Peptide composition

Abstract

The present invention provides peptide compositions and methods for inhibiting angiogenesis or the development of pathological or abnormal blood vessels in humans or other animals. [Solution] A composition of substance is provided comprising a peptide consisting solely of the amino acid sequence Gly-X-Gly-Y-Thr-Pro (where X is Asp and Y is Arg; or X is Lys and Y is Asp). The composition is administered to a human or animal subject in a therapeutically effective amount to inhibit angiogenesis or pathological or abnormal vascular development in that subject. The composition is also administered to the eye of a subject to treat eye diseases or disorders in which angiogenesis or pathological or abnormal vascular development is occurring.

Description

Technical Field

[0001] Related Applications This patent application claims priority to U.S. Provisional Patent Application No. 62 / 521,984, filed Jun. 19, 2017, entitled "Peptide Compositions and Related Methods," the entire disclosure of which is hereby expressly incorporated by reference.

[0002] The present invention generally relates to the fields of biology and medicine, and more specifically, to peptide compositions and methods of using them.

Background Art

[0003] In accordance with 37 CFR 1.71(e), this patent document contains material subject to copyright protection, and the owner of this patent document reserves all copyrights whatsoever. Throughout this patent application, amino acids may be referred to interchangeably using the following names, three-letter codes, and one-letter codes:

[0004]

Table 1

[0005] The applicant has developed a synthetic oligopeptide glycinyl-arginyl-glycinyl-cysteine(acid)-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC) that inhibits numerous integrins and has been shown to have significant anti-angiogenic, anti-inflammatory, neuroprotective, and other effects. When administered to the eye, ALG-1001 causes vitreolysis and posterior vitreoretinal detachment (PVD) and can be used to treat eye diseases such as exudative macular degeneration (WMD), non-exudative macular degeneration (DMD), diabetic retinopathy (PDR), diabetic macular edema (DME), and vitreomacular traction (VMT). Further information regarding ALG-1001 and related compounds can be found in U.S. Patent No. 9,018,352, entitled "Peptide Compositions and Therapeutic Uses Thereof," No. 9,872,886, entitled "Compositions and Methods for Inhibiting Cellular Adhesion or Directing Diagnostic or Therapeutic Agents to RGD Binding Sites," No. 9,896,480, entitled "Integrin Receptor Antagonists and Their Methods of Use," and the pending U.S. Patent Application No. 15 / 874,814, entitled "Therapeutic and Neuroprotective Peptides," the full disclosures of such patents and patent applications being expressly incorporated herein by reference.

[0006] The applicant conceived and synthesized the peptides listed in Table 1 below.

[0007] [Table 2]

[0008] As described below, the applicant has synthesized numerous additional novel peptides and conducted initial trials, many of which have shown therapeutic efficacy in in vivo trials. [Overview of the project] [Means for solving the problem]

[0009] The present invention provides peptide compounds and methods for inhibiting angiogenesis, which is the development of pathological or abnormal blood vessels, in human or animal subjects. According to one aspect of the present invention, formula: YXZ A composition of a substance comprising an amino acid sequence having or a peptide containing such amino acids, During the ceremony: Y = R, H, K, Cys (acid), G, or D. X = G, A, Cys (acid), R, G, D, or E. A composition is provided in which Z = Cys(acid), G, C, R, D, N, or E. Such peptides include, or may consist of, the amino acid sequences: RG-Cys(acid), RR-Cys, R-Cys(acid)-G, Cys(acid)-RG, Cys(acid)-GR, RGD, RG-Cys(acid), HG-Cys(acid), RGN, DGR, RDG, RAE, KGD, RG-Cys(acid)-GGGDG (SEQ ID NO: 16), cyclo-{RG-Cys(acid)-FN-Me-V} (SEQ ID NO: 4), RA-Cys(acid), RGC, KGD, Cys(acid)-RG, Cys(acid)-GR, cyclo-{RGDDF-NMe-V} (SEQ ID NO: 24), HG-Cys(acid), and salts thereof. Possible salts include, but are not limited to, acetates, trifluoroacetates (TFAs), and hydrochlorides. Such peptides are useful, at least, for inhibiting angiogenesis, which is the development of pathological or abnormal blood vessels, in human or animal subjects.

[0010] Furthermore, in some embodiments, the composition of the substance comprises or consists solely of a peptide having the following general formula 1: Gly-X-Thr-Pro In the formula, X is selected from Arg-Ala-Cys(acid); Arg-Gly-Cys; Arg-Asp-Gly; Arg-Ala-Glu; Arg-Gly-Asn; Asp-Gly-Arg; Cys(acid)-Gly-Arg and Lys-Gly-Asp.

