CA2326771A1 - Agents and methods for modulation of zinc transfer by metallothionein - Google Patents
Agents and methods for modulation of zinc transfer by metallothionein Download PDFInfo
- Publication number
- CA2326771A1 CA2326771A1 CA002326771A CA2326771A CA2326771A1 CA 2326771 A1 CA2326771 A1 CA 2326771A1 CA 002326771 A CA002326771 A CA 002326771A CA 2326771 A CA2326771 A CA 2326771A CA 2326771 A1 CA2326771 A1 CA 2326771A1
- Authority
- CA
- Canada
- Prior art keywords
- chelates
- glutathione
- zinc
- metallothionein
- disulfide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 97
- 102000003792 Metallothionein Human genes 0.000 title claims abstract description 53
- 108090000157 Metallothionein Proteins 0.000 title claims abstract description 53
- DIGQNXIGRZPYDK-WKSCXVIASA-N (2R)-6-amino-2-[[2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[[(2R,3S)-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S,3S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[2-[[2-[[2-[(2-amino-1-hydroxyethylidene)amino]-3-carboxy-1-hydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxypropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1,5-dihydroxy-5-iminopentylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxybutylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1,3-dihydroxypropylidene]amino]-1-hydroxyethylidene]amino]-1-hydroxy-3-sulfanylpropylidene]amino]-1-hydroxyethylidene]amino]hexanoic acid Chemical compound C[C@@H]([C@@H](C(=N[C@@H](CS)C(=N[C@@H](C)C(=N[C@@H](CO)C(=NCC(=N[C@@H](CCC(=N)O)C(=NC(CS)C(=N[C@H]([C@H](C)O)C(=N[C@H](CS)C(=N[C@H](CO)C(=NCC(=N[C@H](CS)C(=NCC(=N[C@H](CCCCN)C(=O)O)O)O)O)O)O)O)O)O)O)O)O)O)O)N=C([C@H](CS)N=C([C@H](CO)N=C([C@H](CO)N=C([C@H](C)N=C(CN=C([C@H](CO)N=C([C@H](CS)N=C(CN=C(C(CS)N=C(C(CC(=O)O)N=C(CN)O)O)O)O)O)O)O)O)O)O)O)O DIGQNXIGRZPYDK-WKSCXVIASA-N 0.000 title claims abstract description 50
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 229910052725 zinc Inorganic materials 0.000 title claims abstract description 49
- 239000011701 zinc Substances 0.000 title claims abstract description 49
- 238000012546 transfer Methods 0.000 title abstract description 5
- 239000003795 chemical substances by application Substances 0.000 title description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 230000001413 cellular effect Effects 0.000 claims abstract description 5
- 241001465754 Metazoa Species 0.000 claims abstract 3
- 230000007987 cellular zinc ion homeostasis Effects 0.000 claims abstract 2
- 239000003814 drug Substances 0.000 claims abstract 2
- 230000003647 oxidation Effects 0.000 claims abstract 2
- 238000007254 oxidation reaction Methods 0.000 claims abstract 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims description 47
- 230000001575 pathological effect Effects 0.000 claims description 25
- 210000004027 cell Anatomy 0.000 claims description 23
- 239000007800 oxidant agent Substances 0.000 claims description 21
- 108010053070 Glutathione Disulfide Proteins 0.000 claims description 20
- YPZRWBKMTBYPTK-BJDJZHNGSA-N glutathione disulfide Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@H](C(=O)NCC(O)=O)CSSC[C@@H](C(=O)NCC(O)=O)NC(=O)CC[C@H](N)C(O)=O YPZRWBKMTBYPTK-BJDJZHNGSA-N 0.000 claims description 20
- 229940045883 glutathione disulfide Drugs 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical compound [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 claims description 12
- 230000006907 apoptotic process Effects 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 9
- 208000035475 disorder Diseases 0.000 claims description 7
- 208000024827 Alzheimer disease Diseases 0.000 claims description 5
- 208000023275 Autoimmune disease Diseases 0.000 claims description 5
- 208000018737 Parkinson disease Diseases 0.000 claims description 5
- 230000002401 inhibitory effect Effects 0.000 claims description 5
- 241000282414 Homo sapiens Species 0.000 claims description 4
- 206010015037 epilepsy Diseases 0.000 claims description 4
- 239000000427 antigen Substances 0.000 claims description 3
- 102000036639 antigens Human genes 0.000 claims description 3
- 108091007433 antigens Proteins 0.000 claims description 3
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims 32
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims 30
- 108010024636 Glutathione Proteins 0.000 claims 23
- 239000003638 chemical reducing agent Substances 0.000 claims 23
- 229960003180 glutathione Drugs 0.000 claims 23
- ZKZBPNGNEQAJSX-UHFFFAOYSA-N selenocysteine Natural products [SeH]CC(N)C(O)=O ZKZBPNGNEQAJSX-UHFFFAOYSA-N 0.000 claims 20
- JULROCUWKLNBSN-UHFFFAOYSA-N selenocystine Chemical compound OC(=O)C(N)C[Se][Se]CC(N)C(O)=O JULROCUWKLNBSN-UHFFFAOYSA-N 0.000 claims 18
- 229940072107 ascorbate Drugs 0.000 claims 16
- 235000010323 ascorbic acid Nutrition 0.000 claims 16
- 239000011668 ascorbic acid Substances 0.000 claims 16
- UFULAYFCSOUIOV-UHFFFAOYSA-N cysteamine Chemical compound NCCS UFULAYFCSOUIOV-UHFFFAOYSA-N 0.000 claims 16
- 229960003151 mercaptamine Drugs 0.000 claims 16
- RGJOEKWQDUBAIZ-IBOSZNHHSA-N CoASH Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCS)O[C@H]1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-IBOSZNHHSA-N 0.000 claims 15
- DYEFUKCXAQOFHX-UHFFFAOYSA-N Ebselen Chemical compound [se]1C2=CC=CC=C2C(=O)N1C1=CC=CC=C1 DYEFUKCXAQOFHX-UHFFFAOYSA-N 0.000 claims 15
- YPZRHBJKEMOYQH-UYBVJOGSSA-N FADH2 Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1O)O[C@@H]1COP(O)(=O)OP(O)(=O)OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C(NC(=O)NC2=O)=C2NC2=C1C=C(C)C(C)=C2 YPZRHBJKEMOYQH-UYBVJOGSSA-N 0.000 claims 15
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 claims 15
- 229930003427 Vitamin E Natural products 0.000 claims 15
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 claims 15
- 239000005516 coenzyme A Substances 0.000 claims 15
- 229940093530 coenzyme a Drugs 0.000 claims 15
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 claims 15
- 229950010033 ebselen Drugs 0.000 claims 15
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims 15
- 229940046009 vitamin E Drugs 0.000 claims 15
- 235000019165 vitamin E Nutrition 0.000 claims 15
