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

Antimicrob Agents Chemother. 2012 Mar;56(3):1630-4. doi: 10.1128/AAC.05729-11. Epub 2011 Dec 12.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Base Sequence
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase / metabolism*
  • Deoxyadenosines / metabolism
  • Deoxyadenosines / pharmacology*
  • Deoxyadenosines / toxicity
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • Humans
  • Kinetics
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Proteins / metabolism*
  • Models, Molecular
  • Molecular Sequence Data
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology*
  • Reverse Transcriptase Inhibitors / toxicity


  • Deoxyadenosines
  • Mitochondrial Proteins
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • DNA Polymerase gamma
  • DNA-Directed DNA Polymerase
  • islatravir