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Compounds for enhancing hypoxia inducible factor activity and methods of use

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Title: Compounds for enhancing hypoxia inducible factor activity and methods of use.
Abstract: The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide. ...


USPTO Applicaton #: #20090215687 - Class: 514 12 (USPTO) - 08/27/09 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Peptide Containing (e.g., Protein, Peptones, Fibrinogen, Etc.) Doai >Cyclopeptides >25 Or More Peptide Repeating Units In Known Peptide Chain Structure

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The Patent Description & Claims data below is from USPTO Patent Application 20090215687, Compounds for enhancing hypoxia inducible factor activity and methods of use.

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US 20090215686 A1 20090827 1 59 1 182 PRT Homo sapiens 1 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 2 182 PRT Mus musculus MISC_FEATURE What is shown is the portion of the Mus musculus NK1 protein thatis homogolous with the homo sapien NK1 2 Tyr Ala Glu Gly Gln Lys Lys Arg Arg Asn Thr Leu His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Thr Lys Glu Asp Pro Leu Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Ser Ala Asp Glu Cys Ala Asn Arg Cys Ile 35 40 45 Arg Asn Arg Gly Phe Thr Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ser Arg Lys Arg Cys Tyr Trp Tyr Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Gly Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Gly Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Asn Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 3 182 PRT Rattus norvegicus MISC_FEATURE What is shown is the portion of the Rattus norvegicus NK1 protein that is homogolous with the homo sapien NK1 3 Tyr Ala Glu Gly His Lys Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Asn Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 4 182 PRT Bos taurus MISC_FEATURE What is shown is the portion of the Bos taurus NK1 protein that is homogolous with the homo sapien NK1 4 Tyr Ala Glu Gly Gln Lys Lys Arg Arg Asn Thr Leu His Glu Phe Lys 1 5 10 15 Arg Ser Ala Lys Thr Thr Leu Ile Lys Glu Asp Pro Leu Leu Lys Ile 20 25 30 Lys Thr Lys Lys Met Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Ile 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Arg Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Gly Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Asn Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 5 182 PRT Felis catus MISC_FEATURE What is shown is the portion of the Felis catus NK1 protein that is homogolous with the homo sapien NK1 5 Tyr Ala Glu Gly Gln Lys Lys Arg Arg Asn Thr Leu His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Glu Asp Pro Leu Leu Lys Ile 20 25 30 Lys Thr Lys Lys Met Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Ile 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Arg Cys Leu Trp Phe Pro Phe Asn Ser Met Thr Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Gly Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Asn Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 6 182 PRT Canis familiaris MISC_FEATURE What is shown is the portion of the Canis familiaris NK1 protein that is homogolous with the homo sapien NK1 6 Arg Ala Glu Gly Gln Lys Lys Arg Arg Asn Thr Leu His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Glu Asp Pro Leu Leu Lys Ile 20 25 30 Lys Thr Lys Lys Met Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Ile 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Arg Cys Leu Trp Phe Pro Phe Asn Ser Met Thr Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Gly Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Asn Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 7 182 PRT Gallus gallus MISC_FEATURE What is shown is the portion of the Gallus gallus NK1 protein that is homogolous with the homo sapien NK1 7 Ala Ala Glu Gly Lys Gly Lys Arg Arg Asn Pro Leu His Asp Tyr Lys 1 5 10 15 Lys Thr Gly Glu Leu Met Leu Ile Lys Val Asn Lys Thr Leu Glu Val 20 25 30 Lys Thr Lys Leu Leu Asn Thr Thr Glu Gln Cys Ala Lys Arg Cys Ser 35 40 45 Arg Asn Lys Gly Leu Ser Phe Thr Cys Lys Ala Phe Ala Tyr Asp Arg 50 55 60 Val Thr Lys Arg Cys His Trp Leu Ser Phe Asn Ser Leu Thr Asn Gly 65 70 75 80 Val Arg Lys Lys Gln Asp His Ala Phe Asp Leu Phe Glu Lys Lys Asp 85 90 95 Tyr Val Arg Asn Cys Ile Ile Gly Lys Gly Ala Glu Tyr Lys Gly Thr 100 105 110 Ile Ser Ile Thr Lys Ser Gly Ile Gln Cys Gln Ala Trp Asn Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Arg Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Thr Ser Pro Gln Met Arg His Glu Val Cys Asp Ile 165 170 175 Pro Leu Cys Ser Glu Val 180 8 182 PRT Artificial Sequence Human mutated peptide 8 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Ala Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 9 182 PRT Artificial Sequence Human mutated peptide 9 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 10 182 PRT Artificial Sequence Human mutated peptide 10 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 11 182 PRT Artificial Sequence Human mutated peptide 11 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 12 182 PRT Artificial Sequence Human mutated peptide 12 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 13 182 PRT Artificial Sequence Human mutated peptide 13 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 14 182 PRT Artificial Sequence Human mutated peptide 14 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Xaa Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 15 182 PRT Artificial Sequence Human mutated peptide 15 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 16 182 PRT Artificial Sequence Human mutated peptide 16 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 17 182 PRT Artificial Sequence Human mutated peptide 17 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 18 182 PRT Artificial Sequence Human mutated peptide 18 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 19 182 PRT Artificial Sequence Human mutated peptide 19 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 20 182 PRT Artificial Sequence Human mutated peptide 20 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Ala Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 21 182 PRT Artificial Sequence Human mutated peptide 21 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Ala Ala Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 22 182 PRT Artificial Sequence Human mutated peptide 22 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Ala Lys Gly Leu Pro Ala Ala Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 23 182 PRT Artificial Sequence Human mutated peptide 23 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Ala Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 24 182 PRT Artificial Sequence Human mutated peptide 24 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Ala Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 25 182 PRT Artificial Sequence Human mutated peptide 25 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Ala Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 26 182 PRT Artificial Sequence Human mutated peptide 26 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 27 182 PRT Artificial Sequence Human mutated peptide 27 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Ala Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 28 182 PRT Artificial Sequence Human mutated peptide 28 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Ala Ser Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 29 182 PRT Artificial Sequence Human mutated peptide 29 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Ala 100 105 110 Val Ala Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 