WO1996031217A1 - Inhibition de la replication des retrovirus - Google Patents
Inhibition de la replication des retrovirus Download PDFInfo
- Publication number
- WO1996031217A1 WO1996031217A1 PCT/US1996/004084 US9604084W WO9631217A1 WO 1996031217 A1 WO1996031217 A1 WO 1996031217A1 US 9604084 W US9604084 W US 9604084W WO 9631217 A1 WO9631217 A1 WO 9631217A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- nitroso
- nitric oxide
- retrovirus
- animal
- Prior art date
Links
- 230000010076 replication Effects 0.000 title claims abstract description 51
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 30
- 230000001177 retroviral effect Effects 0.000 title claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 77
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 71
- 238000000034 method Methods 0.000 claims abstract description 50
- 241001430294 unidentified retrovirus Species 0.000 claims abstract description 38
- 239000000203 mixture Substances 0.000 claims abstract description 32
- 241001465754 Metazoa Species 0.000 claims abstract description 29
- 239000003443 antiviral agent Substances 0.000 claims abstract description 23
- 208000005074 Retroviridae Infections Diseases 0.000 claims abstract description 18
- 239000000236 nitric oxide synthase inhibitor Substances 0.000 claims abstract description 18
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 229940123921 Nitric oxide synthase inhibitor Drugs 0.000 claims abstract description 13
- 210000004027 cell Anatomy 0.000 claims description 73
- 241000725303 Human immunodeficiency virus Species 0.000 claims description 26
- 241000282414 Homo sapiens Species 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 229940024606 amino acid Drugs 0.000 claims description 18
- 230000007420 reactivation Effects 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 150000002431 hydrogen Chemical class 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229920001184 polypeptide Polymers 0.000 claims description 16
- -1 hydroxy, carbamoyl Chemical group 0.000 claims description 13
- 239000005541 ACE inhibitor Substances 0.000 claims description 10
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 229960002429 proline Drugs 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- ICRHORQIUXBEPA-UHFFFAOYSA-N thionitrous acid Chemical compound SN=O ICRHORQIUXBEPA-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 6
- 241000714260 Human T-lymphotropic virus 1 Species 0.000 claims description 5
- MRAUNPAHJZDYCK-BYPYZUCNSA-N L-nitroarginine Chemical group OC(=O)[C@@H](N)CCCNC(=N)N[N+]([O-])=O MRAUNPAHJZDYCK-BYPYZUCNSA-N 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 102000014150 Interferons Human genes 0.000 claims description 4
- 108010050904 Interferons Proteins 0.000 claims description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 claims description 4
- 229940079322 interferon Drugs 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 229910052717 sulfur Chemical group 0.000 claims description 4
- BQOFFLKXAZPNNX-BYPYZUCNSA-N (2s)-5-(diaminomethylideneamino)-2-hydrazinylpentanoic acid Chemical compound NN[C@H](C(O)=O)CCCNC(N)=N BQOFFLKXAZPNNX-BYPYZUCNSA-N 0.000 claims description 3
- GZEWDUYXKDCZJU-LURJTMIESA-N (2s)-5-amino-2-(2-iminoethylamino)pentanoic acid Chemical compound NCCC[C@@H](C(O)=O)NCC=N GZEWDUYXKDCZJU-LURJTMIESA-N 0.000 claims description 3
- BXZVVICBKDXVGW-NKWVEPMBSA-N Didanosine Chemical compound O1[C@H](CO)CC[C@@H]1N1C(NC=NC2=O)=C2N=C1 BXZVVICBKDXVGW-NKWVEPMBSA-N 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- NTNWOCRCBQPEKQ-YFKPBYRVSA-N N(omega)-methyl-L-arginine Chemical group CN=C(N)NCCC[C@H](N)C(O)=O NTNWOCRCBQPEKQ-YFKPBYRVSA-N 0.000 claims description 3
- NTWVQPHTOUKMDI-YFKPBYRVSA-N N-Methyl-arginine Chemical compound CN[C@H](C(O)=O)CCCN=C(N)N NTWVQPHTOUKMDI-YFKPBYRVSA-N 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 claims description 3
- 229960004150 aciclovir Drugs 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000002738 chelating agent Substances 0.000 claims description 3
- 229960002656 didanosine Drugs 0.000 claims description 3
- QFXKXRXFBRLLPQ-UHFFFAOYSA-N diphenyleneiodonium Chemical compound C1=CC=C2[I+]C3=CC=CC=C3C2=C1 QFXKXRXFBRLLPQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960002591 hydroxyproline Drugs 0.000 claims description 3
- 239000000138 intercalating agent Substances 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 claims description 3
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 239000002718 pyrimidine nucleoside Substances 0.000 claims description 3
- 239000011593 sulfur Chemical group 0.000 claims description 3
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims description 3
- 229960002555 zidovudine Drugs 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 2
- AZGHTMLGGMHOBH-UHFFFAOYSA-N 1,2,2-trifluoropiperazine Chemical compound FN1CCNCC1(F)F AZGHTMLGGMHOBH-UHFFFAOYSA-N 0.000 claims description 2
- ZSRSLWKGWFFVCM-WDSKDSINSA-N Cys-Pro Chemical compound SC[C@H](N)C(=O)N1CCC[C@H]1C(O)=O ZSRSLWKGWFFVCM-WDSKDSINSA-N 0.000 claims description 2
- KCWZGJVSDFYRIX-YFKPBYRVSA-N N(gamma)-nitro-L-arginine methyl ester Chemical compound COC(=O)[C@@H](N)CCCN=C(N)N[N+]([O-])=O KCWZGJVSDFYRIX-YFKPBYRVSA-N 0.000 claims description 2
- 125000005118 N-alkylcarbamoyl group Chemical group 0.000 claims description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 claims description 2
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 claims description 2
- 108091005623 S-nitrosylated proteins Proteins 0.000 claims description 2
- WREGKURFCTUGRC-POYBYMJQSA-N Zalcitabine Chemical compound O=C1N=C(N)C=CN1[C@@H]1O[C@H](CO)CC1 WREGKURFCTUGRC-POYBYMJQSA-N 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 claims description 2
- 125000005110 aryl thio group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000001589 carboacyl group Chemical group 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
- AZLYZRGJCVQKKK-UHFFFAOYSA-N dioxohydrazine Chemical class O=NN=O AZLYZRGJCVQKKK-UHFFFAOYSA-N 0.000 claims description 2
- ZZVUWRFHKOJYTH-UHFFFAOYSA-N diphenhydramine Chemical group C=1C=CC=CC=1C(OCCN(C)C)C1=CC=CC=C1 ZZVUWRFHKOJYTH-UHFFFAOYSA-N 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical class I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 150000002500 ions Chemical class 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 150000002823 nitrates Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical class ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 claims description 2
- 229960003104 ornithine Drugs 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 150000003834 purine nucleoside derivatives Chemical class 0.000 claims description 2
- 125000000565 sulfonamide group Chemical group 0.000 claims description 2
- VSQQQLOSPVPRAZ-RRKCRQDMSA-N trifluridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(C(F)(F)F)=C1 VSQQQLOSPVPRAZ-RRKCRQDMSA-N 0.000 claims description 2
- 229960003962 trifluridine Drugs 0.000 claims description 2
- 229960000523 zalcitabine Drugs 0.000 claims description 2
- 239000002777 nucleoside Substances 0.000 claims 4
- 150000003833 nucleoside derivatives Chemical class 0.000 claims 4
- 239000002516 radical scavenger Substances 0.000 claims 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 150000004006 C-nitroso compounds Chemical class 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- MGFYSGNNHQQTJW-UHFFFAOYSA-N iodonium Chemical compound [IH2+] MGFYSGNNHQQTJW-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- MRWXACSTFXYYMV-FDDDBJFASA-N nebularine Chemical group O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC=C2N=C1 MRWXACSTFXYYMV-FDDDBJFASA-N 0.000 claims 1
- 229940088382 Nitric oxide scavenger Drugs 0.000 abstract description 8
- 239000003937 drug carrier Substances 0.000 abstract description 5
- 206010038997 Retroviral infections Diseases 0.000 abstract description 2
- ZIIQCSMRQKCOCT-YFKPBYRVSA-N S-nitroso-N-acetyl-D-penicillamine Chemical compound CC(=O)N[C@@H](C(O)=O)C(C)(C)SN=O ZIIQCSMRQKCOCT-YFKPBYRVSA-N 0.000 description 25
- 229930195733 hydrocarbon Natural products 0.000 description 23
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 21
- 230000000694 effects Effects 0.000 description 20
- 150000002430 hydrocarbons Chemical class 0.000 description 19
- MNNBCKASUFBXCO-YFKPBYRVSA-N N-acetyl-D-penicillamine Chemical compound CC(=O)N[C@@H](C(O)=O)C(C)(C)S MNNBCKASUFBXCO-YFKPBYRVSA-N 0.000 description 18
- 235000001014 amino acid Nutrition 0.000 description 17
- 239000004215 Carbon black (E152) Substances 0.000 description 16
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 15
- 150000001413 amino acids Chemical class 0.000 description 15
- QTJKCQPXTOYYHJ-BYPYZUCNSA-N (2r)-2-acetamido-3-nitrososulfanylpropanoic acid Chemical compound CC(=O)N[C@H](C(O)=O)CSN=O QTJKCQPXTOYYHJ-BYPYZUCNSA-N 0.000 description 14
- 208000015181 infectious disease Diseases 0.000 description 13
- 102000004196 processed proteins & peptides Human genes 0.000 description 12
- 108090000765 processed proteins & peptides Proteins 0.000 description 12
- 239000006228 supernatant Substances 0.000 description 12
