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Antimicrobial Agents and Chemotherapy, January 2000, p. 217-221, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Mechanism of Inhibition of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase by d4TTP: an Equivalent Incorporation Efficiency Relative to the Natural Substrate dTTPdagger

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

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066

Received 12 April 1999/Returned for modification 31 July 1999/Accepted 2 October 1999

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.

* Corresponding author. Mailing address: 333 Cedar St., New Haven, CT 06520-8066. Phone: (203) 785-4526. Fax: (203) 785-7670. E-mail: karen.anderson{at}yale.edu.

dagger We dedicate this paper to William H. Prusoff, one of the codiscoverers of d4T, on the occasion of his 79th birthday.

Antimicrobial Agents and Chemotherapy, January 2000, p. 217-221, Vol. 44, No. 1
0066-4804/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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