WO2015183985A2 - Compositions thérapeutiques comprenant des naphthoquinones et leurs utilisations - Google Patents

Compositions thérapeutiques comprenant des naphthoquinones et leurs utilisations Download PDF

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WO2015183985A2
WO2015183985A2 PCT/US2015/032716 US2015032716W WO2015183985A2 WO 2015183985 A2 WO2015183985 A2 WO 2015183985A2 US 2015032716 W US2015032716 W US 2015032716W WO 2015183985 A2 WO2015183985 A2 WO 2015183985A2
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phe
arg
lys
aromatic
dmt
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WO2015183985A3 (fr
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D. Travis Wilson
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Stealth Peptides International Inc
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Stealth Peptides International Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • compositions related to the treatment and/or amelioration of diseases and conditions comprising administration of naphthoquinones and/or naturally or artificially occurring derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide).
  • active agents e.g., an aromatic-cationic peptide
  • the present technology relates generally to aromatic-cationic peptide compositions where the aromatic-cationic peptide is conjugated to a naphthoquinone and their use in the prevention and treatment of medical diseases and conditions.
  • Biological cells are generally highly selective as to the molecules that are allowed to pass through the cell membrane. As such, the delivery of compounds, such as small molecules and biological molecules into a cell is usually limited by the physical properties of the compound.
  • the small molecules and biological molecules may, for example, be pharmaceutically active compounds.
  • the present technology provides compositions and methods useful in the prevention, treatment and/or amelioration of diseases and conditions.
  • the present disclosure provides a composition comprising
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the composition further comprises one or more additional active agents such as cyclosporine, a cardiac drug, an anti-inflammatory, an anti-hypertensive drug, an antibody, an ophthalmic drug, an antioxidant, a metal complexer, and an
  • the present disclosure provides a method for treating or preventing mitochondrial permeability transition in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method of treating a disease or condition characterized by mitochondrial permeability transition, comprising administering a therapeutically effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the 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
  • the neurological or neurodegenerative disease or condition comprises Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Huntington's disease or Multiple Sclerosis.
  • ALS Amyotrophic Lateral Sclerosis
  • Parkinson's disease Huntington's disease or Multiple Sclerosis.
  • 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.
  • the present disclosure provides a method for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic- cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for treating or preventing a disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the subject is diagnosed as having, 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.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's Disease, diabetes, diabetic nephropathy, or obesity.
  • the present disclosure provides a method for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present disclosure provides a method for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present disclosure provides a method of reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the neurodegenerative disease comprises Alzheimer's disease, Parkinson's disease, or ALS.
  • the present disclosure provides a method for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic- cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for preventing
  • norepinephrine uptake in a subject in need of analgesia comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for treating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 .
  • the present disclosure provides a method for treating atherosclerotic renal vascular disease (ARVD) in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising naphthoquinones, or derivatives, analogues, or pharmaceutically acceptable salts thereof, alone or in combination with one or more active agents.
  • the active agents include any one or more of the aromatic-cationic peptides shown in Section II.
  • the aromatic-cationic peptide is 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 . .
  • the composition comprises naphthoquinones, derivatives, analogues, or pharmaceutically acceptable salts thereof.
  • the composition further comprises one or more of at least one pharmaceutically acceptable pH-lowering agent; and at least one absorption enhancer effective to promote bioavailability of the active agent, and one or more lamination layers.
  • the pH-lowering agent is selected from the group consisting of citric acid, tartaric acid and an acid salt of an amino acid.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone as well as methods for their use.
  • Such molecules are referred to hereinafter as "peptide conjugates.”
  • At least one naphthoquinone and at least one aromatic-cationic peptide associate to form a peptide conjugate.
  • the naphthoquinone and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds. Chemical bonds include, for example, covalent bonds and coordinate bonds. Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-naphthoquinone
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-naphthoquinone
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the present technology provides a peptide conjugate comprising a naphthoquinone 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 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the naphthoquinone is a compound described in Section I.
  • the naphthoquinone of the peptide conjugates of the present technology has the formula:
  • R is selected from the group consisting of hydrogen;— 0(Ci-Ce)alkyl;— (CH 2 ) 0 _i 9 — CH 3 ;— ((CH 2 ) 2 — CH (CH 3 )) ! _ 20 — CH 3 ;
  • each unit independently in each occurrence double or single and each unit can be the same or different;
  • R 2 and R 3 are independently of each other hydrogen;— (Ci-Ce)alkyl; or— 0(Ci-Ce)alkyl; n is 0-12, wherein when n is 2-12 each unit can be the same or different; and m is 1-12, wherein when m is 2-12 each unit can be the same or different; with the proviso that when R 1 and R 2 are hydrogen, and R 3 is— (Ci-Ce)alkyl, then R is not hydrogen or
  • the naphthoquinone is conjugated to the aromatic-cationic peptide by a linker. In some embodiments, the naphthoquinone and aromatic-cationic peptide are chemically bonded. In some embodiments, the naphthoquinone and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the naphthoquinone are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the naphthoquinone.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for delivering an aromatic-cationic peptide and/or naphthoquinone to a cell, the method comprising contacting the cell with a peptide conjugate, wherein the peptide conjugate comprises a naphthoquinone 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 , or D-Arg-2',6'-Dmt-Lys-Phe-NH 2 , or any peptide described in Section II; and wherein the naphthoquinone is a compound described in Section I.
  • the naphthoquinone of the peptide conjugates of the present technology has the formula:
  • R is selected from the group consisting of hydrogen;— 0(Ci-Ce)alkyl;— (CH 2 )o-isr CH 3 ;— ((CH 2 ) 2 — CH (CH 3 ))i_ 2 o— CH 3 ;
  • each unit independently in each occurrence double or single and each unit can be the same or different;
  • R 2 and R 3 are independently of each other hydrogen;— (Ci-Ce)alkyl; or— 0(Ci-Ce)alkyl; n is 0-12, wherein when n is 2-12 each unit can be the same or different; and m is 1-12, wherein when m is 2-12 each unit can be the same or different; with the proviso that when R 1 and R 2 are hydrogen, and R 3 is— (Ci-Ce)alkyl, then R is not hydrogen or
  • the naphthoquinone is conjugated to the aromatic-cationic peptide by a linker.
  • the naphthoquinone and aromatic-cationic peptide are chemically bonded.
  • the naphthoquinone and aromatic-cationic peptide are physically bonded.
  • the aromatic-cationic peptide and the naphthoquinone are linked using a labile linkage that is hydrolyzed in vivo to uncouple the aromatic-cationic peptide and the naphthoquinone.
  • the labile linkage comprises an ester linkage.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition in a subject in need thereof, comprising administering a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone to the subject thereby treating, amelioration or preventing the medical disease or condition.
  • the medical disease or condition is characterized by mitochondrial permeability transition.
  • 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.
  • the neurological or neurodegenerative disease or condition comprises
  • Alzheimer's disease Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease,
  • 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.
  • the present technology provides methods for reducing CD36 expression in a subject in need thereof, comprising administering to the subject an effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for treating, ameliorating or preventing a medical disease or condition characterized by CD36 elevation in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • 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.
  • ischemia such as cerebral ischemia and myocardial ischemia, ischemia-reperfusion, ureteral obstruction, stroke, Alzheimer's disease, diabetes, diabetic nephropathy, or obesity.
  • the present technology provides methods for reducing oxidative damage in a removed organ or tissue, comprising administering to the removed organ or tissue a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the removed organ comprises a heart, lung, pancreas, kidney, liver, or skin.
  • the present technology provides methods for preventing the loss of dopamine-producing neurons in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the subject is diagnosed as having, suspected of having, or at risk of having Parkinson's disease or ALS.
  • the present technology provides methods for reducing oxidative damage associated with a neurodegenerative disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the neurodegenerative diseases comprise Alzheimer's disease
  • Parkinson's disease or ALS.
  • the present technology provides methods for preventing or treating a burn injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for treating or preventing mechanical ventilation-induced diaphragm dysfunction in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for treating or preventing no reflow following ischemia-reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for preventing norepinephrine uptake in a subject in need of analgesia, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for treating,
  • ameliorating or preventing drug-induced peripheral neuropathy or hyperalgesia in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for inhibiting or suppressing pain in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • the present technology provides methods for treating
  • Atherosclerotic renal vascular disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a composition comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • ARVD atherosclerotic renal vascular disease
  • the aromatic-cationic peptide is defined by Formula A.
  • R 1 and R 2 are each independently selected from
  • R 3 and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W). In some embodiments, the Aromatic residue may be substituted with
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with Norleucine (Nle), and 2-amino-heptanoic acid (Ahe).
  • Figure 1 shows an illustrative example of an aromatic-cationic peptide of the present disclosure linked by a labile bond to a naphthoquinone.
  • Figure 2 shows illustrative examples of aromatic-cationic peptides of the present disclosure linked by covalent attachment to self-immolating moieties.
  • Figure 3 shows an illustrative example of aromatic-cationic peptides of the present disclosure incorporating spacer units to link the additional moieties to the peptide.
  • Figure 4 shows illustrative peptide chemistry to form amide bonds, where the R 2 free amine is 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 and Ri is selected from a linker bearing the formula:— (linker)— COOH; or where linker consists of one or more carbon atoms. In some embodiments, the linker consists of two or more carbon atoms.
  • Figures 5A and 5B show exemplary linking chemistry of the present disclosure.
  • R is a naphthoquinone containing a pendant COOH group and R' is a linker bearing the formula:— (linker)— OH where linker consists of at least one or more carbon atoms.
  • R is a linker bearing the formula:— (linker)— COOH where linker consists of at least one or more carbon atoms; and R' is a naphthoquinone containing a pendant OH group.
  • compositions comprising an aromatic-cationic peptide of the present technology conjugated to a naphthoquinone.
