The biochemical basis for the differential anti-human immunodeficiency virus activity of two cis enantiomers of 2',3'-dideoxy-3'-thiacytidine.

Abstract

Two cis stereoisomers of 2',3'-dideoxy-3'-thiacytidine (SddC) were investigated for their activity against human immunodeficiency virus type 1 (HIV-1) in human acute lymphoblastic leukemia H-9 cells. (-)-SddC is six times more potent against HIV-1 and at least 1.7-fold less cytotoxic than (+)-SddC. Metabolism studies showed that the intracellular accumulation of the active triphosphate form of (-)-SddC is more than 2-fold greater than that of (+)-SddCTP in H-9 cells. In contrast, (+)-SddCTP is approximately 1.5 times more potent than (-)-SddCTP as an inhibitor of HIV-1 reverse transcriptase using a rRNA template (Ki = 0.22 and 0.034 microM, respectively) and gapped DNA (Ki = 0.53 and 1.02 microM, respectively). The enantiomers are comparable as substrates for incorporation into DNA by the RNA-dependent HIV-1 reverse transcriptase; however, neither analog is incorporated as readily as dCTP. The above observations do not explain the difference in the anti-HIV potency between the enantiomers. A novel 3'-5' exonuclease was partially purified from the cytosol of H-9 cells and assayed for the removal of (+)- and (-)-SddCMP-terminated DNA. Removal of (+)-SddCMP was approximately two to three times faster from 3'-terminals of single-stranded and double-stranded DNA, whereas on DNA/RNA substrates, the exonucleolytic cleavage of (+)-SddCMP proceeded approximately six times faster than that of (-)-SddCMP. This result correlates with the observed difference in the anti-HIV effect between the two compounds and suggests that this novel enzyme may be an important determinant of their antiviral activities.

• Authors: V Skalski, C N Chang, G Dutschman, Y C Cheng
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 268 Issue 31 Pg. 23234-8 (Nov 05 1993) ISSN: 0021-9258 [Print] United States
• PMID: 7693686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antiviral Agents
• Oligoribonucleotides
• Reverse Transcriptase Inhibitors
• Lamivudine
• Zalcitabine
• HIV Reverse Transcriptase
• Exonucleases

Topics

• Antiviral Agents
• Base Sequence
• Exonucleases (metabolism)
• HIV Reverse Transcriptase
• HIV-1 (drug effects, growth & development)
• Humans
• In Vitro Techniques
• Lamivudine
• Molecular Sequence Data
• Oligoribonucleotides (chemistry)
• Phosphorylation
• Reverse Transcriptase Inhibitors
• Stereoisomerism
• Structure-Activity Relationship
• Zalcitabine (analogs & derivatives, chemistry, metabolism)