30 182 PRT Artificial Sequence Human mutated peptide 30 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Ala 100 105 110 Val Ala Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 31 182 PRT Artificial Sequence Human mutated peptide 31 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Ala 100 105 110 Ala Ser Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 32 182 PRT Artificial Sequence Human mutated peptide 32 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Ala Ala Cys Ala Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 33 182 PRT Artificial Sequence Human mutated peptide 33 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 34 182 PRT Artificial Sequence Human mutated peptide 34 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Ala 100 105 110 Ala Ser Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 35 182 PRT Artificial Sequence Human mutated peptide 35 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Ala 100 105 110 Val Ala Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 36 182 PRT Artificial Sequence Human mutated peptide 36 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Ala 85 90 95 Tyr Ile Arg Ala Cys Ile Ile Gly Lys Gly Arg Ser Tyr Ala Gly Ala 100 105 110 Ala Ser Ala Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 37 182 PRT Artificial Sequence Human mutated peptide 37 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Xaa Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 38 182 PRT Artificial Sequence Human mutated peptide 38 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Xaa Xaa Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 39 182 PRT Artificial Sequence Human mutated peptide 39 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Xaa Lys Gly Leu Pro Xaa Xaa Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 40 182 PRT Artificial Sequence Human mutated peptide 40 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Xaa Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 41 182 PRT Artificial Sequence Human mutated peptide 41 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Xaa Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 42 182 PRT Artificial Sequence Human mutated peptide 42 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Xaa Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 43 182 PRT Artificial Sequence Human mutated peptide 43 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 44 182 PRT Artificial Sequence Human mutated peptide 44 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Xaa Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 45 182 PRT Artificial Sequence Human mutated peptide 45 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Xaa Ser Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 46 182 PRT Artificial Sequence Human mutated peptide 46 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Xaa 100 105 110 Val Xaa Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 47 182 PRT Artificial Sequence Human mutated peptide 47 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Xaa 100 105 110 Val Xaa Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 48 182 PRT Artificial Sequence Human mutated peptide 48 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Xaa 100 105 110 Xaa Ser Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 49 182 PRT Artificial Sequence Human mutated peptide 49 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Xaa Xaa Cys Xaa Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 50 182 PRT Artificial Sequence Human mutated peptide 50 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 51 182 PRT Artificial Sequence Human mutated peptide 51 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Xaa 100 105 110 Xaa Ser Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 52 182 PRT Artificial Sequence Human mutated peptide 52 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Xaa 100 105 110 Val Xaa Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 53 182 PRT Artificial Sequence Human mutated peptide 53 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Xaa 85 90 95 Tyr Ile Arg Xaa Cys Ile Ile Gly Lys Gly Arg Ser Tyr Xaa Gly Xaa 100 105 110 Xaa Ser Xaa Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 54 182 PRT Artificial Sequence Human mutated peptide 54 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Arg Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 55 182 PRT Artificial Sequence Human mutated peptide 55 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Tyr Ile Arg Asn Cys Ile Ile Gly Lys Gly Arg Ser Tyr Lys Gly Thr 100 105 110 Xaa Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 56 549 DNA homo sapiens 56 tatgcagagg gacaaaggaa aagaagaaat acaattcatg aattcaaaaa atcagcaaag 60 actaccctaa tcaaaataga tccagcactg aagataaaaa ccaaaaaagt gaatactgca 120 gaccaatgtg ctaatagatg tactaggaat aaaggacttc cattcacttg caaggctttt 180 gtttttgata aagcaagaaa acaatgcctc tggttcccct tcaatagcat gtcaagtgga 240 gtgaaaaaag aatttggcca tgaatttgac ctctatgaaa acaaagacta cattagaaac 300 tgcatcattg gtaaaggacg cagctacaag ggaacagtat ctatcactaa gagtggcatc 360 aaatgtcagc cctggagttc catgatacca cacgaacaca gctttttgcc ttcgagctat 420 cggggtaaag acctacagga aaactactgt cgaaatcctc gaggggaaga agggggaccc 480 tggtgtttca caagcaatcc agaggtacgc tacgaagtct gtgacattcc tcagtgttca 540 gaagtttaa 549 57 549 DNA homo sapiens 57 tatgcagagg gacaaaggaa aagaagaaat acaattcatg aattcaaaaa atcagcaaag 60 actaccctaa tcaaaataga tccagcactg aagataaaaa ccaaaaaagt gaatactgca 120 gaccaatgtg ctaatagatg tactaggaat aaaggacttc cattcacttg caaggctttt 180 gtttttgata aagcaagaaa acaatgcctc tggttcccct tcaatagcat gtcaagtgga 240 gtgaaaaaag aatttggcca tgaatttgac ctctatgaaa acaaagacgc cattagaaac 300 tgcatcattg gtaaaggagg cagctacaag ggaacagtat ctatcactaa gagtggcatc 360 aaatgtcagc cctggagttc catgatacca cacgaacaca gctttttgcc ttcgagctat 420 cggggtaaag acctacagga aaactactgt cgaaatcctc gaggggaaga agggggaccc 480 tggtgtttca caagcaatcc agaggtacgc tacgaagtct gtgacattcc tcagtgttca 540 gaagtttaa 549 58 182 PRT Artificial Sequence Human mutated peptide 58 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Ala Ile Arg Asn Cys Ile Ile Gly Lys Gly Gly Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 59 182 PRT Artificial Sequence Human mutated peptide 59 Tyr Ala Glu Gly Gln Arg Lys Arg Arg Asn Thr Ile His Glu Phe Lys 1 5 10 15 Lys Ser Ala Lys Thr Thr Leu Ile Lys Ile Asp Pro Ala Leu Lys Ile 20 25 30 Lys Thr Lys Lys Val Asn Thr Ala Asp Gln Cys Ala Asn Arg Cys Thr 35 40 45 Arg Asn Lys Gly Leu Pro Phe Thr Cys Lys Ala Phe Val Phe Asp Lys 50 55 60 Ala Arg Lys Gln Cys Leu Trp Phe Pro Phe Asn Ser Met Ser Ser Gly 65 70 75 80 Val Lys Lys Glu Phe Gly His Glu Phe Asp Leu Tyr Glu Asn Lys Asp 85 90 95 Xaa Ile Arg Asn Cys Ile Ile Gly Lys Gly Xaa Ser Tyr Lys Gly Thr 100 105 110 Val Ser Ile Thr Lys Ser Gly Ile Lys Cys Gln Pro Trp Ser Ser Met 115 120 125 Ile Pro His Glu His Ser Phe Leu Pro Ser Ser Tyr Arg Gly Lys Asp 130 135 140 Leu Gln Glu Asn Tyr Cys Arg Asn Pro Arg Gly Glu Glu Gly Gly Pro 145 150 155 160 Trp Cys Phe Thr Ser Asn Pro Glu Val Arg Tyr Glu Val Cys Asp Ile 165 170 175 Pro Gln Cys Ser Glu Val 180 US 20090215687 A1 20090827 US 12083891 20061020 12 20060101 A
A
61 K 38 00 F I 20090827 US B H
20060101 A
A
61 K 31 352 L I 20090827 US B H
20060101 A
A
61 K 31 343 L I 20090827 US B H
20060101 A
A
61 K 31 24 L I 20090827 US B H
20060101 A
A
61 P 25 00 L I 20090827 US B H
US 514 12 514455 514468 514510 Compounds for Enhancing Hypoxia Inducible Factor Activity and Methods of Use US 60729059 00 20051021 Ratan Rajiv R.
Scarsdale NY US
omitted US
Siddiq Ambreena
White Plains NY US
omitted US
Chavez Juan C.
Limerick PA US
omitted US
Irving N Feit;HOFFMANN & BARON
6900 Jericoh Turnpike Syosset NY 11791 US
CORNELL RESEARCH FOUNDATION, INC. 02
Ithaca NY US
WO PCT/US2006/041179 00 20061020 20090427

