Phosphorylation of 3'-azido-2',3'-dideoxyuridine and preferential inhibition of human and simian immunodeficiency virus reverse transcriptases by its 5'-triphosphate.

Antimicrobial Agents and Chemotherapy
B F ErikssonRaymond F Schinazi

Abstract

3'-Azido-2',3'-dideoxyuridine-5'-triphosphate was found to be a potent and highly selective inhibitor of human immunodeficiency virus type 1 and simian immunodeficiency virus reverse transcriptases. The affinity of 3'-azido-2',3'-dideoxyuridine-5'-triphosphate for the reverse transcriptases was similar to that observed for 3'-azido-3'-deoxythymidine-5'-triphosphate. Both compounds were competitive inhibitors with respect to the normal substrate dTTP and served at least 100 times better as substrates than did dTTP. In contrast, cellular DNA polymerase alpha showed an about 60-times-higher preference for dTTP as substrate than for either inhibitor. The phosphorylation of thymidine in human peripheral blood mononuclear cell extracts was inhibited in a competitive manner by both 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine, with apparent inhibition constants of 290 and 3.4 microM, respectively. The Michaelis-Menten constant, Km, for thymidine was 7.0 microM. 3'-Azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine both served as substrates, with apparent Km values of 67 and 1.4 microM, respectively. The maximal rates of phosphorylation with 3'-azido-2',3'-dideoxyuridine and 3'-azido-3'-deoxythymidine were 40 and...Continue Reading

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Citations

Jan 1, 1990·Pharmacology & Therapeutics·G E Wright, N C Brown
Aug 1, 1991·Journal of Virological Methods·N K AyisiL F Qualtiere
Oct 3, 2003·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Linghui KongF Douglas Boudinot
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Sep 19, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·Lorena Gonzalez Palmén, Jan-Olov Kvassman
Sep 28, 1990·Science·H MitsuyaS Broder

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