ArticleAntimicrobial agents and chemotherapy2014
Inhibition of hepatitis C virus replication by GS-6620, a potent C-nucleoside monophosphate prodrug.
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 21 papers.
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Who cites it
21 citing papers in PubMed, 41 citations in OpenAlex.
- Novel tricycle expanded purine nucleosides with pan-viral activity.Bioorganic & medicinal chemistry · 2025Article
- Remdesivir triphosphate blocks DNA synthesis and increases exonucleolysis by the replicative mitochondrial DNA polymerase, Pol γ.Mitochondrion · 2021Article
- Off-TargetAntimicrobial agents and chemotherapy · 2021Article
- Remdesivir against COVID-19 and Other Viral Diseases.Clinical microbiology reviews · 2020Review
- Analysis of the Potential forAntimicrobial agents and chemotherapy · 2020Article
- New Nucleoside Analogues for the Treatment of Hemorrhagic Fever Virus Infections.Chemistry, an Asian journal · 2019Review
- The evolution of antiviral nucleoside analogues: A review for chemists and non-chemists. Part II: Complex modifications to the nucleoside scaffold.Antiviral research · 2019Review
- Nucleotide Prodrug Containing a Nonproteinogenic Amino Acid To Improve Oral Delivery of a Hepatitis C Virus Treatment.Antimicrobial agents and chemotherapy · 2018Article
- Current therapy for chronic hepatitis C: The role of direct-acting antivirals.Antiviral research · 2017Review
- Synthetic Approaches for the Preparation of Phosphoramidate Prodrugs of 2'-Deoxypseudoisocytidine.ChemistryOpen · 2017Article
- Antiviral Nucleotide Incorporation by Recombinant Human Mitochondrial RNA Polymerase Is Predictive of Increased In Vivo Mitochondrial Toxicity Risk.Antimicrobial agents and chemotherapy · 2016Article
- A Complex Network of Interactions between S282 and G283 of Hepatitis C Virus Nonstructural Protein 5B and the Template Strand Affects Susceptibility to Sofosbuvir and Ribavirin.Antimicrobial agents and chemotherapy · 2016Article
- Role of Mitochondrial RNA Polymerase in the Toxicity of Nucleotide Inhibitors of Hepatitis C Virus.Antimicrobial agents and chemotherapy · 2016Article
- In Vitro Antiviral Activity and Resistance Profile Characterization of the Hepatitis C Virus NS5A Inhibitor Ledipasvir.Antimicrobial agents and chemotherapy · 2016Article
- Discovery and Synthesis of C-Nucleosides as Potential New Anti-HCV Agents.ACS medicinal chemistry letters · 2014Article
- Metabolism and pharmacokinetics of the anti-hepatitis C virus nucleotide prodrug GS-6620.Antimicrobial agents and chemotherapy · 2014Article
- Phosphoramidates and phosphonamidates (ProTides) with antiviral activity.Antiviral chemistry & chemotherapyReview
- The antiretroviral 2',3'-dideoxycytidine causes mitochondrial dysfunction in proliferating and differentiated HepaRG human cell cultures.The Journal of biological chemistryArticle
- Nucleosides for the treatment of respiratory RNA virus infections.Antiviral chemistry & chemotherapyReview
- Addressing the selectivity and toxicity of antiviral nucleosides.Antiviral chemistry & chemotherapyReview
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Authors and funding
27 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As a class, nucleotide inhibitors (NIs) of the hepatitis C virus (HCV) nonstructural protein 5B (NS5B) RNA-dependent RNA polymerase offer advantages over other direct-acting antivirals, including properties, such as pangenotype activity, a high barrier to resistance, and reduced potential for drug-drug interactions. We studied the in vitro pharmacology of a novel C-nucleoside adenosine analog monophosphate prodrug, GS-6620. It was found to be a potent and selective HCV inhibitor against HCV replicons of genotypes 1 to 6 and against an infectious genotype 2a virus (50% effective concentration [EC50], 0.048 to 0.68 μM). GS-6620 showed limited activities against other viruses, maintaining only some of its activity against the closely related bovine viral diarrhea virus (EC50, 1.5 μM). The active 5'-triphosphate metabolite of GS-6620 is a chain terminator of viral RNA synthesis and a competitive inhibitor of NS5B-catalyzed ATP incorporation, with Ki/Km values of 0.23 and 0.18 for HCV NS5B genotypes 1b and 2a, respectively. With its unique dual substitutions of 1'-CN and 2'-C-Me on the ribose ring, the active triphosphate metabolite was found to have enhanced selectivity for the HCV NS5B polymerase over host RNA polymerases. GS-6620 demonstrated a high barrier to resistance in vitro. Prolonged passaging resulted in the selection of the S282T mutation in NS5B that was found to be resistant in both cellular and enzymatic assays (>30-fold). Consistent with its in vitro profile, GS-6620 exhibited the potential for potent anti-HCV activity in a proof-of-concept clinical trial, but its utility was limited by the requirement of high dose levels and pharmacokinetic and pharmacodynamic variability.
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