# US 2014/0194342 A1 · Peptide-Based Peroxidase Inhibitors and Methods of Using Same > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0194342 A1 - Document ID: US20140194342A1 - Status: Published application - Kind: A1 - Application number: 14/081,695 - Filed: 2013-11-15 - Published: 2014-07-10 - Earliest claimed: 2009-10-05 - Assignees: The Medical College of Wisconsin, Inc. - Inventors: Hao Zhang; Yang Shi; Hao Xu; Kirkwood A. Pritchard, JR. - Web page: https://patentgrep.com/patent/US20140194342A1 ## CPC - C07K 5/0815: {with the first amino acid being basic} - A61P 9/12: Antihypertensives - A61P 19/02: for joint disorders, e.g. arthritis, arthrosis - C07K 5/0821: {with the first amino acid being heterocyclic, e.g. His, Pro, Trp} - A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) ## Abstract The present invention provides peptide-based peroxidase inhibitors having the formula AA1-AA2-AA3, wherein AA1 is a positively charged, negatively charged or neutral amino acid, AA2 is a redox active amino acid, and AA3 is an amino acid possessing a reducing potential such that AA3 is capable of undergoing a redox reaction with a radical of amino acid AA2 or a retro or retro-inverso analog thereof. The result of such a combination is a highly effective inhibitor of peroxidase activity that has potent anti-inflammatory properties in widely diverse models of vascular disease and injury. Exemplary tripeptides effectively inhibit peroxidase mediated LDL oxidation, increase vasodilation in SCD mice, inhibit eosinophil infiltration and collagen deposition in asthma mice, inhibit acute lung injury, and decrease ischemic injury of the heart. ## Claims ### Claim 1 A method of inhibiting peroxidase activity in a subject, the method comprising administering to the subject a peptide-based peroxidase inhibitor having the formula AA1-AA2-AA3, wherein AA1 is a positively charged, negatively charged or neutral amino acid, AA2 is a redox active amino acid, and AA3 is an amino acid possessing a reducing potential such that AA3 is capable of undergoing a redox reaction with a radical of amino acid AA2; or a retro or retro-inverso analog thereof. ### Claim 2 (depends on 1) The method according to claim 1 wherein AA1 is lysine, arginine, or histidine and AA2 is tyrosine, tryptophan, chlorotyrosine, nitrotyrosine, or dimethyltyrosine and AA3 is cysteine, selenocysteine, or homocysteine. ### Claim 3 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor has the formula KYC or KWC. ### Claim 4 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor has the retro or retro-inverso formula of KYC or KWC. ### Claim 5 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor comprises L-amino acids or D-amino acids. ### Claim 6 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor further comprises a protecting group coupled to its amino or carboxyl terminus. ### Claim 7 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor further comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus. ### Claim 8 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor comprises an acetyl protecting group coupled to its amino terminus or an amide protecting group coupled to its carboxyl terminus. ### Claim 9 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor comprises an acetyl protecting group coupled to its amino terminus and an amide protecting group coupled to its carboxyl terminus. ### Claim 10 (depends on 1) The method according to claim 1 wherein the peptide-based peroxidase inhibitor has the formula Ac-KYC-amide or Ac-KWC-amide. ### Claim 11 (depends on 1) The method according to claim 1 wherein said method results in the treatment of a disease or condition attributable to aberrant peroxidase activity in the subject. ### Claim 12 (depends on 1) The method according to claim 1 wherein the disease or condition attributable to aberrant peroxidase activity is selected from the group consisting of wound inflammation, hypersensitivity, digestive disease, cardiovascular disease, neuronal disease, lung disease, autoimmune disease, degenerative neurological disease, degenerative muscle disease, infectious disease, disease associated with graft transplantation, allergic disease, musculo-skeletal inflammation, sepsis, hypertension, peripheral vascular disease, pulmonary inflammation, asthma, atherosclerosis, diabetes, persistent pulmonary hypertension, sickle cell disease, neurodegenerative disease, multiple sclerosis, Alzheimer's disease, lung cancer, lupus, ischemic heart disease, Parkinson's disease, Crone's disease, inflammatory bowel disease, necrotizing enterocolitis, arthritis, polymyocytis, cardiomyopathy, psoriasis, amyotrophic lateral