The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase

Yuki Takamatsu, Debananda Das, Satoru Kohgo, Hironori Hayashi, Nicole S. Delino, Stefan G. Sarafianos, Hiroaki Mitsuya, Kenji Maeda

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)


4ʹ-Ethynyl-2-fluoro-2ʹ-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4ʹ-moiety and potently inhibit the replication of a wide spectrum of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4ʹ-ethynyl- or 4ʹ-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4ʹ-methyl) did not show this activity. Structural analysis indicated that EFdA and 4ʹ-ethynyl-NRTIs (but not other 4ʹ-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics. EFdA exerts potent antiviral activity against multiple-drug-resistant HIV-1 strains and is now undergoing clinical trials. Takamatsu et al. evaluated the antiviral activity and structural analysis of EFdA derivatives and report that 4ʹ-ethynyl or 4ʹ-cyano moiety are the key structural features for the potent antiviral activity against drug-resistant HIV-1 strains.

Original languageEnglish
Pages (from-to)1268-1278.e3
JournalCell chemical biology
Issue number10
Publication statusPublished - 2018 Oct 18
Externally publishedYes


  • 4ʹ-cyano
  • 4ʹ-ethynyl
  • 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA/MK-8591)
  • HIV type 1 (HIV-1)
  • drug resistance
  • nucleoside reverse transcriptase inhibitor (NRTI)
  • reverse transcriptase

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry


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