Peptide compositions

Abstract

To provide peptide compositions and methods for inhibiting neovascularization or development of pathogenic or aberrant blood vessels in human or other animal subjects.SOLUTION: Provided herein is a composition comprising a peptide consisting of an amino acid sequence of Gly-Arg-Gly-Cys-Thr-Pro. The composition is administered to a human or animal subject for inhibiting neovascularization or development of pathogenic or aberrant blood vessel in a therapeutically effective amount. The composition is also administered to the eye of a subject with neovascularization or development of pathogenic or aberrant blood vessels to treat the eye disease or disorder of the subject.SELECTED DRAWING: Figure 5

Description

[Technical Field]

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

[0002] FIELD OF THE INVENTION The present invention relates generally to the fields of biology and medicine, and more specifically to peptide compositions and methods of their use. [Background technology]

[0003] Pursuant to 37 CFR 1.71(e), this patent document contains material that is subject to copyright protection, and the owner of this patent document retains 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] Applicant has developed a synthetic oligopeptide, glycinyl-arginyl-glycinyl-cysteic acid-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC), which has been shown to inhibit multiple integrins and have significant anti-angiogenic, anti-inflammatory, neuroprotective, and other effects. When administered to the eye, ALG-1001 causes vitreolysis, posterior vitreoretinal detachment (PVD), and can be used to treat ocular diseases such as wet macular degeneration (WMD), dry 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. Pat. No. 9,018,352, entitled "Peptide Compositions and Therapeutic Uses Thereof," U.S. Pat. No. 9,872,886, entitled "Compositions and Methods for Inhibiting Cellular Adhesion or Directing Diagnostic or Therapeutic Agents to RGD Binding Sites," and U.S. Pat. No. 9,896,480, entitled "Integrin Receptor Antagonists and Their Methods of Use," as well as pending U.S. patent application Ser. No. 15 / 874,814, entitled "Therapeutic and Neuroprotective Peptides," the entire disclosures of which are expressly incorporated herein by reference.

[0006] Applicants have conceived and synthesized the peptides listed in Table 1 below.

[0007] [Table 2]

[0008] As described below, applicants have synthesized and conducted initial testing of a number of additional novel peptides, many of which demonstrate therapeutic efficacy in in vivo studies. Summary of the Invention [Means for solving the problem]

[0009] In accordance with the present invention, peptide compounds and methods are provided for inhibiting angiogenesis of pathological or abnormal blood vessel development in a human or animal subject. According to one aspect of the present invention, a compound of the formula: YXZ 1. A composition of matter comprising a peptide consisting of or comprising an amino acid sequence having During the ceremony: Y=R, H, K, Cys(acid), G, or D; X=G, A, Cys (acid), R, G, D, or E; Compositions are provided in which Z = Cys(acid), G, C, R, D, N, or E. Such peptides may comprise or 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, acetate, trifluoroacetate (TFA), and hydrochloride. Such peptides are useful at least for inhibiting angiogenesis of pathological or abnormal blood vessel development in human or animal subjects.

[0010] Additionally, in some embodiments, the composition of matter comprises or consists of a peptide having the following general formula 1: Gly-X-Thr-Pro wherein 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] Further in accordance with the present invention, the peptide of the present invention, or the synthetic oligopeptide glycinyl-arginyl-glycinyl-cysteic acid-threonyl-proline (SEQ ID NO: 1), may be combined with taurine and administered to a human or animal subject for the purpose of inhibiting angiogenesis in pathological or abnormal vascular development.

[0012] Still further in accordance with the present invention, there is provided a method for inhibiting angiogenesis of pathological or abnormal vascular development in a human or animal subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a peptide as summarized above. In some cases, such a method may be performed to treat an ocular disease or disorder in which angiogenesis or pathological or abnormal vascular development occurs. Such ocular diseases or disorders include, but are not necessarily limited to, diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemia-induced retinopathies, and certain ocular inflammatory diseases.

[0013] Still further in accordance with the present invention, methods are provided for inhibiting angiogenesis or pathological or abnormal blood vessel development at a location outside the eye of a human or animal subject. In some cases, such methods may be carried out to inhibit the growth or metastasis of angiogenic tumors.