sclerosis, muscular dystrophy, cystic fibrosis, attention deficiency hyperactive disorder, acute lung injury, acute respiratory distress syndrome, swine flu, heart failure, chemotherapy-induced heart failure, arthritis, rheumatoid arthritis, and acute myocardial infarction. ### Claim 13 (depends on 1) The method according to claim 1 wherein said method results in the promotion of angiogenesis in a tissue of the subject. ### Claim 14 (depends on 13) The method according to claim 13 wherein said method results in the promotion of angiogenesis impaired by persistent pulmonary hypertension, peripheral vascular disease or vascular disease in the myocardium in the subject. ### Claim 15 (depends on 1) The method according to claim 1 wherein said method results in the treatment of a disease or condition associated with abnormal, excessive blood vessel development in the subject. ### Claim 16 (depends on 1) The method according to claim 1 wherein said method results in a reduction in ischemic injury to the subject's heart. ### Claim 17 A peptide-based peroxidase inhibitor having the formula AA1-AA2-AA3, wherein AA1 is a positively charged, negatively charged or neutral amino acid, AA2 is a redox active amino acid, and AA3 is an amino acid possessing a reducing potential such that AA3 is capable of undergoing a redox reaction with a radical of amino acid AA2; or a retro or retro-inverso analog thereof. ### Claim 18 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 wherein AA1 is lysine, arginine, or histidine and AA2 is tyrosine, tryptophan, chlorotyrosine, nitrotyrosine, or dimethyltyrosine and AA3 is cysteine, selenocysteine, or homocysteine. ### Claim 19 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising the formula KYC or KWC. ### Claim 20 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising the retro or retro-inverso formula of KYC or KWC. ### Claim 21 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising L-amino acids or D-amino acids. ### Claim 22 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 further comprising a protecting group coupled to the amino or carboxyl terminus. ### Claim 23 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 further comprising a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus. ### Claim 24 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising an acetyl protecting group coupled to its amino terminus or an amide protecting group coupled to its carboxyl terminus. ### Claim 25 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising an acetyl protecting group coupled to its amino terminus and an amide protecting group coupled to its carboxyl terminus. ### Claim 26 (depends on 17) The peptide-based peroxidase inhibitor according to claim 17 comprising the formula Ac-KYC-amide or Ac-KWC-amide. ### Claim 27 (depends on 17) A pharmaceutical composition capable of inhibiting peroxidase activity in a subject, comprising the peptide-based peroxidase inhibitor of claim 17 and a pharmaceutically acceptable carrier. ### Claim 28 (depends on 17) A method of making a pharmaceutical composition capable of inhibiting peroxidase activity in a subject, comprising the steps of (a) providing a peptide-based inhibitor according to claim 17; and (b) mixing the peptide-based inhibitor with a pharmaceutically acceptable carrier to yield the pharmaceutical composition. ### Claim 29 A method of inhibiting peroxidase activity in a subject, the method comprising administering to the subject a peptide-based peroxidase inhibitor consisting of (a) the tripeptide KYC, or (b) the tripeptide KYC having a protecting group coupled to its amino terminus, its carboxyl terminus, or to both its amino and carboxyl termini. ### Claim 30 (depends on 29) The method according to claim 29 wherein all the amino acids in the peptide-based peroxidase inhibitor are L-amino acids. ### Claim 31 (depends on 29) The method according to claim 29 wherein an acetyl protecting group is coupled to the amino terminus of the tripeptide, and an amide protecting group is coupled to the carboxyl terminus of the tripeptide. ### Claim 32 (depends on 29) The method according to claim 29 wherein said method results in the prevention or treatment of a disease or condition attributable to aberrant peroxidase activity in the subject. ### Claim 33 (depends on 32) The method according to claim 32 wherein the disease or condition attributable to aberrant peroxidase activity is a vascular disease or lung cancer. ### Claim 34 (depends on 33) The method of claim 33, wherein the vascular disease is atherosclerosis. ### Claim 35 (depends on 33) The method of claim 33, wherein lung cancer is effectively treated or prevented.