- PWKSKIMOESPYIA-BYPYZUCNSA-N L-N-acetyl-Cysteine Chemical compound CC(=O)N[C@@H](CS)C(O)=O PWKSKIMOESPYIA-BYPYZUCNSA-N 0.000 description 11
- 229960004308 acetylcysteine Drugs 0.000 description 11
- 239000000427 antigen Substances 0.000 description 11
- 102000036639 antigens Human genes 0.000 description 11
- 108091007433 antigens Proteins 0.000 description 11
- 235000018102 proteins Nutrition 0.000 description 11
- 102000004169 proteins and genes Human genes 0.000 description 11
- 108090000623 proteins and genes Proteins 0.000 description 11
- 210000001519 tissue Anatomy 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 241000700605 Viruses Species 0.000 description 8
- 230000035755 proliferation Effects 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 108010021487 Nitric Oxide Synthase Proteins 0.000 description 7
- 102000008299 Nitric Oxide Synthase Human genes 0.000 description 7
- 101710089543 Nitric oxide synthase, inducible Proteins 0.000 description 7
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 7
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical class Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 7
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 7
- 230000008827 biological function Effects 0.000 description 7
- 239000002773 nucleotide Substances 0.000 description 7
- 125000003729 nucleotide group Chemical group 0.000 description 7
- 229920001308 poly(aminoacid) Polymers 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- 235000000346 sugar Nutrition 0.000 description 7
- 150000008163 sugars Chemical class 0.000 description 7
- 230000000699 topical effect Effects 0.000 description 7
- QLPXHECKUSZTMH-GSVOUGTGSA-N (2r)-2-amino-3-methyl-3-nitrososulfanylbutanoic acid Chemical compound O=NSC(C)(C)[C@H](N)C(O)=O QLPXHECKUSZTMH-GSVOUGTGSA-N 0.000 description 6
- 102000001554 Hemoglobins Human genes 0.000 description 6
- 108010054147 Hemoglobins Proteins 0.000 description 6
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 6
- 150000002391 heterocyclic compounds Chemical class 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 150000003573 thiols Chemical class 0.000 description 6
- 238000002965 ELISA Methods 0.000 description 5
- 210000003719 b-lymphocyte Anatomy 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- 229910052751 metal Inorganic materials 0.000 description 5
- 239000002184 metal Substances 0.000 description 5
- 229960001639 penicillamine Drugs 0.000 description 5
- CSYSULGPHGCBQD-UHFFFAOYSA-N s-ethylisothiouronium diethylphosphate Chemical compound CCSC(N)=N.CCOP(O)(=O)OCC CSYSULGPHGCBQD-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- LJRDOKAZOAKLDU-UDXJMMFXSA-N (2s,3s,4r,5r,6r)-5-amino-2-(aminomethyl)-6-[(2r,3s,4r,5s)-5-[(1r,2r,3s,5r,6s)-3,5-diamino-2-[(2s,3r,4r,5s,6r)-3-amino-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-6-hydroxycyclohexyl]oxy-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl]oxyoxane-3,4-diol;sulfuric ac Chemical compound OS(O)(=O)=O.N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)N)O[C@@H]1CO LJRDOKAZOAKLDU-UDXJMMFXSA-N 0.000 description 4
- 108010002350 Interleukin-2 Proteins 0.000 description 4
- 102000001708 Protein Isoforms Human genes 0.000 description 4
- 108010029485 Protein Isoforms Proteins 0.000 description 4
- 241000713311 Simian immunodeficiency virus Species 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 231100000673 dose–response relationship Toxicity 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 230000007246 mechanism Effects 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- YUFCOOWNNHGGOD-UMMCILCDSA-N 8-bromo-3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1Br YUFCOOWNNHGGOD-UMMCILCDSA-N 0.000 description 3
- 101001124991 Homo sapiens Nitric oxide synthase, inducible Proteins 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 3
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 239000002299 complementary DNA Substances 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000012091 fetal bovine serum Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000002840 nitric oxide donor Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000009885 systemic effect Effects 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 2
- 108010078321 Guanylate Cyclase Proteins 0.000 description 2
- 102000014469 Guanylate cyclase Human genes 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 2
- 229930064664 L-arginine Natural products 0.000 description 2
- 235000014852 L-arginine Nutrition 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- NTNWOCRCBQPEKQ-UHFFFAOYSA-N NG-mono-methyl-L-arginine Natural products CN=C(N)NCCCC(N)C(O)=O NTNWOCRCBQPEKQ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 210000001744 T-lymphocyte Anatomy 0.000 description 2
- IQFYYKKMVGJFEH-XLPZGREQSA-N Thymidine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](O)C1 IQFYYKKMVGJFEH-XLPZGREQSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000009697 arginine Nutrition 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 150000001768 cations Chemical class 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 102000055708 human NOS2 Human genes 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000002101 lytic effect Effects 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 210000005087 mononuclear cell Anatomy 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 125000004354 sulfur functional group Chemical group 0.000 description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 description 2
- 238000001262 western blot Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 239000012130 whole-cell lysate Substances 0.000 description 2
- HNIULCDUASSKOM-RQJHMYQMSA-N (2s)-1-[(2s)-2-methyl-3-nitrososulfanylpropanoyl]pyrrolidine-2-carboxylic acid Chemical compound O=NSC[C@@H](C)C(=O)N1CCC[C@H]1C(O)=O HNIULCDUASSKOM-RQJHMYQMSA-N 0.000 description 1
- QWPCKAAAWDCDCW-VKHMYHEASA-N (2s)-2-amino-4-nitrososulfanylbutanoic acid Chemical compound OC(=O)[C@@H](N)CCSN=O QWPCKAAAWDCDCW-VKHMYHEASA-N 0.000 description 1
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- DWRXFEITVBNRMK-UHFFFAOYSA-N Beta-D-1-Arabinofuranosylthymine Natural products O=C1NC(=O)C(C)=CN1C1C(O)C(O)C(CO)O1 DWRXFEITVBNRMK-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000000584 Calmodulin Human genes 0.000 description 1
- 108010041952 Calmodulin Proteins 0.000 description 1
- 102000014914 Carrier Proteins Human genes 0.000 description 1
- 108010078791 Carrier Proteins Proteins 0.000 description 1
- 102000004225 Cathepsin B Human genes 0.000 description 1
- 108090000712 Cathepsin B Proteins 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- 229930028154 D-arginine Natural products 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 206010011878 Deafness Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 206010061978 Genital lesion Diseases 0.000 description 1
- 208000031886 HIV Infections Diseases 0.000 description 1
- 208000037357 HIV infectious disease Diseases 0.000 description 1
- 102000008015 Hemeproteins Human genes 0.000 description 1
- 108010089792 Hemeproteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000998969 Homo sapiens Inositol-3-phosphate synthase 1 Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 102100036881 Inositol-3-phosphate synthase 1 Human genes 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000003996 Interferon-beta Human genes 0.000 description 1
- 108090000467 Interferon-beta Proteins 0.000 description 1
- KLDXJTOLSGUMSJ-JGWLITMVSA-N Isosorbide Chemical compound O[C@@H]1CO[C@@H]2[C@@H](O)CO[C@@H]21 KLDXJTOLSGUMSJ-JGWLITMVSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 206010024774 Localised infection Diseases 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 108010076864 Nitric Oxide Synthase Type II Proteins 0.000 description 1
- 102000011779 Nitric Oxide Synthase Type II Human genes 0.000 description 1
- KEJOCWOXCDWNID-UHFFFAOYSA-N Nitrilooxonium Chemical compound [O+]#N KEJOCWOXCDWNID-UHFFFAOYSA-N 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical group [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- 208000025157 Oral disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 101001124313 Rattus norvegicus Nitric oxide synthase, inducible Proteins 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 108010001742 S-Nitrosoglutathione Proteins 0.000 description 1
- XOWVFANEOZMPKG-REOHCLBHSA-N S-nitroso-L-cysteine Chemical compound OC(=O)[C@@H](N)CSN=O XOWVFANEOZMPKG-REOHCLBHSA-N 0.000 description 1
- HYHSBSXUHZOYLX-WDSKDSINSA-N S-nitrosoglutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CSN=O)C(=O)NCC(O)=O HYHSBSXUHZOYLX-WDSKDSINSA-N 0.000 description 1
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000000389 T-cell leukemia Diseases 0.000 description 1
- 208000028530 T-cell lymphoblastic leukemia/lymphoma Diseases 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical class [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000003978 Tissue Plasminogen Activator Human genes 0.000 description 1
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 1
- 241000133063 Trixis Species 0.000 description 1
