ArticleProceedings of the National Academy of Sciences of the United States of America2016
Structural basis of HIV inhibition by translocation-defective RT inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA).
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 61 papers, 1 of them a synthesis that pooled it.
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Who cites it
61 citing papers in PubMed, 1 synthesis or guideline pooled it, 101 citations in OpenAlex.
- Current ARTs, Virologic Failure, and Implications for AIDS Management: A Systematic Review.Viruses · 2023Pooled it
- Islatravir distribution in plasma, peripheral blood mononuclear cells, and mucosal tissues after monthly oral dosing.AIDS (London, England) · 2026Trial
- Efficacy and safety of doravirine/islatravir in heavily treatment-experienced participants living with HIV-1: results from a randomized trial.AIDS (London, England) · 2026Trial
- Thorough QT/QTc study to evaluate the effect of a single supratherapeutic dose of islatravir on QTc interval prolongation in healthy adults.Antimicrobial agents and chemotherapy · 2024Trial
- Development of Human Immunodeficiency Virus Type 1 Resistance to 4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine Starting with Wild-Type or Nucleoside Reverse Transcriptase Inhibitor-Resistant Strains.Antimicrobial agents and chemotherapy · 2021Trial
- Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial.Nature medicine · 2021Trial
- Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.Clinical and translational science · 2021Trial
- Substrate and target selectivity of 4'-fluoroadenosine against viral and host polymerases.The Journal of biological chemistry · 2026Article
- Enhanced strand transfer and mismatch extension by HIV-1C reverse transcriptase promote sequence motif duplication.Journal of virology · 2026Article
- Unraveling the Mechanism of HIV-1 Hypersusceptibility to Tenofovir Imparted by Islatravir Resistance Mutations.bioRxiv : the preprint server for biology · 2026Article
- Structural Basis of Polypurine Track Strand Displacement by HIV-1 Reverse Transcriptase.bioRxiv : the preprint server for biology · 2026Article
- Discovery ofInternational journal of molecular sciences · 2025Article
- MK-8527 is a novel inhibitor of HIV-1 reverse transcriptase translocation with potential for extended-duration dosing.PLoS biology · 2025Article
- Mechanism and spectrum of inhibition of viral polymerases by 2'-deoxy-2'-β-fluoro-4'-azidocytidine or azvudine.NAR molecular medicine · 2025Article
- Article
- Pharmacokinetics of Atorvastatin and Metformin after Coadministration with Islatravir in Healthy Adults.Journal of clinical pharmacology · 2025Article
- Pharmacokinetics of islatravir in participants with moderate hepatic impairment.Antimicrobial agents and chemotherapy · 2025Article
- Nonclinical and clinical characterization of the absorption, metabolism, and excretion of islatravir.Antimicrobial agents and chemotherapy · 2025Article
- A Phase 1 Study to Evaluate the Pharmacokinetic Drug-Drug Interaction Between Islatravir and Methadone in Participants on Stable Methadone Therapy.Clinical pharmacology in drug development · 2025Article
- Structural basis of deoxynucleotide addition by HIV-1 RT during reverse transcription.Nature communications · 2024Article
1 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
Abstract
4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is the most potent nucleoside analog inhibitor of HIV reverse transcriptase (RT). It retains a 3'-OH yet acts as a chain-terminating agent by diminishing translocation from the pretranslocation nucleotide-binding site (N site) to the posttranslocation primer-binding site (P site). Also, facile misincorporation of EFdA-monophosphate (MP) results in difficult-to-extend mismatched primers. To understand the high potency and unusual inhibition mechanism of EFdA, we solved RT crystal structures (resolutions from 2.4 to 2.9 Å) that include inhibition intermediates (i) before inhibitor incorporation (catalytic complex, RT/DNA/EFdA-triphosphate), (ii) after incorporation of EFdA-MP followed by dT-MP (RT/DNAEFdA-MP(P)• dT-MP(N) ), or (iii) after incorporation of two EFdA-MPs (RT/DNAEFdA-MP(P)• EFdA-MP(N) ); (iv) the latter was also solved with EFdA-MP mismatched at the N site (RT/DNAEFdA-MP(P)• EFdA-MP(*N) ). We report that the inhibition mechanism and potency of EFdA stem from interactions of its 4'-ethynyl at a previously unexploited conserved hydrophobic pocket in the polymerase active site. The high resolution of the catalytic complex structure revealed a network of ordered water molecules at the polymerase active site that stabilize enzyme interactions with nucleotide and DNA substrates. Finally, decreased translocation results from favorable interactions of primer-terminating EFdA-MP at the pretranslocation site and unfavorable posttranslocation interactions that lead to observed localized primer distortions.
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