- 239000011709 vitamin E Substances 0.000 claims 15
- 150000001875 compounds Chemical class 0.000 claims 14
- OOTFVKOQINZBBF-UHFFFAOYSA-N cystamine Chemical compound CCSSCCN OOTFVKOQINZBBF-UHFFFAOYSA-N 0.000 claims 14
- 229940099500 cystamine Drugs 0.000 claims 14
- OESHPIGALOBJLM-REOHCLBHSA-N dehydroascorbate Chemical compound OC[C@H](O)[C-]1OC(=O)C(=O)C1=O OESHPIGALOBJLM-REOHCLBHSA-N 0.000 claims 12
- 235000020960 dehydroascorbic acid Nutrition 0.000 claims 12
- 239000011615 dehydroascorbic acid Substances 0.000 claims 12
- FDKWRPBBCBCIGA-REOHCLBHSA-N (2r)-2-azaniumyl-3-$l^{1}-selanylpropanoate Chemical compound [Se]C[C@H](N)C(O)=O FDKWRPBBCBCIGA-REOHCLBHSA-N 0.000 claims 11
- FDKWRPBBCBCIGA-UWTATZPHSA-N D-Selenocysteine Natural products [Se]C[C@@H](N)C(O)=O FDKWRPBBCBCIGA-UWTATZPHSA-N 0.000 claims 11
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 claims 11
- BOPGDPNILDQYTO-NNYOXOHSSA-N nicotinamide-adenine dinucleotide Chemical compound C1=CCC(C(=O)N)=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]2[C@H]([C@@H](O)[C@@H](O2)N2C3=NC=NC(N)=C3N=C2)O)O1 BOPGDPNILDQYTO-NNYOXOHSSA-N 0.000 claims 11
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 claims 11
- 229940055619 selenocysteine Drugs 0.000 claims 11
- 235000016491 selenocysteine Nutrition 0.000 claims 11
- YAISMNQCMHVVLO-ODFVJXNFSA-N CoA-disulfide Chemical compound C1=NC2=C(N)N=CN=C2N1[C@@H]([C@H](O)[C@@H]1OP(O)(O)=O)O[C@@H]1COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSSCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](OP(O)(O)=O)[C@@H](O)[C@H](N2C3=NC=NC(N)=C3N=C2)O1 YAISMNQCMHVVLO-ODFVJXNFSA-N 0.000 claims 9
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 claims 9
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 claims 9
- VTLYFUHAOXGGBS-UHFFFAOYSA-N Fe3+ Chemical compound [Fe+3] VTLYFUHAOXGGBS-UHFFFAOYSA-N 0.000 claims 9
- BAWFJGJZGIEFAR-NNYOXOHSSA-O NAD(+) Chemical compound NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](COP(O)(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 BAWFJGJZGIEFAR-NNYOXOHSSA-O 0.000 claims 9
- QNGIKJLVQNCRRC-UHFFFAOYSA-N Selenocystamine Chemical compound NCC[Se][Se]CCN QNGIKJLVQNCRRC-UHFFFAOYSA-N 0.000 claims 9
- 208000015181 infectious disease Diseases 0.000 claims 6
- 108010007337 Azurin Proteins 0.000 claims 5
- 102100030497 Cytochrome c Human genes 0.000 claims 4
- 108010075031 Cytochromes c Proteins 0.000 claims 4
- 208000000103 Anorexia Nervosa Diseases 0.000 claims 3
- 241000725303 Human immunodeficiency virus Species 0.000 claims 3
- 208000008589 Obesity Diseases 0.000 claims 3
- 210000000750 endocrine system Anatomy 0.000 claims 3
- 235000003969 glutathione Nutrition 0.000 claims 3
- 208000027866 inflammatory disease Diseases 0.000 claims 3
- 230000004770 neurodegeneration Effects 0.000 claims 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims 3
- 235000020824 obesity Nutrition 0.000 claims 3
- 230000001737 promoting effect Effects 0.000 claims 3
- 208000020016 psychiatric disease Diseases 0.000 claims 3
- 208000030814 Eating disease Diseases 0.000 claims 2
- 208000019454 Feeding and Eating disease Diseases 0.000 claims 2
- 241000711549 Hepacivirus C Species 0.000 claims 2
- 241000724277 Ilarvirus Species 0.000 claims 2
- 241001631646 Papillomaviridae Species 0.000 claims 2
- 241000700605 Viruses Species 0.000 claims 2
- 208000015114 central nervous system disease Diseases 0.000 claims 2
- 235000014632 disordered eating Nutrition 0.000 claims 2
- 230000003612 virological effect Effects 0.000 claims 2
- 208000007848 Alcoholism Diseases 0.000 claims 1
- 208000032841 Bulimia Diseases 0.000 claims 1
- 206010006550 Bulimia nervosa Diseases 0.000 claims 1
- 208000011231 Crohn disease Diseases 0.000 claims 1
- 206010012335 Dependence Diseases 0.000 claims 1
- 208000020401 Depressive disease Diseases 0.000 claims 1
- 241000709661 Enterovirus Species 0.000 claims 1
- 208000005176 Hepatitis C Diseases 0.000 claims 1
- 206010020880 Hypertrophy Diseases 0.000 claims 1
- 201000005505 Measles Diseases 0.000 claims 1
- 241000712079 Measles morbillivirus Species 0.000 claims 1
- 208000009608 Papillomavirus Infections Diseases 0.000 claims 1
- 206010060862 Prostate cancer Diseases 0.000 claims 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
- 241000710961 Semliki Forest virus Species 0.000 claims 1
- 210000004100 adrenal gland Anatomy 0.000 claims 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims 1
- 239000011230 binding agent Substances 0.000 claims 1
- 239000006172 buffering agent Substances 0.000 claims 1
- 206010009887 colitis Diseases 0.000 claims 1
- 210000004748 cultured cell Anatomy 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 206010013663 drug dependence Diseases 0.000 claims 1
- 230000000694 effects Effects 0.000 claims 1
- 239000003995 emulsifying agent Substances 0.000 claims 1
- 208000010710 hepatitis C virus infection Diseases 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 238000001990 intravenous administration Methods 0.000 claims 1
- 201000009240 nasopharyngitis Diseases 0.000 claims 1
- 210000001672 ovary Anatomy 0.000 claims 1
- 208000003154 papilloma Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000035755 proliferation Effects 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 201000000980 schizophrenia Diseases 0.000 claims 1
- 208000011117 substance-related disease Diseases 0.000 claims 1
- 239000000829 suppository Substances 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 239000000080 wetting agent Substances 0.000 claims 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 abstract 1
- 239000000370 acceptor Substances 0.000 abstract 1
- 229940124597 therapeutic agent Drugs 0.000 abstract 1
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- 150000002739 metals Chemical class 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 230000007850 degeneration Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 206010010904 Convulsion Diseases 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 150000001945 cysteines Chemical class 0.000 description 3
- 230000006870 function Effects 0.000 description 3
