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.
Muftuoglu, Yagmur a,1; Sohl, Christal D. a,1; Mislak, Andrea C. a; Mitsuya, Hiroaki b,c,d; Sarafianos, Stefan G. e,f; Anderson, Karen S. a,*
[Miscellaneous Article] Antiviral Research. 106 Supplement 1:1-4, June 2014.

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* EFdA is a novel nucleoside reverse transcriptase inhibitor (NRTI) in clinical trials.

* Pre-steady-state kinetic experiments show HIV-1 reverse transcriptase (RT) prefers EFdA over dATP.

* Due to a 3'-hydroxyl group on EFdA, RT can slowly incorporate additional nucleotides past it.

* Phosphorolytic excision of EFdA by RT is a possible mode of resistance.

* EFdA potently inhibits RT by delayed chain termination.

: 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.

(C) 2014Elsevier, Inc.