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 AIDS, (-)-beta-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is the only one with the unnatural (-)-beta-L configuration. The fluorinated derivative (-)-beta-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
JY
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Shi
J
J
Schinazi
R F
RF
Anderson
K S
KS
D001483:Base Sequence; D000068679:Emtricitabine / Q000031:analogs & derivatives; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D019259:Lamivudine / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity; D014779:Virus Replication / Q000187:drug effects*; D016047:Zalcitabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D009838:Oligodeoxyribonucleotides; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine; D016047:Zalcitabine; D054303:HIV Reverse Transcriptase; D000068679:Emtricitabine; C075889:Racivir