- GLNADSQYFUSGOU-GPTZEZBUSA-J Trypan blue Chemical compound [Na+].[Na+].[Na+].[Na+].C1=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(/N=N/C3=CC=C(C=C3C)C=3C=C(C(=CC=3)\N=N\C=3C(=CC4=CC(=CC(N)=C4C=3O)S([O-])(=O)=O)S([O-])(=O)=O)C)=C(O)C2=C1N GLNADSQYFUSGOU-GPTZEZBUSA-J 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000012062 aqueous buffer Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 150000001483 arginine derivatives Chemical class 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- YEESUBCSWGVPCE-UHFFFAOYSA-N azanylidyneoxidanium iron(2+) pentacyanide Chemical compound [Fe++].[C-]#N.[C-]#N.[C-]#N.[C-]#N.[C-]#N.N#[O+] YEESUBCSWGVPCE-UHFFFAOYSA-N 0.000 description 1
- 238000003287 bathing Methods 0.000 description 1
- IQFYYKKMVGJFEH-UHFFFAOYSA-N beta-L-thymidine Natural products O=C1NC(=O)C(C)=CN1C1OC(CO)C(O)C1 IQFYYKKMVGJFEH-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 150000004662 dithiols Chemical class 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960000848 foscarnet sodium Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 150000003278 haem Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 1
- 208000033519 human immunodeficiency virus infectious disease Diseases 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 239000007943 implant Substances 0.000 description 1
- 238000010874 in vitro model Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 210000004347 intestinal mucosa Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- JJWLVOIRVHMVIS-UHFFFAOYSA-N isopropylamine Chemical compound CC(C)N JJWLVOIRVHMVIS-UHFFFAOYSA-N 0.000 description 1
- 229960002479 isosorbide Drugs 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002826 nitrites Chemical class 0.000 description 1
- 229960002460 nitroprusside Drugs 0.000 description 1
- 230000009935 nitrosation Effects 0.000 description 1
- 238000007034 nitrosation reaction Methods 0.000 description 1
- 125000000018 nitroso group Chemical group N(=O)* 0.000 description 1
- 108091005622 nitrosylated proteins Proteins 0.000 description 1
- ODUCDPQEXGNKDN-UHFFFAOYSA-N nitroxyl Chemical compound O=N ODUCDPQEXGNKDN-UHFFFAOYSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 229910052711 selenium Inorganic materials 0.000 description 1
- 239000011669 selenium Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940104230 thymidine Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 150000003624 transition metals Chemical class 0.000 description 1
- DFHAXXVZCFXGOQ-UHFFFAOYSA-K trisodium phosphonoformate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)P([O-])([O-])=O DFHAXXVZCFXGOQ-UHFFFAOYSA-K 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000007419 viral reactivation Effects 0.000 description 1
- 238000009736 wetting Methods 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/19—Cytokines; Lymphokines; Interferons
- A61K38/21—Interferons [IFN]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/556—Angiotensin converting enzyme inhibitors
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/0005—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts
- A61L2/0082—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor for pharmaceuticals, biologicals or living parts using chemical substances
- A61L2/0094—Gaseous substances
Definitions
- This invention relates to the field of inhibiting retroviral replication in vitro and in vivo and to the treatment in humans and other animals of active and latent retroviral infections.
- the invention is based on the discovery by the inventors that nitric oxide and adducts thereof which are nitric oxide donors inhibit retroviral replication and provides a method for inhibiting the replication of a retrovirus by exposing the retrovirus to nitric oxide or a nitric oxide-releasing, donating or transferring substance.
- the present invention provides a method for inhibiting retroviral replication in a retrovirally infected cell or tissue culture in vitro which comprises contacting said retrovirally infected cell or tissue culture with an amount of nitric oxide or a nitric oxide-delivering, releasing or transferring compound sufficient to inhibit retroviral replication in said retrovirally infected cell or tissue culture.
- Another aspect of the invention provides a method for inhibiting retroviral replication in a retrovirally infected animal which comprises administering to said retrovirally infected animal an amount of nitric oxide or a nitric oxide-delivering, releasing or transferring compound sufficient to inhibit retroviral replication in said retrovirally infected animal.
- Another aspect of the invention provides a method for inhibiting retroviral replication in a retrovirally infected individual which comprises administering to said retrovirally infected individual an amount of nitric oxide or a nitric oxide-delivering, releasing or transferring compound sufficient to inhibit retroviral replication in said retrovirally infected individual.
- Another aspect of the invention provides a method for inhibiting the reactivation of latent retrovirus in a retrovirally infected cell or tissue culture which comprises contacting said retrovirally infected cell or tissue culture with a retrovirus reactivation inhibiting amount of nitric oxide, or a nitric oxide releasing, donating, or transferring substance which may be used prophylactically to prevent reactivation of latent retrovirus. This is very useful in mitigating the dangers of sample handling for research, laboratory and hospital personnel.
- Another aspect of the invention provides a method for inhibiting the reactivation of a latent retrovirus infection in an animal in need thereof which comprises administering to said animal in need thereof an amount of nitric oxide, or a nitric oxide releasing, donating, or transferring substance sufficient to inhibit reactivation of latent retrovirus in said animal.
- Another aspect of the invention provides a method for inhibiting the reactivation of a latent retrovirus infection in an individual in need thereof which comprises administering to an individual in need thereof an amount of nitric oxide, or a nitric oxide releasing, donating, or transferring substance sufficient to inhibit reactivation of latent retrovirus in said individual.
- This is very useful, for example, in an lmmunocompromised host in which reactivation at an inopportune time (e.g. when defenses are low due to chemotherapy) would cause significant morbidity.
- the invention is further based on the discovery by the inventors that nitric oxide synthase inhibitors and nitric oxide scavengers activate latent retrovirus. This is the first demonstration of a mechanism for eradicating the latent state, i.e.. once activated, the retrovirus can then be eliminated with antiviral therapy. Thus, this aspect of the present invention is directed to the use of nitric oxide synthase inhibitors as a means to eradicate latent virus.
- another aspect of the invention provides a method for preventing or reversing retroviral latency in a retrovirally infected cell or tissue culture in vitro which comprises contacting a retrovirally infected cell or tissue culture in vitro with a nitric oxide synthase inhibitor or nitric oxide scavenger, such as hemoglobin, in an amount sufficient to render the latent retrovirus in the retrovirally infected cell or tissue culture replication-competent.
- a nitric oxide synthase inhibitor or nitric oxide scavenger such as hemoglobin
- compositions for the treatment of a latent retrovirus infection in an animal infected with a latent retrovirus infection which comprises (i) a nitric oxide synthase inhibitor or nitric oxide scavenger, such as hemoglobin, in an amount sufficient to render the retrovirus infecung said animal rep cauon-competent and (ii) a retrovirus replication inhibitory amount of an antiviral agent in a pharmaceutically acceptable carrier.
- Another aspect of the invention provides a method for the treatment of a latent retrovirus infection in an animal infected with a latent retrovirus infection which comprises administering thereto (i) a nitric oxide synthase inhibitor or nitric oxide scavenger, such as hemoglobin, in an amount sufficient to render the retrovirus infecting said animal replication-competent and (ii) a retroviral replication inhibitory amount of an antiviral agent.
- a nitric oxide synthase inhibitor or nitric oxide scavenger such as hemoglobin
- compositions for the treatment of a latent retrovirus infection in an individual infected with a latent retrovirus infection which comprises (i) a nitric oxide synthase inhibitor or nitric oxide scavenger, such as hemoglobin, in an amount sufficient to render the retrovirus infecting said individual replication-competent and (ii) a retrovirus replication inhibitory amount of an antiviral agent in a pharmaceutically acceptable carrier.
- Another aspect of the invention provides a method for the treatment of a latent retrovirus infection in an individual infected with a latent retrovirus infection which comprises administering thereto (i) a nitric oxide synthase inhibitor or nitric oxide scavenger, such as hemoglobin, in an amount sufficient to render the retrovirus infecting said individual replication-competent and (ii) a retroviral replication inhibitory amount of an antiviral agent.
