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

Overview

Journal Antimicrob Agents Chemother

Publisher American Society for Microbiology

Specialty Pharmacology

Date 2011 Dec 14

PMID 22155823

Citations 18

Authors

Christal D Sohl

Kamlendra Singh

Rajesh Kasiviswanathan

William C Copeland

Hiroaki Mitsuya

Stefan G Sarafianos

Karen S Anderson

Affiliations

Soon will be listed here.

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.

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