Mechanism of inhibition of the human immunodeficiency virus type 1 reverse transcriptase by d4TTP: An equivalent incorporation efficiency relative to the natural substrate dTTP

Joseph A. Vaccaro, K. Mark Parnell, Stephanie A. Terezakis, Karen S. Anderson

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Among the clinically used nucleoside analogue inhibitors that target human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), there is little detailed mechanistic information on the interactions of 2',Y- didehydro-2',3'-dideoxythymidine-5'-triphosphate (d4TTP) with the enzyme primer-template complex and how these interactions compare with those of the natural substrate, dTTP. Using a pre-steady-state kinetic analysis, we found that d4TTP was incorporated by HIV-1 RT just as efficiently as dTTP during both DNA- and RNA-dependent DNA synthesis. To our knowledge, these results represent the first observation of a 3'-modified nucleoside triphosphate analogue that has an incorporation efficiency comparable to that observed for the natural substrate during DNA synthesis by HIV-1 RT. This information provides a mechanistic basis for understanding the inhibition of HIV-1 RT by d4TTP as well as insight into the clinically observed lack of d4T resistance mutations in HIV-1 RT isolated from AIDS patients.

Original languageEnglish (US)
Pages (from-to)217-221
Number of pages5
JournalAntimicrobial agents and chemotherapy
Volume44
Issue number1
DOIs
StatePublished - Jan 1 2000
Externally publishedYes

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