[0011] Furthermore, according to the present invention, the peptide of the present invention, or the synthetic oligopeptide glycinyl-arginyl-glycinyl-cysteic acid(acid)-threonyl-proline (SEQ ID NO: 1), may be combined with taurine and administered to human or animal subjects for the purpose of inhibiting angiogenesis, which is the development of pathological or abnormal blood vessels.

[0012] Furthermore, the present invention provides a method for inhibiting angiogenesis of pathological or abnormal vascular development in human or animal subjects requiring inhibition of angiogenesis of pathological or abnormal vascular development, the method comprising administering to such subjects a therapeutically effective amount of a composition comprising the peptide summarized above. In some cases, such a method may be carried out to treat eye diseases or disorders resulting in angiogenesis or pathological or abnormal vascular development. Such eye diseases or disorders include, but are not limited to, diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemic retinopathy, and certain inflammatory diseases of the eye.

[0013] Furthermore, according to the present invention, methods are provided for inhibiting angiogenesis or the development of pathological or abnormal blood vessels in the lateral region of the eye of a human or animal subject. In some cases, such methods may be employed to inhibit the growth or metastasis of angiogenic tumors.

[0014] Further aspects and details of the present invention will be understood by reading the detailed description and examples set forth below in this specification. [Brief explanation of the drawing]

[0015] [Figure 1] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-His-Gly-Cys(acid)-Thr-Pro (SEQ ID NO: 10) (test compound 14) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 2] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Ala-Cys-Thr-Pro (SEQ ID NO: 28) (test compound 3), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 3] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (test compound 1 / positive control), Gly-Arg-Ala-Asp-Thr-Pro (SEQ ID NO: 5) (test compound 23), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 4] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Ala-Cys(acid)-Thr-Pro (SEQ ID NO: 11) (test compound 3), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 5] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Gly-Cys-Thr-Pro (SEQ ID NO: 14) (test compound 4), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 6]Bar graph of the retinal neovascularization area in the eyes of ROP mice after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (masked) (Test Compound No. 1), or a control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 7] Bar graph of the retinal neovascularization area in the eyes of ROP mice after treatment with either Gly-Lys-Gly-Asp-Thr-Pro (SEQ ID NO: 3) (Test Compound No. 20), or a control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 8] Bar graph of the retinal neovascularization area in the eyes of ROP mice after treatment with either Gly-His-Gly-Cys(acid)-Thr-Pro (SEQ ID NO: 10) (Test Compound No. 14), or a control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 9] Bar graph of the retinal neovascularization area in the eyes of ROP mice after treatment with either Gly-Lys-Gly-Cys(acid)-Thr-Pro (SEQ ID NO: 12) (Test Compound No. 6), or a control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 10] Bar graph of the retinal neovascularization area in the eyes of ROP mice after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Cys(acid)-Gly-Thr-Pro (SEQ ID NO: 9) (Test Compound No. 5), or a control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 11]Bar graph of the retinal neovascularization area in CNV mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Gly-Cys(acid)-Thr-Pro acetate (SEQ ID NO: 7) (test compound No. 2), or control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 12] Bar graph of the retinal neovascularization area in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Arg-Gly-Cys(acid)-Thr-Pro acetate (SEQ ID NO: 7) (test compound No. 2), or control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 13] Bar graph of the retinal neovascularization area in ROP mouse eyes after treatment with either Gly-Asp-Gly-Arg-Thr-Pro (SEQ ID NO: 18) (test compound No. 17), or control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 14] Bar graph of the retinal neovascularization area in ROP mouse eyes after treatment with either Gly-Arg-Gly-Asp-Thr-Pro (SEQ ID NO: 2) (test compound No. 15), or control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 15] Bar graph of the retinal neovascularization area in ROP mouse eyes after treatment with either Gly-Arg-Cys(acid)-Gly-Thr-Pro (SEQ ID NO: 9) (test compound No. 18), or control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 16]This is a bar graph showing the retinal neovascularization area in ROP mouse eyes after treatment with either Arg-Gly-Cys(acid)-Gly-Gly-Asp-Gly (SEQ ID NO: 29) (test compound 7) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). The figure discloses SEQ ID NO: 16. [Figure 17] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Ala-Glu-Thr-Pro (SEQ ID NO: 20) (test compound 19) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 18] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Gly-Cys(acid)-Arg-Thr-Pro (SEQ ID NO: 21) (test compound 11) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 19] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Cys(acid)-Ala-Arg-Thr-Pro (SEQ ID NO: 22) (test compound 10) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 20] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Glu-Gly-Thr-Pro (SEQ ID NO: 30) (test compound 22) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 21] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Cys(acid)-Arg-Gly-Thr-Pro (SEQ ID NO: 31) (test compound 8) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 22]This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Asn-Thr-Pro (SEQ ID NO: 13) (test compound 16) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 23] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), cyclo-{RGDDF-NMe-V} (SEQ ID NO: 24) (test compound No. 13), or the control peptide (Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 32)). [Figure 24] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), cyclo-{RG-Cys(acid)-FN-Me-V} (SEQ ID NO: 4) (test compound 12), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 25] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), Gly-Cys(acid)-Gly-Arg (SEQ ID NO: 33) (test compound 9), or the control peptide (Gly-Arg-Gly-Glu (SEQ ID NO: 34)). [Figure 26] This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-His-Gly-Cys(acid) (SEQ ID NO: 35) (test compound No. 14) or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Figure 27]This bar graph shows the area of ​​retinal neovascularization in ROP mouse eyes after treatment with either Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 27) (positive control), taurine (test compound 25), Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA + taurine (SEQ ID NO: 36) (test compound 24), or the control peptide (Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26)). [Modes for carrying out the invention]

