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.

Autor: Muftuoglu Y; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States., Sohl CD; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States., Mislak AC; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States., Mitsuya H; 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., Sarafianos SG; 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., Anderson KS; Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, United States. Electronic address: karen.anderson@yale.edu.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2014 Jun; Vol. 106, pp. 1-4. Date of Electronic Publication: 2014 Mar 12.
DOI: 10.1016/j.antiviral.2014.03.001
Abstrakt: 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.
(Copyright © 2014 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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