title: Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication.
abstract: Glutathione depletion may play a pivotal role in the pathogenesis of human immunodeficiency virus type-1 (HIV-1) infection. Since certain compounds prevent experimental carcinogenesis by elevating the levels of glutathione and phase II detoxication enzymes, we compared the potencies of several inducers with their ability to inhibit basal levels of HIV-1 replication in H9 cutaneous T-cell lymphoma cells. All monofunctional inducers tested elevated the levels of glutathione and quinone reductase, a marker for phase II enzyme induction. However, only oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] was effective at inhibiting HIV-1 replication (IC50 = 14.8 +/- 3.1 microM). The antiviral effect of oltipraz was potentiated by 3'-azido-3'-deoxythymidine. Thus, 1,2-dithiole-3-thiones represent a hitherto unrecognized class of anti-HIV-1 agents. Oltipraz behaves kinetically as an irreversible inhibitor of HIV-1 reverse transcriptase in the template-primer binding domain. Oltipraz has been used to treat schistosomiasis in humans and is undergoing clinical evaluation as an anticarcinogen. Thus, oltipraz (and other 1,2-dithiole-3-thiones) may have therapeutic utility in HIV-1-infected individuals, not only because of their antiretroviral activity, but also by preventing the development of HIV-1-associated neoplasms.
authors.affiliation: Laboratory for Chemical-Biological Interactions, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
authors.forename: H J
authors.initials: HJ
authors.lastname: Prochaska
authors.forename: Y
authors.initials: Y
authors.lastname: Yeh
authors.forename: P
authors.initials: P
authors.lastname: Baron
authors.forename: B
authors.initials: B
authors.lastname: Polsky
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D016410:Lymphoma, T-Cell, Cutaneous; D015394:Molecular Structure; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors; D012878:Skin Neoplasms; D013871:Thiones; D013876:Thiophenes; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D011719:Pyrazines; D018894:Reverse Transcriptase Inhibitors; D013871:Thiones; D013876:Thiophenes; D015215:Zidovudine; C026209:oltipraz; D016660:NAD(P)H Dehydrogenase (Quinone); D054303:HIV Reverse Transcriptase; D005978:Glutathione