic intracerebral hemorrhage, iii. other and unspecified non-traumatic intracranial hemorrhage, iv. cerebral infarction, v. occlusion and stenosis of the anterior cerebral artery that did not lead to cerebral infarction, vi. occlusion and stenosis of cerebral arteries that did not lead to cerebral infarction, vii. other cerebrovascular diseases, viii. cerebrovascular disorders associated with other diseases (cerebrovascular disorders classified elsewhere), and ix. sequelae of cerebrovascular disease A medicament for use according to claim 49, selected from the group consisting of.

59. The disease of the artery, arteriole, or capillary is i. atherosclerosis, ii. aortic aneurysm and aortic dissection, iii. other aneurysms, iv. other peripheral vascular diseases, v. arterial embolism and thrombosis, vi. atheroembolism, vii. septic arterial embolism, viii. other disorders of arteries and arterioles, ix. diseases of capillaries, and x. disorders of arteries, arterioles, or capillaries associated with another disease (disorders of arteries, arterioles, or capillaries in diseases classified elsewhere) A medicament for use according to claim 49, selected from the group consisting of.

60. The disease of the artery, arteriole, or capillary is chronic arterial occlusion, such as atherosclerotic thrombotic chronic arterial occlusion or arteriosclerosis, a medicament for use according to claim 49.

61. The symptoms, signs, or clinical findings of the cardiovascular system are symptoms or signs occurring in the cardiovascular system, such as abnormal blood pressure measurements without a diagnosis, such as cardiac arrest, a medicament for use according to claim 49.

62. The disease of the myocardium or ventricle is cardiomyopathy, such as dilated cardiomyopathy, a medicament for use according to claim 49.

63. The disease of the immune system is an organ-nonspecific systemic autoimmune disease, such as vasculitis, such as thromboangiitis obliterans (Buerger's disease), a medicament for use according to claim 48.

64. The disease of the nervous system is i. movement disorders, such as Parkinson's syndrome, such as Parkinson's disease, ii. multiple sclerosis or other white matter abnormalities, such as multiple sclerosis, and iii. disorders accompanied by neurocognitive impairment as a major feature, such as Alzheimer's disease A medicament for use according to claim 48, selected from the group consisting of.

65. The medicament for use according to claim 48, wherein the disease of the skeletal muscle system or connective tissue is a pathological condition related to the spine, for example, intervertebral disc herniation.

66. The medicament for use according to claim 48, wherein the disease of the circulatory system, the disease of the immune system, the disease of the nervous system, or the disease of the skeletal muscle system or connective tissue is diabetes or is related to diabetes.

67. The medicament for use according to claim 66, wherein the diabetes is selected from type 1 diabetes and type 2 diabetes.

68. The medicament for use according to any one of the preceding claims, wherein the subject is suffering from diabetes.

69. The medicament for use according to any one of the preceding claims, wherein the subject is a mammal.

70. The medicament for use according to claim 69, wherein the mammal is a human.

71. A method for treating or preventing a disease or disorder in a subject, wherein the disease or disorder is i. a disease of the circulatory system, ii. damage by external factors, iii. a disease of the immune system, iv. a disease of the nervous system, and v. a disease of the skeletal muscle system or connective tissue selected from the group consisting of, the method comprising administering to a subject in need thereof a therapeutically effective amount of the medicament according to any one of claims 1 to 47.

72. i. a disease of the circulatory system, ii. damage by external factors, iii. a disease of the immune system, iv. a disease of the nervous system, and v. a disease of the skeletal muscle system or connective tissue Use of the medicament according to any one of claims 1 to 47 in the manufacture of a medicament for treating or preventing a disease or disorder selected from the group consisting of.