  • Such molecules are referred to hereinafter as peptide conjugates.
  • At least one naphthoquinone as described in Section I and at least one aromatic- cationic peptide as described in Section II associate to form a peptide conjugate.
  • the naphthoquinone and aromatic-cationic peptide can associate by any method known to those in the art. Suitable types of associations include chemical bonds and physical bonds.
  • Chemical bonds include, for example, covalent bonds and coordinate bonds.
  • Physical bonds include, for instance, hydrogen bonds, dipolar interactions, van der Waal forces, electrostatic interactions, hydrophobic interactions and aromatic stacking.
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-naphthoquinone
  • the peptide conjugates have the general structure shown below: aromatic-cationic peptide-linker-naphthoquinone
  • the peptide conjugate linker may be nonlabile or labile.
  • the peptide conjugate linker may be enzymatically cleavable.
  • the peptide conjugates described herein can occur and can be used as the neutral (non-salt) peptide conjugate, the description is intended to embrace all salts of the peptide conjugates described herein, as well as methods of using such salts of the peptide conjugates.
  • the salts of the peptide conjugates comprise
  • Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
  • the desired salt of a basic peptide conjugate may be prepared by methods known to those of skill in the art by treating the compound with an acid.
  • inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid.
  • Salts of basic peptide conjugates with amino acids such as aspartate salts and glutamate salts, can also be prepared.
  • the desired salt of an acidic peptide conjugate can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • inorganic salts of acid conjugates include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid peptide conjugates include, but are not limited to, procaine, dibenzylamine, N-ethylpiperidine, ⁇ , ⁇ '-dibenzylethylenediamine, and
  • salts of acidic peptide conjugates with amino acids can also be prepared.
  • the present technology also includes all stereoisomers and geometric isomers of the peptide conjugates, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
  • the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
  • the "administration" of an agent, drug, or peptide to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or
  • Administration includes self-administration and the administration by another.
  • alkyl refers to saturated aliphatic groups including straight-chain, branched-chain, cyclic groups, and combinations thereof, having the number of carbon atoms specified, or if no number is specified, having up to 12 carbon atoms.
  • “Straight-chain alkyl” or “linear alkyl” groups refer to alkyl groups that are neither cyclic nor branched, commonly designated as “n-alkyl” groups.
  • alkyl groups are— (Ci-C 6 ) alkyls which include groups such as methyl, ethyl, n-propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, n-pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and any other alkyl group containing between one and five carbon atoms, where the— (Ci-C 6 )alkyl groups can be attached via any valence on the— (Ci-C 6 ) alkyl groups.
  • amino acid includes naturally-occurring amino acids and synthetic amino acids, as well as amino acid analogues and amino acid mimetics that function in a manner similar to the naturally-occurring amino acids.
  • Naturally-occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ -carboxyglutamate, and O-phosphoserine.
  • Amino acid analogues refer to compounds that have the same basic chemical structure as a naturally-occurring amino acid, i.e., an a-carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogues have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally-occurring amino acid.
  • Amino acid mimetics refer to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally- occurring amino acid. Amino acids can be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission.
  • the term "effective amount" refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or disorder or one or more signs or symptoms associated with a disease or disorder.
  • the amount of a composition administered to the subject will depend on the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors.
  • the compositions can also be administered in combination with one or more additional therapeutic compounds.
  • the therapeutic compounds may be administered to a subject having one or more signs or symptoms of a disease or disorder.
  • an "isolated” or “purified” polypeptide or peptide is substantially free of cellular material or other contaminating polypeptides from the cell or tissue source from which the agent is derived, or substantially free from chemical precursors or other chemicals when chemically synthesized.
  • an isolated aromatic-cationic peptide would be free of materials that would interfere with diagnostic or therapeutic uses of the agent.
  • interfering materials may include enzymes, hormones and other proteinaceous and nonproteinaceous solutes.
  • non-naturally-occurring refers to a composition which is not found in this form in nature.
  • a non-naturally-occurring composition can be derived from a naturally-occurring composition, e.g., as non-limiting examples, via purification, isolation, concentration, chemical modification (e.g., addition or removal of a chemical group), and/or, in the case of mixtures, addition or removal of ingredients or compounds.
  • a non-naturally-occurring composition can comprise or be derived from a non-naturally- occurring combination of naturally-occurring compositions.
  • a non-naturally-occurring composition can comprise a mixture of purified, isolated, modified and/or concentrated naturally-occurring compositions, and/or can comprise a mixture of naturally-occurring compositions in forms, concentrations, ratios and/or levels of purity not found in nature.
  • net charge refers to the balance of the number of positive charges and the number of negative charges carried by the amino acids present in the aromatic-cationic peptides of the present technology.
  • net charges are measured at physiological pH.
  • the naturally occurring amino acids that are positively charged at physiological pH include L-lysine, L-arginine, and L-histidine.
  • the naturally occurring amino acids that are negatively charged at physiological pH include L- aspartic acid and L-glutamic acid.
  • polypeptide As used herein, the terms "polypeptide,” “peptide,” and “protein” are used interchangeably herein to mean a polymer comprising two or more amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres.
  • Polypeptide refers to both short chains, commonly referred to as peptides, glycopeptides or oligomers, and to longer chains, generally referred to as proteins.
  • Polypeptides may contain amino acids other than the 20 gene-encoded amino acids.
  • Polypeptides include amino acid sequences modified either by natural processes, such as post-translational processing, or by chemical modification techniques that are well known in the art.
  • prevention or “preventing” of a disorder or condition refers to one or more compounds that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset of one or more symptoms of the disorder or condition relative to the untreated control sample.
  • protecting group refers to a chemical group that exhibits the following characteristics: 1) reacts selectively with the desired functionality in good yield to give a protected substrate that is stable to the projected reactions for which protection is desired; 2) is selectively removable from the protected substrate to yield the desired functionality; and 3) is removable in good yield by reagents compatible with the other functional group(s) present or generated in such projected reactions. Examples of suitable protecting groups can be found in Greene et al. (1991) Protective Groups in Organic Synthesis, 3rd Ed. (John Wiley & Sons, Inc., New York).
  • Amino protecting groups include, but are not limited to, mesitylenesulfonyl (Mts), benzyloxycarbonyl (CBz or Z), t- butyloxycarbonyl (Boc), t-butyldimethylsilyl (TBS or TBDMS), 9- fluorenylmethyloxycarbonyl (Fmoc), tosyl, benzenesulfonyl, 2-pyridyl sulfonyl, or suitable photolabile protecting groups such as 6-nitroveratryloxy carbonyl (Nvoc), nitropiperonyl, pyrenylmethoxycarbonyl, nitrobenzyl, ⁇ -, ⁇ -dimethyldimethoxybenzyloxycarbonyl (DDZ), 5- bromo-7-nitroindolinyl, and the like. Hydroxyl protecting groups include, but are not limited to, Fmoc, TBS, photolabile protecting groups (such as nitroveratryl oxymethyl ether
  • the term "separate" therapeutic use refers to an administration of at least two active ingredients at the same time or at substantially the same time by different routes.
  • sequential therapeutic use refers to administration of at least two active ingredients at different times, the administration route being identical or different. More particularly, sequential use refers to the whole administration of one of the active ingredients before administration of the other or others commences. It is thus possible to administer one of the active ingredients over several minutes, hours, or days before administering the other active ingredient or ingredients. There is no simultaneous treatment in this case.
  • the term “simultaneous” therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or at substantially the same time.
  • the terms "subject,” “individual,” or “patient” can be an individual organism, a vertebrate, a mammal, or a human.
  • a "synergistic therapeutic effect” refers to a greater-than-additive therapeutic effect which is produced by a combination of at least two agents, and which exceeds that which would otherwise result from the individual administration of the agents. For example, lower doses of one or more agents may be used in treating a disease or disorder, resulting in increased therapeutic efficacy and decreased side-effects.
  • a "therapeutically effective amount" of a compound refers to compound levels in which the physiological effects of a disease or disorder are, at a minimum, ameliorated.
  • a therapeutically effective amount can be given in one or more administrations.
  • the amount of a compound which constitutes a therapeutically effective amount will vary depending on the compound, the disorder and its severity, and the general health, age, sex, body weight and tolerance to drugs of the subject to be treated, but can be determined routinely by one of ordinary skill in the art.
  • Treating covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, i.e., arresting its development; (ii) relieving a disease or disorder, i.e., causing regression of the disorder; (iii) slowing progression of the disorder; and/or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder.
  • the various modes of treatment or prevention of medical diseases and conditions as described are intended to mean “substantial,” which includes total but also less than total treatment or prevention, and wherein some biologically or medically relevant result is achieved.
  • the treatment may be a continuous prolonged treatment for a chronic disease or a single, or few time administrations for the treatment of an acute condition.
  • Naphthoquinone compounds are useful in the compositions and methods of the present technology.
