Mechanistic studies show that (−)‐FTC‐TP is a better inhibitor of HIV‐1 reverse transcriptase than 3TC‐TP

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Abstract
Of all of the nucleoside inhibitors approved by the FDA for treatment of AIDS, (-)-β-2′,3′-dideoxy-3′-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-β-L configuration. The fluorinated derivative (-)-β-2′,3′-dideoxy-5-fluoro-3′-thiacytidine [(-)-FTC] and its triphosphate form have also been reported to have excellent antiretroviral activity against HIV-1 reverse transcriptase (RT). Preliminary results of clinical trials suggest that (-)-FTC is 6- to 10-fold more potent than 3TC. However, the molecular mechanism for the observed enhanced clinical potency of (-)-FTC to inhibit viral replication is not understood. The present mechanistic studies used a transient kinetic approach and were designed to compare the incorporation of 3TC-TP and (-)-FTC-TP into DNA by HIV-1 RT and illuminate key features that may play a role in the differential potency. Here we show that (-)-FTC-TP is incorporated 10-fold more efficiently than 3TC-TP during HIV-1 RT-catalyzed RNA-dependent DNA synthesis. The enhanced incorporation efficiency of (-)-FTC-TP may be a key mechanistic feature that, in part, is responsible for the enhanced potency of (-)-FTC observed in ongoing clinical trials.—Feng, J. Y., Shi, J., Schinazi, R. F., Anderson, K. S. Mechanistic studies show that (-)-FTC-TP is a better inhibitor of HIV-1 reverse transcriptase than 3TC-TP.
Funding Information
  • National Institutes of Health (GM49551)
  • U.S. Department of Veterans Affairs

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