73. For use in improving angiogenesis in a subject after surgery, a) (i) General formula: X ５ X ６ SX ７ X ８ a peptide comprising or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), wherein, X ５ is D or G, X ６ is I or G, X ７ is V or L, X ８ is the peptide which is V or A; (ii) General formula: X １４ LX １５ a peptide comprising or consisting of the amino acid sequence of YGIK (SEQ ID NO: 105), wherein, X １４ is E or G, and X １５ is the peptide that is S or T; (iii) VDTYDGDISVVYGL (SEQ ID NO: 34), VDTYDGDISVVYG (SEQ ID NO: 35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGGRGDSVVYGLR (SEQ ID NO: 40), VDVPNGDISLAYGL (SEQ ID NO: 41), VDVPNGDISLAYG (SEQ ID NO: 42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR (SEQ ID NO: 45), LDGLVRRAYDNISPVG (SEQ ID NO: 46), GDPNGDISVVYGLR (SEQ ID NO: 47), VDVPNGDISLAYRLR (SEQ ID NO: 48), VDVPEGDISLAYRLR (SEQ ID NO: 49), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52), CLAEIDS C (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK (circular) (SEQ ID NO: 131), Circular CFKPLAEIDSIEC (SEQ ID NO: 132), KPLAEIDSIELSYGI (SEQ ID NO: 133), KPLAEIDSIELSYG (SEQ ID NO: 134), KPLAEIDSIELSY (SEQ ID NO: 135), KPLAEIDSIELS (SEQ ID NO: 136), KPLAEIDSIEL (SEQ ID NO: 137), and A peptide comprising or consisting of an amino acid sequence selected from the group consisting of KPLAEIDSIE (SEQ ID NO: 138); A peptide selected from the group consisting of; b) A polynucleotide encoding the peptide of a) upon expression; c) A vector comprising the polynucleotide of b); or d) A cell comprising the polynucleotide of b) or the vector of c); A drug comprising.

74. The drug for use according to claim 73, wherein the surgery is a cardiovascular surgery.

75. The drug for use according to any one of claims 73 or 74, wherein the cardiovascular surgery is a vascular graft.

76. The drug for use according to any one of claims 73 to 75, wherein the subject has received a transplant.

77. The drug for use according to claim 76, wherein the transplant is an organ transplant, a tissue transplant, or a cell transplant.

78. The drug for use according to claim 77, wherein the cell transplant is a bone marrow cell transplant.

79. The drug for use according to claim 77, wherein the organ transplant is a heart transplant or a cardiovascular tissue transplant.

80. A method for inducing angiogenesis, the method comprising administering the drug according to any one of claims 1 to 47 to a subject.

81. (i) General formula: X ５ X ６ SX ７ X ８ A peptide comprising or consisting of the amino acid sequence of YGLR (SEQ ID NO: 1), Wherein X ５ is D or G, and X ６ is I or G, X ７ is V or L, X ８ is the peptide which is V or A; (ii) General formula: X １４ LX １５ A peptide comprising or consisting of the amino acid sequence of YGIK (SEQ ID NO: 105), Wherein X １４ is E or G, X １５ is the peptide which is S or T; (iii) VDTYDGDISVVYL (SEQ ID NO: 34), VDTYDGDISVVYG (SEQ ID NO: 35), VDTYDGDISVVY (SEQ ID NO: 36), VDTYDGDISVV (SEQ ID NO: 37), VDTYDGDISV (SEQ ID NO: 38), VDTYDGDIS (SEQ ID NO: 39), VDTYDGRGDSVVYGLR (SEQ ID NO: 40), VDVPNGDISLAYGL (SEQ ID NO: 41), VDVPNGDISLAYG (SEQ ID NO: 42), VDVPNGDISLA (SEQ ID NO: 43), VDVPNGDIS (SEQ ID NO: 44), GDPNDGRGDSVVYGLR (SEQ ID NO: 45), LDGLVRAYDNISPVG (SEQ ID NO: 46), GDPNGDISVVYGLR (SEQ ID NO: 47), VDVPNGDISLAYRLR (SEQ ID NO: 48), VDVPEDISLAYRLR (SEQ ID NO: 49), V(β-D)TYDGDISVVYGLR (SEQ ID NO: 50), VDTY(β-D)GDISVVYGLR (SEQ ID NO: 51), VDTYDG(β-D)ISVVYGLR (SEQ ID NO: 52), CLAEIDS C (circular) (SEQ ID NO: 130), CFKPLAEIDSIECSYGIK (circular) (SEQ ID NO: 131), Circular CFKPLAEIDSIE (SEQ ID NO: 132), KPLAEIDSIELSYYGI (SEQ ID NO: 133), KPLAEIDSIELSYYG (SEQ ID NO: 134), KPLAEIDSIELSYY (SEQ ID NO: 135), KPLAEIDSIELSY (SEQ ID NO: 136), KPLAEIDSIELS (SEQ ID NO: 137), and A peptide comprising, or consisting of, an amino acid sequence selected from the group consisting of KPLAEIDSIE (SEQ ID NO: 138); A graft comprising a peptide selected from the group consisting of.

82. The graft according to claim 81, wherein the graft is coated with a composition comprising the agent according to any one of the preceding claims.

83. The graft according to claim 81, wherein the graft is a biomaterial.

84. The graft according to claim 83, wherein the biomaterial is bone.

85. The graft according to claim 81, wherein the graft is a medical device.

86. The graft according to claim 85, wherein the medical device is a stent.

Images