  • naphthoquinone compounds of Formula I are useful as naphthoquinones of the peptide conjugates of the compositions of the present technology:
  • R is selected from the group consisting of hydrogen;— 0(Ci-C 6 )alkyl;— (CH 2 )o_i — CH 3 ;— ((CH 2 ) 2 — CH (CH 3 )) ! _ 20 — CH 3 ;
  • each unit independently in each occurrence double or single and each unit can be the same or different;
  • R 2 and R 3 are independently of each other hydrogen;— (Ci-Ce)alkyl; or— 0(Ci-Ce)alkyl; n is 0-12, wherein when n is 2-12 each unit can be the same or different; and m is 1-12, wherein when m is 2-12 each unit can be the same or different; with the proviso that when R 1 and R 2 are hydrogen, and R 3 is— (Ci-Ce)alkyl, then R is not hydrogen or
  • compounds of Formula I are compounds where R is selected from the group consisting of— (CH 2 )o-i9— CH 3 ;— ((CH 2 ) 2 — CH(CH 3 ))i_ 20 — CH 3 ;
  • R 1 and R 2 are independently of each other hydrogen;— (Ci-C 6 )alkyl; or— 0(Ci- C 6 )alkyl;
  • R 3 is hydrogen or— (Ci-Ce)alkyl;
  • n is 0-12, wherein when n is 2-12 each unit can be the same or different; and
  • m is 1-12, wherein when m is 2-12 each unit can be the same or different; with the proviso that when R 1 and R 2 are hydrogen, and R 3 is— (Ci-Ce)alkyl, then R is not hydrogen or
  • R 1 , R 2 and R 3 are independently of each other— (Ci-C 6 )alkyl. In another embodiment, R 1 , R 2 and R 3 are methyl. In another embodiment, R 1 and R 2 are hydrogen and R 3 is— (Ci-C 6 )alkyl. In another embodiment, R 1 and R 2 are hydrogen and R 3 is methyl. In another embodiment, R 1 and R 2 are independently of each other— 0(Ci- C 6 )alkyl and R 3 is— (Ci-C 6 )alkyl. In another embodiment, R 1 and R 2 are methoxy and R 3 is methyl. In some embodiments, m is 1. In some embodiments, n is 1. In other embodiments, m is 2.
  • n is 2. In other embodiments, m is 3. In some embodiments, n is 3. In other embodiments, m is 4. In some embodiments, n is 4. In other embodiments, m is 5. In some embodiments, n is 5. In other embodiments, m is 6. In some embodiments, n is 6. In other embodiments, m is 7. In some embodiments, n is 7. In other embodiments, m is 8. In some embodiments, n is 8. In other embodiments, m is 9. In some embodiments, n is 9. In other embodiments, m is 10. In some embodiments, n is 10. In other
  • n is 1 1. In some embodiments, n is 1 1. In other embodiments, m is 12. In some embodiments, n is 12.
  • R 1 and R 2 are hydrogen and R and R 3 are— (Ci-Ce)alkyl. In another embodiment, R 1 and R 2 are hydrogen and R and R 3 are methyl. In another embodiment, R, R 1 and R 2 are hydrogen and R 3 is— 0(Ci-C 6 )alkyl.
  • R, R 1 and R 2 are hydrogen and R 3 is methoxy.
  • R, R 1 , R 2 , and R 3 are hydrogen.
  • R 1 and R 2 are hydrogen and R and R 3 are— 0(Ci-C 6 )alkyl.
  • R 1 and R 2 are hydrogen and R and R 3 are methoxy.
  • the compounds of Formula la are useful as
  • Formula la wherein the bond indicated by a dashed line can be independently in each occurrence double or single and where each unit can be the same or different;
  • R la and R 2a are independently of each other,— (Ci-C 6 )alkyl or— 0(Ci-C 6 )alkyl;
  • R 3a is hydrogen or— (Ci-C 6 )alkyl;
  • n' is 0-12, wherein when n' is 2-12 each unit can be the same or different; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
  • R la , R 2a and R 3a are independently of each other— (Ci-C 6 )alkyl. In another embodiment, R la , R 2a and R 3a are methyl. In another embodiment, R la and R 2a are independently of each other— 0(Ci-Ce)alkyl and R 3a is— (Ci-C 6 )alkyl. In another embodiment, R la and R 2a are independently of each other methoxy and R 3a is methyl.
  • R la and R 2a are methoxy and R 3a is methyl. In another embodiment, R la and R 2a are independently of each other— 0(Ci-Ce)alkyl and R a is hydrogen. In another embodiment, R la and R 2a are independently of each other methoxy and R 3a is hydrogen. In some embodiments, n' is 1. In other embodiments, n' is 2. In other embodiments, n' is 3. In other embodiments, n' is 4. In other embodiments, n' is 5. In other embodiments, n' is 6. In other embodiments n' is 7. In other embodiments, n' is 8. In other embodiments, n' is 9. In other embodiments, n' is 10.
  • n' is 1 1. In other embodiments, n' is 12. In another embodiment, the bond indicated with a dashed line is a single bond in every unit. In another embodiment, the bond indicated with a dashed line is a double bond in every unit.
  • the compound of Formula I or la is not a Vitamin K2 compound.
  • the compound of Formula I is not selected from vitamin MK-2, vitamin MK-3, vitamin MK-4, vitamin MK-5, vitamin MK-6, vitamin MK-7, vitamin MK-8, vitamin MK-9, vitamin MK-10, vitamin MK-1 1 , vitamin MK-12 and vitamin MK-13.
  • the compound of Formula I wherein the bond indicated with a dashed line is a single bond is not Vitamin Kl also known as Phylloquinone.
  • the compound of Formula I or la is selected from:
  • the compounds of Formula lb are useful as
  • R lb and R 2b are independently of each other hydrogen;— (Ci-C 6 )alkyl; or— 0(Ci-Ce)alkyl; R 3b is hydrogen or— (Ci-Ce)alkyl; m' is 1-12, wherein when m' is 2-12 each unit can be the same or different; or any stereoisomer, mixture of stereoisomers, prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
  • R lb , R 2b and R 3b are independently of each other— (Ci-C 6 )alkyl. In another embodiment, R lb , R 2b and R 3b are methyl. In another embodiment, R lb and R 2b are hydrogen and R 3b is— (Ci-Ce)alkyl. In another embodiment, R lb and R 2b are hydrogen and R 3b is methyl. In another embodiment, R lb and R 2b are independently of each other— 0(Ci- C 6 )alkyl and R 3b is— (Ci-Ce)alkyl. In another embodiment, R lb and R 2b are independently of each other methoxy and R 3b is methyl. In some embodiments, m' is 1. In other embodiments, m' is 2. In other embodiments, m' is 3. In other embodiments, m' is 4. In other
  • m' is 5. In other embodiments, m' is 6. In other embodiments, m' is 7. In other embodiments, m' is 8. In other embodiments, m' is 9. In other embodiments, m' is 10. In other embodiments, m' is 1 1. In other embodiments, m' is 12. In another embodiment, the bond indicated by a dashed line is a double bond in every unit. In another embodiment the bond indicated by a dashed line is a single bond in every unit.
  • the compound of Formula I or lb is 2-(3-hydroxy-3,7, l 1 ,15- tetramethylhexadeca-6, 10,14-trien-l-yl)-3-methylnaphthalene-l ,4-dione with the following formula:
  • the compound of Formula I or lb is 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10, 14-trien- 1 -yl)naphthalene- 1 ,4-dione :
  • the compound of Formula I or lb is 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6, 10,14-trien- 1 -yl)-3 ,6,7-trimethylnaphthalene- 1 ,4-dione:
  • the compound of Formula I or lb is 2-(3-hydroxy-3,7,l 1,15- tetramethylhexadeca-6,10,14-trien-l-yl)-6,7-dimethoxy-3-methylnaphthalene-l,4-dione:
  • the compound of Formula I or lb is selected from:
  • R lc and R 2c are independently of each other hydrogen;— (Ci-Ce)alkyl; or— 0(Ci- C 6 )alkyl; R 3c is— (Ci-Ce)alkyl; or any prodrug, metabolite, salt, crystalline form, noncrystalline form, hydrate or solvate thereof.
  • R lc , R 2c and R 3c are independently of each other— (Ci- Ce)alkyl. In another embodiment, R lc , R 2c and R 3c are methyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is— (Ci-C 6 )alkyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is methyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is ethyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is propyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is butyl.
  • R lc and R 2c are hydrogen and R 3c is pentyl. In another embodiment, R lc and R 2c are hydrogen and R 3c is hexyl. In another embodiment, R lc and R 2c are independently of each other— 0(Ci-Ce)alkyl and R 3c is— (Ci-C 6 )alkyl. In another embodiment, R lc and R 2c are independently of each other methoxy and R 3c is methyl.
  • the compound of Formula I or Ic is selected from:
  • R ld and R 2d are independently of each other hydrogen;— (Ci-Ce)alkyl or— 0(Ci- C 6 )alkyl; R 3d is hydrogen or— (Ci-Ce)alkyl; or any prodrug, metabolite, salt, crystalline form, non-crystalline form, hydrate or solvate thereof.
  • R ld , R 2d and R 3d are independently of each other— (Ci-C6)alkyl. In another embodiment, R ld , R 2d , and R 3d are methyl. In another embodiment, R ld and R 2d are hydrogen and R 3d is— (Ci-Ce)alkyl. In another embodiment, R ld and R 2d are hydrogen and R 3d is methyl. In another embodiment, R ld and R 2d are independently of each other— 0(Ci-C 6 )alkyl and R id is— (Ci-C 6 )alkyl. In another embodiment, R ld and R a are independently of each other methoxy and R 3d is methyl.
  • the compound of Formula I or Id is selected from:
  • the compound of Formula I is selected from:
  • the naphthoquinone form can also be used in its reduced (naphthoquinol) form when desired.
  • Other compounds which are useful as naphthoquinones of the peptide conjugates of the compositions of the present technology include:
  • naphthalene- 1,4-dione (CAS Registry Number 130-15-4);
  • the salts of the compounds comprise pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts are those salts which can be administered as drugs or pharmaceuticals to humans and/or animals and which, upon administration, retain at least some of the biological activity of the free compound (neutral compound or non-salt compound).
  • the desired salt of a basic compound may be prepared by methods known to those of skill in the art by treating the compound with an acid.
  • inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.
  • organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acids, and salicylic acid. Salts of basic compounds with amino acids, such as aspartate salts and glutamate salts, can also be prepared.
  • the desired salt of an acidic compound can be prepared by methods known to those of skill in the art by treating the compound with a base.
  • inorganic salts of acid compounds include, but are not limited to, alkali metal and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts, and calcium salts; ammonium salts; and aluminum salts.
