ArticleCell chemical biology2018
The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.
Article in Cell chemical biology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 30 citations in OpenAlex.
- 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
- Current evidence on islatravir drug resistance and implications for future HIV treatment.Topics in antiviral medicine · 2026Review
- Modeling of HIV-1 prophylactic efficacy and toxicity with islatravir shows non-superiority for oral dosing, but promise as a subcutaneous implant.CPT: pharmacometrics & systems pharmacology · 2024Article
- No antagonism or cross-resistance and a high barrier to the emergence of resistanceAntimicrobial agents and chemotherapy · 2024Article
- HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes.Viruses · 2023Article
- A novel anti-HBV agent, E-CFCP, restores Hepatitis B virus (HBV)-induced senescence-associated cellular marker perturbation in human hepatocytes.Virus research · 2023Article
- Structural basis of HIV inhibition by L-nucleosides: Opportunities for drug development and repurposing.Drug discovery today · 2022Review
- Islatravir Has a High Barrier to Resistance and Exhibits a Differentiated Resistance Profile from Approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs).Antimicrobial agents and chemotherapy · 2022Article
- Intriguing Antiviral Modified Nucleosides: A Retrospective View into the Future Treatment of COVID-19.ACS medicinal chemistry letters · 2021Article
- Evolving understanding of HIV-1 reverse transcriptase structure, function, inhibition, and resistance.Current opinion in structural biology · 2020Review
- Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine.Scientific reports · 2020Article
- Management of Virologic Failure and HIV Drug Resistance.Infectious disease clinics of North America · 2019Review
- Novel Protease Inhibitors Containing C-5-ModifiedAntimicrobial agents and chemotherapy · 2019Article
- Design, Synthesis, and Biological Evaluation of EdAP, a 4'-Ethynyl-2'-Deoxyadenosine 5'-Monophosphate Analog, as a Potent Influenza a Inhibitor.Molecules (Basel, Switzerland) · 2019Article
- Long-Acting Anti-HIV Drugs Targeting HIV-1 Reverse Transcriptase and Integrase.Pharmaceuticals (Basel, Switzerland) · 2019Review
- Discovery and Development of Anti-HIV Therapeutic Agents: Progress Towards Improved HIV Medication.Current topics in medicinal chemistry · 2019Review
- Application of human lymphoid cells for the evaluation of antivirals against human adenovirus type 19: Zalcitabine has superior activity compared to cidofovir.Antiviral chemistry & chemotherapyArticle
Corrections and comments
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Authors and funding
8 authors at 5 institutions in 2 countries.
Funding
Abstract
4'-Ethynyl-2-fluoro-2'-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 4'-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 4'-ethynyl- or 4'-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4'-methyl) did not show this activity. Structural analysis indicated that EFdA and 4'-ethynyl-NRTIs (but not other 4'-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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.