- a nitric oxide synthase inhibitor or nitric oxide scavenger such as hemoglobin
- Retroviruses whose growth may be inhibited in accordance with the method of the present invention include, but are not limited to, human immunodeficiency virus (HIV), human T-cell leukemia virus-1 (HTLV-1) and simian immunodeficiency virus (SIV).
- HIV human immunodeficiency virus
- HTLV-1 human T-cell leukemia virus-1
- SIV simian immunodeficiency virus
- the administration can be topical, by inhalation, oral, or parenteral.
- the treated infection can be localized or systemic.
- Figures 1A-1D show that NO generating compounds inhibit HIV-1 replication in human peripheral blood mononuclear cells and in the chronically infected human T cell line H9:
- Figure 1A shows results when human peripheral blood mononuclear cells (PBMCs) stimulated with PHA and IL-2 were infected with HIV-1. and then grown in the presence or absence of the NO generating compound S-nitroso-N- acetyl-penicillamine (SNAP), or the parent compound N-acetyl-penicillamine (NAP);
- Figure IB shows the results when the same experiment as shown in Figure 1A was performed using the NO-generating compound S-nitroso-N-acetyl- cysteine (SNAC) or the parent compound N-acetyl cysteine (NAC);
- Figure IC shows the results when H9 cells were grown in the presence or absence of the NO generating compound SNAP.
- Figure ID shows the results when the same experiment as shown in Figure IC was performed using the NO generating compound S-nitroso-penicillamine (SNP) or the control compound penicillamine (P).
- SNP S-nitroso-penicillamine
- P control compound penicillamine
- Figures 2A-2B show the effect of NO on PBMC proliferation:
- Figure 2A shows the results when human peripheral blood mononuclear cells are stimulated with PHA and IL-2 were grown in the presence or absence of the NO-generating compound SNAP or the parent compound NAP; and Figure 2B shows the results when the same experiment as shown in Figure 2A was performed using the NO-generating compound S-nitroso-N-acetyl cysteine (SNAC) or the control compound N-acetyl cysteine (NAC).
- SNAC S-nitroso-N-acetyl cysteine
- NAC N-acetyl cysteine
- Figures 3A-3B show that iNOS is expressed constitutively in U-937 cells
- Figure 3A shows cDNA that was made from whole cell RNA from U- 937 or from the control B cell line B-958 which is known to express iNOS;
- Figure 3B shows a western blot that was performed on whole cell lysates made from 0.5xl0 6 U-937 cells (U-937), the human B cell line BL-30. and rat macrophages stimulated with LPS (Rat).
- Figures 4A-4B show that endogenously produced NO inhibits HIV replication and HIV reactivation:
- FIG. 4A shows the results when U-937 cells were infected with HIV-1 and then grown in the presence or absence of the NOS inhibitor L-NMA:
- Figure 4B shows the results when the latently infected Ul cell line was grown in the presence or absence of L-NMA and TNF ⁇ .
- Figure 5 shows the effect of cGMP on HIV replication. Peripheral blood mononuclear cells were infected with HIV-1 and then grown in the presence or absence of SNAP. NAP or the cGMP analog 8-bromo-cGMP.
- nitric oxide and compounds that release nitric oxide or otherwise directly or indirectly deliver or transfer nitric oxide to a site of its activity, such as on a cell membrane, in vivo.
- nitric oxide encompasses uncharged nitric oxide(NO») and charged nitric oxide species, particularly including nitrosonium ion(NO 'f ) and nitroxyl ion(NO ).
- the reactive form of nitric oxide can be provided by gaseous nitric oxide.
- nitric oxide releasing, delivering or transferring compounds having the structure X-NO wherein X is a nitric oxide releasing, delivering or transferring moiety, include any and all such compounds which provide nitric oxide to its intended site of action in a form active for their intended purpose.
- NO adducts encompasses any of such nitric oxide releasing, delivering or transferring compounds, including, for example, S-nitrosothiols, S- nitroso amino acids, S-nitroso-polypeptides, and nitrosoamines. It is contemplated that any or all of these "NO adducts can be mono- or poly- nirosylated at a variety of naturally susceptible or artificially provided binding sites for nitric oxide.
- S-nitrosothiols which are compounds that include at least one -S-NO group.
- Such compounds include S-nitroso- polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof): S- nitrosylated amino acids(including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); S-nitrosated sugars, S- nitrosated-modified and unmodified oligonucleotides (preferably of at least 5.
- S-nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon: S-nitroso hydrocarbons having one or more substituent groups in addition to the S-nitroso group; and heterocyclic compounds.
- S-nitrosothiols and the methods for preparing them are described in U.S. Patent Application No. 07/943.834, filed September 14. 1992, Oae et al.. Org. Prep. Proc. Int., 15.(3): 165-198 (1983); Loscalzo et al.. J. Pharmacol. Exp. Ther.. 242(3):726729 (1989) and Kowaluk et al.. J. Pharmacol. Exp. Ther., 2-5£: 1256- 1264 (1990), all of which are incorporated in their entirety by reference.
- One particularly preferred embodiment of this aspect relates to S-nitroso amino acids where the nitroso group is linked to a sulfur group of a sulfur-containing amino acid or derivative thereof.
- such compounds include the following: S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine. S-nitroso-cysteine and S-nitroso-glutathione.
- Suitable S-nitrosylated proteins include thiol-containing proteins(where the NO group is attached to one or more sulfur group on an amino acid or amino acid derivative thereof) from various functional classes including enzymes, such as tissue- type plasminogen activator(TPA) and cathepsin B; transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin: and biologically protective proteins, such as the immunoglobulins and the cytokines.
- TPA tissue- type plasminogen activator
- cathepsin B transport proteins, such as lipoproteins, heme proteins such as hemoglobin and serum albumin: and biologically protective proteins, such as the immunoglobulins and the cytokines.
- nitrosylated proteins are described in PCT Publ. Applic. No. WO 93/09806, published May 27, 1993. Examples include polynitrosylated albumin where multiple thiol or other nucleophilic centers in the protein are modified.
- S-nitrosothiols include those having the structures:
- aryl includes benzyl, naphthyl. and anthracenyl groups.
- S-nitroso-ACE inhibitors S-nitroso-angiotensin converting enzyme inhibitors
- S-nitroso-ACE inhibitors S-nitroso-angiotensin converting enzyme inhibitors
- R is hydroxy, NH 2 , NHR 4 , NR 4 R ⁇ or C,-C 7 alkoxy, wherein R 4 and R 5 are C,-C 4 alkyl, or phenyl, or C,-C 4 alkyl substituted by phenyl;
- R 1 is hydrogen, C C 7 alkyl, or C,-C 7 alkyl substituted by phenyl, amino, guanidino, NHR 6 , NR 6 R 7 , wherein R 6 and R 7 are methyl or C r C 4 alkanoyl;
- R 2 is hydrogen, hydroxy, C,-C 4 alkoxy, phenoxy, or C,-C 7 alkyl
- R 3 is hydrogen, C r C 4 or C,-C 7 alkyl substituted by phenyl; m is 1 to 3; and n is 0 to 2.
- S-nitroso-ACE inhibitors include N-acetyl-S-nitroso-D-- cysteinyl-L-proline, N-acetyl-S-nitroso-D,L-cysteinyl-L-proline, l-[4-amino-2-(S- nitroso)mercaptomethyl butanoyl]-L-proline, l-[2-hexanoyl]-L-proline.
- S-nitroso-ACE inhibitors include those having structures
- A is ON-S-CH,-CH-C;
- R is selected from hydrogen, lower (C,-C 4 ) alkyl, benzyl, benzhydryl, and salt forming ion:
- R, and R are independently selected from hydrogen, halogen, lower alkyl, lower alkoxy. halo substituted lower alkyl, nitro. and S0 2 NH 2 ; 0 0 0
- Z is -C- or -S-
- R 3 is hydrogen, lower alkyl, halo substituted lower alkyl, phenyl, benzyl, phenethyi, or cycloalkyl;
- R 4 is hydrogen, lower alkyl, halo substituted lower alkyl, hydroxy substituted lower alkyl, -(CH 2 ) q -N (lower alkyl), or -(CH 2 ) q -NH, and q is one, two, three or four.
- the S-nitroso-ACE inhibitors can be prepared by various methods of synthesis.
- Acids which may be used for this purpose include aqueous sulfuric. acetic and hydrochloric acids.
- Thiol precursors are prepared as described in the following: U.S. Pat. Nos. 4.046,889 ( 1977); 4.052,51 1 : 4,053,651 ; 4, 1 13,751 , 4.154,840, 4129,571 ( 1978), and 4.