  • organic salts of acid compounds include, but are not limited to, procaine, dibenzylamine, N- ethylpiperidine, ⁇ , ⁇ '-dibenzylethylenediamine, and triethylamine salts. Salts of acidic compounds with amino acids, such as lysine salts, can also be prepared.
  • the present technology also includes all stereoisomers and geometric isomers of the compounds, including diastereomers, enantiomers, and cis/trans (E/Z) isomers.
  • the present technology also includes mixtures of stereoisomers and/or geometric isomers in any ratio, including, but not limited to, racemic mixtures.
  • aromatic-cationic peptides of the present technology are water-soluble, highly polar, and can readily penetrate cell membranes.
  • aromatic-cationic peptides of the present technology include a minimum of three amino acids, covalently joined by peptide bonds.
  • the maximum number of amino acids present in the aromatic-cationic peptides of the present technology is about twenty amino acids covalently joined by peptide bonds. In some embodiments, the maximum number of amino acids is about twelve. In some embodiments, the maximum number of amino acids is about nine. In some embodiments, the maximum number of amino acids is about six. In some embodiments, the maximum number of amino acids is four.
  • the present technology provides an aromatic-cationic peptide or a pharmaceutically acceptable salt thereof such as acetate salt or trifluoroacetate salt.
  • the peptide comprises at least one net positive charge; a minimum of three amino acids; a maximum of about twenty amino acids; a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1 ; and
  • the peptide comprises the amino acid sequence 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 .
  • the peptide comprises one or more of the peptides of Table A:
  • the aromatic-cationic peptide is defined by Formula A:
  • R 1 and R 2 are each independently selected from
  • R 3 and R 4 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo;
  • R 5 , R 6 , R 7 , R 8 , and R 9 are each independently selected from (i) hydrogen;
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 and R 2 are hydrogen; R 3 and R 4 are methyl; R 5 , R 6 , R 7 , R 8 , and R 9 are all hydrogen; and n is 4.
  • the peptide is defined by Formula B:
  • R 1 and R 2 are each independently selected from
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently selected from
  • halogen encompasses chloro, fluoro, bromo, and iodo; and n is an integer from 1 to 5.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; and n is 4.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 are all hydrogen; R 8 and R 12 are methyl; R 10 is hydroxyl; and n is 4.
  • the aromatic-cationic peptides of the present technology have a core structural motif of alternating aromatic and cationic amino acids.
  • the peptide may be a tetrapeptide defined by any of Formulas C to F set forth below:
  • Aromatic is a residue selected from the group consisting of: Phe (F), Tyr (Y), and Trp (W). In some embodiments, the Aromatic residue may be substituted with
  • the Cationic residue is a residue selected from the group consisting of: Arg (R), Lys (K), and His (H).
  • the Cationic residue may be substituted with Norleucine (Nle), and 2-amino-heptanoic acid (Ahe).
  • amino acids of the aromatic-cationic peptides of the present technology can be any amino acid.
  • amino acid is used to refer to any organic molecule that contains at least one amino group and at least one carboxyl group. In some embodiments, at least one amino group is at the a position relative to the carboxyl group.
  • the amino acids may be naturally occurring.
  • Naturally occurring amino acids include, for example, the twenty most common levorotatory (L,) amino acids normally found in mammalian proteins, i.e., alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (He), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan, (Trp), tyrosine (Tyr), and valine (Val).
  • L levorotatory amino acids normally found in mammalian proteins
  • amino acids include, for example, amino acids that are synthesized in metabolic processes not associated with protein synthesis.
  • amino acids ornithine and citrulline are synthesized in mammalian metabolism during the production of urea.
  • the peptides useful in the present technology can contain one or more non-naturally occurring amino acids.
  • the non-naturally occurring amino acids may be (L-), dextrorotatory (D-), or mixtures thereof.
  • the peptide has no amino acids that are naturally occurring.
  • Non-naturally occurring amino acids are those amino acids that typically are not synthesized in normal metabolic processes in living organisms, and do not naturally occur in proteins.
  • the non-naturally occurring amino acids useful in the present technology are also not recognized by common proteases.
  • the non-naturally occurring amino acid can be present at any position in the peptide.
  • the non-naturally occurring amino acid can be at the N terminus, the C-terminus, or at any position between the N-terminus and the C-terminus.
  • the non-natural amino acids may, for example, comprise alkyl, aryl, or alkylaryl groups.
  • alkyl amino acids include a-aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminobutyric acid, ⁇ -aminovaleric acid, and ⁇ -aminocaproic acid.
  • aryl amino acids include ortho-, meta, and para-aminobenzoic acid.
  • alkylaryl amino acids include ortho-, meta-, and para-aminophenyl acetic acid, and ⁇ -phenyl- ⁇ -aminobutyric acid.
  • Non-naturally occurring amino acids also include derivatives of naturally occurring amino acids.
  • the derivatives of naturally occurring amino acids may, for example, include the addition of one or more chemical groups to the naturally occurring amino acid.
  • one or more chemical groups can be added to one or more of the 2', 3', 4', 5', or 6' position of the aromatic ring of a phenylalanine or tyrosine residue, or the 4', 5', 6', or 7' position of the benzo ring of a tryptophan residue.
  • the group can be any chemical group that can be added to an aromatic ring.
  • Some examples of such groups include branched or unbranched C 1 -C 4 alkyl, such as methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, or t-butyl, C 1 -C 4 alkyloxy (i.e., alkoxy), amino, C 1 -C 4 alkylamino and C 1 -C 4 dialkylamino (e.g., methylamino, dimethylamino), nitro, hydroxyl, halo (i.e., fluoro, chloro, bromo, or iodo).
  • Some specific examples of non-naturally occurring derivatives of naturally occurring amino acids include norvaline (Nva), norleucine (Nle), and hydroxyproline (Hyp).
  • Another example of a modification of an amino acid in a peptide useful in the present methods is the derivatization of a carboxyl group of an aspartic acid or a glutamic acid residue of the peptide.
  • derivatization is amidation with ammonia or with a primary or secondary amine, e.g., methylamine, ethylamine, dimethylamine or diethylamine.
  • Another example of derivatization includes esterification with, for example, methyl or ethyl alcohol.
  • Another such modification includes derivatization of an amino group of a lysine, arginine, or histidine residue.
  • amino groups can be acylated.
  • suitable acyl groups include, for example, a benzoyl group or an alkanoyl group comprising any of the C 1 -C4 alkyl groups mentioned above, such as an acetyl or propionyl group.
  • the non-naturally occurring amino acids are resistant, and in some embodiments insensitive, to common proteases.
  • non-naturally occurring amino acids that are resistant or insensitive to proteases include the dextrorotatory (D-) form of any of the above-mentioned naturally occurring L-amino acids, as well as L- and/or D non- naturally occurring amino acids.
  • D-amino acids do not normally occur in proteins, although they are found in certain peptide antibiotics that are synthesized by means other than the normal ribosomal protein synthetic machinery of the cell, as used herein, the D-amino acids are considered to be non-naturally occurring amino acids.
  • the peptides useful in the methods of the present technology should have less than five, less than four, less than three, or less than two contiguous L-amino acids recognized by common proteases, irrespective of whether the amino acids are naturally or non-naturally occurring. In some embodiments, the peptide has only D-amino acids, and no L-amino acids. [0148] If the peptide contains protease sensitive sequences of amino acids, at least one of the amino acids is a non-naturally-occurring D-amino acid, thereby conferring protease resistance.
  • protease sensitive sequence includes two or more contiguous basic amino acids that are readily cleaved by common proteases, such as endopeptidases and trypsin.
  • basic amino acids include arginine, lysine and histidine.
  • the aromatic-cationic peptides have a minimum number of net positive charges at physiological pH in comparison to the total number of amino acid residues in the peptide.
  • the minimum number of net positive charges at physiological pH is referred to below as (p m ).
  • the total number of amino acid residues in the peptide is referred to below as (r).
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH refers to the normal pH in the cells of the tissues and organs of the mammalian body.
  • physiological pH of a human is normally approximately 7.4, but normal physiological pH in mammals may be any pH from about 7.0 to about 7.8.
  • a peptide has a positively charged N-terminal amino group and a negatively charged C-terminal carboxyl group. The charges cancel each other out at physiological pH.
  • the peptide Tyr-Arg-Phe-Lys- Glu-His-Trp-Arg has one negatively charged amino acid (i.e., Glu) and four positively charged amino acids (i.e., two Arg residues, one Lys, and one His). Therefore, the above peptide has a net positive charge of three.
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges at physiological pH (p m ) and the total number of amino acid residues (r) wherein 3p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) wherein 2p m is the largest number that is less than or equal to r + 1.
  • the relationship between the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) is as follows:
  • the minimum number of net positive charges (p m ) and the total number of amino acid residues (r) are equal.
  • the peptides have three or four amino acid residues and a minimum of one net positive charge, or a minimum of two net positive charges, or a minimum of three net positive charges.
  • aromatic-cationic peptides have a minimum number of aromatic groups in comparison to the total number of net positive charges (p t ).
  • the minimum number of aromatic groups will be referred to below as (a).
  • Naturally-occurring amino acids that have an aromatic group include the amino acids histidine, tryptophan, tyrosine, and phenylalanine.
  • the hexapeptide Lys-Gln-Tyr-D-Arg-Phe-Trp has a net positive charge of two (contributed by the lysine and arginine residues) and three aromatic groups (contributed by tyrosine, phenylalanine and tryptophan residues).
  • the aromatic-cationic peptides should also have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges at physiological pH (p t ) wherein 3 a is the largest number that is less than or equal to p t + 1, except that when p t is 1 , a may also be 1.
  • the relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) is as follows:
  • the aromatic-cationic peptides have a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (p t ) wherein 2a is the largest number that is less than or equal to p t + 1.
  • the number of aromatic groups (a) and the total number of net positive charges (pt) are equal.