[0016] The following detailed description and accompanying drawings referencing it are intended to describe some examples or embodiments, but not necessarily all of them. It should be noted that the embodiments described are in all respects merely descriptive and not limiting. The detailed description and accompanying drawings of the invention do not limit the scope of the invention in any way.

[0017] Numerous diseases and disorders, including diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemic retinopathy, certain inflammatory diseases of the eye, and the growth or metastasis of neovascular tumors, are known to cause neovascularization or pathological or abnormal vascular development. The applicant has identified several compounds that have been shown to be active in an anti-angiogenic mouse ROP model, as described below. Based on this, such compounds are potentially useful in the treatment of diseases and disorders known to cause neovascularization or pathological or abnormal vascular development, including but not limited to the diseases and disorders described above.

[0018] Each test compound was prepared for injection in sterile water containing 0.08 mg / 100 μL of sodium chloride and 0.005 mg / 100 μL of trisodium citrate, with a peptide concentration of 2.0 mg / 100 μL and pH = 2.7. The mixture was then dispensed into sterile vials by sterile filtration. The taurine test compound was obtained from Sigma Aldrich company, with a purity of >99%, and prepared in the same manner as previously described, with a concentration of 3.0 mg / 100 μL. 2.0 mg / 100 μL of RG-Cys(acid) + 3.0 mg / 100 μL of taurine was prepared in the same manner as described above.

[0019] To screen test compounds for activity against ischemia-induced retinal neovascularization, a well-established mouse model of retinopathy of prematurity (ROP) was used. C57BI / 6 littermates were placed in 75% oxygen on postnatal day (P)7 and returned to room air on postnatal day (P)12. The offspring were randomly assigned to treatment groups of 4 to 10 animals per group. The offspring were treated as follows: The treatment eye was treated by intravitreal injection of a 1.0 microliter solution containing 20 micrograms of the test compound.

[0020] On the 17th day after birth, five days after intravitreal injection, animals were sacrificed, their retinas were flat-mounted, and neovascularization areas in each retina were measured by fluorescence dextran imaging analysis. The applicant identified RG-cysteic acid as the active motif of the oligopeptide glycinyl-arginyl-glycinyl-cysteic acid-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC). The trifluoroacetate (TFA) and acetate of the RG-cysteic acid tripeptide (test compounds 1 and 2) were tested in both the ROP mouse model described above and in a mouse model of laser photocoagulation-induced choroidal neovascularization ("CNV mouse model") as commonly described by Lambert, V et al., Laser-Induced Choroidal Neovascarization Model to Study Age Related Macular Degeneration in Mice, Nature Protocols, 8;2197-2211 (2013). Animals assigned to the "control" group were treated with intravitreous injection of Gly-Arg-Gly-Glu-Thr-Pro (SEQ ID NO: 26) (an inactive control peptide), which is known to be inactive in this model. Some experiments included an additional "positive control" group. Animals assigned to the "positive control" group were treated with intravitreous injection of Gly-Arg-Gly-Cys(acid)-Thr-Pro TFA (SEQ ID NO: 37), which is known to be active in this model.

[0021] Table 2 below summarizes the angiogenic inhibitory effects of each test compound at the tested doses. In each case, data was obtained using ROP mouse models, with the exception of two table entries specifically labeled "CNV". Only the table entries labeled "CNV" show data obtained from CNV mouse models. Bar graphs showing the test results summarized in Table 2 are also provided herein as Figures 1–27. Where shown in the figures, the tests were conducted in a blinded manner so that the researchers did not know the identity or structure of each test compound.

