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

• Published in: The FASEB journal 1999-09, Vol.13 (12), p.1511-1517
• Main Authors: Feng, Joy Y., Shi, Junxing, Schinazi, Raymond F., Anderson, Karen S.
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Base Sequence; HIV Reverse Transcriptase - antagonists & inhibitors; HIV-1 - drug effects; HIV-1 - physiology; Human immunodeficiency virus 1; Humans; incorporation efficiency; Kinetics; Lamivudine - pharmacology; Molecular Sequence Data; Oligodeoxyribonucleotides - metabolism; pre‐steady‐state analysis; rapid chemical quench; Reverse Transcriptase Inhibitors - pharmacology; RNA‐dependent DNA polymerization; Substrate Specificity; transient kinetics; Virus Replication - drug effects; Zalcitabine - analogs & derivatives; Zalcitabine - pharmacology
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fasebj.13.12.1511

ABSTRACTOf 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′‐thia‐cytidine [(−)‐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. FASEB J. 13, 1511–1517 (1999)