  • carboxyl groups are amidated with, for example, ammonia to form the C-terminal amide.
  • the terminal carboxyl group of the C-terminal amino acid may be amidated with any primary or secondary amine.
  • the primary or secondary amine may, for example, be an alkyl, especially a branched or unbranched C1-C4 alkyl, or an aryl amine.
  • amino acid at the C-terminus of the peptide may be converted to an amido, N-methylamido, N-ethylamido, N,N-dimethylamido, ⁇ , ⁇ -diethyl amido, N-methyl-N- ethylamido, N-phenylamido or N-phenyl-N-ethylamido group.
  • the free carboxylate groups of the asparagine, glutamine, aspartic acid, and glutamic acid residues not occurring at the C-terminus of the aromatic-cationic peptides of the present technology may also be amidated wherever they occur within the peptide.
  • the amidation at these internal positions may be with ammonia or any of the primary or secondary amines described herein.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and at least one aromatic amino acid.
  • the aromatic-cationic peptide useful in the methods of the present technology is a tripeptide having two net positive charges and two aromatic amino acids.
  • Aromatic-cationic peptides useful in the methods of the present technology include, but are not limited to, the following peptide examples:
  • the aromatic-cationic peptide is a peptide having:
  • 2p m is the largest number that is less than or equal to r+1, and a may be equal to p t .
  • the aromatic-cationic peptide may be a water-soluble peptide having a minimum of two or a minimum of three positive charges.
  • the peptide comprises one or more non-naturally occurring amino acids, for example, one or more D-amino acids.
  • the C-terminal carboxyl group of the amino acid at the C-terminus is amidated.
  • the peptide has a minimum of four amino acids. The peptide may have a maximum of about 6, a maximum of about 9, or a maximum of about 12 amino acids.
  • the peptides have a tyrosine residue or a tyrosine derivative at the N-terminus (i.e., the first amino acid position).
  • Suitable derivatives of tyrosine include 2'- methyltyrosine (Mmt); 2',6'-dimethyltyrosine (2'6'-Dmt); 3 ',5 '-dimethyltyrosine (3'5'Dmt); N,2',6'-trimethyltyrosine (Tmt); and 2'-hydroxy-6'-methyltyrosine (Hmt).
  • a peptide has the formula Tyr-D-Arg-Phe-Lys-NH 2 .
  • Tyr-D- Arg-Phe-Lys-NH 2 has a net positive charge of three, contributed by the amino acids tyrosine, arginine, and lysine and has two aromatic groups contributed by the amino acids
  • the tyrosine of Tyr-D-Arg-Phe-Lys-NH 2 can be a modified derivative of tyrosine such as in 2',6'-dimethyltyrosine to produce the compound having the formula 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 .
  • 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 has a molecular weight of 640 and carries a net three positive charge at physiological pH.
  • the aromatic-cationic peptide does not have a tyrosine residue or a derivative of tyrosine at the N-terminus (i.e., amino acid position 1).
  • the amino acid at the N-terminus can be any naturally-occurring or non-naturally-occurring amino acid other than tyrosine.
  • the amino acid at the N-terminus is phenylalanine or its derivative.
  • Exemplary derivatives of phenylalanine include 2'- methylphenylalanine (Mmp), 2',6'-dimethylphenylalanine (2',6'-Dmp), N,2',6'- trimethylphenylalanine (Tmp), and 2'-hydroxy-6'-methylphenylalanine (Hmp).
  • an aromatic-cationic peptide that does not have a tyrosine residue or a derivative of tyrosine at the N-terminus is a peptide with the formula Phe-D-Arg-Phe-Lys- NH 2 .
  • the N-terminal phenylalanine can be a derivative of phenylalanine such as 2',6'-dimethylphenylalanine (2'6'-Dmp).
  • the amino acid sequence of 2',6'-Dmt-D-Arg-Phe-Lys-NH 2 is rearranged such that Dmt is not at the N-terminus.
  • An example of such an aromatic-cationic peptide is a peptide having the formula of D-Arg-2'6'- Dmt-Lys-Phe-NH 2 .
  • Suitable substitution variants of the peptides listed herein include conservative amino acid substitutions.
  • Amino acids may be grouped according to their physicochemical characteristics as follows:
  • Non-polar amino acids Ala(A) Ser(S) Thr(T) Pro(P) Gly(G) Cys (C);
  • Aromatic amino acids Phe(F) Tyr(Y) Trp(W) His (H).
  • substitutions of an amino acid in a peptide by another amino acid in the same group are referred to as a conservative substitution and may preserve the physicochemical characteristics of the original peptide.
  • substitutions of an amino acid in a peptide by another amino acid in a different group are generally more likely to alter the
  • Examples of peptides that have a tyrosine residue or a tyrosine derivative at the N- terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 6.
  • Tmt N, 2',6'-trimethyltyrosine
  • Examples of peptides that do not have a tyrosine residue or a tyrosine derivative at the N-terminus include, but are not limited to, the aromatic-cationic peptides shown in Table 7. TABLE 7. Peptide Analogs Lacking Mu-Opioid Activity
  • amino acids of the peptides shown in Table 6 and 7 may be in either
  • the methods disclosed herein provide therapies for the treatment of medical disease or conditions and/or side effects associated with existing therapeutics against medical diseases or conditions comprising administering an effective amount of
  • naphthoquinones alone or in combination with one or more aromatic-cationic peptides or pharmaceutically acceptable salts thereof, such as acetate, tartrate or trifluoroacetate.
  • the present technology provides methods for treating,
  • one or more peptide conjugate(s) may be: (1) co-formulated and administered or delivered alone or simultaneously in a combined formulation with other naphthoquinones or aromatic-cationic peptides; (2) delivered by alternation or in parallel as separate
  • the methods described herein may comprise administering or delivering the active ingredients sequentially, e.g., in separate solution, emulsion, suspension, tablets, pills or capsules, or by different injections in separate syringes.
  • an effective dosage of each active ingredient is administered sequentially, i.e., serially, whereas in simultaneous therapy, effective dosages of two or more active ingredients are administered together.
  • Various sequences of intermittent combination therapy may also be used.
  • Administering combinations of aromatic peptides and naphthoquinones can result in synergistic biological effect when administered in a therapeutically effective amount to a subject suffering from a medical disease or condition and in need of treatment.
  • An advantage of such an approach is that lower doses of aromatic-cationic peptide and/or naphthoquinone may be needed to prevent, ameliorate or treat a medical disease or condition in a subject. Further, potential side-effects of treatment may be avoided by use of lower dosages of aromatic-cationic peptide and/or naphthoquinone.
  • the combination therapy comprises administering to a subject in need thereof an aromatic-cationic peptide composition combined with one or more naphthoquinones.
  • the naphthoquinone and the aromatic-cationic peptide are chemically linked. In some embodiments, the naphthoquinone and the aromatic-cationic peptide are physically linked. In some embodiments, the naphthoquinone and the aromatic-cationic peptide are not linked.
  • Ischemia in a tissue or organ of a mammal is a multifaceted pathological condition which is caused by oxygen deprivation (hypoxia) and/or glucose (e.g., substrate) deprivation.
  • Oxygen and/or glucose deprivation in cells of a tissue or organ leads to a reduction or total loss of energy generating capacity and consequent loss of function of active ion transport across the cell membranes.
  • Oxygen and/or glucose deprivation also leads to pathological changes in other cell membranes, including permeability transition in the mitochondrial membranes.
  • other molecules, such as apoptotic proteins normally
  • Ischemia or hypoxia in a particular tissue or organ may be caused by a loss or severe reduction in blood supply to the tissue or organ.
  • the loss or severe reduction in blood supply may, for example, be due to thromboembolic stroke, coronary atherosclerosis, or peripheral vascular disease.
  • the tissue affected by ischemia or hypoxia is typically muscle, such as cardiac, skeletal, or smooth muscle.
  • the organ affected by ischemia or hypoxia may be any organ that is subject to ischemia or hypoxia.
  • organs affected by ischemia or hypoxia include brain, heart, kidney, and prostate.
  • cardiac muscle ischemia or hypoxia is commonly caused by atherosclerotic or thrombotic blockages which lead to the reduction or loss of oxygen delivery to the cardiac tissues by the cardiac arterial and capillary blood supply.
  • Such cardiac ischemia or hypoxia may cause pain and necrosis of the affected cardiac muscle, and ultimately may lead to cardiac failure.
  • Ischemia or hypoxia in skeletal muscle or smooth muscle may arise from similar causes.
  • ischemia or hypoxia in intestinal smooth muscle or skeletal muscle of the limbs may also be caused by atherosclerotic or thrombotic blockages.
  • Reperfusion is the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked.
  • blood flow can be restored to any organ or tissue affected by ischemia or hypoxia.
  • the restoration of blood flow can occur by any method known to those in the art. For instance, reperfusion of ischemic cardiac tissues may arise from angioplasty, coronary artery bypass graft, or the use of thrombolytic drugs.
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in reducing oxLDL-induced CD36 mRNA and protein levels, and foam cell formation in mouse peritoneal macrophages.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in reducing oxLDL- induced CD36 mRNA and protein levels, and foam cell formation in mouse peritoneal macrophages.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing infarct volume and hemispheric swelling in a subject suffering from acute cerebral ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing the decrease in reduced glutathione (GSH) in post-ischemic brain in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing CD36 expression in post-ischemic brain in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing CD36 expression in renal tubular cells after unilateral ureteral obstruction (UUO) in a subject in need thereof.
  • UUO unilateral ureteral obstruction
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing lipid peroxidation in a kidney after UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing tubular cell apoptosis in an obstructed kidney after UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing macrophage infiltration in an obstructed kidney induced by UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing interstitial fibrosis in an obstructed kidney after UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing up-regulation of CD36 expression in cold storage of isolated hearts.
