ArticlePloS one2010
Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 40 citations in OpenAlex.
- Article
- Synthesis of Fluorinated Nucleosides/Nucleotides and Their Antiviral Properties.Molecules (Basel, Switzerland) · 2024Review
- Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities.Molecular pharmaceutics · 2023Review
- Biochemical and Structural Properties of Entecavir-Resistant Hepatitis B Virus Polymerase with L180M/M204V Mutations.Journal of virology · 2021Article
- Mutational characterization of HBV reverse transcriptase gene and the genotype-phenotype correlation of antiviral resistance among Chinese chronic hepatitis B patients.Emerging microbes & infections · 2020Article
- Non-nucleoside hepatitis B virus polymerase inhibitors identified by an in vitro polymerase elongation assay.Journal of gastroenterology · 2020Article
- Hepatitis B virus mutation pattern rtL180M+A181C+M204V may contribute to entecavir resistance in clinical practice.Emerging microbes & infections · 2019Article
- Modeling the functional state of the reverse transcriptase of hepatitis B virus and its application to probing drug-protein interaction.BMC bioinformatics · 2016Article
- Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches.OncoTargets and therapy · 2016Article
- Substitution at rt269 in Hepatitis B Virus Polymerase Is a Compensatory Mutation Associated with Multi-Drug Resistance.PloS one · 2015Article
- Differential binding of tenofovir and adefovir to reverse transcriptase of hepatitis B virus.PloS one · 2014Article
- Hepatitis B virus reverse transcriptase: diverse functions as classical and emerging targets for antiviral intervention.Emerging microbes & infections · 2013Review
- Extensive mutagenesis of the conserved box E motif in duck hepatitis B virus P protein reveals multiple functions in replication and a common structure with the primer grip in HIV-1 reverse transcriptase.Journal of virology · 2012Article
- Review
- Discovery and development of anti-HBV agents and their resistance.Molecules (Basel, Switzerland) · 2010Review
- Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundEntecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. METHODS/PRINCIPAL
findingsTo determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position.
conclusionsAltogether, ETVr occurred through exclusion of ETV-TP from the dNTP-binding site, through different, novel mechanisms that involved lamivudine-resistance, ETV-specific substitutions, and the primer-template.
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