Therapeutic compositions including gramicidin s peptidyl conjugates or imidazole-substituted fatty acids, variants thereof and uses thereof

Patent metadata

Field	Value
Publication number	US-2018354991-A1
Application number	US-201715850843-A
Country	US
Kind code	A1
Filing date	Dec 21, 2017
Priority date	Jun 26, 2015
Publication date	Dec 13, 2018
Grant date	—

Abstract

Disclosed herein are methods and compositions for the treatment and/or prevention of diseases or conditions comprising administration of Gramicidin S peptidyl conjugates (and/or derivatives, analogues, or pharmaceutically acceptable salts thereof), or imidazole-substituted fatty acids (and/or derivatives, analogues, or pharmaceutically acceptable salts thereof), alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide). The present technology provides compositions related to aromatic-cationic peptides linked to imidazole-substituted fatty acids or Gramicidin S peptidyl conjugates of the present technology and uses of the same. In some embodiments, the aromatic-cationic peptide comprises 2′,6′-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 .

First claim

1 . A peptide conjugate comprising an aromatic-cationic peptide conjugated to a Gramicidin S peptidyl conjugate, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 , and wherein the Gramicidin S peptidyl conjugate is selected from the group consisting of:

2 . A peptide conjugate comprising an imidazole-substituted fatty acid conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 , and wherein the imidazole-substituted fatty acid is selected from the group consisting of:

3 . A peptide conjugate according to claim 2 , wherein:
(a) the imidazole-substituted fatty acid is conjugated to the aromatic-cationic peptide by a linker; (b) the imidazole-substituted fatty acid and aromatic-cationic peptide are chemically bonded; (c) the imidazole-substituted fatty acid and aromatic-cationic peptide are physically bonded; or (d) the aromatic-cationic peptide and the imidazole-substituted fatty acid are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the imidazole-substituted fatty acid.

4 .- 6 . (canceled)

7 . A peptide conjugate according to claim 3 , wherein the labile linkage comprises an ester linkage.

8 . A method for delivering an aromatic-cationic peptide and/or a Gramicidin S peptidyl conjugate to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises an aromatic-cationic peptide conjugated to a Gramicidin S peptidyl conjugate, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 ; and wherein the Gramicidin S peptidyl conjugate is selected from the group consisting of:

9 . A method for delivering an aromatic-cationic peptide and/or an imidazole-substituted fatty acid to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises an imidazole-substituted fatty acid conjugated to an aromatic-cationic peptide, wherein the aromatic-cationic peptide is selected from the group consisting of: 2′,6′-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , and D-Arg-2′,6′-Dmt-Lys-Phe-NH 2 ; and wherein the imidazole-substituted fatty acid is selected from the group consisting of:

10 . A method according to claim 9 , wherein:
(a) the imidazole-substituted fatty acid is conjugated to the aromatic-cationic peptide by a linker; (b) the imidazole-substituted fatty acid and aromatic-cationic peptide are chemically bonded; (c) the imidazole-substituted fatty acid and aromatic-cationic peptide are physically bonded; or (d) the aromatic-cationic peptide and the imidazole-substituted fatty acid are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the imidazole-substituted fatty acid.

11 .- 13 . (canceled)

14 . A method according claim 10 , wherein the labile linkage comprises an ester linkage.

15 . A method for treating, ameliorating or preventing a medical disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of the peptide conjugate of claim 1 to the subject thereby treating, amelioration or preventing the medical disease or condition.

16 . A method according to claim 15 , wherein:
(a) the medical disease or condition is characterized by mitochondrial permeability transition; (b) the medical disease or condition comprises a neurological or neurodegenerative disease or condition, ischemia, reperfusion, hypoxia, atherosclerosis, ureteral obstruction, diabetes, complications of diabetes, arthritis, liver damage, insulin resistance, diabetic nephropathy, acute renal injury, chronic renal injury, acute or chronic renal injury due to exposure to nephrotoxic agents and/or radiocontrast dyes, hypertension, metabolic syndrome, an ophthalmic disease or condition such as dry eye, diabetic retinopathy, cataracts, retinitis pigmentosa, glaucoma, macular degeneration, choroidal neovascularization, retinal degeneration, oxygen-induced retinopathy, cardiomyopathy, ischemic heart disease, heart failure, hypertensive cardiomyopathy, vessel occlusion, vessel occlusion injury, myocardial infarction, coronary artery disease, oxidative damage; or (c) the subject is suffering from ischemia or has an anatomic zone of no-reflow in one or more of cardiovascular tissue, skeletal muscle tissue, cerebral tissue and renal tissue.

17 . (canceled)

18 . The method according to claim 16 , wherein the neurological or neurodegenerative disease or condition comprises Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Huntington's disease or Multiple Sclerosis.

19 . (canceled)

20 . A method for:
(a) reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of the peptide conjugate of claim 1 ; or (b) treating, ameliorating or preventing a disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide conjugate of claim 1 .

21 . (canceled)

22 . The method according to claim 20 , wherein the subject is diagnosed as having, is suspected of having, or at risk of having atherosclerosis, inflammation, abnormal angiogenesis, abnormal lipid metabolism, abnormal removal of apoptotic cells, ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.

23 . A method for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue a therapeutically effective amount of the peptide conjugate of claim 1 .

24 . The method according to claim 23 , wherein the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.

25 . A method for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide conjugate of claim 1 .

26 . The method of claim 25 , wherein the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.

27 . A method of reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the peptide conjugate of claim 1 .

28 . The method according to claim 27 , wherein the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, or ALS.

29 . A method for:
(a) preventing or treating a burn injury in a subj

Assignees

• Stealth Biotherapeutics Corp

Inventors

• Wilson D Travis

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61K47/6455

  Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title

• A61K38/12

  Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)} · CPC title