The present invention relates to methods for enhancing Hypoxia inducible factor-1 (HIF) activity in a cell by contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide.

The invention described in this application was made with funds from the National Institutes of Health, Grant Numbers NS 39170, NS 40591, and NS 46239. The United States Government has certain rights in this invention.

The invention was also made with funds from New York State, contract number CO19772. New York State has certain rights in this invention.

BACKGROUND OF THE INVENTION

Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcriptional activator that regulates the expression of genes involved in adaptation to hypoxic stress. HIF-1 is composed of two subunits referred to as HIF-1α and HIF-1β. These subunits are expressly constitutively. During normal conditions, HIF-1α is targeted to ubiquitination and proteosomal degradation following hydroxylation of HIF-1 at proline 402 and 564 by the enzyme, prolyl hydroxylase.

Prolyl hydroxylases are reported to be oxygen-dependent. For example, under conditions of reduced oxygen, these enzymes function with low efficiency. As a result, HIF-1α is not hydroxylated, and thus not targeted to ubiquitination and degradation. Accordingly, HIF-1α becomes stabilized, and can bind HIF-1β to activate genes involved in adaptation to oxidative stress.

Oxidative stress is reported to be associated with numerous diseases and conditions, including stroke, hypoxia, ischemia, spinal cord injury and neurodegenerative conditions. Thus, compounds which enhance the activity of HIF-1α protein are beneficial for treating conditions and diseases associated with oxidative stress.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method for enhancing HIF activity in a cell in need thereof. The method comprises contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide.

In another embodiment, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In yet another embodiment, the invention provides a method for treating hypoxia in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

In a further embodiment, the invention provides a method for treating stroke in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine.

In yet a further embodiment, the invention provides a method for treating spinal cord injury in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine.

In another embodiment, the invention provides a method for treating ischemia in a mammal in need thereof. The method comprises administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. Chemical structures of compounds.

FIG. 2. Amino acid sequence of HIFα protein, NCBI GenBank Accession No. Q16665.

FIG. 3. Tilorone analogues increase HIF-1 transcriptional activity.

FIG. 4. Tilorone analogues induce the expression of HIF-1 target genes in the rat cerebral cortex.

FIG. 5. A cell permeant, peptide inhibitor of the HIF prolyl 4-hydroxylase, but not a mutant control, induces expression of HIF-dependent genes. Tat-HIF/wt peptide (100 μM) but not a corresponding peptide with the C-terminal proline hydroxylation site of HIF-1α mutated (Tat-HIF/mut, 100 μM) significantly enhances the activity of a hypoxia response element driven reporter in cortical neurons (* corresponds to p<0.05 compared to control by paired T-test). The low molecular weight P4H inhibitor, FG-0041(40 μM) was used as a positive control.

FIG. 6. A cell permeant, peptide inhibitor of the HIF 4-hydroxylase, but not a mutant control, prevents oxidative glutamate toxicity. The glutamate analog, homocysteate (HCA) (5 mM) was added to cortical neurons (1 DIV) with or without Tat-HIF/wt peptide (30, 40, 50, 100 and 200 μM), Tat-HIF/mut peptide (200 μM), DFO (100 μM) and 3,4 DHB (10 μM). Twenty-four hours later cell viability was determined using the MTT assay. Graph depicts mean +/− SE for three experiments performed in triplicate (* denotes p<0.05 from HCA treated cultures by ANOVA and Student-Newman Keuls tests for control, Tat-HIF/wt, Tat-HIF/mut, DFO and 3,4 DHB).

DETAILED DESCRIPTION OF THE INVENTION Method for Enhancing HIF Activity

In another aspect, the invention provides a method for enhancing HIF activity in a cell in need thereof. The method comprises contacting the cell with an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIFalpha protein fused to a carrier peptide.

The HIF activity can be enhanced in any cell in need thereof. A cell in need of enhancing HIF activity includes cells that are, for example, suffering from trauma, injury, hypoxia, etc. Such cells include those discussed above.

The cell can be contacted with the compound by any method known to those in the art. For example, the cell can be contacted with the compound by incubating the cell and compound in vitro.

Alternatively, the cell can be contacted with the compound in vivo. The compound and cell can be contacted in vivo by any suitable method known to in the art, including the administration methods described below.

Method for Treating Neurodegenerative Disease or Condition

In one aspect, the invention provides a method for treating a neurodegenerative disease or condition in a mammal in need thereof. The method for treating a neurodegenerative disease or condition comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Neurodegenerative disease or condition typically refers to a disorder generally characterized by gradual and progressive loss of cells, tissue and/or organ of the central or peripheral nervous system. Examples of such cells, tissues and organs include, the brain, spinal cord, neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia.

Any mammal suffering from any neurodegenerative disease or condition can be treated in accordance with the method of the present invention. For example, the neurodegenerative disease or condition can be an acute condition. Acute conditions generally occur as a result of trauma to a cell, tissue and/or organ of the nervous system. The trauma can, for example, partially or completely block blood flow to the cell, tissue and/or organ. Examples of acute neurodegenerative conditions include head injury and brain injury.

Alternatively, the neurodegenerative disease or condition can be a chronic neurodegenerative condition. Examples of chronic neurodegenerative diseases and conditions include Parkinson's disease, Alzheimer's disease, Huntington's disease and Amyotrophic Lateral Sclerosis (also known as Lou Gherig's disease).

