ArticleThe Journal of antimicrobial chemotherapy2018
Antiretroviral potency of 4'-ethnyl-2'-fluoro-2'-deoxyadenosine, tenofovir alafenamide and second-generation NNRTIs across diverse HIV-1 subtypes.
Article in The Journal of antimicrobial chemotherapy, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Current evidence on islatravir drug resistance and implications for future HIV treatment.Topics in antiviral medicine · 2026Review
- Weekly Oral Tenofovir Alafenamide Protects Macaques from Vaginal and Rectal Simian HIV Infection.Pharmaceutics · 2024Article
- Antiviral potency of long-acting islatravir subdermal implant in SHIV-infected macaques.Journal of controlled release : official journal of the Controlled Release Society · 2024Article
- Novel Naturally Occurring Dipeptides and Single-Stranded Oligonucleotide Act as Entry Inhibitors and Exhibit a Strong Synergistic Anti-HIV-1 Profile.Infectious diseases and therapy · 2022Article
- Doravirine and Islatravir Have Complementary Resistance Profiles and Create a Combination with a High Barrier to Resistance.Antimicrobial agents and chemotherapy · 2022Article
- Approved HIV reverse transcriptase inhibitors in the past decade.Acta pharmaceutica Sinica. B · 2022Review
- Mechanistic cross-talk between DNA/RNA polymerase enzyme kinetics and nucleotide substrate availability in cells: Implications for polymerase inhibitor discovery.The Journal of biological chemistry · 2020Review
- Discordance between Etravirine Phenotype and Genotype-Based Predicted Phenotype for Subtype C HIV-1 from First-Line Antiretroviral Therapy Failures in South Africa.Antimicrobial agents and chemotherapy · 2020Article
- 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
- Strain-specific effect on biphasic DNA binding by HIV-1 integrase.AIDS (London, England) · 2019Article
Corrections and comments
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Authors and funding
7 authors at 4 institutions in 3 countries.
Funding
Abstract
Objectives: 4'-Ethnyl-2'-fluoro-2'-deoxyadenosine (EFdA) is a novel translocation-defective reverse transcriptase inhibitor. We investigated the virological and biochemical inhibitory potentials of EFdA against a broad spectrum of subtype-specific chimeric viruses and compared it with tenofovir alafenamide, nevirapine, efavirenz, rilpivirine and etravirine. Methods: pNL4.3 chimeric viruses encoding gag-pol from treatment-naive patients (n = 24) and therapy-failure patients (n = 3) and a panel of reverse transcriptase inhibitor-resistant strains (n = 7) were used to compare the potency of reverse transcriptase inhibitor drugs. The phenotypic drug susceptibility assay was performed using TZM-bl cells. In vitro inhibition assays were done using patient-derived reverse transcriptase. IC50 values of NNRTIs were calculated using a PicoGreen-based spectrophotometric assay. Steady-state kinetics were used to determine the apparent binding affinity (Km.dNTP) of triphosphate form of EFdA (EFdA-TP) and dATP. Results: Among the chimeric treatment-naive viruses, EFdA had an ex vivo antiretroviral activity [median (IQR) EC50 = 1.4 nM (0.6-2.1 nM)] comparable to that of tenofovir alafenamide [1.6 nM (0.5-3.6 nM)]. Subtype-specific differences were found for etravirine (P = 0.004) and rilpivirine (P = 0.017), where HIV-1C had the highest EC50 values. EFdA had a greater comparative efficiency [calculated by dividing the efficiency of monophosphate form of EFdA (EFdA-MP) incorporation (kcat.EFdA-TP/Km.EFdA-TP) over the efficiency of dATP incorporation (kcat.dATP/Km.dATP)] compared with the natural substrate dATP, with a fold change of between 1.6 and 3.2. Ex vivo analysis on reverse transcriptase inhibitor-resistant strains showed EFdA to have a higher potency. Despite the presence of rilpivirine DRMs, some non-B strains showed hypersusceptibility to rilpivirine. Conclusions: Our combined virological and biochemical data suggest that EFdA inhibits both WT and reverse transcriptase inhibitor-resistant viruses efficiently in a subtype-independent manner. In contrast, HIV-1C is least susceptible to etravirine and rilpivirine.
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