- Such compounds include O-nitroso-polypeptides(the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); O-nitrosylated amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); O-nitrosated sugars; O-nitrosated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200. nucleotides); and an O-nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched.
- NO adducts saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon: O-nitroso hydrocarbons having one or more substituent groups in addition to the O-nitroso group; and heterocyciic compounds.
- Another group of such NO adducts is the nitrites which have an -O-NO group wherein R is a protein, polypeptide. amino acid, branched or unbranched and saturated or unsaturated alkyl. aryl or a heterocyclic.
- R is a protein, polypeptide. amino acid, branched or unbranched and saturated or unsaturated alkyl. aryl or a heterocyclic.
- a preferred example is tJne nitosylated form of isosorbide.
- Compounds in this group form S-nitrosothiol intermediates in vivo in the recipient human or other animal to be treated and can therefore include any structurally analogous precursor R-O-NO of the S-rutrosothio
- N-nitrosoammes are compounds that include at least one -N-NO group.
- Such compounds include N- mtroso-polypeptides (the term “polypepnde” includes proteins and also polyamino acids that do not possess an ascertained biological function, and denvauves thereof); N-nitrosylated ammo acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures); N-rutrosated sugars; N-mtrosated-modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and an N-nitrosated hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; N-nitroso hydrocarbons having one or more substituent groups in addition to the N-mtroso group; and heterocyclic compounds.
- C-rutroso compounds that include at least one -C-NO group.
- Such compounds include C-nitroso-polypepUdes (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and denvatives thereof); C-nitrosylated amino acids (including natural and synthetic ammo acids and their stereoisomers and racemic mixtures); C-nitrosated sugars; C-rutrosated-modified and unmodified oligonucleotides (preferably of at least 5.
- hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic 96/31217 PCI7US96/04084
- hydrocarbon C-nitroso hydrocarbons having one or more substituent groups in addition to the C-nitroso group; and heterocyclic compounds.
- polypeptides include proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof: amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars: modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200. nucleotides); and a hydrocarbon where the hydrocarbon can be a branched or unbranched. and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; hydrocarbons having one or more substituent groups; and heterocyclic compounds.
- a preferred example is nitroglycerin.
- R includes polypeptides(the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); amino acids (including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5.
- A is S, O, or N
- n and x are each integers independently selected from 1. 2 and 3.
- M is a metal, preferably a transition metal.
- Prefened metals include iron, copper, manganese, cobalt, selenium and luthidium. Also contemplated are N-rutrosylated metal centers such as nitroprusside.
- R includes polypeptides (the term "polypeptide” includes proteins and also polyamino acids that do not possess an ascertained biological function, and derivatives thereof); ammo ac ⁇ ds( including natural and synthetic amino acids and their stereoisomers and racemic mixtures and derivatives thereof); sugars; modified and unmodified oligonucleotides (preferably of at least 5, and more particularly 5-200, nucleotides); and a hydrocarbon where the hydrocarbon can be a branched or unbranched, and saturated or unsaturated aliphatic hydrocarbon, or an aromatic hydrocarbon; hydrocarbons having one or more substituent groups; and heterocyclic compounds.
- R is preferably a nucleophilic (basic) moiety.
- M + is a metal cation, such as, for example, a Group 1 metal cation
- thionitrates which have the structure R-(S) x -NO wherein x is an integer of at least 2.
- R is as described above for the S- nitrosothiols.
- dithiols wherein x is 2.
- Particularly preferred are those compounds where R is a polypeptide or hydrocarbon and a par or pairs of thiols are sufficiently structurally proximate, i.e. vicinal, that the pair of thiols will be reduced to a disulfide.
- Those compounds which form disulfide species release nitroxyl ⁇ on(NO ) and uncharged nitric ox ⁇ de(NO»).
- Those compounds where the thiol groups are not sufficiently close to form disulfide bridges generally only provide nitric oxide as the NO form but not as the uncharged NO* form.
- Agents which stimulate endogenous NO synthesis are also suitable for use in accordance with the invention.
- Viruses whose replication may be inhibited or prevented by the compounds described hereinabove include retroviruses such as human immunodeficiency virus (HIV), human T-cell leukemia v ⁇ rus- 1 (HTLV-1), and simian immunodeficiency virus (SIV).
- retroviruses such as human immunodeficiency virus (HIV), human T-cell leukemia v ⁇ rus- 1 (HTLV-1), and simian immunodeficiency virus (SIV).
- these compounds can be employed in various therapeutic treatments, including: 1 ) the incorporation of NO donors into creams, salves or lotions for the treatment of topical infections: 2) the use of inhaled nitric oxide and other NO donors for the treatment of lung infections: 3) the use of topical drops and creams for the treatment of mucocutaneous membrane infections, such as infections of the eye, mouth and genitourinary tract; and 4) oral or parenteral administration for systemic or localized infections.
- the nitric oxide When administered in vivo, the nitric oxide may be administered in combination with pharmaceutical carriers and in dosages described herein.
- Certain viruses can both replicate (lytic phase) and also incorporate themselves into the genome (latency).
- the virus When latent, the virus may serve as a protooncogene. thereby promoting cancer; and it is also resistant to antiviral therapy. Thus, the establishment of latency prevents elimination of virus with antiviral therapy.
- Another aspect of the invention is based on the discovery that nitric oxide synthase inhibitors activate latent retrovirus. This is the first demonstration of a mechanism for eradicating the latent state, i.e., once activated, the retrovirus can then be eliminated with antiviral therapy. Thus, this aspect of the present invention is directed to the use of nitric oxide synthase inhibitors as a means to eradicate latent virus.
- the invention provides a method for preventing or reversing retroviral latency in a cell, tissue or animal infected therewith which comprises administering thereto a nitric oxide synthase inhibitor in an amount sufficient to render the retrovirus replication-competent.
- this aspect of the invention provides a method for the treatment of a latent retrovirus infection in a cell, tissue or animal so-infected, which comp ⁇ ses administering thereto (i) a nitric oxide synthase inhibitor in an amount sufficient to render the retrovirus replication-competent and (ii) a replication inhibitory amount of an antiviral agent.
- this aspect of the invention provides a composition for the treatment of a latent retrovirus infection in a cell, tissue or animal so- infected, which comprises (i) a nitric oxide synthase inhibitor in an amount sufficient to render the retrovirus replication-competent and (ii) a replication inhibitory amount of an antiviral agent in a pharmaceutically acceptable carrier.
- Suitable nitric oxide synthase inhibitors include arginine derivatives such as N G -monomethyl-L-arginine (NMA), nitro-arginine, diphenylene iodonium and related iodonium derivatives, N-nitro-L-arginine methyl ester, N-methyl-L-arginine, N- amino-L-arginine, ornithine, N-imino-ethyl-L-ornithine and ornithine derivatives, N- nitro-L-arginine, methylene blue, heme binders, trifluoropiperazine, and calcinarin and other calmodulin binders, such as methotrexate.
- NMA N G -monomethyl-L-arginine
- NMA nitro-arginine
- diphenylene iodonium and related iodonium derivatives N-nitro-L-arginine methyl ester
- antiviral agent refers to any agent that inhibits, prevents, or destroys the growth or replication of a retrovirus.
- the antiviral agent can be a purine nucleoside analog such as acyclovir or didanosine.
- the antiviral agent can be a pyrimidine nucleoside analog such as zidovudine, trifluridine and zalcitabine.
- the antiviral agent can also be a chelating agent such as foscarnet sodium.
- the antiviral agent can be an intercalating agent.
- the antiviral agent can be an interferon, preferably an ⁇ -interferon, a ⁇ -interferon or a 7- interferon.
- Treatment of localized topical infection with the nitnc oxide or rutnc oxide releasing agent compnses contacting the surface so as to cause the surface to be coated with the nitnc oxide or nitnc oxide releasing agent.
- Coating may be accomplished using standard methods well known to those of ordinary skill in the art. For example, coating a surface with nitnc oxide adducts can be achieved by bathing the surface in a solution containing the nitnc oxide adduct.
- synthetic mtnc oxide adducts may be coated onto an artificial surface such as a bandage or covenng by a vanety of chemical techmques which are well known in the art.
- Modes of administration include but are not limited to topical, transdermal, intramuscular, intrapentoneal, intravenous, vaginal, subcutaneous, intranasal. topical and oral routes.
- the compounds may be administered by any convenient route, for example by infusion or bolus injection by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa. rectal and intestinal mucosa. etc.) and may be administered together with other biologically active agents.
- Pnncipal approaches to therapeutic uses of the invention include topical administration to treat skin infections; topical administration to treat genital and oral lesions; topical administration to treat eye infections; topical or inhalation administration of NO/or SNAC to treat respiratory infections; and particularly intravenous administration to treat systemic infection.
