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Mechanism of interaction of human mitochondrial DNA polymerase γ with the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine indicates a low potential for host toxicity.

Abstract
The potent antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a promising experimental agent for treating HIV infection. Pre-steady-state kinetics were used to characterize the interaction of EFdA-triphosphate (EFdA-TP) with human mitochondrial DNA polymerase γ (Pol γ) to assess the potential for toxicity. Pol γ incorporated EFdA-TP 4,300-fold less efficiently than dATP, with an excision rate similar to ddATP. This strongly indicates EFdA is a poor Pol γ substrate, suggesting minimal Pol γ-mediated toxicity, although this should be examined under clinical settings.
AuthorsChristal D Sohl, Kamlendra Singh, Rajesh Kasiviswanathan, William C Copeland, Hiroaki Mitsuya, Stefan G Sarafianos, Karen S Anderson
JournalAntimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 56 Issue 3 Pg. 1630-4 (Mar 2012) ISSN: 1098-6596 [Electronic] United States
PMID22155823 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)
Chemical References
  • Deoxyadenosines
  • Mitochondrial Proteins
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • islatravir
Topics
  • Base Sequence
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase (metabolism)
  • Deoxyadenosines (metabolism, pharmacology, toxicity)
  • HIV Reverse Transcriptase (antagonists & inhibitors, metabolism)
  • HIV-1 (drug effects, physiology)
  • Humans
  • Kinetics
  • Mitochondria (drug effects, metabolism)
  • Mitochondrial Proteins (metabolism)
  • Models, Molecular
  • Molecular Sequence Data
  • Reverse Transcriptase Inhibitors (metabolism, pharmacology, toxicity)

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