Biochemical studies of the antihuman immunodeficiency virus activities of two enantiomers of 2',3'-dideoxy-3'-thiacytidine (Meeting abstract).

Important note: Information in this article was accurate in 1993. The state of the art may have changed since the publication date.

Biochemical studies of the antihuman immunodeficiency virus activities of two enantiomers of 2',3'-dideoxy-3'-thiacytidine (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 34:A1671 1993. Unique Identifier : AIDSLINE ICDB/93692612
Skalski V; Chang CN; Dutschman GE; Cheng YC; Dept. of Pharmacology, Yale Univ., New Haven, CT 06510

Abstract: Two ClS enantiomers of 2',3'-dideoxy-3'-Thiacytidine((+)- and (--)-SddC) were evaluated for their activities against the human immunodeficiency vs (HIV-1) in cultured H-9 cells. (--)-SddC was six times more inhibitory to HIV-1 and three times less cytotoxic than (+)-SddC. Whereas the intracellular accumulation of the triphosphate (TP) metabolite of (--)-SddC is 2-fold higher than that of (+)-SddCTP, the incorporation of the former into DNA by HIV-1 reverse transcriptase (RT) is 2-fold less efficient as reflected by the Ki values, making (+)-SddCTP a more effective chain terminator. These observed biochemical differences fail to explain the differential anti-HIV effect of these enantiomers. A novel 3'-5' exonuclease was partially purified from the cytoplasm of H-9 cells. It was shown to remove (+)-SddC monophosphate (MP) at least five times faster than (-)-SddCMP from the 5'-end of DNA annealed to a complementary DNA or RNA sequence. Since the anti-HIV activity of these two compounds is determined by the amount of analog incorporated, the selectivity of this exonuclease for (+) or (--)-SddCMP-terminated DNA could explain the differences in the anti-HIV action between the two enantiomers.

Keywords: Antiviral Agents/*THERAPEUTIC USE Cytidine Monophosphate/METABOLISM Cytidine Triphosphate/METABOLISM DNA/METABOLISM Exonucleases/METABOLISM HIV Infections/*DRUG THERAPY/METABOLISM HIV-1 RNA-Directed DNA Polymerase/METABOLISM Zalcitabine/*ANALOGS & DERIVATIVES/THERAPEUTIC USE ABSTRACT
930730
M9370991

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