- 229910052742 iron Inorganic materials 0.000 description 3
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 3
- 230000001537 neural effect Effects 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 235000001014 amino acid Nutrition 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229910052793 cadmium Inorganic materials 0.000 description 2
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 210000003710 cerebral cortex Anatomy 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 210000004558 lewy body Anatomy 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 230000007170 pathology Effects 0.000 description 2
- 230000035790 physiological processes and functions Effects 0.000 description 2
- 230000008961 swelling Effects 0.000 description 2
- 206010048998 Acute phase reaction Diseases 0.000 description 1
- 208000026872 Addison Disease Diseases 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 108020004414 DNA Proteins 0.000 description 1
- 206010012289 Dementia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010001515 Galectin 4 Proteins 0.000 description 1
- 102100039556 Galectin-4 Human genes 0.000 description 1
- 208000003807 Graves Disease Diseases 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 108700021154 Metallothionein 3 Proteins 0.000 description 1
- 102100028708 Metallothionein-3 Human genes 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000007399 Nuclear hormone receptor Human genes 0.000 description 1
- 108020005497 Nuclear hormone receptor Proteins 0.000 description 1
- 206010035148 Plague Diseases 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000018359 Systemic autoimmune disease Diseases 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 241000607479 Yersinia pestis Species 0.000 description 1
- 101710185494 Zinc finger protein Proteins 0.000 description 1
- 102100023597 Zinc finger protein 816 Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000001640 apoptogenic effect Effects 0.000 description 1
- -1 aromatic amino acids Chemical class 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000000133 brain stem Anatomy 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 208000035269 cancer or benign tumor Diseases 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 208000025302 chronic primary adrenal insufficiency Diseases 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 150000001879 copper Chemical class 0.000 description 1
- 230000003436 cytoskeletal effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000006735 deficit Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000003291 dopaminomimetic effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000013020 embryo development Effects 0.000 description 1
- 230000037149 energy metabolism Effects 0.000 description 1
- 230000002397 epileptogenic effect Effects 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 208000013403 hyperactivity Diseases 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000006058 immune tolerance Effects 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 230000002109 interictal effect Effects 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 235000018977 lysine Nutrition 0.000 description 1
- 150000002669 lysines Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000002739 subcortical effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 210000000331 sympathetic ganglia Anatomy 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K31/355—Tocopherols, e.g. vitamin E
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/06—Tripeptides
- A61K38/063—Glutathione
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
A method is provided for the treatment of diseases of plants and animals whe re such diseases involve disturbance of zinc homeostasis. The method involves administration of therapeutic agents that after cellular oxidation potential so as to oxidize metallothionein and thereby release zinc ions, or as to maintain metallothionein in a reduced state so as to prevent transfer of zin c from metallothionein to zinc acceptors.
Description
AGENTS AND METHODS FOR MODULATION OF ZINC TRANSFER BY
METALLOTHIONEIN -This application claims priority to U.S. provisional applications Serial Number 60/079,969, filed March 30, 1998, and Serial Number 60/084,953, filed May 11, 1998.
1. INTRODUCTION
The present invention relates to control of zinc metabolism mediated by metallothioneins. Metallothioneins are both the predominant cellular reservoir for bioavailable zinc and the primary shuttle for zinc transfer among biomolecules. Agents are provided that enhance or prevent the release of zinc from metallothioneins and thereby affect metabolic pathways that depend on the availability or uptake of zinc.
2. BACKGROUND OF THE INVENTION
2.1. METALLOTHIONEIN
Metallothionein (MT) was discovered in 1957 (Margoshes, M. and Vallee, B.
L., 1957, J. Am. Chem. Soc. 79. 4813). By all counts it is a most unusual and unconventional protein (Vallee, B.L., 1979, Experientia Suppl. 34, 19-40;
Vallee, B.L., 1987, Experientia Suppl. 52, 5-16; Vallee, B. L., 1991, Meth. Enzymol. 205, 3-7; Vallee, B.L. and Maret, W., 1993, in Metallothionein III, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), 1; Vallee, 1995. Neurochem. Interntl. 27, 23). One third of its 60+
amino acids are cysteines and eight are lysines. It contains neither aromatic amino acids nor histidine. MT usually binds seven zinc atoms, but it can also contain copper, cadmium, iron and traces of other metals. In an evolutionary sense it is a very old protein.
The composition of its two major isoproteins has changed only imperceptibly over time. The number of genes that code for human MTs could be as high as 17. MT-1 and MT-2 are the two prevalent forms, which are expressed, but whose physiological functions are unknown.
MT-3 was discovered only recently in brains from patients afflicted with Alzheimer's disease (Uchida, Y., Takio, K., Titani, K., Ihara, Y., and Tomonaga, M. ( I
991 ) Neuron 7, 337). Its discovery was based on the fact that it inhibits the growth of neurons. Thus far, it is the only MT that is known to exhibit such a specific biological function.