- the compounds of this invention can be employed in combination with conventional excipients, 1. e., pharmaceutically acceptable organic or inorganic earner substances suitable for parenteral application which do not deletenously react with the active compounds.
- suitable pharmaceutically acceptable earners include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycendes and diglycendes, petroethral fatty acid esters, hydroxymethylcellulose. polyvinylpyrrolidone, etc.
- the pharmaceutical preparations can be sten zed and if desired, mixed with auxiliary agents, e.g.
- lubncants for influencing osmotic pressure, buffers, colonngs, flavonng and/or aromatic substances and the like which do not deletenously react with the active compounds.
- suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants.
- Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
- the suspension may also contain stabilizers.
- the composition can also contain minor amounts of wetting or emulsifying agents, or pH buffe ⁇ ng agents.
- the composition can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder.
- the composition can be formulated as a suppository, with traditional binders and earners such as tnglyce ⁇ des.
- Oral formulations can include standard earners such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate. sodium saccha ⁇ ne, cellulose, magnesium carbonate, etc.
- Vanous delivery systems are known and can be used to admimster a therapeutic compound or composition of the invention, e.g. , encapsulation in liposomes, microparticies, microcapsules and the like.
- the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
- compositions for intravenous administration are solutions in stenle lsotoruc aqueous buffer.
- the composition may also include a solubilizing agent and a local anesthetic to ameliorate any pain at the sue of the injection.
- the ingredients are supplied either separately or mixed together in umt dosage form, for example, as a drylyophihzed powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
- composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
- an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to admimstration.
- the therapeutics of the invention can be formulated as neutral or salt forms.
- Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, sulfuric, acetic, oxalic, tartaric acids, etc. , and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanoi. histidine. procaine, etc.
- terapéuticaally effective amount refers to the amount of the nitric oxide adduct which is effective to achieve its intended purpose. While individual needs vary, determination of optimal ranges for effective amounts of each nitric oxide adduct is within the skill of the art. Generally, the dosage required to provide an effective amount of the composition, and which can be adjusted by one of ordinary skill in the art will vary, depending on the age, health, physical condition, sex, weight, extent of disease of the recipient, frequency of treatment and the nature and scope of the disorder.
- the amount of the therapeutic of the invention which will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. The precise dose to be employed in the formulation will also depend on the route of admimstration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances.
- suitable dosage ranges for intravenous administration are generally about 20-500 micrograms of active compound per kilogram body weight.
- Suitable dosage ranges for intranasal administration are generally about 0.01 pg/kg body weight to 1 mg/kg body weight.
- Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems and are in the same ranges or less than as described for the commercially available compounds in the Physician's Desk Reference. Medical Economics Company, Inc., Oradell, N.J. 1990.
- the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
- a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
- Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
- Peripheral blood mononuclear cells isolated from HIV-1 negative adult donors were stimulated for 48 hours with 10 ⁇ g/ml of PHA.
- the cells were then infected with HIV- 1 strain MN at an MO1 of 0.1 for 1-2 hours at 37°C, washed three times and resuspended at 500,000 cells/ml in complete medium (RPMI 1640 10% fetal bovine serum) supplemented with 10 units/ml of 1L-10 with or without various concentrations of SNAP, NAP, SNAC or NAC.
- the cells were then plated in 24 well plates with 2 ml of cells per well. After 4 days, the cells were split and refed with the same media in which they were originally resuspended. After 5-8 days in culture, cell supernatants were collected, and p24 antigen levels determined using the HIV- 1 p24 Core Profile assay (NEN) as per the manufacturer's instructions.
- H9 cells were pelleted and infected with HIV-1 strain MN at an MOI of 0.1 for 1-2 hours at 37° C. washed three times, resuspended at a concentration of 100,000 cells/ml in complete medium supplemented with or without SNAP, NAP, SNOP or penicillamine, and plated in 24 well plates with 2 ml of cells per well. After 3 days, p24 antigen levels were measured in the H9 cell supernatants using the method described above.
- U937 cells were pelleted and infected with HIV-1 strain MN at an MOI of 0.2 for 1-2 hours at 37°C, washed three times and then resuspended at 100,000 cells/ml in RPMI 1640 containing 10% FBS and 0.1 mM arginine with or without L- NMA. The cells were then plated in 24 well plates containing 2 ml of cells per well. Twice a week the cells were split and refed with the same media in which they were originally resuspended. After 8-14 days, p24 antigen levels were measured in the cell supernatants using the method described above.
- Ul cells were resuspended at a concentration of 100.000 cells per ml in RPMI 1640 (GIBCO) containing 10% FBS and 0.1 mM arginine with or without TNF- ⁇ or L-NMA. The cells were then plated in 24 well plates containing 2 ml of cells per well. After 48-72 hours in culture, p24 antigen levels were measured in the cell supernatants using the method described above.
- the effect of NO generating compounds on HIV- 1 replication was determined by growing human peripheral blood mononuclear cells (PBMCs) infected with HIV-1 (MN strain) in the presence or absence of NO-generating compounds or control parent compounds which do not generate NO. The extent of HIV-1 replication was determined 5 to 8 days after infection by measuring p24 antigen levels in the cell supernatants.
- Figures 1A-1D shew that NO generating compounds inhibit HIV-1 replication in human peripheral blood mononuclear cells and in the chronically infected human T cell line H9.
- Figure 1A shows results when human peripheral blood mononuclear cells (PBMCs) stimulated with PHA and IL-2 were infected with HIV-1 , and then grown in the presence or absence of the NO generating compound S-nitroso-N-acetyl- penicillamine (SNAP), or the parent compound N-acetyl-penicillamine (NAP).
- SNAP S-nitroso-N-acetyl- penicillamine
- NAP N-acetyl-penicillamine
- the data are expressed as the percent of control p24 levels. Since SNAP and NAP were diluted in ETOH, the effect of 0.2 % ETOH (the concentration present in 200 uM SNAP and NAP cultures) was determined. The results represent the mean of 9 separate experiments ⁇ SEM for 100. 200. and 300 uM SNAP or NAP. and the mean of 2 separate experiments for 10, 50, 150 and 250 uM SNAP or NAP concentrations.
- Figure IB shows the results when the same experiment as shown in Figure 1 A was performed using the NO-generating compound S-nitroso-N-acetyl-cysteine (SNAC) or the parent compound N-acetyl cysteine (NAC). Similar effects were seen with the NO-generating compound S-nitroso-N-acetyl-cysteine (SNAC) and the control parent compound N-acetyl-cysteine (NAC). The data are expressed as the mean of duplicate cultures.
- Figure IC shows the results when H9 cells were grown in the presence or absence of the NO generating compound SNAP; and After three days in the culture. p24 levels in the cell supernatants were measured by ELISA. Again, the NO donor SNAP inhibited HIV replication in a dose dependent fashion. The data are expressed as the mean of duplicate cultures and are repesentative of one of three expenments.
- Figure ID shows the results when the same expenment as shown in Figure IC was performed using the NO generating compound S-nitroso-penicillamine (SNP) or the control compound penicillamine (P). Similar results were seen with the NO donor S-nitroso-penicillamine (SNP) but not with the parent compound penicillamine (P). The data are expressed as the mean of duplicate cultures.
- Figures 2A-2B show the effect of NO on PBMC proliferation.
- Figure 2A shows the results when human pe ⁇ pheral blood mononuclear cells stimulated with PHA and IL-2 were grown in the presence or absence of the NO- generating compound SNAP or the parent compound NAP.
- the effects of SNAP or NAP on PBMC proliferation were analyzed by tntiated thymidine uptake. Higher concentrations of SNAP (i.e. 200 uM-500 uM) inhibited PBMC proliferation, however, 50-150 uM SNAP did not inhibit PBMC proliferation and yet inhibited p24 antigen production (Figure 1A). After 6 days in culture, [ 3 H]-thym ⁇ d ⁇ ne uptake was measured.
- SNAP and NAP were diluted in ETOH and therefore, as a control, the effect of ETOH on PBMC proliferation was measured.
- concentrations of ETOH present in 100. 200. 300. and 400 uM SNAP or NAP were 0.1 %. 0.2%, 0.3 %. and 0.4 % ETOH. respectively.
- Figure 2B shows the results when the same experiment as shown in Figure 2A was performed using the NO-generating compound S-nitroso-N-acetyl cysteine (SNAC) or the control compound N-acetyl cysteine (NAC). After 6 days in culture the number of viable cells was determined by trypan blue staining. Concentrations of SNAC which inhibited HIV replication (Figure IB) had no effect on PBMC proliferation. Thus NO appears to have an inhibitory effect on HIV replication which is independent of its anti-proliferative effect.
- SNAC S-nitroso-N-acetyl cysteine
- NAC N-acetyl cysteine
- NO synthase (NOS) activity is difficult to demonstrate in human mononuclear cells, presumably because they express very low levels of NOS.
