ArticleAntimicrobial agents and chemotherapy2014
Efficiency of incorporation and chain termination determines the inhibition potency of 2'-modified nucleotide analogs against hepatitis C virus polymerase.
Article in Antimicrobial agents and chemotherapy, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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42 citing papers in PubMed.
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- 1'- and 4'-Cyano Modified Adenosine Analogs Against Prototypic Flavivirus RNA-Dependent RNA Polymerases.Viruses · 2026Article
- Towards Explainable Computational Toxicology: Linking Antitargets to Rodent Acute Toxicity.Pharmaceutics · 2025Article
- Mechanism of Inhibition of the Active Triphosphate Form of 2'-α-Fluoro,2'-β-bromouridine against Yellow Fever Virus RNA-Dependent RNA Polymerase.ACS infectious diseases · 2025Article
- Combinations of approved oral nucleoside analogues confer potent suppression of alphavirusesbioRxiv : the preprint server for biology · 2025Article
- Sofosbuvir Suppresses the Genome Replication of DENV1 in Human Hepatic Huh7 Cells.International journal of molecular sciences · 2024Article
- 2-thiouridine is a broad-spectrum antiviral nucleoside analogue against positive-strand RNA viruses.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Heparin Precursors with Reduced Anticoagulant Properties Retain Antiviral and Protective Effects That Potentiate the Efficacy of Sofosbuvir against Zika Virus Infection in Human Neural Progenitor Cells.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Fitness-Dependent, Mild Mutagenic Activity of Sofosbuvir for Hepatitis C Virus.Antimicrobial agents and chemotherapy · 2023Article
- Structure-Based Drug Design of RdRp Inhibitors against SARS-CoV-2.Topics in current chemistry (Cham) · 2023Review
- Inhibition of Viral RNA-Dependent RNA Polymerases by Nucleoside Inhibitors: An Illustration of the Unity and Diversity of Mechanisms.International journal of molecular sciences · 2022Review
- An evaluation of ledipasvir + sofosbuvir for the treatment of chronic hepatitis C infection.Expert opinion on pharmacotherapy · 2021Review
- Profiling the physiological pitfalls of anti-hepatitis C direct-acting agents in budding yeast.Microbial biotechnology · 2021Article
- Article
- Inhibition of viral RNA-dependent RNA polymerases with clinically relevant nucleotide analogs.The Enzymes · 2021Article
- Molecular Dynamics Simulations Reveal the Interaction Fingerprint of Remdesivir Triphosphate Pivotal in Allosteric Regulation of SARS-CoV-2 RdRp.Frontiers in molecular biosciences · 2021Article
- Repurposing existing drugs for the treatment of COVID-19/SARS-CoV-2 infection: A review describing drug mechanisms of action.Biochemical pharmacology · 2021Review
- Antiviral and Antimicrobial Nucleoside Derivatives: Structural Features and Mechanisms of Action.Molecular biology · 2021Article
- Recapitulating Trafficking of Nucleosides Into the Active Site of Polymerases of RNA Viruses: The Challenge and the Prize.Frontiers in medical technology · 2021Article
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6 authors.
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Abstract
Ribonucleotide analog inhibitors of the RNA-dependent RNA polymerase of hepatitis C virus (HCV) represent one of the most exciting recent developments in HCV antiviral therapy. Although it is well established that these molecules cause chain termination by competing at the triphosphate level with natural nucleotides for incorporation into elongating RNA, strategies to rationally optimize antiviral potency based on enzyme kinetics remain elusive. In this study, we used the isolated HCV polymerase elongation complex to determine the pre-steady-state kinetics of incorporation of 2'F-2'C-Me-UTP, the active metabolite of the anti-HCV drug sofosbuvir. 2'F-2'C-Me-UTP was efficiently incorporated by HCV polymerase with apparent Kd (equilibrium constant) and kpol (rate of nucleotide incorporation at saturating nucleotide concentration) values of 113 ± 28 μM and 0.67 ± 0.05 s(-1), respectively, giving an overall substrate efficiency (kpol/Kd) of 0.0059 ± 0.0015 μM(-1) s(-1). We also measured the substrate efficiency of other UTP analogs and found that substitutions at the 2' position on the ribose can greatly affect their level of incorporation, with a rank order of OH > F > NH2 > F-C-Me > C-Me > N3 > ara. However, the efficiency of chain termination following the incorporation of UMP analogs followed a different order, with only 2'F-2'C-Me-, 2'C-Me-, and 2'ara-UTP causing complete and immediate chain termination. The chain termination profile of the 2'-modified nucleotides explains the apparent lack of correlation observed across all molecules between substrate efficiency at the single-nucleotide level and their overall inhibition potency. To our knowledge, these results provide the first attempt to use pre-steady-state kinetics to uncover the mechanism of action of 2'-modified NTP analogs against HCV polymerase.
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