Method for Treating Hypoxia

In another aspect, the invention provides a method for treating hypoxia in a mammal in need thereof. The method for treating hypoxia comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Any mammal suffering from hypoxia can be treated in accordance with the method of the present invention. Hypoxia generally refers to a lack of oxygen to cells, organs, and/or tissues. Hypoxia can be caused by, for example, ischemia, anemia and chemical modification of blood, such as carboxyhemoglobin, etc.

Hypoxia can occur in any cell, organ, and/or tissue. Examples of cells, organs, and/or tissues which can be subjected to hypoxia include neuronal cells (e.g., neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia), brain, spinal cord, kidney cells, intestinal cells, heart and cardiac muscle cells such as myocytes, skin cells, etc.

Method for Treating Stroke

In yet another aspect, the invention provides a method for treating stroke in a mammal in need thereof. The method for treating stroke comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine.

Any mammal suffering from stroke can be treated in accordance with the method of the present invention. Stroke is a type of cardiovascular disease that generally involves the interruption of blood flow to and/or within the brain. The interruption of blood flow can be due to, for example, a blockage or rupture of an artery or vessel. The blockage typically occurs from a blood clot. As a result of the interruption of blood flow, the brain does not receive sufficient amounts of blood.

Method for Treating Spinal Cord Injury

In a further aspect, the invention provides a method for treating spinal cord injury in a mammal in need thereof. The method for treating spinal cord injury comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine.

Any mammal suffering from spinal cord injury can be treated in accordance with the method of the present invention. The spinal cord is the major bundle of nerves that carry nerve impulses to and from the brain to the rest of the body. The spinal cord is surrounded by rings of bone referred to as vertebra.

Spinal cord injury refers to any damage to the spinal cord. The damage typically results in loss of function, such as mobility or feeling. Damage to the spinal cord can occur, for example, as a result or trauma (car accident, gunshot, falls, etc.) or disease (polio, spina bifida, Friedreich's Ataxia, etc).

Any injury to the spinal cord can be treated in accordance with the method of the present invention. For example, the injury can be a complete injury to the spinal cord. Complete injury typically refers to the lack of function (e.g., no sensation and no voluntary movement) below the site of injury. Both sides of the body are usually affected.

Alternatively, the injury may be an incomplete injury to the spinal cord. An incomplete injury generally refers to some function below the site of injury. For instance, a person with an incomplete injury may be able to move one limb more than another, may be able to feel parts of the body that cannot be moved, or may have more functioning on one side of the body than the other, etc.

Method for Treating Ischemia

In yet a further aspect, the invention provides a method for treating ischemia in a mammal in need thereof. The method comprises administering to the mammal an effective amount of any one, or any combination, of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.

Any mammal suffering from ischemia can be treated in accordance with the method of the present invention. Ischemia generally refers to a condition of decreased blood flow to an organ, tissue and/or cell. The decrease in blood flow can be caused by, for example, constriction (e.g., hypoxemic vasoconstriction) or obstruction (e.g., clot, atherosclerotic plaque) of a blood vessel.

Ischemia can occur in any cell, organ, and/or tissue. Examples of cells, organs, and/or tissues which can be subjected to ischemia include neuronal cells (e.g., neurons, ganglia, Schwann cells, astrocytes, oligodendrocytes and microglia), brain, spinal cord, intestinal cells, kidney cells, heart and cardiac muscle cells such as myocytes, etc.

Compounds

Compounds useful in the methods of the present invention are 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine, the chemical structures of which are shown in FIG. 1.

The brand name, generic name, chemical name, alternative spelling, etc. of some of the compounds are listed in FIG. 1. For example, the compound “phenazopyridine hydrochloride” may also be referred to as “phenazopyrinine hydrochloride.”

The compounds can be in the form of a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt” refers to a well-tolerated, nontoxic salt prepared from any one of the compounds mentioned above, and an acid or base. The acids may be inorganic or organic acids of any one of the compounds mentioned above. Examples of inorganic acids include hydrochloric, hydrobromic, nitric hydroiodic, sulfuric, and phosphoric acids. Examples of organic acids include carboxylic and sulfonic acids. The radical of the organic acids may be aliphatic or aromatic. Some examples of organic acids include formic, acetic, phenylacetic, propionic, succinic, glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic, stearic, sulfanilic, alginic, tartaric, citric, gluconic, gulonic, arylsulfonic, and galacturonic acids. Appropriate organic bases may be selected, for example, from N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine.

Throughout this specification, parameters are defined by maximum and minimum amounts. Each minimum amount can be combined with each maximum amount to define a range.

In one aspect of the invention, the compound is HIF alpha (HIFα) protein fused to a carrier peptide. The HIFα protein portion of the fusion protein can include all of the amino acid sequence of HIFα. The amino acid sequence of HIFα is shown in FIG. 2.

Alternatively, the HIFα protein portion of the fusion protein is a fragment of the amino acid sequence of HIFα containing either one or both prolines at amino acid position numbers 402 and 564 of full length HIFα. Thus, the fragment can be any fragment containing the proline at position 402 and/or position 564 of full length HIFα.

The fragment of HIFα comprises a minimum of four amino acid, preferably about six amino acids, more preferably about eight, even more preferably about twelve, yet even more preferably about fifteen, and most preferably a minimum of about nineteen amino acids. The maximum number of amino acids in the fragment is 825, preferably about 750, more preferably about 600, even more preferably about 500, yet even more preferably about 400, further more preferably about 200, and most preferably a maximum of about 100.

For example, the fragment can comprise the fifteen to nineteen, 31 to 79, or 121 to 200, etc. amino acid sequence corresponding to the residues adjacent to, and/or surrounding, proline residue 402 and/or 564, of HIFα.

In a preferred embodiment, the fragment comprises proline residues 402 and 562 and all residues between the proline residues.

The HIFα portion of the fusion protein can comprise functional analogs of, the entire HIFα amino acid sequence, or fragments described above. The functional analogs must satisfy function and contain either one or both prolines at amino acid position numbers 402 and 564 of full length HIFα. The functional analog may, for example, be a substitution variant of full length HIFα, or a substitution variant of a fragment described above.

Suitable substitution variants of full length HIFα or fragment include conservative amino acid substitutions. Amino acids may be grouped according to their physicochemical characteristics as follows:

(a) Non-polar amino acids: Ala(A) Ser(S) Thr(T) Pro(P) Gly(G);

(b) Acidic amino acids: Asn(N) Asp(D) Glu(E) Gln(Q);

(c) Basic amino acids: His(H) Arg(R) Lys(K);

(d) Hydrophobic amino acids: Met(M) Leu(L) Ile(I) Val(V); and

(e) 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 is referred to as a conservative substitution. Conservative substitutions tend to preserve the physicochemical characteristics of the original peptide. In contrast, substitutions of an amino acid in a peptide by another amino acid in a different group is generally more likely to alter the characteristics of the original peptide.

