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Oltipraz, an inhibitor of human immunodeficiency virus type 1 replication
H J Prochaska1, Y Yeh, P Baron
1Laboratory for Chemical-Biological Interactions, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
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.
Insights
Oltipraz, a compound that boosts glutathione, effectively inhibits human immunodeficiency virus type-1 (HIV-1) replication. This 1,2-dithiole-3-thione may offer dual therapeutic benefits for HIV-1 patients by fighting the virus and preventing associated cancers.
Area of Science:
- Biochemistry
- Virology
- Pharmacology
Background:
- Glutathione depletion is implicated in human immunodeficiency virus type-1 (HIV-1) pathogenesis.
- Elevating glutathione and phase II detoxication enzymes can prevent experimental carcinogenesis.
- Investigating compounds that modulate glutathione for potential antiviral activity is warranted.
Purpose of the Study:
- To compare the efficacy of various glutathione inducers in inhibiting HIV-1 replication.
- To identify novel anti-HIV-1 agents from compounds that elevate glutathione and phase II enzymes.
- To explore the therapeutic potential of oltipraz and related compounds in HIV-1 infection.
Main Methods:
- Assessed the ability of several inducers to inhibit basal HIV-1 replication in H9 T-cell lymphoma cells.
- Measured the elevation of glutathione and quinone reductase (a phase II enzyme marker).
- Determined the half-maximal inhibitory concentration (IC50) for effective compounds.
Main Results:
- All tested monofunctional inducers increased glutathione and quinone reductase levels.
- Oltipraz [4-methyl-5-(2-pyrazinyl)-1,2-dithiole-3-thione] significantly inhibited HIV-1 replication (IC50 = 14.8 +/- 3.1 microM).
- The antiviral effect of oltipraz was enhanced when combined with 3'-azido-3'-deoxythymidine.
Conclusions:
- 1,2-dithiole-3-thiones, including oltipraz, represent a new class of anti-HIV-1 agents.
- Oltipraz acts as an irreversible inhibitor of HIV-1 reverse transcriptase.
- Oltipraz's established safety profile and potential dual action (antiviral and antineoplastic) suggest therapeutic utility for HIV-1-infected individuals.