title: 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.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Christal D
authors.initials: CD
authors.lastname: Sohl
authors.forename: Kamlendra
authors.initials: K
authors.lastname: Singh
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kasiviswanathan
authors.forename: William C
authors.initials: WC
authors.lastname: Copeland
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D001483:Base Sequence; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D003839:Deoxyadenosines / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D003839:Deoxyadenosines; D024101:Mitochondrial Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase; D000074002:DNA Polymerase gamma; D004259:DNA-Directed DNA Polymerase; C558823:islatravir