  • naphthoquinones or derivatives, analogues, or
  • aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing lipid peroxidation in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in abolishing endothelial apoptosis in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • naphthoquinones or derivatives, analogues, or
  • aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preserving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged cold ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preventing damage to renal proximal tubules in diabetic subjects.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preventing renal tubular epithelial cell apoptosis in diabetic subjects.
  • naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in methods for reducing elevated CD36 expression associated with various diseases and conditions.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • diseases and conditions characterized by increased CD36 expression include, but are not limited to 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 and obesity.
  • naphthoquinones or derivatives, analogues, or
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • Complications of diabetes include, but are not limited to, nephropathy, neuropathy, retinopathy, coronary artery disease, and peripheral vascular disease.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the method comprises contacting the removed organ or tissue with an effective amount of a composition described herein.
  • An organ or tissue may, for example, be removed from a donor for autologous or heterologous transplantation.
  • organs and tissues amenable to methods of the present technology include, but are not limited to, heart, lungs, pancreas, kidney, liver, skin, etc.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in protecting against mitochondrial permeability transition (MPT) induced by Ca 2+ overload and 3-nitropropionic acid (3NP).
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in inhibiting mitochondrial swelling and cytochrome c release.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in protecting myocardial contractile force during ischemia-reperfusion in cardiac tissue.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology e.g., those including 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
  • a cardioplegic solution e.g., those including 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
  • a cardioplegic solution e.g., those including 2',6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-L
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology e.g., those including 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 ) are useful in treating any disease or condition that is associated with, for example, MPT.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • Such diseases and conditions include, but are not limited to, e.g., ischemia and/or reperfusion of a tissue or organ, hypoxia, diseases and conditions of the eye, myocardial infarction and any of a number of neurodegenerative diseases.
  • Mammals in need of treatment or prevention of MPT are those mammals suffering from these diseases or conditions.
  • compositions of the present disclosure can also be used in the treatment or prophylaxis of neurodegenerative diseases associated with MPT.
  • Neurodegenerative diseases associated with MPT include, for instance, Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS, also known as Lou Gehrig's disease).
  • ALS Amyotrophic Lateral Sclerosis
  • the methods and compositions disclosed herein can be used to delay the onset or slow the progression of these and other neurodegenerative diseases associated with MPT.
  • the methods and compositions of the present technology are useful in the treatment of humans suffering from the early stages of neurodegenerative diseases associated with MPT and in humans predisposed to these diseases.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preserving an organ of a mammal prior to
  • compositions of the present disclosure can be administered to a subject prior to organ removal, for example, and used to prevent MPT in the removed organ.
  • the removed organ may be placed in a standard buffered solution, such as those commonly used in the art.
  • a removed heart may be placed in a cardioplegic solution containing the compositions described herein.
  • concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.1 nM to about 10 ⁇ .
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • a side effect of the drug includes MPT
  • mammals taking such drugs would greatly benefit from administration of the compositions disclosed herein.
  • An example of a drug which induces cell toxicity by effecting MPT is the chemotherapy drug Adriamycin.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in ameliorating, diminishing or preventing the side effects of drugs such as adriamycin.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2 ⁇ 6'-dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • peptide conjugates of the present technology are useful in dose-dependently scavenging H 2 0 2 .
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in dose-dependently inhibiting linoleic acid peroxidation induced by ABAP and reducing the rate of linoleic acid peroxidation induced by ABAP.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in dose-dependently inhibiting linoleic acid peroxidation induced by ABAP and reducing the rate of linoleic acid peroxidation induced by ABAP
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in inhibiting mitochondrial production of hydrogen peroxide, e.g., as measured by luminol chemiluminescence under basal conditions and/or upon stimulation by antimycin.
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology ⁇ e.g., those including 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 ) are useful in reducing spontaneous generation of hydrogen peroxide by mitochondria in certain stress or disease states.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology ⁇ e.g., those including 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 ) are useful in inhibiting spontaneous production of hydrogen peroxide in mitochondria and hydrogen peroxide production, e.g., as stimulated by antimycin.
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in decreasing intracellular ROS (reactive oxygen species) and increasing survival in cells of a subject in need thereof.
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in decreasing intracellular ROS (reactive oxygen species) and increasing survival in cells of a
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in preventing loss of cell viability in subjects suffering from a disease or condition characterized by mitochondrial permeability transition.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in decreasing the percent of cells showing increased caspase activity in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg- Phe-Lys-NH 2 ,
  • naphthoquinones are useful in inhibiting lipid peroxidation in a subject in need thereof.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in inhibiting lipid peroxidation in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , P
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in preventing apoptosis in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in improving coronary flow in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • naphthoquinones or derivatives, analogues, or
  • compositions thereof are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preventing apoptosis in endothelial cells and myocytes in cardiac tissue (e.g., heart) subjected to warm reperfusion after prolonged (e.g., 18 hours) cold ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in improving survival of pancreatic cells in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing apoptosis and increasing viability in islet cells of pancreas in subjects in need thereof.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof are useful in reducing oxidative damage in pancreatic islet cells in subjects in need thereof.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in reducing oxidative damage in pancreatic islet cells in subjects in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in protecting dopaminergic cells against MPP+ toxicity in subjects in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in preventing loss of dopaminergic neurons in subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in increasing striatal dopamine, DOPAC and HVA levels in subjects in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • mammals in need of reducing oxidative damage are those mammals suffering from a disease, condition or treatment associated with oxidative damage.
  • the oxidative damage is caused by free radicals, such as reactive oxygen species (ROS) and/or reactive nitrogen species (RNS).
  • ROS and RNS include hydroxyl radical ( ⁇ ' ), superoxide anion radical (0 2 ' ⁇ ), nitric oxide (NO ' ), hydrogen peroxide (H 2 O 2 ), hypochlorous acid (HOC1), and peroxynitrite anion (ONOO ).
  • a mammal in need thereof may be a mammal undergoing a treatment associated with oxidative damage.
  • the mammal may be undergoing reperfusion.
  • “Reperfusion” refers to the restoration of blood flow to any organ or tissue in which the flow of blood is decreased or blocked. The restoration of blood flow during reperfusion leads to respiratory burst and formation of free radicals.
  • a mammal in need thereof is a mammal suffering from a disease or condition associated with oxidative damage.
  • the oxidative damage can occur in any cell, tissue or organ of the mammal.
  • cells, tissues or organs affected by oxidative damage include, but are not limited to, endothelial cells, epithelial cells, nervous system cells, skin, heart, lung, kidney, eye and liver.
  • lipid peroxidation and an inflammatory process are associated with oxidative damage for a disease or condition.
  • Lipid peroxidation refers to oxidative modification of lipids.
  • the lipids can be present in the membrane of a cell. This modification of membrane lipids typically results in change and/or damage to the membrane function of a cell.
  • lipid peroxidation can also occur in lipids or lipoproteins exogenous to a cell. For example, low-density lipoproteins are susceptible to lipid peroxidation.
  • An example of a condition associated with lipid peroxidation is atherosclerosis. Reducing oxidative damage associated with
  • Atherosclerosis is important because atherosclerosis is implicated in, for example, heart attacks and coronary artery disease.
  • Intravirus process refers to the activation of the immune system.
  • the immune system is activated by an antigenic substance.
  • the antigenic substance can be any substance recognized by the immune system, and include self-derived and foreign- derived substances.
  • diseases or conditions resulting from an inflammatory response to self-derived substances include arthritis and multiple sclerosis.
  • foreign substances include viruses and bacteria.
  • the virus can be any virus which activates an inflammatory process, and associated with oxidative damage.
  • viruses include, hepatitis A, B or C virus, human immunodeficiency virus, influenza virus, and bovine diarrhea virus.
  • hepatitis virus can elicit an inflammatory process and formation of free radicals, thereby damaging the liver.
  • the bacteria can be any bacteria, and include gram-negative and gram-positive bacteria.
  • Gram-negative bacteria contain lipopolysaccharide in the bacteria wall. Examples of gram-negative bacteria include Escherichia coli, Klebsiella pneumoniae, Proteus species, Pseudomonas aeruginosa, Serratia, and Bacteroides. Examples of gram-positive bacteria include pneumococci and streptococci.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the neurodegenerative disease can affect any cell, tissue or organ of the central and peripheral nervous system.
  • Non-limiting examples of such cells, tissues and organs include, the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.
  • the neurodegenerative condition can be an acute condition, such as a stroke or a traumatic brain or spinal cord injury.
  • the neurodegenerative disease or condition is a chronic neurodegenerative condition.
  • the free radicals can, for example, cause damage to a protein.
  • An example of such a protein is amyloid precursor protein.
  • Non-limiting examples of chronic neurodegenerative diseases associated with damage by free radicals include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (ALS).
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in treating preeclampsia, diabetes, and symptoms of and conditions associated with aging, such as macular degeneration, and wrinkles.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • the compositions of the present technology can be used to reduce oxidative damage from reperfusion of the transplanted organ.
  • the organ can be any organ suitable for transplantation.
  • the organ is a removed organ.
  • examples of such organs include, the heart, liver, kidney, lung, and pancreatic islets.
  • the removed organ is placed in a suitable medium, such as in a standard buffered solution commonly used in the art.
  • the concentration of disclosed compositions in the standard buffered solution can be easily determined by those skilled in the art. Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • Cells in need of reducing oxidative damage are generally those cells in which the cell membrane or DNA has been damaged by free radicals, for example, ROS and/or RNS.
  • free radicals for example, ROS and/or RNS.
  • Examples of cells capable of sustaining oxidative damage include, but are not limited to, pancreatic islet cells, myocytes, endothelial cells, neuronal cells, stem cells, and other cell types discussed herein.
  • the cells can be tissue culture cells. Alternatively, the cells may be obtained from a mammal. In one instance, the cells can be damaged by oxidative damage as a result of a cellular insult.