This isoform contains zinc and copper(I), but not cadmium or other metals. Multiple factors among them members of the nuclear hormone receptor family, interferons, inducers of the acute phase response, and metalloregulatory proteins, affect tissue- and isoprotein-specific gene expression. In addition there are numerous other agents that induce it but whose signalling pathways remain obscure. Thionein, the apoform of MT has never been isolated as such from any biological material. Apparently, upon its formation, it instantaneously combines with zinc, whose "free" concentration in the cell has been reported to be exceedingly low, i.e. in the nanomolar to picomolar range. All these facts suggest that MT must be biologically essential. This, indeed, has now been proven to be correct. MT-1/-2 knock-out mice become obese, demonstrating the involvement of MT in energy metabolism (Beattie, J.
H, Wood, A. M., Newman, A. M., Bremner, L, Choo, K. H. A., Michalska, A. E., Duncan, J. S., and Trayhurn, P., 1998, Proc. Natl. Acad. Sci. USA 95, 358).
While MT was discovered 40 years ago, the 3D structure of MT by both X-ray crystallography (Robbins, A. H. and Stout, C. D., 1991, Meth. Enzymol. 205, 485) and NMR spectroscopy (Wiithrich, K., 1991, Meth. Enzymol. 205, 502) has been reported only seven years ago. The structure has proved critical to efforts designed to establish its function. The protein has the shape of a dumb-bell and envelops the metals which it 1 S contains in two separate domains in a manner which effectively shields them from the environment. It is most remarkable that the metals are arranged in a cluster structure unique to biology. In one cluster four atoms are bound to eleven cysteines, five of which bridge the metals, and the other has three metal atoms and nine cysteines with three bridges.
The biological importance of zinc does not require elaboration at this point, since catalytic functions of zinc in enzymes and its structural functions in zinc finger proteins have been documented amply (Vallee, B. L. and Falchuk, K. F., 1993, Physiol.
Rev. 73, 79-118; Vallee, B. L. and Auld, D. S., 1993, Acc. Chem. Res. 26, 543). Zinc in MT is bound extremely tightly (KD about 10-'3 M) (Kagi, J. H. R., 1993, in Metallothionein lll, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), pp. 29).
There have not been any indications how it is removed or added.
Findings that cast light on the circumstances under which zinc is released from MT have been reported. For example, the oxidative metal release from MT
by glutathione disulfide has been reported (Maret, W., 1994, Proc. Natl. Acad.
Sci. USA 91, 237), and exchange between MT and the zinc cluster in the Gal4 transcription factor has been demonstrated (Maret, W., Larsen, K. S., and Vallee, B. L., 1997, Proc.
Natl. Acad. Sci.
USA 94, 2233). These previous reports, however, do not report or suggest the methods and compositions of the present invention, and in fact, failed to appreciate the synergistic release of zinc by oxidants in the presence of glutathione; and failed to provide for zinc transfer on a physiologically significant time scale.
Zinc, in contrast to copper or iron, is redox-inert. Hence, the properties of zinc complexes are not altered by valence changes of the central atom: in a manner akin to those in iron or copper complexes. However, the redox state of the sulfur ligands can be changed.
2.2. DISORDERS OF THE CENTRAL NERVOUS SYSTEM
2.2.1. ALZHEIMER'S DISEASE
The cerebral cortexes of Alzheimer's disease ("AD") patients contain neurofibrillary tangles and senile (amyloid) plagues (D. M. A. Mann et al., 1988, Neuropathol. Appl. Neurol., 14, 177). These structures are associated with the dementia and memory loss that are characteristic of the disease.
2.2.2. PARKINSON'S DISEASE
Parkinson's disease involves degeneration of pigmented neuronal systems in the brain stem that leads to neuromediator dysfunction. The principal cytoskeletal pathology associated with Parkinson's disease is the Lewy body which predominately occurs in aminergic and other subcortical, spinal cord, and sympathetic ganglia neurons, and also to a lesser extent in the cerebral cortex. Lewy bodies in Parkinson's disease lead to a degeneration of the dopaminergic pathway of the pigmented neuronal systems as well as to a degeneration of other neuronal systems, and this degeneration leads to a complex set of functional deficits (M. Ebadi et al., 1996, Progr. Neurobiol., 48, l, and references therein).
2.2.3. EPILEPSY
Epilepsy, as a term, is broadly used to describe a group of disorders that are characterized by transient, recurrent, spontaneous paroxysms of a hyperactive brain resulting in seizures. The interictal (between seizures) state of the epileptogenic cortex displays brief, high-amplitude electrical impulses. Seizures are characterized by loss of inhibitory signals so as to foster hyperexcitability and hyperactivity.
2.3. APOPTOSIS AND INJURY FROM RADIATION OR CHEMOTHERAPY
Apoptosis is a physiological process whereby cells die without swelling, necrosis, or inflammation (J. F. R. Kerr et al., 1972, Brit. J. Cancer, 26, 239). Apoptosis, in a non-pathological context, is considered responsible for the selective deletion of cells during embryogenesis and for homeostasis in continuously renewing tissues (S.
Sen, 1992, Biol. Rev., 67, 287). In a pathological context, apoptosis is exhibited by cells in response to irradiation, oxidative stress, and to various chemical stimuli such as glucocorticoids (M. J.
Arends, A. H. Wyllie. 1991, Int. Rev. Exper. Pathol., 32, 223). Apoptosis has also been implicated as a process leading to aging (Z. Zakeri and R. A. Lockshin, 1994, Ann. Rev. NY
Acad. Sci., 719, 212) and cancer (J. F. R. Kerr et al., 1994, Cancer, 73, 2013). Biophysical and morphological indicators of apoptosis include fragmentation of endonuclear and chromatin DNA (Arends et al., 1990, Amer. J. Pathol., 136, 593) and compaction of cytoplasmic organelles into so-called "apoptotic bodies" (A. H. Wyllie et al., 1980, Int. Rev.
Cytol., 68, 251 ).
2.4. CARCINOGENESIS
A neoplasm, or tumor, is a cellular mass resulting from abnormal uncontrolled cell growth, which may cause swelling on the body surface, and which can be benign or malignant. Benign tumors generally remain localized. Malignant tumors are collectively termed cancers. The term "malignant" generally means that the tumor can invade and destroy neighboring body structures and spread to distant sites to cause death (for review, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B.
Saunders Co., Philadelphia, 68).
Effective treatment and prevention of cancer remains a long-felt need, and a major goal of biomedical research.
