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

Of all of the nucleoside inhibitors approved by the FDA for treatment of AI DS, (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only on e with the unnatural (-)-beta-L configuration, The fluorinated derivative ( -)-beta-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and its triphospha te form have also been reported to have excellent antiretroviral activity a gainst HIV-1 reverse transcriptase (RT). Preliminary results of clinical tr ials suggest that (-)-FTC is 6- to 10-fold more potent than 3TC, However, t he molecular mechanism for the observed enhanced clinical potency of (-)-FT C to inhibit viral replication is not understood. The present mechanistic s tudies used a transient kinetic approach and were designed to compare the i ncorporation of 3TC-TP and (-)-FTC-TP into DNA by HIV-1 RT and illuminate k ey 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, i s responsible for the enhanced potency of (-)-FTC observed in ongoing clini cal trials.