A carrier peptide, in general, refers to any synthetic or naturally occurring amino acid sequence that can transduce or assist in the transduction of a protein or peptide into a cell. Carrier peptides are also referred to a protein transduction domains.

The carrier peptide portion of the fusion protein can be any protein transduction domain or carrier peptide known to those skilled in the art. Examples of protein transduction domains include HIV tat, herpes simplex virus VP22 transcription factor, and Drosophila homeotic transcription factor encoded by antennapedia gene. Such transduction domains are disclosed in Schwarze et al., 2000, Trends in Pharmacol. Sci., 21:45-48.

Other examples of suitable carrier peptides include the protein transduction domains disclosed in U.S. Pat. Nos. 6,221,355 to Dowdy; 5,652,122 to Frankel et al. The protein transduction domains of U.S. Pat. Nos. 6,221,355 and 5,652,122 are hereby incorporated by reference.

Further examples of carrier peptides include aromatic-cationic peptides comprising (i) at least one net positive charge, (ii) a minimum of three amino acids, (iii) a maximum of about twenty amino acids, (iv) a relationship between the minimum number of net positive charges (pm) and the total number of amino acid residues (r) wherein 3pm is the largest number that is less than or equal to r+1, and (v) a relationship between the minimum number of aromatic groups (a) and the total number of net positive charges (pt) wherein 3a is the largest number that is less than or equal to pt+1, except that when a is 1, pt may also be 1.

The definition and description of aromatic-cationic peptides, and tables listing examples of aromatic-cationic peptides are disclosed in U.S. application Ser. No. 10/838,135 filed on May 3, 2004 of Szeto, et al. and assigned to Cornell Research Foundation, Inc.: The definition, description, tables and examples of aromatic-cationic peptides disclosed in U.S. application Ser. No. 10/838,135 are hereby incorporated by reference.

For example, the carrier peptide can be any one of the aromatic-cationic peptides shown below in Tables 1 and 2.

TABLE 1 Amino Acid Amino Acid Amino Acid Amino Acid Amino Acid Position 5 (if C-Terminal Position 1 Position 2 Position 3 Position 4 present) Modification Tyr D-Arg Phe Lys NH2 Tyr D-Arg Phe Orn NH2 Tyr D-Arg Phe Dab NH2 Tyr D-Arg Phe Dap NH2 2′6′Dmt D-Arg Phe Lys NH2 2′6′Dmt D-Arg Phe Lys Cys NH2 2′6′Dmt D-Arg Phe Lys—NH(CH2)2—NH-dns NH2 2′6′Dmt D-Arg Phe Lys—NH(CH2)2—NH-atn NH2 2′6′Dmt D-Arg Phe dnsLys NH2 2′6′Dmt D-Cit Phe Lys NH2 2′6′Dmt D-Cit Phe Ahp NH2 2′6′Dmt D-Arg Phe Orn NH2 2′6′Dmt D-Arg Phe Dab NH2 2′6′Dmt D-Arg Phe Dap NH2 2′6′Dmt D-Arg Phe Ahp(2-aminoheptanoic acid) NH2 Bio-2′6′Dmt D-Arg Phe Lys NH2 3′5′Dmt D-Arg Phe Lys NH2 3′5′Dmt D-Arg Phe Orn NH2 3′5′Dmt D-Arg Phe Dab NH2 3′5′Dmt D-Arg Phe Dap NH2 Tyr D-Arg Tyr Lys NH2 Tyr D-Arg Tyr Orn NH2 Tyr D-Arg Tyr Dab NH2 Tyr D-Arg Tyr Dap NH2 2′6′Dmt D-Arg Tyr Lys NH2 2′6′Dmt D-Arg Tyr Orn NH2 2′6′Dmt D-Arg Tyr Dab NH2 2′6′Dmt D-Arg Tyr Dap NH2 2′6′Dmt D-Arg 2′6′Dmt Lys NH2 2′6′Dmt D-Arg 2′6′Dmt Orn NH2 2′6′Dmt D-Arg 2′6′Dmt Dab NH2 2′6′Dmt D-Arg 2′6′Dmt Dap NH2 3′5′Dmt D-Arg 3′5′Dmt Arg NH2 3′5′Dmt D-Arg 3′5′Dmt Lys NH2 3′5′Dmt D-Arg 3′5′Dmt Orn NH2 3′5′Dmt D-Arg 3′5′Dmt Dab NH2 Tyr D-Lys Phe Dap NH2 Tyr D-Lys Phe Arg NH2 Tyr D-Lys Phe Lys NH2 Tyr D-Lys Phe Orn NH2 2′6′Dmt D-Lys Phe Dab NH2 2′6′Dmt D-Lys Phe Dap NH2 2′6′Dmt D-Lys Phe Arg NH2 2′6′Dmt D-Lys Phe Lys NH2 3′5′Dmt D-Lys Phe Orn NH2 3′5′Dmt D-Lys Phe Dab NH2 3′5′Dmt D-Lys Phe Dap NH2 3′5′Dmt D-Lys Phe Arg NH2 Tyr D-Lys Tyr Lys NH2 Tyr D-Lys Tyr Orn NH2 Tyr D-Lys Tyr Dab NH2 Tyr D-Lys Tyr Dap NH2 2′6′Dmt D-Lys Tyr Lys NH2 2′6′Dmt D-Lys Tyr Orn NH2 2′6′Dmt D-Lys Tyr Dab NH2 2′6′Dmt D-Lys Tyr Dap NH2 2′6′Dmt D-Lys 2′6′Dmt Lys NH2 2′6′Dmt D-Lys 2′6′Dmt Orn NH2 2′6′Dmt D-Lys 2′6′Dmt Dab NH2 2′6′Dmt D-Lys 2′6′Dmt Dap NH2 2′6′Dmt D-Arg Phe dnsDap NH2 2′6′Dmt D-Arg Phe atnDap NH2 3′5′Dmt D-Lys 3′5′Dmt Lys NH2 3′5′Dmt D-Lys 3′5′Dmt Orn NH2 3′5′Dmt D-Lys 3′5′Dmt Dab NH2 3′5′Dmt D-Lys 3′5′Dmt Dap NH2 Tyr D-Lys Phe Arg NH2 Tyr D-Orn Phe Arg NH2 Tyr D-Dab Phe Arg NH2 Tyr D-Dap Phe Arg NH2 2′6′Dmt D-Arg Phe Arg NH2 2′6′Dmt D-Lys Phe Arg NH2 2′6′Dmt D-Orn Phe Arg NH2 2′6′Dmt D-Dab Phe Arg NH2 3′5′Dmt D-Dap Phe Arg NH2 3′5′Dmt D-Arg Phe Arg NH2 3′5′Dmt D-Lys Phe Arg NH2 3′5′Dmt D-Orn Phe Arg NH2 Tyr D-Lys Tyr Arg NH2 Tyr D-Orn Tyr Arg NH2 Tyr D-Dab Tyr Arg NH2 Tyr D-Dap Tyr Arg NH2 2′6′Dmt D-Arg 2′6′Dmt Arg NH2 2′6′Dmt D-Lys 2′6′Dmt Arg NH2 2′6′Dmt D-Orn 2′6′Dmt Arg NH2 2′6′Dmt D-Dab 2′6′Dmt Arg NH2 3′5′Dmt D-Dap 3′5′Dmt Arg NH2 3′5′Dmt D-Arg 3′5′Dmt Arg NH2 3′5′Dmt D-Lys 3′5′Dmt Arg NH2 3′5′Dmt D-Orn 3′5′Dmt Arg NH2 Mmt D-Arg Phe Lys NH2 Mmt D-Arg Phe Orn NH2 Mmt D-Arg Phe Dab NH2 Mmt D-Arg Phe Dap NH2 Tmt D-Arg Phe Lys NH2 Tmt D-Arg Phe Orn NH2 Tmt D-Arg Phe Dab NH2 Tmt D-Arg Phe Dap NH2 Hmt D-Arg Phe Lys NH2 Hmt D-Arg Phe Orn NH2 Hmt D-Arg Phe Dab NH2 Hmt D-Arg Phe Dap NH2 Mmt D-Lys Phe Lys NH2 Mmt D-Lys Phe Orn NH2 Mmt D-Lys Phe Dab NH2 Mmt D-Lys Phe Dap NH2 Mmt D-Lys Phe Arg NH2 Tmt D-Lys Phe Lys NH2 Tmt D-Lys Phe Orn NH2 Tmt D-Lys Phe Dab NH2 Tmt D-Lys Phe Dap NH2 Tmt D-Lys Phe Arg NH2 Hmt D-Lys Phe Lys NH2 Hmt D-Lys Phe Orn NH2 Hmt D-Lys Phe Dab NH2 Hmt D-Lys Phe Dap NH2 Hmt D-Lys Phe Arg NH2 Mmt D-Lys Phe Arg NH2 Mmt D-Orn Phe Arg NH2 Mmt D-Dab Phe Arg NH2 Mmt D-Dap Phe Arg NH2 Mmt D-Arg Phe Arg NH2 Tmt D-Lys Phe Arg NH2 Tmt D-Orn Phe Arg NH2 Tmt D-Dab Phe Arg NH2 Tmt D-Dap Phe Arg NH2 Tmt D-Arg Phe Arg NH2 Hmt D-Lys Phe Arg NH2 Hmt D-Orn Phe Arg NH2 Hmt D-Dab Phe Arg NH2 Hmt D-Dap Phe Arg NH2 Hmt D-Arg Phe Arg NH2 Dab = diaminobutyric Dap = diaminopropionic acid Dmt = dimethyltyrosine Mmt = 2′-methyltyrosine Tmt = N,2′,6′-trimethyltyrosine Hmt = 2′-hydroxy,6′-methyltyrosine dnsDap = β-dansyl-L-α,β-diaminopropionic acid atnDap = β-anthraniloyl-L-α,β-diaminopropionic acid Bio = biotin