2.5. AUTOIMMUNE DISEASES
Autoimmune diseases are estimated to affect from 1 to 2 percent of the human population. Such diseases fall into two broad categories: organ-specific, and systemic diseases. Organ-specific autoimmune diseases include myasthenia gravis, Grave's disease, juvenile insulin-dependent diabetes, Addison's disease, and a host of others.
Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, rheumatic fever, as well as others. Such diseases result from a breakdown of immune tolerance to self antigens. Such breakdown may be due to any of one or several mechanisms: lack of elimination of self reactive clones, activation of anergic self reactive cells, or the release of sequestered self antigens that previously were inaccessible to the immune system.
2.5.1. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is characterized by inflammation in many different organ systems, as well as by excessive production of antibodies to nuclear, cytoplasmic an
METALLOTHIONEIN -This application claims priority to U.S. provisional applications Serial Number 60/079,969, filed March 30, 1998, and Serial Number 60/084,953, filed May 11, 1998.
1. INTRODUCTION
The present invention relates to control of zinc metabolism mediated by metallothioneins. Metallothioneins are both the predominant cellular reservoir for bioavailable zinc and the primary shuttle for zinc transfer among biomolecules. Agents are provided that enhance or prevent the release of zinc from metallothioneins and thereby affect metabolic pathways that depend on the availability or uptake of zinc.
2. BACKGROUND OF THE INVENTION
2.1. METALLOTHIONEIN
Metallothionein (MT) was discovered in 1957 (Margoshes, M. and Vallee, B.
L., 1957, J. Am. Chem. Soc. 79. 4813). By all counts it is a most unusual and unconventional protein (Vallee, B.L., 1979, Experientia Suppl. 34, 19-40;
Vallee, B.L., 1987, Experientia Suppl. 52, 5-16; Vallee, B. L., 1991, Meth. Enzymol. 205, 3-7; Vallee, B.L. and Maret, W., 1993, in Metallothionein III, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), 1; Vallee, 1995. Neurochem. Interntl. 27, 23). One third of its 60+
amino acids are cysteines and eight are lysines. It contains neither aromatic amino acids nor histidine. MT usually binds seven zinc atoms, but it can also contain copper, cadmium, iron and traces of other metals. In an evolutionary sense it is a very old protein.
The composition of its two major isoproteins has changed only imperceptibly over time. The number of genes that code for human MTs could be as high as 17. MT-1 and MT-2 are the two prevalent forms, which are expressed, but whose physiological functions are unknown.
MT-3 was discovered only recently in brains from patients afflicted with Alzheimer's disease (Uchida, Y., Takio, K., Titani, K., Ihara, Y., and Tomonaga, M. ( I
991 ) Neuron 7, 337). Its discovery was based on the fact that it inhibits the growth of neurons. Thus far, it is the only MT that is known to exhibit such a specific biological function.
This isoform contains zinc and copper(I), but not cadmium or other metals. Multiple factors among them members of the nuclear hormone receptor family, interferons, inducers of the acute phase response, and metalloregulatory proteins, affect tissue- and isoprotein-specific gene expression. In addition there are numerous other agents that induce it but whose signalling pathways remain obscure. Thionein, the apoform of MT has never been isolated as such from any biological material. Apparently, upon its formation, it instantaneously combines with zinc, whose "free" concentration in the cell has been reported to be exceedingly low, i.e. in the nanomolar to picomolar range. All these facts suggest that MT must be biologically essential. This, indeed, has now been proven to be correct. MT-1/-2 knock-out mice become obese, demonstrating the involvement of MT in energy metabolism (Beattie, J.
H, Wood, A. M., Newman, A. M., Bremner, L, Choo, K. H. A., Michalska, A. E., Duncan, J. S., and Trayhurn, P., 1998, Proc. Natl. Acad. Sci. USA 95, 358).
While MT was discovered 40 years ago, the 3D structure of MT by both X-ray crystallography (Robbins, A. H. and Stout, C. D., 1991, Meth. Enzymol. 205, 485) and NMR spectroscopy (Wiithrich, K., 1991, Meth. Enzymol. 205, 502) has been reported only seven years ago. The structure has proved critical to efforts designed to establish its function. The protein has the shape of a dumb-bell and envelops the metals which it 1 S contains in two separate domains in a manner which effectively shields them from the environment. It is most remarkable that the metals are arranged in a cluster structure unique to biology. In one cluster four atoms are bound to eleven cysteines, five of which bridge the metals, and the other has three metal atoms and nine cysteines with three bridges.
The biological importance of zinc does not require elaboration at this point, since catalytic functions of zinc in enzymes and its structural functions in zinc finger proteins have been documented amply (Vallee, B. L. and Falchuk, K. F., 1993, Physiol.
Rev. 73, 79-118; Vallee, B. L. and Auld, D. S., 1993, Acc. Chem. Res. 26, 543). Zinc in MT is bound extremely tightly (KD about 10-'3 M) (Kagi, J. H. R., 1993, in Metallothionein lll, eds. Suzuki, K. T., Imura, N. & Kimura, M. (Birkhauser, Basel), pp. 29).
There have not been any indications how it is removed or added.
Findings that cast light on the circumstances under which zinc is released from MT have been reported. For example, the oxidative metal release from MT
by glutathione disulfide has been reported (Maret, W., 1994, Proc. Natl. Acad.
Sci. USA 91, 237), and exchange between MT and the zinc cluster in the Gal4 transcription factor has been demonstrated (Maret, W., Larsen, K. S., and Vallee, B. L., 1997, Proc.
Natl. Acad. Sci.
USA 94, 2233). These previous reports, however, do not report or suggest the methods and compositions of the present invention, and in fact, failed to appreciate the synergistic release of zinc by oxidants in the presence of glutathione; and failed to provide for zinc transfer on a physiologically significant time scale.
Zinc, in contrast to copper or iron, is redox-inert. Hence, the properties of zinc complexes are not altered by valence changes of the central atom: in a manner akin to those in iron or copper complexes. However, the redox state of the sulfur ligands can be changed.
2.2. DISORDERS OF THE CENTRAL NERVOUS SYSTEM
2.2.1. ALZHEIMER'S DISEASE
The cerebral cortexes of Alzheimer's disease ("AD") patients contain neurofibrillary tangles and senile (amyloid) plagues (D. M. A. Mann et al., 1988, Neuropathol. Appl. Neurol., 14, 177). These structures are associated with the dementia and memory loss that are characteristic of the disease.
