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* Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066; USA; and
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine/VAMC, Decatur, Georgia 30033, USA
1Correspondence: Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8066, USA. E-mail:karen.anderson{at}yale.edu
Of all of the nucleoside inhibitors approved by the FDA for treatment of AIDS, (-)-ß-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-ß-L configuration. The fluorinated derivative (-)-ß-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.
Key Words: transient kinetics • rapid chemical quench • pre-steady-state analysis • RNA-dependent DNA polymerization • incorporation efficiency
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