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Antiviral Res. 2014 Jun;106:1-4. doi: 10.1016/j.antiviral.2014.03.001. Epub 2014 Mar 12.

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.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States.
2
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.
3
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.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: karen.anderson@yale.edu.

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.

KEYWORDS:

EFdA; Enzyme kinetics; HIV; Polymerase; Reverse transcriptase

PMID:
24632447
PMCID:
PMC4020981
DOI:
10.1016/j.antiviral.2014.03.001
[Indexed for MEDLINE]
Free PMC Article

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