Mechanism of inhibition of the human immunodeficiency virus type 1 reverse transcriptase by d4TTP: an equivalent incorporation efficiency relative to the natural substrate dTTP.
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.
Vaccaro
J A
JA
Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, USA.
Parnell
K M
KM
Terezakis
S A
SA
Anderson
K S
KS
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D004247:DNA / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D016914:Ribonuclease H / Q000494:pharmacology; D013942:Thymine Nucleotides / Q000378:metabolism* / Q000494:pharmacology*; D018119:Stavudine / Q000031:analogs & derivatives
D019380:Anti-HIV Agents; D004247:DNA; D054303:HIV Reverse Transcriptase; D018894:Reverse Transcriptase Inhibitors; D016914:Ribonuclease H; D013942:Thymine Nucleotides; C053197:stavudine triphosphate; D018119:Stavudine; C024157:thymidine 5'-triphosphate