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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.