[0014] Still further aspects and details of the present invention will be understood from reading the detailed description and examples set forth herein below. [Brief explanation of the drawings]

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

[0016] The following detailed description and the accompanying drawings to which it refers are intended to describe some, but not necessarily all, examples or embodiments of the present invention. The described embodiments are to be considered in all respects only as illustrative and not restrictive. The contents of this detailed description of the present invention and the accompanying drawings are not intended to limit the scope of the present 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, ischemia-induced retinopathy, certain ocular inflammatory diseases, and angiogenic tumor growth or metastasis, are known to cause angiogenesis, or pathological or abnormal blood vessel development. Applicants have discovered a number of compounds that have been shown to be active in antiangiogenic mouse ROP models, as described below. Based on this, such compounds are potentially useful in the treatment of diseases and disorders known to cause angiogenesis, or pathological or abnormal blood vessel 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 sodium chloride and 0.005 mg / 100 μL trisodium citrate, with a peptide concentration of 2.0 mg / 100 μL and pH=2.7, and dispensed into sterile vials by sterile filtration. Taurine test compound was obtained from Sigma-Aldrich, was >99% pure, and was prepared in the same manner as previously described, with a concentration of 3.0 mg / 100 μL. 2.0 mg / 100 μL RG-Cys(acid) + 3.0 mg / 100 μL taurine was prepared in the same manner as above.

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

[0020] On postnatal day 17, 5 days after intravitreal injection, the animals were sacrificed, the retinas were flat-mounted, and the area of ​​neovascularization in each retina was measured by fluorescent dextran image analysis. Applicant identified RG-cysteic acid (acid) as the active motif of the oligopeptide glycinyl-arginyl-glycinyl-cysteic acid (acid)-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC). The trifluoroacetate (TFA) and acetate salts of RG-cysteic acid (acid) tripeptide (Test Compounds 1 and 2) were tested in both the ROP mouse model described above and in a mouse model of choroidal neovascularization induced by laser photocoagulation ("CNV mouse model") as generally 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 intravitreal injections 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 intravitreal injections 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 antiangiogenic effects of each test compound at the doses tested. In each case, data were obtained using the ROP mouse model, except for two table entries specifically marked "CNV." Only the table entries marked "CNV" show data obtained from the CNV mouse model. Bar graphs illustrating the test results summarized in Table 2 are also provided herein as Figures 1-27. Where indicated in the figures, the tests were conducted in a blinded manner so that the testers were unaware of the identity or structure of each test compound.

[0022] [Table 3]

[0023] In each of the test compounds, except for 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 replaced with three different amino acid motifs having the amino acid sequences defined in General Formula 2 (below), resulting in test compounds having the general formula defined in General Formula 2 (below).

[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 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 RG-Cys and RA-Cys sequences, plays an important role in the inhibition of angiogenesis. Furthermore, in the presence of arginine, the replacement of cysteic acid with neutral amino acids showed a strong inhibitory effect in these experiments.

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

[0028] If the amino acid G (i.e., the X component) of the RG-cysteic acid active motif is replaced by a basic or acidic amino acid, the antiangiogenic effect of the peptide is reduced. However, in the presence of arginine (strong hydrogen bond), the two carbon length spacing for hydrophobic interactions (alanine and aspartic acid) will not affect the antiangiogenic effect of the peptide.

[0029] When the Cys (i.e., Z component) of the RG-cysteic acid (acid) activity motif is replaced by a neutral amino acid, the anti-angiogenic activity of the peptide is increased, whereas replacement of the Z component by an acidic or basic amino acid results in a decrease in anti-angiogenic activity.

[0030] All of these findings indicate that the RG-cysteic acid of the oligopeptide glycinyl-arginyl-glycinyl-cysteic acid-threonyl-proline (SEQ ID NO: 1) (ALG-1001 or Luminate®, Allegro Ophthalmics, LLC) is important for the inhibition of angiogenesis. Furthermore, the addition of three taurine moieties to one glycinyl-arginyl-glycinyl-cysteic acid-threonyl-proline (SEQ ID NO: 1) (ALG-1001) moiety enhances angiogenesis-inhibitory activity.

[0031] While the present invention has been described hereinabove with reference to specific examples or embodiments of the invention, it should be understood that various additions, deletions, modifications, and variations may be made to the described examples and embodiments without departing from the intended spirit and scope of the invention. For example, any element, step, member, component, composition, reactant, part, or portion of one embodiment or example may be incorporated into or used with another embodiment or example, unless otherwise specified or would not render the embodiment or example unsuitable for its intended use. Also, where steps of a method or process are described or listed in a particular order, the order of such steps may be changed unless otherwise specified or would not render the method or process unsuitable for its intended use. Furthermore, any element, step, member, component, composition, reactant, part, or portion of any invention or example described herein may be optionally present or utilized in the absence, or substantial absence, of any other element, step, member, component, composition, reactant, part, or portion, unless otherwise noted. All reasonable additions, deletions, modifications, and variations are considered equivalents of the described examples and embodiments and are included within the scope of the following claims.