TABLE 2 Amino Acid Amino Acid Amino Acid Amino Acid C-Terminal Position 1 Position 2 Position 3 Position 4 Modification D-Arg Dmt Lys Phe NH2 D-Arg Dmt Phe Lys NH2 D-Arg Phe Lys Dmt NH2 D-Arg Phe Dmt Lys NH2 D-Arg Lys Dmt Phe NH2 D-Arg Lys Phe Dmt NH2 Phe Lys Dmt D-Arg NH2 Phe Lys D-Arg Dmt NH2 Phe D-Arg Dmt Lys NH2 Phe D-Arg Lys Dmt NH2 Phe D-Arg Phe Lys NH2 Phe Dmt D-Arg Lys NH2 Phe Dmt Lys D-Arg NH2 Lys Phe D-Arg Dmt NH2 Lys Phe Dmt D-Arg NH2 Lys Dmt D-Arg Phe NH2 Lys Dmt Phe D-Arg NH2 Lys D-Arg Phe Dmt NH2 Lys D-Arg Dmt Phe NH2 D-Arg Dmt D-Arg Phe NH2 D-Arg Dmt D-Arg Dmt NH2 D-Arg Dmt D-Arg Tyr NH2 D-Arg Dmt D-Arg Trp NH2 Trp D-Arg Phe Lys NH2 Trp D-Arg Tyr Lys NH2 Trp D-Arg Trp Lys NH2 Trp D-Arg Dmt Lys NH2 D-Arg Trp Lys Phe NH2 D-Arg Trp Phe Lys NH2 D-Arg Trp Lys Dmt NH2 D-Arg Trp Dmt Lys NH2 D-Arg Lys Trp Phe NH2 D-Arg Lys Trp Dmt NH2 Cha D-Arg Phe Lys NH2 Ala D-Arg Phe Lys NH2 Cha = cyclohexy

Administration

The compounds are administered to a mammal. Any mammal can be treated in accordance with the methods of the present invention. Suitable mammals include, for example farm animals, such as sheep, pigs, cows, and horses; pet animals, such as dogs and cats; laboratory animals, such as rats, mice and rabbits; and primates, such a monkeys and humans. In a preferred embodiment, the mammal is a human.

The compound is administered to the mammal in an amount effective in achieving its purpose. The effective amount of the compound to be administered can be readily determined by those skilled in the art during pre-clinical trials and clinical trials by methods familiar to physicians and clinicians.

In one aspect, the compound is considered to be effective in enhancing HIF activity if the activity of HIF is enhanced by at least about 10%, preferably at least about 25%, more preferably at least about 50%, even more preferably at least about 75%, and most preferably at least about 90%.