  • Cellular insults include, for example, a disease or condition (e.g., diabetes, etc.) or ultraviolet radiation (e.g., sun, etc.).
  • pancreatic islet cells damaged by oxidative damage as a result of diabetes can be obtained from a mammal.
  • the treated cells may be capable of regenerating.
  • Such regenerated cells may be re-introduced into the mammal from which they were derived as a therapeutic treatment for a disease or condition.
  • a disease or condition is diabetes.
  • Oxidative damage is considered to be "reduced” if the amount of oxidative damage in a mammal, a removed organ, or a cell is decreased after administration of an effective amount of the compositions described herein. Typically, oxidative damage is considered to be reduced if the oxidative damage is decreased by at least about 1%, 5%, 10%, at least about 25%, at least about 50%>, at least about 75%, or at least about 90%.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology are useful in regulating oxidation state of muscle tissue in lean and obese human subjects.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the peptide conjugates of the present technology e.g., those including D-Arg-2'6'-Dmt-Lys-Phe-NH 2
  • insulin resistance induced by obesity or a high-fat diet affects mitochondrial bioenergetics.
  • mitochondrial bioenergetics it is thought that the oversupply of metabolic substrates causes a reduction on the function of the mitochondrial respiratory system, and an increase in ROS production and shift in the overall redox environment to a more oxidized state. If persistent, this leads to development of insulin resistance.
  • Linking mitochondrial bioenergetics to the etiology of insulin resistance has a number of clinical implications.
  • insulin resistance (NIDDM) in humans often results in weight gain and, in selected individuals, increased variability of blood sugar with resulting metabolic and clinical consequences.
  • NIDDM insulin resistance
  • the examples shown herein demonstrate that treatment of mitochondrial defects with the compositions disclosed herein provides a new and surprising approach to treating or preventing insulin resistance without the metabolic side-effects of increased insulin.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in reducing insulin resistance.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • insulin resistance is generally associated with type II diabetes, coronary artery disease, renal dysfunction, atherosclerosis, obesity, hyperlipidemia
  • nonalcoholic steatohepatitis fibrosis
  • cirrhosis fibrosis
  • cirrhosis cirrhosis
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in methods for the prevention and/or treatment of insulin resistance and associated syndromes in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in methods for the prevention and/or treatment of insulin resistance and associated syndromes in a subject in need thereof.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in improving the sensitivity of mammalian skeletal muscle tissues to insulin.
  • naphthoquinones or derivatives, analogues, or
  • pharmaceutically acceptable salts thereof are useful in preventing drug-induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g., olanzapine,
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in preventing drug-induced obesity, insulin resistance, and/or diabetes, wherein the compound is administered with a drug that shows the side-effect of causing one or more of these conditions (e.g., olanzapine, Zyprexa®).
  • a drug that shows the side-effect of causing one or more of these conditions e.g., olanzapine, Zyprexa®.
  • Increased or decreased insulin resistance or sensitivity can be readily detected by quantifying body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • OGTT oral glucose tolerance
  • markers of insulin signaling e.g., Akt-P, IRS-P
  • mitochondrial function e.g., respiration or H 2 0 2 production
  • markers of intracellular oxidative stress e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
  • mitochondrial enzyme activity e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity
  • naphthoquinones or derivatives, analogues, or
  • pharmaceutically acceptable salts thereof are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • signs or markers of insulin resistance e.g., body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic- cationic peptide such as 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
  • peptide conjugates of the present technology are useful in methods for preventing, in a subject, a disease or condition associated with insulin resistance in skeletal muscle tissues via modulating one or more signs or markers of insulin resistance, e.g. , body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intracellular oxidative stress (e.g., lipid peroxidation, GSH/GSSG ratio or aconitase activity), or mitochondrial enzyme activity.
  • signs or markers of insulin resistance e.g. , body weight, fasting glucose/insulin/free fatty acid, oral glucose tolerance (OGTT), in vitro muscle insulin sensitivity, markers of insulin signaling (e.g., Akt-P, IRS-P), mitochondrial function (e.g., respiration or H 2 0 2 production), markers of intra
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in treating subjects at risk for a disease that is caused or contributed to by aberrant mitochondrial function or insulin resistance.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic- cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in treating subjects at risk for a disease that is caused or contributed to by aberrant mitochondrial function or insulin resistance.
  • compositions of the present technology are administered to a subject susceptible to, or otherwise at risk of a disease or condition in an amount sufficient to eliminate or reduce the risk, or delay the onset of the disease, including biochemical, histological and/or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease.
  • prophylactic naphthoquinones or derivatives, analogues, or
  • compositions of the present technology will act to enhance or improve mitochondrial function, and can be used for treating the subject.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in methods of modulating insulin resistance or sensitivity in a subject for therapeutic purposes.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • peptide conjugates of the present technology are useful in curing or partially arresting the symptoms of the disease (biochemical, histological and/or behavioral), including its complications and intermediate pathological phenotypes in development of the disease.
  • the present technology provides methods of treating an individual afflicted with an insulin resistance-associated disease or disorder.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in improving the histopathological score resulting from ischemia and reperfusion.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in increasing the rate of ATP production after reperfusion in renal tissue following ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in improving renal mitochondrial respiration following ischemia.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in decreasing medullary fibrosis in UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in decreasing interstitial fibrosis in UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • peptide conjugates of the present technology are useful in decreasing tubular apoptosis in UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in decreasing macrophage infiltration in UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in increasing tubular proliferation in UUO.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic- cationic peptide such as 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
  • active agents e.g., an aromatic- cationic peptide such as 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
  • peptide conjugates of the present technology are useful in decreasing oxidative damage in UUO.
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in reducing renal dysfunction caused by a radiocontrast dye.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in reducing renal dysfunction caused by a radiocontrast dye.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • peptide conjugates of the present technology are useful in protecting renal tubules from radiocontrast dye injury.
  • naphthoquinones or derivatives, analogues, or
  • peptide conjugates of the present technology are useful in preventing renal tubular apoptosis induced by radiocontrast dye injury.
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • peptide conjugates of the present technology are useful in preventing renal tubular apoptosis induced by radiocontrast dye injury.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • Acute renal injury refers to a reduction of renal function and filtration of waste products from a patient's blood.
  • ARI is typically characterized as including a decline of glomerular filtration rate (GFR) to a level so low that little or no urine is formed. Therefore, substances usually eliminated by the kidney remain in the body.
  • GFR glomerular filtration rate
  • ARI causes of ARI may be caused by various factors, falling into three categories: (1) pre -renal ARI, in which the kidneys fail to receive adequate blood supply, e.g., due to reduced systemic blood pressure as in shock/cardiac arrest, or subsequent to hemorrhage; (2) intrinsic ARI, in which the failure occurs within the kidney, e.g., due to drug-induced toxicity; and (3) post-renal ARI, caused by impairment of urine flow out of the kidney, as in ureteral obstruction due to kidney stones or bladder/prostate cancer. ARI may be associated with any one or a combination of these categories.
  • Ischemia is a major cause of ARI. Ischemia of one or both kidneys is a common problem experienced during aortic surgery, renal transplantation, or during cardiovascular anesthesia. Surgical procedures involving clamping of the aorta and/or renal arteries, e.g., surgery for supra- and juxta-renal abdominal aortic aneurysms and renal transplantation, are also particularly liable to produce renal ischemia, leading to significant postoperative complications and early allograft rejection. In high-risk patients undergoing these surgeries, the incidence of renal dysfunction has been reported to be as high as 50%. The skilled artisan will understand that the above described causes of ischemia are not limited to the kidney, but may occur in other organs during surgical procedures.
  • Renal ischemia may be caused by loss of blood, loss of fluid from the body as a result of severe diarrhea or burns, shock, and ischemia associated with storage of the donor kidney prior to transplantation. In these situations, the blood flow to the kidney may be reduced to a dangerously low level for a time period great enough to cause ischemic injury to the tubular epithelial cells, sloughing off of the epithelial cells into the tubular lumen, obstruction of tubular flow that leads to loss of glomerular filtration and ARI.
  • Subjects may also become vulnerable to ARI after receiving anesthesia, surgery, or a-adrenergic agonists because of related systemic or renal vasoconstriction.
  • systemic vasodilation caused by anaphylaxis, and anti-hypertensive drugs, sepsis or drug overdose may also cause ARI because the body's natural defense is to shut down, i.e., vasoconstriction of non-essential organs such as the kidneys.
  • a subject at risk for ARI may be a subject undergoing an interruption or reduction of blood supply or blood pressure to the kidney.
  • these subjects may be administered naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology prior to or simultaneously with such interruption or reduction of blood supply.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents ⁇ e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology may be administered after the therapeutic agent to treat ischemia.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as
  • Nephrotoxins can cause direct toxicity on tubular epithelial cells.
  • Nephrotoxins include, but are not limited to, therapeutic drugs, e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides ⁇ e.g., paraquat), and environmental contaminants ⁇ e.g., trichloroethylene and dichloroacetylene).
  • therapeutic drugs e.g., cisplatin, gentamicin, cephaloridine, cyclosporin, amphotericin, radiocontrast dye (described in further detail below), pesticides ⁇ e.g., paraquat), and environmental contaminants ⁇ e.g., trichloroethylene and dichloroacetylene).
  • PAN puromycin aminonucleoside
  • aminoglycosides such as gentamicin
  • cephalosporins such as cephaloridine
  • calcineurin inhibitors such as tacrolimus or sirolimus.
  • Drug-induced nephrotoxicity may also be caused by non-steroidal anti-inflammatories, anti- retrovirals, anticytokines, immunosuppressants, oncological drugs, or angiotensin-converting- enzyme (ACE) inhibitors.
