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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.




 

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



 




Information in this article was accurate in March 30, 2000. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.