The compound can be administered by any method known to those skilled in the art. Some examples of suitable modes of administration include oral and systemic administration. Systemic administration can be enteral or parenteral. Liquid or solid (e.g., tablets, gelatin capsules) formulations can be employed for systemic administration. Parenteral administration of the compound include, for example intravenous, intramuscular, and subcutaneous injections. For instance, a compound may be administered to a mammal by sustained release, as is known in the art. Sustained release administration is a method of drug delivery to achieve a certain level of the drug over a particular period of time.

Other routes of administration include oral, intrabronchial, or intranasal administration. For oral administration, liquid or solid formulations may be used. Some examples of formulations suitable for oral administration include tablets, gelatin capsules, pills, troches, elixirs, suspensions, syrups, and wafers. Intrabronchial administration can include an inhaler spray. For intranasal administration, administration of a compound can be accomplished by a nebulizer or liquid mist.

The compound is preferably in a suitable pharmaceutical composition comprising a pharmaceutical carrier. In this specification, a pharmaceutical carrier is considered to be synonymous with a vehicle or an excipient as is understood by practitioners in the art. Examples of carriers include starch, milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, magnesium or calcium stearate, talc, vegetable fats or oils, gums and glycols.

The pharmaceutical composition may also comprises one or more of the following: a stabilizer, a surfactant, preferably a nonionic surfactant, and optionally a salt and/or a buffering agent.

The stabilizer may, for example, be an amino acid, such as for instance, glycine; or an oligosaccharide, such as for example, sucrose, tetralose, lactose or a dextran. Alternatively, the stabilizer may be a sugar alcohol, such as for instance, mannitol; or a combination thereof. Preferably the stabilizer or combination of stabilizers constitutes from about 0.1% to about 10% weight for weight of the compound.

The surfactant is preferably a nonionic surfactant, such as a polysorbate. Some examples of suitable surfactants include Tween 20, Tween 80; a polyethylene glycol or a polyoxyethylene polyoxypropylene glycol, such as Pluronic F-68 at from about 0.001% (w/v) to about 10% (w/v).

The salt or buffering agent may be any salt or buffering agent, such as for example sodium chloride, or sodium/potassium phosphate, respectively. Preferably, the buffering agent maintains the pH of the pharmaceutical composition in the range of about 5.5 to about 7.5. The salt and/or buffering agent is also useful to maintain the osmolality at a level suitable for administration to a mammal. Preferably the salt or buffering agent is present at a roughly isotonic concentration of about 150 mM to about 300 mM.

The pharmaceutical composition may additionally contain one or more conventional additives. Some examples of such additives include a solubilizer such as, for example, glycerol; an antioxidant such as for example, benzalkonium chloride (a mixture of quaternary ammonium compounds, known as “quart”), benzyl alcohol, chloretone or chlorobutanol; anaesthetic agent such as for example a morphine derivative; or an isotonic agent etc., such as those described above. As a further precaution against oxidation or other spoilage, the compound may be stored under nitrogen gas in vials sealed with impermeable stoppers.

EXAMPLES Example 1 Tilorone Analogues R-10,874-DA, R-11,567-DA, and R-9536-DA Enhances Hypoxia Inducible Factor-1 in the Nervous System

HT22 murine hippocampal cells were stably transfected with an enolase 1 promoter-luciferase reporter construct and selected with puromycin. Tilorone analogues R-10,874-DA, R-11,567-DA, and R-9536-DA were tested for their ability to activate a HIF-luciferase reporter. Luciferase activity was measured using a Luciferase Assay System (PROMEGA) according to the manufacture's protocol.

HIF-1α protein levels were determined in nuclear extracts using a monoclonal anti-HIF-1a antibody (NOVUS Biologicals). Real time RT-PCR was performed in a ABI-7500 instruments using commercial Taqman gene expression assays (Applied BioSystems).

Male Sprague Dawley rats, weighing 275-350 gm, were used in these experiments. For surgical procedures, anesthesia was induced with 5% isofluorane delivered in oxygen and maintained at 1.5% throughout surgery. Core body temperature was maintained at 37° C. by a homeothermic heating blanket.

Animals were subjected to MCAo by the intraluminal filament method. The right external carotid artery was ligated, cauterized, and cut, and its branches were coagulated. A 35 mm length of 4-0 nylon monofilament (Ethicon) with a rounded tip was then inserted into the internal carotid artery via the proximal end of the external carotid artery stump. The filament was advanced 20 mm beyond the carotid artery bifurcation with slight resistance was encountered. The tilorone analogues R-10,874-DA, R-11,567-DA, and R-9536-DA were injected 100 mg/kg i.p. 24 h pre-MCAo. Equivalent volume of saline was injected i.p. to control rats. Animals were sacrificed 24 h post-MCAo.

FIG. 3 shows that tilorone analogues R-10,874-DA, R-11,567-DA, and R-9536-DA increase HIF-1 transcriptional activity. Tilorone analogues R-10,874-DA, R-11,567-DA, and R-9536-DA induce the expression of HIF-1 target genes (FIG. 4) in the rat cerebral cortex.

Example 2 HIF1α/Carrier Peptide Fusion Protein Enhances HIF Activity

The peptide designated HIF/ODD/wt contains part of the oxygen dependent domain, including the C-terminal hydroxylation site of human HIF-1α at proline 564 (DDLDEMLAPYIPMDDDFQL; bold P=praline 564). The HIF/ODD/wt peptide and the peptide control with mutation of both prolines to alanine (HIF/ODD/mut; DDLEMLAAYIAMDDDFQL) were rendered cell permeant by fusing each of these peptides to the cell-membrane transduction domain of the human immunodeficiency virus-type 1 tat protein (YGRKKKRRQRR) to obtain two 30 amino acid peptides Tat-HIF/ODD/wt and Tat-HIF/ODD/mut.

To evaluate the ability of Tat-HIF/ODD peptide to be delivered to cortical neurons efficiently and without toxicity, the chromophore fluorescein isothiocyanate was conjugated to the tat-HIF/ODD/Wt peptide. Tat-HIF/ODD/Wt/FITC peptides (10 μM) were bath applied to rat cortical neuronal cultures from E17 rat embryos. These cultures are approximately 90% neurons after one day in vitro. The balance of the cells in the culture is glial in origin.