- inducible NOS(iNOS) expression and activity was evident in the U-937 human promonocytic cell line.
- Figures 3A-3B show that iNOS is expressed constitutively in U-937 cells.
- Figure 3A shows cDNA that was made from whole cell RNA from U-937 or from the control B cell line B-958 which is known to express iNOS. Samples to which reverse transcriptase was ( + RT) or was not (-RT) added are indicated. Equal amounts of each sample were PCR amplified using primers specific for human iNOS. The markers on the left indicate the base pair size of OX DNA fragments generated from an Hae III digest. iNOS RNA expression was detected in U-937 cells by RT- PCR using human iNOS-specific primers. This RT-PCR product was sequenced and found to be identical to the human hepatic iNOS cDNA sequence.
- Figure 3B shows a western blot that was performed on whole cell lysates made from 0.5xl0 6 U-937 cells (U-937).
- INOS expression was detected using an affinity purified rabbit antiserum was raised against the C-terminal 20 amino acids of the rat isoform and recognizes both human and rat iNOS (Kobzik et al. 1993).
- the rat isoform which shares 80 % homology with the human isoform. runs slightly below the human isoform on polyacrylamide gels.
- NO production by U- 937 cells was detected by a photolysis/chemilumincesence assay.
- Figure 4A shows the results when U-937 cells were infected with HIV-1 and then grown in the presence or absence of the NOS inhibitor L-NMA; and After 8-10 days in culture, p24 levels in the cell supernatants were determined by ELISA. Inhibition of endogenous NO synthesis by L-NMA caused a small but statistically significant increase in p24 antigen levels, with maximal effects seen between 100-250 uM L-NMA. The L-NMA-induced increase in p24 levels was abrogated by the addition of excess L-arginine, the NOS substrate. Thus, both endogenously synthesized NO and exogenous NO appear to inhibit HIV replication. The data represent the mean of 5 duplicate cultures and are representative of three separate experiments.
- Figure 4B shows the results when the latently infected Ul cell line was grown in the presence or absence of L-NMA and TNF ⁇ . and after 2-3 days in culture p24 antigen levels were measured in the cell supernatants by ELISA.
- L-NMA caused a dose dependent increase in p24 antigen levels with maximal effects seen at a concentration of ImM ( Figure 4B).
- the L-NMA-induced increase in p24 levels was abrogated by excess L-arginine but not D-arginine.
- the actions of NO can be broadly classified as either cGMP dependent or independent. For example, much of the inhibitory effect of NO on platelets and smooth muscle is mediated by increases in cGMP levels due to activation of guanylate cyclase.
- Figure 5 shows the effect of cGMP on HIV replication.
- Peripheral blood mononuclear cells were infected witii HIV-1 and then grown in the presence or absence of SNAP.
- NAP or the cGMP analog 8-bromo-cGMP.
- p24 antigen levels were measured in the cell supernatants.
- activation of guanylate cyclase may be one of the mechanisms by which NO inhibits HIV replication since ImM 8-bromo-cGMP (a cGMP analog) caused a three- fold inhibition of HIV replication (Figure 5); however, other mechanisms may also be involved in the NO- induced inhibition of HIV replication since NO-generating compounds can decrease HIV replication 7 fold without significantly inhibiting cellular proliferation (150 uM).
- the data represent the mean of duplicate cultures.
- the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other than as particularly described and still be within the scope of the accompanying claims.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Molecular Biology (AREA)
- Emergency Medicine (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Vascular Medicine (AREA)
- Marine Sciences & Fisheries (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Méthode de traitement d'une infection par rétrovirus, dans une cellule, un tissu ou un animal infectés, par l'administration d'une quantité capable d'inhiber la réplication du rétrovirus de monoxyde d'azote ou d'un composé donnant, libérant ou transférant du monoxyde d'azote. L'invention concerne également une méthode permettant d'empêcher ou de supprimer la latence du rétrovirus dans une cellule, un tissu ou un animal par l'administration à ces derniers d'un inhibiteur de synthase de monoxyde d'azote en quantité suffisante pour rendre le rétrovirus capable de réplication. Le traitement de l'infection par un rétrovirus latent dans une cellule, un tissu ou un animal consiste à administrer i)) un inhibiteur de synthase de monoxyde d'azote ou un capteur de monoxyde d'azote en quantité suffisante pour rendre le rétrovirus capable de réplication et ii) une quantité inhibant la réplication d'un agent antiviral. L'invention concerne une composition constituée i) d'un inhibiteur de synthase de monoxyde d'azote ou capteur de monoxyde d'azote en quantité suffisante pour rendre le rétrovirus capable de réplication et ii) une quantité, permettant l'inhibition de la réplication, d'un agent antiviral, dans un excipient pharmaceutiquement acceptable.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU55271/96A AU5527196A (en) | 1995-04-04 | 1996-03-26 | Inhibiting retroviral replication |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41604695A | 1995-04-04 | 1995-04-04 | |
US08/416,046 | 1995-04-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1996031217A1 true WO1996031217A1 (fr) | 1996-10-10 |
WO1996031217A9 WO1996031217A9 (fr) | 1996-11-28 |
Family
ID=23648310
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/004084 WO1996031217A1 (fr) | 1995-04-04 | 1996-03-26 | Inhibition de la replication des retrovirus |
Country Status (2)
Country | Link |
---|---|
AU (1) | AU5527196A (fr) |
WO (1) | WO1996031217A1 (fr) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999033823A1 (fr) * | 1997-12-23 | 1999-07-08 | Nycomed Imaging As | Chelateurs liberant de l'oxyde nitrique et leur emploi a des fins therapeutiques |
WO2000030659A1 (fr) * | 1998-11-23 | 2000-06-02 | Pulmonox Medical Corporation | Procede et appareil permettant de traiter des infections respiratoires par inhalation d'oxyde nitrique |
DE10303196A1 (de) * | 2003-01-28 | 2004-08-12 | Märtz, Hans Helmut | Verwendung von Erzeugnissen, Stoffen oder Stoffgemischen, aus welchen im menschlichen oder tierischen Körper Stickoxid (Formel: NO) entsteht, zur Behandlung oder Prophylaxe von Infektionskrankheiten des menschlichen oder tierischen Körpers |
US6793644B2 (en) | 2000-12-26 | 2004-09-21 | Sensormedics Corporation | Device and method for treatment of surface infections with nitric oxide |
WO2004087212A2 (fr) * | 2003-04-03 | 2004-10-14 | Aga Ab | Utilisation d'oxyde nitrique dans le traitement de l'inflammation |
WO2007057763A2 (fr) * | 2005-11-18 | 2007-05-24 | Pulmonox Technologies Corporation | Oxyde nitrique utilisé comme agent antiviral, vaccin et adjuvant de vaccin |
US7335181B2 (en) | 2000-12-26 | 2008-02-26 | Pulmonox Technologies Corporation | Nitric oxide decontamination of the upper respiratory tract |
WO2008005313A3 (fr) * | 2006-06-30 | 2008-02-28 | Noxilizer Inc | Système et dispositif de stérilisation |
US7503322B2 (en) * | 2003-09-12 | 2009-03-17 | Harris Michael F | Methods for the treatment of HIV and other viruses |
US8425837B2 (en) | 2009-02-23 | 2013-04-23 | Noxilizer, Inc. | Device and method for gas sterilization |
US20140038963A1 (en) * | 2011-04-04 | 2014-02-06 | Sidney Hecht | Multifunctional Radical Quenchers For The Treatment Of Mitochondrial Dysfunction |
US8703066B2 (en) | 2004-01-07 | 2014-04-22 | Noxilizer, Inc. | Sterilization system and method |
US10364227B2 (en) | 2015-02-17 | 2019-07-30 | Arizona Board Of Regents On Behalf Of Arizona State University | Therapeutic compounds |
US10472340B2 (en) | 2015-02-17 | 2019-11-12 | Arizona Board Of Regents On Behalf Of Arizona State University | Substituted phenothiazines as mitochondrial agents |
US11390605B2 (en) | 2016-08-25 | 2022-07-19 | Arizona Board Of Regents On Behalf Of Arizona State University | Substituted pyrimidine compounds as multifunctional radical quenchers and their uses |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002964A (en) * | 1988-06-15 | 1991-03-26 | Brigham & Women's Hospital | S-nitrosocaptopril compounds and the use thereof |
