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Mechanism of inhibition of the human immunodeficiency virus type 1 reverse transcriptase by d4TTP: an equivalent incorporation efficiency relative to the natural substrate dTTP.
Vaccaro JA; Parnell KM; Terezakis SA; Anderson KS; Department of
March 30, 2000
Antimicrob Agents Chemother. 2000 Jan;44(1):217-21. Unique Identifier :

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',3'-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.

JOURNAL ARTICLE Anti-HIV Agents/*PHARMACOLOGY Base Sequence DNA/METABOLISM Human HIV-1 Reverse Transcriptase/*ANTAGONISTS & INHIB Molecular Sequence Data Reverse Transcriptase Inhibitors/*PHARMACOLOGY Ribonuclease H, Calf Thymus/PHARMACOLOGY Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S. Thymine Nucleotides/*METABOLISM/*PHARMACOLOGY