2.2.2. PARKINSON'S DISEASE
Parkinson's disease involves degeneration of pigmented neuronal systems in the brain stem that leads to neuromediator dysfunction. The principal cytoskeletal pathology associated with Parkinson's disease is the Lewy body which predominately occurs in aminergic and other subcortical, spinal cord, and sympathetic ganglia neurons, and also to a lesser extent in the cerebral cortex. Lewy bodies in Parkinson's disease lead to a degeneration of the dopaminergic pathway of the pigmented neuronal systems as well as to a degeneration of other neuronal systems, and this degeneration leads to a complex set of functional deficits (M. Ebadi et al., 1996, Progr. Neurobiol., 48, l, and references therein).
2.2.3. EPILEPSY
Epilepsy, as a term, is broadly used to describe a group of disorders that are characterized by transient, recurrent, spontaneous paroxysms of a hyperactive brain resulting in seizures. The interictal (between seizures) state of the epileptogenic cortex displays brief, high-amplitude electrical impulses. Seizures are characterized by loss of inhibitory signals so as to foster hyperexcitability and hyperactivity.
2.3. APOPTOSIS AND INJURY FROM RADIATION OR CHEMOTHERAPY
Apoptosis is a physiological process whereby cells die without swelling, necrosis, or inflammation (J. F. R. Kerr et al., 1972, Brit. J. Cancer, 26, 239). Apoptosis, in a non-pathological context, is considered responsible for the selective deletion of cells during embryogenesis and for homeostasis in continuously renewing tissues (S.
Sen, 1992, Biol. Rev., 67, 287). In a pathological context, apoptosis is exhibited by cells in response to irradiation, oxidative stress, and to various chemical stimuli such as glucocorticoids (M. J.
Arends, A. H. Wyllie. 1991, Int. Rev. Exper. Pathol., 32, 223). Apoptosis has also been implicated as a process leading to aging (Z. Zakeri and R. A. Lockshin, 1994, Ann. Rev. NY
Acad. Sci., 719, 212) and cancer (J. F. R. Kerr et al., 1994, Cancer, 73, 2013). Biophysical and morphological indicators of apoptosis include fragmentation of endonuclear and chromatin DNA (Arends et al., 1990, Amer. J. Pathol., 136, 593) and compaction of cytoplasmic organelles into so-called "apoptotic bodies" (A. H. Wyllie et al., 1980, Int. Rev.
Cytol., 68, 251 ).
2.4. CARCINOGENESIS
A neoplasm, or tumor, is a cellular mass resulting from abnormal uncontrolled cell growth, which may cause swelling on the body surface, and which can be benign or malignant. Benign tumors generally remain localized. Malignant tumors are collectively termed cancers. The term "malignant" generally means that the tumor can invade and destroy neighboring body structures and spread to distant sites to cause death (for review, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B.
Saunders Co., Philadelphia, 68).
Effective treatment and prevention of cancer remains a long-felt need, and a major goal of biomedical research.
2.5. AUTOIMMUNE DISEASES
Autoimmune diseases are estimated to affect from 1 to 2 percent of the human population. Such diseases fall into two broad categories: organ-specific, and systemic diseases. Organ-specific autoimmune diseases include myasthenia gravis, Grave's disease, juvenile insulin-dependent diabetes, Addison's disease, and a host of others.
Systemic autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, scleroderma, rheumatic fever, as well as others. Such diseases result from a breakdown of immune tolerance to self antigens. Such breakdown may be due to any of one or several mechanisms: lack of elimination of self reactive clones, activation of anergic self reactive cells, or the release of sequestered self antigens that previously were inaccessible to the immune system.
2.5.1. SYSTEMIC LUPUS ERYTHEMATOSUS
Systemic lupus erythematosus is characterized by inflammation in many different organ systems, as well as by excessive production of antibodies to nuclear, cytoplasmic an
Claims (76)
1. A method for modulating the release of zinc from metallothionein within a cell comprising altering the concentrations of glutathione and glutathione disulfide within the cell.
2. A method of promoting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione disulfide within the cell.
3. A method of promoting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione disulfide within the cell in the presence of naturally occurring glutathione.
4. A method of promoting the release of zinc from metallothionein within a cell comprising administering to the cell a zinc-releasing amount of an oxidizing agent.
5. The method according to claim 4 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
6. The method according to claim 4 wherein said oxidizing agent is selected from the group consisting of ebselen, glutathione disulfide, and combinations thereof.
7. The method according to claim 4 wherein said oxidizing agent is ebselen.
8. A method of inhibiting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione within the cell.
9. A method of inhibiting the release of zinc from metallothionein within a cell comprising increasing the concentration of glutathione within the cell in the presence of naturally occurring glutathione disulfide.
10. A method of inhibiting the release of zinc from metallothionein within a cell comprising administering to the cell an amount of a reducing agent effective to inhibit the release of zinc from metallothionein.
11. The method according to claim 10 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH,, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
12. The method according to claim 10 wherein said reducing agent is selected from the group consisting of glutathione, ascorbate, vitamin E, and combinations thereof.
13. The method according to claim 1 wherein said cell is a cultured cell.
14. The method according to claim 1 wherein said cell is contained in a host organism.
15. The method according to claim 14 wherein said organism is a plant.
16. The method according to claim 14 wherein said organism is an animal.
17. The method according to claim 16 wherein said animal is a human.
18. A method of treating a subject having a pathological condition in which zinc homeostasis is perturbed, comprising administering to the subject an amount of a compound effective to treat said condition, wherein said compound changes the cellular oxidation state to effect an action selected from the group consisting of causing a release of zinc from metallothionein and preventing release of zinc from metallothionein.
19. The method according to claim 18 wherein said compound is selected from the group consisting of ebselen, cytochrome c, ascorbate, dehydroascorbate, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, vitamin E, N-acetyl-1,-cysteine, .alpha.-lipoate, and combinations thereof.
20. The method according to claim 18 wherein said compound is ebselen, ascorbate, dehydroascorbate, glutathione, glutathione disulfide, cystamine, cysteamine, azurin, vitamin E, N-acetyl-L-cysteine, or .alpha.-lipoate.