[0022] [Table 3]

[0023] In each of the test compounds, with the exception of the cyclic test compounds 12 and 13, the RG-Cys(acid) active motif of the positive control GRG-Cys(acid)-TP (SEQ ID NO: 1) (ALG-1001) was rearranged and / or substituted by three different amino acid motifs having the amino acid sequence defined in General Formula 2 (below). As a result, test compounds having the general formula defined in General Formula 2 (below) were obtained.

[0024] [ka]

[0025] During the ceremony, Y = R*, H, K, Cys(acid), G, or D. X = G*, A, Cys (acid), R, G, D, or E. Z = Cys(acid)*, G, cysteine, R, D, N, or E.

[0026] * indicates the components of the RGCys(acid) binding motif in GRGCYs(acid)TP (SEQ ID NO: 1) (ALG-1001), which was used as a positive control. Based on the results of the ROP and CNV studies summarized above, the presence of arginine, alanine, and cysteic acid in the GRGCys(acid)TP peptide (SEQ ID NO: 1) (ALG-1001 / Luminate), particularly the sequences of RG-Cys and RA-Cys, plays a crucial role in inhibiting angiogenesis. Furthermore, in the presence of arginine, substitution of cysteic acid (acid) with a neutral amino acid showed a potent inhibitory effect in these experiments.

[0027] Based on the initial data presented herein, specific structure / activity relationships are suggested for certain modifications made to the RG-cysteic acid active motif. For example, when amino acid R (i.e., component Y) of the RG-cysteic acid (acid) binding motif is substituted with a basic or acidic amino acid, the peptide's anti-angiogenic effect is reduced, while in the presence of arginine in the active motif, aspartic acid as component Y appears to promote the peptide's anti-angiogenic effect.

[0028] When amino acid G (i.e., component X) of the RG-cysteic acid active motif is substituted with a basic or acidic amino acid, the peptide's anti-angiogenic effect is reduced. However, in the presence of arginine (strong hydrogen bond), the two carbon length spaces for hydrophobic interactions (alanine and aspartic acid) will not affect the peptide's anti-angiogenic effect.

[0029] When the Cys (acid) component (i.e., the Z component) of the RG-cysteic acid (acid) active motif is substituted with a neutral amino acid, the angiogenic inhibitory activity of the peptide increases. On the other hand, substitution of the Z component with an acidic or basic amino acid leads to a decrease in angiogenic inhibitory activity.

[0030] All of this indicates that RG-cysteic acid (of the oligopeptide glycinyl-arginyl-glycinyl-cysteic acid (acid)-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC) is important for inhibiting angiogenesis. Furthermore, the addition of three parts taurine to one part glycinyl-arginyl-glycinyl-cysteic acid (acid)-threonyl-proline (SEQ ID NO: 1) (ALG-1001) enhances its angiogenic inhibitory activity.

[0031] While the present invention has been described herein with reference to specific examples or embodiments, it should be understood that various additions, deletions, modifications, and alterations may be made to the described examples and embodiments without departing from the spirit and scope intended of the invention. Unless otherwise specified or without creating an embodiment or embodiment unsuitable for its intended use, for example, any element, process, member, component, composition, reactant, part, or portion of one embodiment or embodiment may be incorporated into another embodiment or embodiment, or used in conjunction with another embodiment or embodiment. Also, if the steps of a method or process are described or enumerated in a specific order, the order of such steps may be changed unless otherwise specified or without creating a method or process unsuitable for its intended use. Furthermore, unless otherwise noted, any element, process, member, component, composition, reactant, part, or portion of any invention or embodiment described herein may be present or used in the absence or substantial absence of any other element, process, member, component, composition, reactant, part, or portion. All reasonable additions, deletions, modifications, and alterations are deemed equivalent to the described examples and embodiments and are included within the following claims.

[0032] The technical concepts that can be understood from the above embodiments are described below as an addendum. [Note 1] formula: YXZ A composition of a substance comprising an amino acid sequence having or a peptide containing such amino acids, During the ceremony, Y = R, H, K, Cys (acid), G, or D. X = G, A, Cys (acid), R, G, D, or E. Z = Cys (acid), G, C, R, D, N, or E. composition.

[0033] [Note 2] The composition according to Appendix 1, wherein the amino acid sequence is RG-Cys(acid). [Note 3] The composition according to Appendix 2, wherein the peptide comprises RG-Cys(acid).

