Interaction of novel 2',3'-dideoxy-beta-L-cytosine nucleoside triphosphates with human immunodeficiency virus type 1 reverse transcriptase (Meeting abstract).

Important note: Information in this article was accurate in 1995. The state of the art may have changed since the publication date.

Interaction of novel 2',3'-dideoxy-beta-L-cytosine nucleoside triphosphates with human immunodeficiency virus type 1 reverse transcriptase (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A2347 1994. Unique Identifier : AIDSLINE ICDB/95604032
Skalski V; Liu SH; Lin TS; Cheng YC; Dept. of Pharmacology, Yale University School of Medicine, New; Haven, CT 06510

Abstract: 2',3'-beta-L-dideoxycytidine (beta-L-ddC) as well as its 5-fluoro analog (beta-L-FddC) are potent inhibitors of human immunodeficiency type 1 virus (HIV-1) in culture (beta-L-FddC greater than-L-ddC) and exhibit low cytotoxicity and minimal effect on host mitochondrial DNA synthesis as compared to the D anomers. The antiviral effect of this class of compounds is partly determined by the extent to which the active 5-triphosphate (TP) metabolites interact with HIV-1 reverse transcriptase (RT). Both L and D forms of ddC and FddC are substrates for HIV-1 RT on DNA/RNA heteroduplexes and inhibit the incorporation of dCTP with Ki values in the range of 0.14-1 uM (D-ddCTP less than D-FddCTP less than L-ddCTP less than L-FddCTP). At saturating concentrations (5 uM), the apparent incorporation of each analog differed (D-ddC greater than D-FddC greater than L-ddC greater than L-FddC) as determined by primer extension assays. Additionally, the incorporation of the L forms, and D-FddC, could trigger HIV-1 RT to behave as a 3'-5' exonuclease resulting in removal of the analogs from 3'-terminals of DNA. This suggests that the L-configuration as well as the 5-fluoro moiety are important determinants for the interaction of ddCTP analogs with HIV-1 RT. These observations may partially account for the substantial differences in the anti-HIV-1 activity among these compounds.

Keywords: Antiviral Agents/*PHARMACOLOGY Cytosine Dideoxynucleosides/*PHARMACOLOGY DNA, Mitochondrial/BIOSYNTHESIS/DRUG EFFECTS HIV-1/*ENZYMOLOGY RNA-Directed DNA Polymerase/*METABOLISM Substrate Specificity ABSTRACT
950330
M9530825

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