Twenty-four hours after addition of the peptide to the bathing medium, the level of intracellular accumulation of the peptide was monitored by fluorescence microscopy. In every field examined (>10), each cell nucleus, identified by DNA intercalating chromophore DAPI, was found to be associated with fluorescein label in its cell bodies and processes reflecting the uptake of the Tat-HIF/ODD/wt FITC peptide. Similar high efficiency transduction was observed when cortical neuronal cultures were incubated with the Tat-HIF/ODD/mut FITC peptide. In parallel, viability measurements verified that the Tat-HIF/ODD peptides do not negatively alter basal viability in our cortical neuronal cultures.

To determine whether the Tat-HIF/ODD/wt peptide stabilizes HIF-1 leading to activation of HIF-1 dependent gene expression, the levels of a luciferase reporter gene that is regulated by a hypoxia response element found in the enolase gene promoter was monitored. The addition of Tat-HIF/ODD/wt peptide significantly enhanced levels of a hypoxia response element regulated reporter gene in a concentration dependent manner.

The level of induction of the HIF-dependent reporter gene by 100 μM Tat-HIF/ODD/wt peptide was similar to that stimulated by 40 μM FG-0041, a low molecular weight inhibitor of the prolyl hydroxylase (FIG. 5). By contrast, 100 μM Tat-HIF/ODD/mut peptide with proline 564 and its adjacent praline mutated to alanine did not induce the HIF-dependent reporter gene.

To verify that the changes in the HIF-dependent reporter gene reflect changes in endogenous HIF-dependent genes, enolase, p21 waf/cip1, and VEGF were monitored by RT-PCR. β-actin was measured as a control. As expected, the Tat-HIF/ODD/wt peptide increased levels of enolase, p21 waf1/Cip1 and VEGF message but did not alter levels of β-actin. The Tat-HIF/ODD/mut did not affect levels of p21 waf1/cip or β-actin and actually diminished the basal levels of enolase and VEGF, two known HIF-dependent genes. Taken together, these results establish that the Tat-HIF/ODD wt peptide can be delivered to neurons and can enhance the transcriptional activity of well characterized HIF target genes. By contrast, a Tat/HIF/ODD mut in which the conserved proline hydroxylation site (proline 564) and an adjacent proline have been mutated to alanine does not upregulate a HIF-dependent reporter gene or endogenous HIF regulated genes (e.g., enolase, p21 waf1/cip1/or VEGF).

To test whether Tat-HIF/ODD/wt can prevent oxidative neuronal death in cortical neurons induced the glutamate analog, HCA, the peptides were applied 24 hours prior to the addition of HCA. Addition of tat-HIF/ODD/wt peptide but not its mutant control (tat-HIF/ODD/mut) protected cortical neurons from oxidative glutamate toxicity in a concentration dependent manner as assessed by MTT assay (FIG. 6). The morphology of the neurons that were protected from oxidative glutamate toxicity by Tat-HIF/ODD/wt was indistinguishable from the morphology of control neurons as assessed by phase contrast microscopy or calcein/ethidium homodimer staining (not shown). These results suggest that inhibition of HIF Prolyl 4 Hydroxylases prevents oxidative neuronal death in cortical neurons in vitro dioxygenase.

What is claimed is: 1. A method for enhancing HIF activity in a cell in need thereof, the method comprising contacting the cell with any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, tryptophan, ansindione, nabumetone, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, daidzein, tripelennamine citrate, colchicines, aminopyridine, trimethoprim, helenine, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofivric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, hydralazine and HIF alpha protein fused to a carrier peptide. 2. A method according to claim 1, wherein the carrier peptide is tat. 3. A method according to claim 1, wherein the carrier peptide is an aromatic-cationic peptide. 4. A method for treating a neurodegenerative disease or condition in a mammal in need thereof, the method comprising administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, ansindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine. 5. A method for treating hypoxia in a mammal in need thereof, the method comprising administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, albendazole, tropicamide, pramoxine hydrochloride, atenolol, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine, hydrochloride, daidzein, tripelennamine citrate, colchicine, aminopyridine, trimethoprim, hydroxyurea, amiodarone hydrochloride, clindamycin hydrochloride, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine. 6. A method for treating stroke in a mammal in need thereof, the method comprising administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamime, anisindione, oxybendazole, tropicamide, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine, colchicines, aminopyridine, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxalen, and hydralazine. 7. A method for treating spinal cord injury in a mammal in need thereof, the method comprising administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9 onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, indoprofen, ciclopiroxolamine, anisindione, nabumetone, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, zomepirac, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicines, trimethoprim, helenine, sulfachlorpyridazine, mephenesin, semustine, clofibric acid, clofibrate, deferoxamine mesylate, ibuprofen, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen, and hydralazine. 8. A method for treating ischemia in a mammal in need thereof, the method comprising administering to the mammal any one of the following compounds: 3,6-bis[2-(dimethylamino)ethoxy]-9h-xanthen-9-onedihydrochloride, 2,8-bis[dimethylaminoacetyl]dibenzofurin dihydrochloride hydrate, tilorone analogue R-9536-DA, ciclopiroxolamine, tryptophan, anisindione, oxybendazole, tropicamide, pramoxine hydrochloride, mebendazole, carbetapentane citrate, monensin sodium, methoxyvone, hydroxyzine, phenazopyridine, clofoctol, ipraflavone, biochanin A, xylometazoline hydrochloride, fenbendazole, pirenzepine, triprolidine hydrochloride, tripelennamine citrate, colchicine, aminopyridine, hydroxyurea, sulfachlorpyridazine, mephenesin, semustine, clofibrate, hyoscyamime, nafcillin sodium, piperin, clidinium bromide, trioxsalen and hydralazine.


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stats Patent Info
Application #
US 20090215687 A1
Publish Date
08/27/2009
Document #
File Date
08/30/2014
USPTO Class
Other USPTO Classes
International Class
/
Drawings
0


Albendazole
Amiodarone
Amiodarone Hydrochloride
Atenolol
Biochanin A
Ciclopirox
Citrate
Clidinium
Clidinium Bromide
Clindamycin
Clindamycin Hydrochloride
Clofibrate
Colchicine
Daidzein
Hydralazine
Hydroxyurea
Hydroxyzine
Hypoxia
Ibuprofen
Lenin
Mebendazole
Monensin
Mustine
Nabumetone
Nafcil
Nafcillin
Nafcillin Sodium
Phenazo
Phenazopyridine
Pirenzepine
Pramoxine
Pramoxine Hydrochloride
Profen
Semustine
Trimethoprim
Trioxsalen
Tripelennamine Citrate
Triprolidine Hydrochloride
Tropicamide
Tryptophan
Xylometazoline


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