  • ACE angiotensin-converting- enzyme
  • the drug-induced nephrotoxicity may further be caused by analgesic abuse, ciprofloxacin, clopidogrel, cocaine, cox-2 inhibitors, diuretics, foscamet, gold, ifosfamide, immunoglobulin, Chinese herbs, interferon, lithium, mannitol, mesalamine, mitomycin, nitrosoureas, penicillamine, penicillins, pentamidine, quinine, rifampin, streptozocin, sulfonamides, ticlopidine, triamterene, valproic acid, doxorubicin, glycerol, cidofovir, tobramycin, neomycin sulfate, colistimethate, vancomycin, amikacin, cefotaxime, cisplatin, acyclovir, lithium, interleukin-2, cyclosporin, or indinavir.
  • analgesic abuse ciprofloxaci
  • nephrotoxins In addition to direct toxicity on tubular epithelial cells, some nephrotoxins also reduce renal perfusion, causing injury to zones known to have limited oxygen availability (inner medullary region). Such nephrotoxins include amphotericin and radiocontrast dyes. Renal failure can result even from clinically relevant doses of these drugs when combined with ischemia, volume depletion, obstruction, or infection. An example is the use of radiocontrast dye in patients with impaired renal function. The incidence of contrast dye- induced nephropathy (CIN) is 3-8% in the normal patient, but increases to 25% for patients with diabetes mellitus. Most cases of ARI occur in patients with predisposing co-morbidities (McCombs, P.R. & Roberts, B., Surg Gynecol. Obste , 148: 175-178 (1979)).
  • CIN contrast dye- induced nephropathy
  • a subject at risk for ARI is receiving one or more therapeutic drugs that have a nephrotoxic effect.
  • the subject is administered
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology prior to or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology may be administered after the therapeutic agent to treat nephrotoxicity.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2
  • naphthoquinones or derivatives, analogues, or
  • CIN is an important cause of acute renal failure.
  • CIN is defined as acute renal failure occurring within 48 hours of exposure to intravascular radiographic contrast material, and remains a common complication of radiographic procedures.
  • CIN arises when a subject is exposed to radiocontrast dye, such as during coronary, cardiac, or neuro-angiography procedures. Contrast dye is essential for many diagnostic and interventional procedures because it enables doctors to visualize blocked body tissues.
  • a creatinine test can be used to monitor the onset of CIN, treatment of the condition, and efficacy of naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology in treating or preventing CIN.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-d
  • naphthoquinones or derivatives, analogues, or
  • compositions alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology are administered to a subject prior to or simultaneously with the administration of a contrast agent in order to provide protection against CIN.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-d
  • the subject may be administered the compositions at about the same time as the contrast agent. Moreover, administration of the compositions to the subject may continue following administration of the contrast agent. In some embodiments, the subject continues to receive the compositions at intervals of about 1 , 2, 3, 4, 5, 6, 7, 8, 12, 24, and 48 hours following administration of the contrast agent, in order to provide a protective or prophylactic effect against CIN.
  • naphthoquinones or derivatives, analogues, or
  • compositions alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology are administered to a subject after administration of a contrast agent in order to treat CIN.
  • the subject receives the compositions from about 1 to 2 hours, about 1 to 6 hours, about 1 to 12 hours, about 1 to 24 hours, about 1 to 48 hours, or about 1 to 72 hours after receiving the contrast agent.
  • the subject may exhibit one or more signs or symptoms of CIN prior to receiving the compositions of the present technology, such as increased serum creatinine levels and/or decreased urine volume.
  • a subject in need thereof may be a subject having impairment of urine flow. Obstruction of the flow of urine can occur anywhere in the urinary tract and has many possible causes, including but not limited to, kidney stones or
  • UUO is a common clinical disorder associated with obstructed urine flow. It is also associated with tubular cell apoptosis, macrophage infiltration, and interstitial fibrosis. Interstitial fibrosis leads to a hypoxic environment and contributes to progressive decline in renal function despite surgical correction.
  • a subject having or at risk for UUO may be administered naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology to prevent or treat ARI.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic
  • a method for protecting a kidney from renal fibrosis in a mammal in need thereof comprises administering to the mammal an effective amount of naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology as described herein.
  • active agents e.g., an aromatic-cationic peptide such as 2',6'-dimethyl-Tyr-D-Arg-Phe- Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones or derivatives, analogues, or pharmaceutically acceptable salts thereof
  • one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the method comprises administering to the mammal an effective amount of naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) alone or in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ), or peptide conjugates of the present technology as described herein.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • the compositions described herein can be administered to
  • the methods of the present technology may be particularly useful in patients with renal insufficiency, renal failure, or end-stage renal disease attributable at least in part to a nephrotoxicity of a drug or chemical.
  • Other indications may include creatinine clearance levels of lower than 97 (men) and 88 (women) mL/min, or a blood urea level of 20- 25 mg/dl or higher.
  • the treatment may be useful in patients with
  • microalbuminuria, macroalbuminuria, and/or proteinuria levels of over 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 g or more per a 24 hour period, and/or serum creatinine levels of about 1.0, 1.5, 2.0, 2.5, 3, 3.5, 4.0, 4.5, 5, 5.5, 6, 7, 8, 9, 10 mg/dl or higher.
  • the methods of the present technology can be used to slow or reverse the progression of renal disease in patients whose renal function is below normal, relative to control subjects.
  • the methods of the present technology slow the loss of renal function.
  • loss of renal function is slowed by at least 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%), 90%), 100%) or more, relative to control subjects.
  • the methods of the present technology improve the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion.
  • the patient's serum creatinine levels, proteinuria, and/or urinary albumin excretion is improved by at least 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, or more, relative to control subjects.
  • Non-limiting illustrative methods for assessing renal function are described herein and, for example, in WO 01/66140.
  • naphthoquinones or derivatives, analogues, or
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • an aromatic-cationic peptide such as 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
  • a removed kidney can be placed in a solution containing the compositions described herein.
  • concentration of compositions in the standard buffered solution can be easily determined by those skilled in the art.
  • Such concentrations may be, for example, between about 0.01 nM to about 10 ⁇ , about 0.1 nM to about 10 ⁇ , about 1 ⁇ to about 5 ⁇ , or about 1 nM to about 100 nM.
  • naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in preventing or treating ARI and are also applicable to tissue injury and organ failure in other systems besides the kidney.
  • naphthoquinones in combination with one or more active agents (e.g., an aromatic-cationic peptide such as 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 ) will show a synergistic effect in this regard.
  • active agents e.g., an aromatic-cationic peptide such as 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
  • naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) or peptide conjugates of the present technology are useful in minimizing cell death, inflammation, and fibrosis.
  • naphthoquinones (or derivatives, analogues, or pharmaceutically acceptable salts thereof) in combination with one or more active agents e.g., an aromatic-cationic peptide such as 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
  • active agents e.g., an aromatic-cationic peptide such as 2', 6'- dimethyl-Tyr-D-Arg-Phe-Lys-NH 2 , Phe-D-Arg-Phe-Lys-NH 2 , or D-Arg-2',6'-Dmt-Lys-
  • naphthoquinones or derivatives, analogues, or

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Abstract

L'invention concerne des méthodes et des compositions pour le traitement et/ou la prévention de maladies ou d'états pathologiques, méthodes comprenant l'administration de naphthoquinones, et/ou de dérivés d'originie naturelle ou artificielle, d'analogues, ou de sels pharmaceutiquement acceptables de ceux-ci, seuls ou combinés à un ou plusieurs agents actifs (par ex.., un peptide aromatique-cationique). La présente technologie porte sur des compositions associées à des peptides aromatiques-cationiques liés à des naphtoquinones et sur leurs utilisations. Dans certains modes de réalisation, le peptide aromatique-cationique comprend 2',6'-diméthyl-Tyr-D-Arg-Phe-Lys-NH2, Phe-D-Arg-Phe-Lys-NH2, or D-Arg-2',6'-Dmt-Lys-Phe-NH2.
PCT/US2015/032716 2014-05-28 2015-05-27 Compositions thérapeutiques comprenant des naphthoquinones et leurs utilisations Ceased WO2015183985A2 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2625740C1 (ru) * 2016-10-10 2017-07-18 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Средство для лечения ишемии сосудов головного мозга
CN115326958A (zh) * 2022-08-11 2022-11-11 北京大学第三医院（北京大学第三临床医学院） 一种辅助预测或诊断肥胖合并高脂血症儿童的标志物组合物
CN115364221A (zh) * 2022-07-11 2022-11-22 海南医学院第一附属医院 Apelin/APJ通路的上调表达促进剂在百草枯中毒肾损伤药物中的应用

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* Cited by examiner, † Cited by third party
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HK1210953A1 (en) * 2012-08-02 2016-05-13 Stealth Peptides International, Inc. Methods for treatment of atherosclerosis
EP2928562A4 (fr) * 2012-12-06 2016-06-22 Stealth Peptides Int Inc Produits thérapeutiques peptidiques et leurs procédés d'utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2625740C1 (ru) * 2016-10-10 2017-07-18 Федеральное государственное бюджетное учреждение науки Тихоокеанский институт биоорганической химии им. Г.Б. Елякова Дальневосточного отделения Российской академии наук (ТИБОХ ДВО РАН) Средство для лечения ишемии сосудов головного мозга
CN115364221A (zh) * 2022-07-11 2022-11-22 海南医学院第一附属医院 Apelin/APJ通路的上调表达促进剂在百草枯中毒肾损伤药物中的应用
CN115326958A (zh) * 2022-08-11 2022-11-11 北京大学第三医院（北京大学第三临床医学院） 一种辅助预测或诊断肥胖合并高脂血症儿童的标志物组合物
CN115326958B (zh) * 2022-08-11 2023-11-24 北京大学第三医院（北京大学第三临床医学院） 一种辅助预测或诊断肥胖合并高脂血症儿童的标志物组合物

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