21. The method according to claim 18 wherein said compound is ebselen.
22. The method according to claim 18 wherein said pathological condition is a disease of the central nervous system, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the disease of the central nervous system.
23. The method according to claim 22 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
24. The method according to claim 18 wherein said pathological condition is Alzheimer's disease, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the Alzheimer's disease.
25. The method according to claim 24 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
26. The method according to claim 18 wherein said pathological condition is a neurodegenerative disease, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the neurodegenerative disease.
27. The method according to claim 26 wherein said neurodegenerative disease is selected from the group consisting of Parkinson's disease, and amyotrophic lateral sclerosis.
28. The method according to claim 26 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
29. The method according to claim 18 wherein said pathological condition is epilepsy, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the epilepsy.
30. The method according to claim 29 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
31. A The method according to claim 18 wherein said pathological condition is a drug or alcohol addiction, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the addiction.
32. The method according to claim 31 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
33. The method according to claim 18 wherein said pathological condition is a severe mental illness, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the severe mental illness.
34. The method according to claim 33 wherein said severe mental illness is selected from the group consisting of depression and schizophrenia.
35. The method according to claim 33 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
36. The method according to claim 18 wherein said pathological condition is an eating disorder.
37. The method according to claim 36 wherein said eating disorder is selected from the group consisting of anorexia nervosa, bulimia and obesity.
38. The method according to claim 18 wherein said pathological condition is anorexia nervosa, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the anorexia nervosa.
39. The method according to claim 38 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
40. The method according to claim 18 wherein said pathological condition is obesity, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the obesity.
41. The method according to claim 40 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
42. The method according to claim 18 wherein said pathological condition is an inflammatory disease, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the inflammatory disease wherein said inflammatory disease is selected from the group consisting of colitis and Crohn's disease.
43. The method according to claim 42 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
44. The method according to claim 18 wherein said pathological condition is a disorder of the endocrine system, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the disorder of the endocrine system.
45. The method according to claim 44 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
46. The method according to claim 44 wherein said disorder of the endocrine system is selected from prostate cancer, prostate hypertrophy, a disorder of the thyroid, a disorder of the ovaries, and a disorder of the adrenal gland.
47. The method according to claim 18 wherein said pathological condition is pathological apoptosis, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the pathological apoptosis.
48. The method according to claim 47 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
49. The method according to claim 18 wherein said pathological condition is cancer, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for inducing apoptosis of the cells of the cancer.
50. The method according to claim 49 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
51. The method according to claim 18 wherein said pathological condition is cancer, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for inhibiting proliferation of the cells of the cancer.
52. The method according to claim 51 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
53. The method according to claim 18 wherein said pathological condition is an autoimmune disease, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the autoimmune disease.
54. The method according to claim 53 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
55. The method according to claim 18 wherein said pathological condition is a viral disease.
56. The method according to claim 18 wherein said viral disease is selected from the group consisting of infection by the common cold, HIV, hepatitis C, measles, papilloma, and Semliki Forest virus.
57. The method according to claim 18 wherein said pathological condition is an infection with HIV, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the infection with HIV.
58. The method according to claim 57 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
59. The method according to claim 18 wherein said pathological condition is a plant disease.
60. The method according to claim 59 wherein said plant disease is ilarvirus or mosaic virus, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein amount effective for treatment of the infection with the ilarvirus or the mosaic virus.
61. The method according to claim 60 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
62. The method according to claim 18 wherein said pathological condition is infection with papilloma virus, said method comprising administering to the subject an oxidizing agent that promotes release of zinc from metallothionein in an amount effective for treatment of the papilloma virus infection.
63. The method according to claim 62 wherein said oxidizing agent is selected from the group consisting of ebselen, selenocystine, selenocystamine, selenoglutathione disulfide, iron(III) chelates, dehydroascorbate, glutathione disulfide, coenzyme A
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
disulfide, cystamine, FAD, NAD+, copper (II) chelates, and combinations thereof.
64. The method according to claim 18 wherein said pathological condition is infection with hepatitis C virus, said method comprising administering to the subject a reducing agent that inhibits release of zinc from metallothionein in an amount effective for treatment of the hepatitis C virus infection.
65. The method according to claim 64 wherein said reducing agent is selected from the group consisting of selenocysteine, selenoglutathione, selenocysteamine, iron(II) chelates, ascorbate, glutathione, coenzyme A, cysteamine, FADH2, NADH, copper(I) chelates, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
66. The method according to claim 18 further comprising co-administering a cofactor selected from the group consisting of glutathione, ATP and GTP.
67. The method according to claim 18 wherein said compound is combined with one or more ingredients selected from the group consisting of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, a wetting agent, a buffering agent, an emulsifying agent, and a binding agent.
68. The method according to claim 18 wherein said compound is formulated as a pharmaceutically acceptable salt.
69. The method according to claim 18 wherein said compound is purified.
70. The method according to claim 18 further comprising coadministering with said compound an amount of purified metallothionein or a derivative thereof.
71. The method according to claim 70 wherein a metallothionein derivative is coadministered, said derivative being bound to an antibody to a cellular antigen.
72. The method according to claim 18 wherein said compound is adapted for intravenous administration to human beings.
73. A pharmaceutical composition comprising purified glutathione in combination with a purified compound selected from the group consisting of ebselen, cytochrome c, ascorbate, dehydroascorbate, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, vitamin E, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof.
74. A kit comprising in one or more containers purified glutathione and a purified compound selected from the group consisting of cytochrome c, ascorbate, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof, in an amount effective to modulate the release of zinc from metallothionein.
75. A kit comprising in one or more containers a purified compound selected from the group consisting of cytochrome c, glutathione, glutathione disulfide, coenzyme A, cystamine, cysteamine, FAD, FADH2, azurin, N-acetyl-L-cysteine, .alpha.-lipoate, and combinations thereof, in an amount effective to modulate the release of zinc from metallothionein.