[0034] [Note 4] The composition according to Appendix 2, wherein the peptide comprises RG-Cys(acid). [Note 5] The composition according to Appendix 2, wherein the peptide comprises RG-Cys(acid)-GGGDG.

[0035] [Note 6] The composition according to Appendix 2, wherein the peptide comprises cyclo-{RG-Cys(acid)-FN-Me-V}.

[0036] [Note 7] The composition according to Appendix 1, wherein the amino acid sequence is RA-Cys(acid). [Note 8] The composition according to Appendix 1, wherein the amino acid sequence is RG-cysteine.

[0037] [Note 9] The composition according to Appendix 1, wherein the amino acid sequence is R-Cys(acid)-G. [Note 10] The composition according to Appendix 1, wherein the amino acid sequence is Cys(acid)-RG.

[0038] [Note 11] The composition according to Appendix 1, wherein the amino acid sequence is Cys(acid)-GR. [Note 12] The composition according to Appendix 1, wherein the amino acid sequence is RGD.

[0039] [Note 13] The composition according to Appendix 12, wherein the peptide comprises cyclo-{RGDDFN-Me-V}.

[0040] [Note 14] The composition according to Appendix 1, wherein the amino acid sequence is HG-Cys(acid). [Note 15] The composition according to Appendix 1, wherein the amino acid sequence is RGN.

[0041] [Note 16] The composition according to Appendix 1, wherein the amino acid sequence is DGR. [Note 17] The composition according to Appendix 1, wherein the amino acid sequence is RDG.

[0042] [Note 18] The composition according to Appendix 1, wherein the amino acid sequence is RAE. [Note 19] The composition according to Appendix 1, wherein the amino acid sequence is KGD.

[0043] [Note 20] The composition according to any one of the appendices 1 to 19, wherein the peptide comprises a salt. [Note 21] The composition according to Appendix 20, wherein the salt is selected from the forms of trifluoroacetate, acetate, and hydrochloride.

[0044] [Note 22] A composition according to any one of the appendices 1 to 19, further comprising taurine. [Note 23] A composition comprising GRG-Cys(acid)-TP or a salt thereof in combination with taurine.

[0045] [Note 24] A method for inhibiting angiogenesis or the development of pathological or abnormal blood vessels in a human or animal subject requiring inhibition of angiogenesis or the development of pathological or abnormal blood vessels, comprising the step of administering to the subject a therapeutically effective amount of a composition described in any one of appendices 1 to 19.

[0046] [Note 25] The method according to Appendix 24, wherein the composition further comprises taurine. [Note 26] The method described above, performed to inhibit neovascularization or the development of pathological or abnormal blood vessels within the eye, as described in either Appendix 24 or 25.

[0047] [Note 27] The method according to Appendix 26, wherein the method is performed to treat a disease or disorder selected from diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemic retinopathy, and inflammatory diseases of the eye.

[0048] [Note 28] The method described in Appendix 24, wherein the method is performed to inhibit the neovascularization of pathological or abnormal blood vessels outside the eye.

[0049] [Note 29] The method described above, as described in Appendix 28, performed to inhibit the growth or metastasis of an angiogenic tumor.

Claims

1. formula: Gly-X-Gly-Y-Thr-Pro A composition of a substance comprising a peptide consisting only of an amino acid sequence having, X is Asp and Y is Arg; or X is Lys and Y is Asp. composition.

2. The composition according to claim 1, wherein the peptide consists solely of the amino acid sequence Gly-Asp-Gly-Arg-Thr-Pro.

3. The composition according to claim 1, wherein the peptide consists solely of the amino acid sequence Gly-Lys-Gly-Asp-Thr-Pro.

4. The composition according to any one of claims 1 to 3, wherein the peptide is prepared as a solution.

5. The composition according to any one of claims 1 to 3, wherein the peptide is a salt.

6. The composition according to claim 5, wherein the peptide is a salt selected from the forms of trifluoroacetate, acetate, and hydrochloride.

7. A composition according to any one of claims 1 to 6, which can be combined with taurine.

8. A composition according to any one of claims 1 to 7 for inhibiting angiogenesis or the development of pathological or abnormal blood vessels in a human or animal subject that requires such action, wherein a therapeutically effective amount of the composition is administered to the subject.

9. The composition according to claim 8, which is administered to the eye of the subject to treat a disease or disorder of the eye of the subject in which neovascularization or pathological or abnormal vascular development occurs.

10. The composition according to claim 9, wherein the aforementioned eye disease or disorder is selected from diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemic retinopathy, and inflammatory eye disease.

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