Inhibition of HIV-1 reverse transcriptase by 5'-triphosphates of 5-substituted uridine analogs.

Antiviral Research
P Z TaoR Datema

Abstract

The 5'-triphosphates of some 5-substituted 2'-deoxyuridine analogs were investigated for their effects on purified recombinant reverse transcriptase of human immunodeficiency virus type 1 (HIV-1) as well as cellular DNA polymerase alpha. The triphosphates were competitive inhibitors of the viral enzyme with dTTP as the variable substrate and poly(rA)oligo(dT) as template, and preferentially inhibited the viral polymerase. Ordering the compounds according to their decreasing binding affinities, as reflected by their increasing inhibition constants for the reverse transcriptase, gave nPrearaUTP greater than nPrdUTP greater than EtdUTP greater than nPredUTP greater than HMdUTP greater than CEdUTP. Although nPredUTP was less inhibitory than nPrearaUTP under conditions of competitive inhibition, nPredUTP caused a time- and concentration-dependent inactivation of reverse transcriptase activity when preincubated with template. This inactivation was not reversed by excess dTTP. The decrease in template-primer activity did not occur with nPrearaUTP, but was shown with the chain-terminating 5'-triphosphates of 3'-fluoro- and 3'-azidothymidine. As nPredUTP, but not nPrearaUTP, was an alternative substrate, shown by the ability to support ...Continue Reading

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Citations

Dec 3, 2014·Antiviral Research·Luqing ShangZheng Yin
Sep 23, 2010·Chemistry & Biodiversity·Li-Jia XuPei-Gen Xiao

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