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

Important note: Information in this article was accurate in 1990. The state of the art may have changed since the publication date.

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

Antiviral Res. 1989 Dec;12(5-6):269-78. Unique Identifier : AIDSLINE MED/90233802
Tao PZ; Johansson NG; Stening G; Oberg B; Datema R; Department of Virology, Chinese Academy of Medical Sciences,; Bejing.

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 DNA synthesis in absence of competing substrate, the incorporation of nPredUTP into the primer-template apparently leads to increased inhibition of the enzyme.

Keywords: Antiviral Agents/*PHARMACOLOGY Drug Design DNA Polymerase II/ANTAGONISTS & INHIB DNA, Viral/BIOSYNTHESIS HIV-1/DRUG EFFECTS/*ENZYMOLOGY Kinetics RNA-Directed DNA Polymerase/*ANTAGONISTS & INHIB Templates Thymine Nucleotides/METABOLISM Uridine Triphosphate/*ANALOGS & DERIVATIVES/PHARMACOLOGY Zidovudine/PHARMACOLOGY JOURNAL ARTICLE
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M9080699

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