Mechanism of inhibition of human immunodeficiency virus type 1 reverse transcriptase and human DNA polymerases α, β, and γ by the 5'-triphosphates of carbovir, 3'-azido-3'-deoxythymidine, 2',3'-dideoxyguanosine, and 3'-deoxythymidine. A novel RNA template for the evaluation of antiretroviral drugs

W. B. Parker, E. L. White, S. C. Shaddix, L. J. Ross, R. W. Buckheit, J. M. Germany, J. A. Secrist, R. Vince, W. M. Shannon

Research output: Contribution to journalArticle

131 Scopus citations

Abstract

Carbovir (the carbocyclic analog of 2',3'-didehydro-2',3'-dideoxyguanosine)is a potent inhibitor of human immunodeficiency virus type 1 (HIV-1) replication. Assays were developed to assess the mechanism of inhibition by the 5'-triphosphate of carbovir of HIV-1 reverse transcriptase using either RNA or DNA templates that contain all four natural nucleotides. Carbovir-TP was a potent inhibitor of HIV-1 reverse transcriptase using either template with K(i) values similar to that observed by AZT-TP, ddGTP,and ddTTP. The kinetic constants for incorporation of these nucleotide analogs into DNA by HIV-1 reverse transcriptase using either template were similar to the values seen for their respective natural nucleotides. In addition, the incorporation of either carbovir-TP or AZT-TP in the presence of dGTP or dTTP, respectively, indicated that the mechanism of inhibition by these two nucleotide analogs was due to their incorporation into the DNA resulting in chain termination. Carbovir-TP was not a potent inhibitor of DNA polymerase α, β, or γ, or DNA primase. Given the potent activity of carbovir-TP against HIV-1 reverse transcriptase and its lack of activity against human DNA polymerases, we believe that further evaluation of this compound as a potential drug for the treatment of HIV-1 infection is warranted.

Original languageEnglish (US)
Pages (from-to)1754-1762
Number of pages9
JournalJournal of Biological Chemistry
Volume266
Issue number3
StatePublished - 1991
Externally publishedYes

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