[0032] The technical concepts that can be understood from the above-described embodiment will be described below as supplementary notes. [Appendix 1] formula: YXZ 1. A composition of matter comprising a peptide consisting of or comprising an amino acid sequence having 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] [Appendix 2] 2. The composition of claim 1, wherein the amino acid sequence is RG-Cys(acid). [Appendix 3] 3. The composition of claim 2, wherein the peptide comprises RG-Cys(acid).

[0034] [Appendix 4] 3. The composition of claim 2, wherein the peptide comprises RG-Cys(acid). [Appendix 5] 3. The composition of claim 2, wherein the peptide comprises RG-Cys(acid)-GGGDG.

[0035] [Appendix 6] 3. The composition of claim 2, wherein the peptide comprises cyclo-{RG-Cys(acid)-FN-Me-V}.

[0036] [Appendix 7] 2. The composition of claim 1, wherein the amino acid sequence is RA-Cys(acid). [Appendix 8] 2. The composition of claim 1, wherein the amino acid sequence is RG-cysteine.

[0037] [Appendix 9] 2. The composition of claim 1, wherein the amino acid sequence is R-Cys(acid)-G. [Appendix 10] 2. The composition of claim 1, wherein the amino acid sequence is Cys(acid)-RG.

[0038] [Appendix 11] 2. The composition of claim 1, wherein the amino acid sequence is Cys(acid)-GR. [Appendix 12] 2. The composition of claim 1, wherein the amino acid sequence is RGD.

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

[0040] [Appendix 14] 2. The composition of claim 1, wherein the amino acid sequence is HG-Cys(acid). [Appendix 15] 2. The composition of claim 1, wherein the amino acid sequence is RGN.

[0041] [Appendix 16] 2. The composition of claim 1, wherein the amino acid sequence is DGR. [Appendix 17] 2. The composition of claim 1, wherein the amino acid sequence is RDG.

[0042] [Appendix 18] 2. The composition of claim 1, wherein the amino acid sequence is RAE. [Appendix 19] 2. The composition of claim 1, wherein the amino acid sequence is KGD.

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

[0044] [Appendix 22] 20. The composition of any one of appendices 1 to 19, further comprising taurine. [Appendix 23] A composition comprising GRG-Cys(acid)-TP or a salt thereof in combination with taurine.

[0045] [Appendix 24] 20. A method for inhibiting angiogenesis or pathological or abnormal vascular development in a human or animal subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of any one of claims 1 to 19.

[0046] [Appendix 25] 25. The method of claim 24, wherein the composition further comprises taurine. [Appendix 26] 26. The method of any of claims 24 or 25, wherein the method is carried out to inhibit intraocular neovascularization or pathological or abnormal vascular development.

[0047] [Appendix 27] 27. The method of claim 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, ischemia-induced retinopathy, and ocular inflammatory disease.

[0048] [Appendix 28] 25. The method of claim 24, wherein the method is performed to inhibit the neovascular development of pathological or abnormal blood vessels outside the eye.

[0049] [Appendix 29] 29. The method of claim 28, wherein the method is performed to inhibit angiogenic tumor growth or metastasis.

Claims

1. A composition of matter comprising a peptide consisting solely of the amino acid sequence Gly-Arg-Gly-Cys-Thr-Pro.

2. The composition of claim 1 , wherein the peptide is prepared as a solution.

3. The composition of claim 1 or claim 2, wherein the peptide is a salt.

4. 4. The composition of claim 3, wherein the peptide is in a salt form selected from trifluoroacetate, acetate, and hydrochloride salt forms.

5. The composition according to any one of claims 1 to 4, which is combined with taurine.

6. 6. The composition of any one of claims 1 to 5 for inhibiting angiogenesis or pathological or abnormal blood vessel development in a human or animal subject in need thereof, wherein a therapeutically effective amount of the composition is administered to the subject.

7. The composition of claim 6, wherein the composition is administered to the eye of a subject to treat a disease or disorder of the eye of the subject in which neovascularization or pathological or abnormal vascular development is occurring.

8. 8. The composition of claim 7, wherein the ocular disease or disorder is selected from diabetic retinopathy, neovascular age-related macular degeneration, retinopathy of prematurity (ROP), sickle cell retinopathy, retinal vein occlusion, ischemia-induced retinopathy, and ocular inflammatory disease.

Images