title: Probing the molecular mechanism of action of the HIV-1 reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) using pre-steady-state kinetics.
abstract: The novel antiretroviral 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a potent nucleoside HIV-1 reverse transcriptase (RT) inhibitor (NRTI). Unlike other FDA-approved NRTIs, EFdA contains a 3'-hydroxyl. Pre-steady-state kinetics showed RT preferred incorporating EFdA-TP over native dATP. Moreover, RT slowly inserted nucleotides past an EFdA-terminated primer, resulting in delayed chain termination with unaffected fidelity. This is distinct from KP1212, another 3'-hydroxyl-containing RT inhibitor considered to promote viral lethal mutagenesis. New mechanistic features of RT inhibition by EFdA are revealed.
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Yagmur
authors.initials: Y
authors.lastname: Muftuoglu
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Christal D
authors.initials: CD
authors.lastname: Sohl
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States.
authors.forename: Andrea C
authors.initials: AC
authors.lastname: Mislak
authors.affiliation: Department of Infectious Diseases, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan; Department of Hematology, Kumamoto University Graduate School of Medical Sciences, Kumamoto 860-8556, Japan; Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
authors.affiliation: CS Bond Life Sciences Center and Department of Molecular Microbiology and Immunology, University of Missouri, School of Medicine, Columbia, MO 65211, United States; Department of Biochemistry, University of Missouri, School of Medicine, Columbia, MO 65211, United States.
authors.forename: Stefan G
authors.initials: SG
authors.lastname: Sarafianos
authors.affiliation: Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: karen.anderson@yale.edu.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Anderson
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D003839:Deoxyadenosines / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D003839:Deoxyadenosines; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase; C558823:islatravir
keywords: EFdA; Enzyme kinetics; HIV; Polymerase; Reverse transcriptase