US5025001A (en) * | 1988-06-15 | 1991-06-18 | Brigham And Women's Hospital | S-nitroso derivatives of ACE inhibitors and the use thereof |
US5047407A (en) * | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
US5380758A (en) * | 1991-03-29 | 1995-01-10 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
-
1996
- 1996-03-26 AU AU55271/96A patent/AU5527196A/en not_active Abandoned
- 1996-03-26 WO PCT/US1996/004084 patent/WO1996031217A1/fr active Application Filing
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5002964A (en) * | 1988-06-15 | 1991-03-26 | Brigham & Women's Hospital | S-nitrosocaptopril compounds and the use thereof |
US5025001A (en) * | 1988-06-15 | 1991-06-18 | Brigham And Women's Hospital | S-nitroso derivatives of ACE inhibitors and the use thereof |
US5047407A (en) * | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
US5380758A (en) * | 1991-03-29 | 1995-01-10 | Brigham And Women's Hospital | S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof |
Non-Patent Citations (1)
Title |
---|
SCIENCE, Vol. 261, issued 10 September 1993, KARUPIAH et al., "Inhibition of Viral Replication by Interferon-Delta Induced Nitric Oxide Synthase", pages 1445-48. * |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6391895B1 (en) | 1997-12-23 | 2002-05-21 | Amersham Health As | Nitric oxide releasing chelating agents and their therapeutic use |
WO1999033823A1 (fr) * | 1997-12-23 | 1999-07-08 | Nycomed Imaging As | Chelateurs liberant de l'oxyde nitrique et leur emploi a des fins therapeutiques |
WO2000030659A1 (fr) * | 1998-11-23 | 2000-06-02 | Pulmonox Medical Corporation | Procede et appareil permettant de traiter des infections respiratoires par inhalation d'oxyde nitrique |
US6793644B2 (en) | 2000-12-26 | 2004-09-21 | Sensormedics Corporation | Device and method for treatment of surface infections with nitric oxide |
US7335181B2 (en) | 2000-12-26 | 2008-02-26 | Pulmonox Technologies Corporation | Nitric oxide decontamination of the upper respiratory tract |
DE10303196A1 (de) * | 2003-01-28 | 2004-08-12 | Märtz, Hans Helmut | Verwendung von Erzeugnissen, Stoffen oder Stoffgemischen, aus welchen im menschlichen oder tierischen Körper Stickoxid (Formel: NO) entsteht, zur Behandlung oder Prophylaxe von Infektionskrankheiten des menschlichen oder tierischen Körpers |
WO2004087212A2 (fr) * | 2003-04-03 | 2004-10-14 | Aga Ab | Utilisation d'oxyde nitrique dans le traitement de l'inflammation |
WO2004087212A3 (fr) * | 2003-04-03 | 2004-12-16 | Aga Ab | Utilisation d'oxyde nitrique dans le traitement de l'inflammation |
US7503322B2 (en) * | 2003-09-12 | 2009-03-17 | Harris Michael F | Methods for the treatment of HIV and other viruses |
US8017074B2 (en) | 2004-01-07 | 2011-09-13 | Noxilizer, Inc. | Sterilization system and device |
US8808622B2 (en) | 2004-01-07 | 2014-08-19 | Noxilizer, Inc. | Sterilization system and device |
US9180217B2 (en) | 2004-01-07 | 2015-11-10 | Noxilizer, Inc. | Sterilization system and device |
US8703066B2 (en) | 2004-01-07 | 2014-04-22 | Noxilizer, Inc. | Sterilization system and method |
WO2007057763A2 (fr) * | 2005-11-18 | 2007-05-24 | Pulmonox Technologies Corporation | Oxyde nitrique utilisé comme agent antiviral, vaccin et adjuvant de vaccin |
WO2007057763A3 (fr) * | 2005-11-18 | 2008-07-17 | Pulmonox Technologies Corp | Oxyde nitrique utilisé comme agent antiviral, vaccin et adjuvant de vaccin |
WO2008005313A3 (fr) * | 2006-06-30 | 2008-02-28 | Noxilizer Inc | Système et dispositif de stérilisation |
US8425837B2 (en) | 2009-02-23 | 2013-04-23 | Noxilizer, Inc. | Device and method for gas sterilization |
US8721984B2 (en) | 2009-02-23 | 2014-05-13 | Noxilizer, Inc. | Device and method for gas sterilization |
US9102626B2 (en) * | 2011-04-04 | 2015-08-11 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona | Multifunctional radical quenchers for the treatment of mitochondrial dysfunction |
US20140038963A1 (en) * | 2011-04-04 | 2014-02-06 | Sidney Hecht | Multifunctional Radical Quenchers For The Treatment Of Mitochondrial Dysfunction |
US9388163B2 (en) | 2011-04-04 | 2016-07-12 | Arizona Board Of Regents, A Body Corporate Of The State Of Arizona, Acting For And On Behalf Of Arizona State University | Multifunctional radical quenchers for the treatment of mitochondrial dysfunction |
US10364227B2 (en) | 2015-02-17 | 2019-07-30 | Arizona Board Of Regents On Behalf Of Arizona State University | Therapeutic compounds |
US10472340B2 (en) | 2015-02-17 | 2019-11-12 | Arizona Board Of Regents On Behalf Of Arizona State University | Substituted phenothiazines as mitochondrial agents |
US11034662B2 (en) | 2015-02-17 | 2021-06-15 | Arizona Board Of Regents On Behalf Of Arizona State University | Substituted phenothiazines as mitochondrial agents |
US11390605B2 (en) | 2016-08-25 | 2022-07-19 | Arizona Board Of Regents On Behalf Of Arizona State University | Substituted pyrimidine compounds as multifunctional radical quenchers and their uses |
Also Published As
Publication number | Publication date |
---|---|
AU5527196A (en) | 1996-10-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5545614A (en) | Controlling nitrogen oxide concentrations to modulate skeletal muscle contraction | |
WO1996031217A1 (fr) | Inhibition de la replication des retrovirus | |
WO1996031217A9 (fr) | Inhibition de la replication des retrovirus | |
Baba et al. | Potent and selective inhibition of human immunodeficiency virus type 1 (HIV-1) by 5-ethyl-6-phenylthiouracil derivatives through their interaction with the HIV-1 reverse transcriptase. | |
Sappey et al. | Iron Chelation Decreases NF-k B and HIV Type 1 Activation due to Oxidative Stress | |
Mitsuya et al. | Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2', 3'-dideoxynucleosides. | |
Sommadossi et al. | Uridine reverses the toxicity of 3'-azido-3'-deoxythymidine in normal human granulocyte-macrophage progenitor cells in vitro without impairment of antiretroviral activity | |
EP0735890B1 (fr) | Melanges de 2',3'-didesoxy-inosine et d'hydroxycarbamide utilises dans l'inhibition de la propagation d'un retrovirus | |
Malley et al. | Synergistic anti-human immunodeficiency virus type 1 effect of hydroxamate compounds with 2', 3'-dideoxyinosine in infected resting human lymphocytes. | |
KR20010020611A (ko) | 항산화제에 의한 과증식질병 치료의 향상 | |
ES2312884T3 (es) | Composiciones antivirales que comprenden derivados de acido fenilacetico. | |
WO1996002241A9 (fr) | Utilisation d'une espece d'oxyde d'azote et d'adjuvants pour inhiber la contraction des muscles squelettiques | |
Mannick et al. | Nitric oxide modulates HIV-1 replication | |
Baba | Inhibitors of HIV-1 gene expression and transcription | |
DK166715B1 (da) | Farmaceutiske produkt og anvendelse af dette til fremstilling af et kombinationspraeparat til behandling af virusinfektioner | |
US7629382B2 (en) | Use of tellurium containing compounds as nerve protecting agents | |
US5073571A (en) | Method of inhibiting virus | |
WO1996002268A1 (fr) | Inhibition d'un virus par l'oxyde nitrique | |
CA2386325C (fr) | Complexes de gallium de 3-hydroxy-4-pyrones destines au traitement d'infections par des procaryotes intracellulaires, des virus a adn et des retrovirus | |
WO1996003139A1 (fr) | Utilisation de l'oxyde nitrique ou de ses produits d'addition pour la conservation des plaquettes | |
Baba et al. | Anti-human immunodeficiency virus type 1 activities and pharmacokinetics of novel 6-substituted acyclouridine derivatives | |
WO1994022307A1 (fr) | Suppression de l'expression du vih a l'aide de thiophosphate organique | |
US6686333B1 (en) | Inhibition of HIV replication using soluble Tat peptide analogs | |
US7176192B2 (en) | Method for treating patients for radiation exposure | |
CN111315374A (zh) | 合成的赖氨酸类似物和模拟物的用于抗病毒用途的方法和组合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE |
|
COP | Corrected version of pamphlet |
Free format text: PAGES 1-28,DESCRIPTION,REPLACED BY NEW PAGES 1-29;PAGES 29-36,CLAIMS,REPLACED BY NEW PAGES 30-36;PAGES 1/5-5/5,DRAWINGS,REPLACED BY NEW PAGES 1/6-6/6;DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: CA |