ArticleAntimicrobial agents and chemotherapy2013
Effects of substitutions at the 4' and 2 positions on the bioactivity of 4'-ethynyl-2-fluoro-2'-deoxyadenosine.
Article in Antimicrobial agents and chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 43 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
- Safety, tolerability, and pharmacokinetics of single- and multiple-dose administration of islatravir (MK-8591) in adults without HIV.Clinical and translational science · 2021Trial
- A Phase 1 Study to Evaluate the Drug Interaction Between Islatravir (MK-8591) and Doravirine in Adults Without HIV.Clinical drug investigation · 2021Trial
- Exploration of 4'-fluoro fleximer nucleoside analogues as potential broad-spectrum antiviral agents.Bioorganic & medicinal chemistry · 2025Article
- Unmasking the halide effect in diastereoselective Grignard reactions applied to C4´ modified nucleoside synthesis.Nature communications · 2025Article
- 2'-Fluorinated nucleoside chemistry for new drug discovery: achievements and prospects.National science review · 2024Review
- 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
- HIV-1 Resistance to Islatravir/Tenofovir Combination Therapy in Wild-Type or NRTI-Resistant Strains of Diverse HIV-1 Subtypes.Viruses · 2023Article
- Article
- Insights into HIV-1 Reverse Transcriptase (RT) Inhibition and Drug Resistance from Thirty Years of Structural Studies.Viruses · 2022Review
- Lack of a Clinically Meaningful Drug Interaction Between the HIV-1 Antiretroviral Agents Islatravir, Dolutegravir, and Tenofovir Disoproxil Fumarate.Clinical pharmacology in drug development · 2021Article
- Article
- Avoiding Drug Resistance in HIV Reverse Transcriptase.Chemical reviews · 2021Review
- Long-acting approaches for delivery of antiretroviral drugs for prevention and treatment of HIV: a review of recent research.Expert opinion on drug delivery · 2020Review
- CMCdG, a Novel Nucleoside Analog with Favorable Safety Features, Exerts Potent Activity against Wild-Type and Entecavir-Resistant Hepatitis B Virus.Antimicrobial agents and chemotherapy · 2019Article
- The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold.Antiviral research · 2019Review
- 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor.Current opinion in HIV and AIDS · 2018Review
- MK-8591 (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture.Antimicrobial agents and chemotherapy · 2017Article
- Physiological MgBiochemistry · 2017Article
- HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection.The Journal of antimicrobial chemotherapy · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 5 institutions in 2 countries.
Funding
Abstract
Nucleos(t)ide reverse transcriptase inhibitors (NRTIs) form the backbone of most anti-HIV therapies. We have shown that 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a highly effective NRTI; however, the reasons for the potent antiviral activity of EFdA are not well understood. Here, we use a combination of structural, computational, and biochemical approaches to examine how substitutions in the sugar or adenine rings affect the incorporation of dA-based NRTIs like EFdA into DNA by HIV RT and their susceptibility to deamination by adenosine deaminase (ADA). Nuclear magnetic resonance (NMR) spectroscopy studies of 4'-substituted NRTIs show that ethynyl or cyano groups stabilize the sugar ring in the C-2'-exo/C-3'-endo (north) conformation. Steady-state kinetic analysis of the incorporation of 4'-substituted NRTIs by RT reveals a correlation between the north conformation of the NRTI sugar ring and efficiency of incorporation into the nascent DNA strand. Structural analysis and the kinetics of deamination by ADA demonstrate that 4'-ethynyl and cyano substitutions decrease the susceptibility of adenosine-based compounds to ADA through steric interactions at the active site. However, the major determinant for decreased susceptibility to ADA is the 2-halo substitution, which alters the pKa of N1 on the adenine base. These results provide insight into how NRTI structural attributes affect their antiviral activities through their interactions with the RT and ADA active sites.
Indexed as
Identifiers
What OpenQuestion holds
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.