76. The method according to claim 18 wherein said compound is formulated as a suppository.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US7996998P | 1998-03-30 | 1998-03-30 | |
US60/079,969 | 1998-03-30 | ||
US8495398P | 1998-05-11 | 1998-05-11 | |
US60/084,953 | 1998-05-11 | ||
PCT/US1999/007432 WO1999049860A1 (en) | 1998-03-30 | 1999-03-29 | Agents and methods for modulation of zinc transfer by metallothionein |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2326771A1 true CA2326771A1 (en) | 1999-10-07 |
Family
ID=26762632
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002326771A Abandoned CA2326771A1 (en) | 1998-03-30 | 1999-03-29 | Agents and methods for modulation of zinc transfer by metallothionein |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP1067922A1 (en) |
AU (1) | AU3470399A (en) |
CA (1) | CA2326771A1 (en) |
WO (1) | WO1999049860A1 (en) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CZ20013786A3 (en) * | 1999-04-29 | 2002-02-13 | Merck Patent Gmbh | Inhibitors of glycine splitting system as possible antipsychotics |
KR100417623B1 (en) | 2000-03-28 | 2004-02-05 | 주식회사 뉴로테크 | Composition for preventing and treating brain diseases |
JP4881536B2 (en) * | 2001-02-15 | 2012-02-22 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・ユニバーシティ・オブ・イリノイ | Cytotoxic factors that regulate cell death |
US20040110691A1 (en) * | 2001-11-13 | 2004-06-10 | Stamler Jonathan S. | Thiol reactive agents as a therapeutic modality |
AU2003291097A1 (en) * | 2002-11-20 | 2004-06-15 | Errant Gene Therapeutics, Llc | Treatment of lung cells with histone deacetylase inhibitors |
AR057623A1 (en) | 2005-11-28 | 2007-12-05 | Omega Bio Pharma H K Ltd | MATERIALS AND METHODS FOR THE TREATMENT OF VIRAL INFECTIONS |
WO2008148064A1 (en) * | 2007-05-23 | 2008-12-04 | Sunesis Pharmaceuticals, Inc. | Weight loss treatment |
WO2016057882A2 (en) * | 2014-10-09 | 2016-04-14 | Albert Crum | Protective metallothionein analog compounds, their compositions and use thereof in the treatment of pathogenic diseases |
WO2017040370A1 (en) * | 2015-09-03 | 2017-03-09 | The Scripps Research Institute | Small-molecule inhibitors of hiv-1 replication |
GB2550110A (en) * | 2016-04-28 | 2017-11-15 | Univ Oxford Innovation Ltd | Treatment of impulsivity-related disorders |
GB201717629D0 (en) | 2017-10-26 | 2017-12-13 | Univ Oxford Innovation Ltd | Treatment of unipolar depressive disorder |
WO2023196540A1 (en) * | 2022-04-06 | 2023-10-12 | Vanderbilt University | Articles and methods for inhibiting methionine aminopeptidase activity |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5843641A (en) * | 1993-02-26 | 1998-12-01 | Massachusetts Institute Of Technology | Methods for the daignosis, of familial amyotrophic lateral sclerosis |
-
1999
- 1999-03-29 WO PCT/US1999/007432 patent/WO1999049860A1/en not_active Application Discontinuation
- 1999-03-29 CA CA002326771A patent/CA2326771A1/en not_active Abandoned
- 1999-03-29 AU AU34703/99A patent/AU3470399A/en not_active Abandoned
- 1999-03-29 EP EP99916366A patent/EP1067922A1/en not_active Withdrawn
Also Published As
Publication number | Publication date |
---|---|
WO1999049860A1 (en) | 1999-10-07 |
AU3470399A (en) | 1999-10-18 |
EP1067922A1 (en) | 2001-01-17 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Thirumoorthy et al. | A review of metallothionein isoforms and their role in pathophysiology | |
CA2326771A1 (en) | Agents and methods for modulation of zinc transfer by metallothionein | |
Tangpong et al. | Adriamycin‐mediated nitration of manganese superoxide dismutase in the central nervous system: insight into the mechanism of chemobrain | |
Ishibashi | Molecular hydrogen: new antioxidant and anti-inflammatory therapy for rheumatoid arthritis and related diseases | |
Garrett et al. | The crystal structure of poplar apoplastocyanin at 1.8-A resolution. The geometry of the copper-binding site is created by the polypeptide. | |
Sandau et al. | The balance between nitric oxide and superoxide determines apoptotic and necrotic death of rat mesangial cells. | |
US7902255B2 (en) | γ-butyrolactone compound and pharmaceutical composition thereof | |
Veeraraghavan et al. | Impact of curcumin, raspberry extract, and neem leaf extract on rel protein-regulated cell death/radiosensitization in pancreatic cancer cells | |
Kennedy et al. | Selenomethionine protects against adverse biological effects induced by space radiation | |
Wu et al. | Mitochondrial-derived peptides in diabetes and its complications | |
Bégay et al. | The C/EBPβ LIP isoform rescues loss of C/EBPβ function in the mouse | |
CN112076196A (en) | Application of primidone as RIPK1 inhibitor | |
Kim et al. | Silymarin inhibits cytokine-stimulated pancreatic beta cells by blocking the ERK1/2 pathway | |
Linnane et al. | Cellular redox poise modulation; the role of coenzyme Q10, gene and metabolic regulation | |
KR20210093250A (en) | Combination Chemotherapy with Recombinant Proteins | |
Li et al. | Astaxanthin mitigates cobalt cytotoxicity in the MG-63 cells by modulating the oxidative stress | |
Endresen et al. | Protective function of metallothionein against certain anticancer agents | |
Florianczyk | Metallothioneins and its role in metal regulation, binding of reactive oxygen species, apoptosis and cell differentiation | |
EP1244461A2 (en) | INHIBITION OF GSK-3$g(b) | |
Jin | Role of p53 in anticancer drug treatment-and radiation-induced injury in normal small intestine | |
Zamora et al. | Increased binding to sigma sites of N-[1′(2-piperidinyl) ethyl)-4-[I-125]-iodobenzamide (I-125-PAB) with onset of tumor cell proliferation | |
Asanuma et al. | Methamphetamine-induced increase in striatal p53 DNA-binding activity is attenuated in Cu, Zn-superoxide dismutase transgenic mice | |
Frankel et al. | Resolution of type 1 reaction in multibacillary Hansen's disease as a result of treatment with cyclosporine | |
KR20190080814A (en) | Recombinant fusion protein of BAF57 and uses thereof | |
JP2009013131A (en) | Cell proliferation inhibitor |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
FZDE | Discontinued | ||
FZDE | Discontinued |
Effective date: 20030331 |