ArticleAntimicrobial agents and chemotherapy2016
Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus.
Article in Antimicrobial agents and chemotherapy, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.
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Who cites it
46 citing papers in PubMed, 83 citations in OpenAlex.
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- The nucleoside analog CMX521 inhibits coronavirus RNA-dependent RNA polymerase via a two-pronged mechanism.bioRxiv : the preprint server for biology · 2026Article
- Prodrug strategies in developing antiviral nucleoside analogs.RSC medicinal chemistry · 2026Review
- DragonRNA: Generality of DNA-primed RNA-extension activities by DNA-directed RNA polymerases.Nucleic acids research · 2025Article
- Review
- Assessing the mitochondrial safety profile of the molnupiravir active metabolite, β-d-N4-hydroxycytidine (NHC), in the physiologically relevant HepaRG model.Toxicology research · 2024Article
- Remdesivir Discontinuation Decisions Based on Thresholds of Aminotransferase in an Observational Registry.Drugs · 2024Article
- Direct-Acting Antiviral Drug Modulates the Mitochondrial Biogenesis in Different Tissues of Young Female Rats.International journal of molecular sciences · 2023Article
- Recent Advances in Molecular Mechanisms of Nucleoside Antivirals.Current issues in molecular biology · 2023Review
- Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity.Molecules (Basel, Switzerland) · 2023Review
- Kill or corrupt: Mechanisms of action and drug-resistance of nucleotide analogues against SARS-CoV-2.Antiviral research · 2023Review
- Gossypol Broadly Inhibits Coronaviruses by Targeting RNA-Dependent RNA Polymerases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Role of a "Magic" Methyl: 2'-Deoxy-2'-α-F-2'-β-Journal of the American Chemical Society · 2022Article
- Different Kinetics of HBV-DNA and HBsAg in HCV Coinfected Patients during DAAs Therapy.Journal of clinical medicine · 2022Article
- Mitochondrial Genotoxicity of Hepatitis C Treatment among People Who Inject Drugs.Journal of clinical medicine · 2021Article
- NKX3.1 Localization to Mitochondria Suppresses Prostate Cancer Initiation.Cancer discovery · 2021Article
- Y705 and S727 are required for the mitochondrial import and transcriptional activities of STAT3, and for regulation of stem cell proliferation.Development (Cambridge, England) · 2021Article
- Progress and pitfalls of a year of drug repurposing screens against COVID-19.Current opinion in virology · 2021Review
- Off-TargetAntimicrobial agents and chemotherapy · 2021Article
- Targeting Mitochondrial Metabolism and RNA Polymerase POLRMT to Overcome Multidrug Resistance in Cancer.Frontiers in chemistry · 2021Review
Corrections and comments
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Authors and funding
14 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Toxicity has emerged during the clinical development of many but not all nucleotide inhibitors (NI) of hepatitis C virus (HCV). To better understand the mechanism for adverse events, clinically relevant HCV NI were characterized in biochemical and cellular assays, including assays of decreased viability in multiple cell lines and primary cells, interaction with human DNA and RNA polymerases, and inhibition of mitochondrial protein synthesis and respiration. NI that were incorporated by the mitochondrial RNA polymerase (PolRMT) inhibited mitochondrial protein synthesis and showed a corresponding decrease in mitochondrial oxygen consumption in cells. The nucleoside released by the prodrug balapiravir (R1626), 4'-azido cytidine, was a highly selective inhibitor of mitochondrial RNA transcription. The nucleotide prodrug of 2'-C-methyl guanosine, BMS-986094, showed a primary effect on mitochondrial function at submicromolar concentrations, followed by general cytotoxicity. In contrast, NI containing multiple ribose modifications, including the active forms of mericitabine and sofosbuvir, were poor substrates for PolRMT and did not show mitochondrial toxicity in cells. In general, these studies identified the prostate cell line PC-3 as more than an order of magnitude more sensitive to mitochondrial toxicity than the commonly used HepG2 cells. In conclusion, analogous to the role of mitochondrial DNA polymerase gamma in toxicity caused by some 2'-deoxynucleotide analogs, there is an association between HCV NI that interact with PolRMT and the observation of adverse events. More broadly applied, the sensitive methods for detecting mitochondrial toxicity described here may help in the identification of mitochondrial toxicity prior to clinical testing.
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