ArticleAntimicrobial agents and chemotherapy2012
Efficient replication of genotype 3a and 4a hepatitis C virus replicons in human hepatoma cells.
Article in Antimicrobial agents and chemotherapy, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 122 citations in OpenAlex.
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- NS5A-ISGylation via Lysine 26 Has a Critical Role for Efficient Propagation of Hepatitis C Virus Genotype 2a.The Kobe journal of medical sciences · 2021Article
- Discovery of Quinoxaline-Based P1-P3 Macrocyclic NS3/4A Protease Inhibitors with Potent Activity against Drug-Resistant Hepatitis C Virus Variants.Journal of medicinal chemistry · 2021Article
- Design and Synthesis of Novel Symmetric Fluorene-2,7-Diamine Derivatives as Potent Hepatitis C Virus Inhibitors.Pharmaceuticals (Basel, Switzerland) · 2021Article
- A novel substitution in NS5A enhances the resistance of hepatitis C virus genotype 3 to daclatasvir.The Journal of general virology · 2021Article
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- Insights into the unique characteristics of hepatitis C virus genotype 3 revealed by development of a robust sub-genomic DBN3a replicon.The Journal of general virology · 2020Article
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- ISGylation of Hepatitis C Virus NS5A Protein Promotes Viral RNA Replication via Recruitment of Cyclophilin A.Journal of virology · 2020Article
- Sofosbuvir Thio-analogues: Synthesis and Antiviral Evaluation of the First Novel Pyridine- and Pyrimidine-Based Thioglycoside Phosphoramidates.ACS omega · 2020Article
- Viral replicons as valuable tools for drug discovery.Drug discovery today · 2020Review
- Cell Culture Studies of the Efficacy and Barrier to Resistance of Sofosbuvir-Velpatasvir and Glecaprevir-Pibrentasvir against Hepatitis C Virus Genotypes 2a, 2b, and 2c.Antimicrobial agents and chemotherapy · 2020Article
- Article
9 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
Abstract
Despite recent advances in the treatment of hepatitis C, the quest for pan-genotype, effective, and well-tolerated inhibitors continues. To facilitate these efforts, it is desirable to have in vitro replication systems for all major HCV genotypes. However, cell culture replication systems exist for only genotypes 1a, 1b, and 2a. In this study, we generated G418-selectable subgenomic replicons for prototype strains of genotypes 3a (S52) and 4a (ED43). Production of G418-resistant colonies by S52 and ED43 in Huh-7.5 cells required the amino acid substitutions S2210I and R2882G, respectively, cell culture adaptive mutations originally reported for genotype 1b replicons. RNA replication was confirmed by quantitative reverse transcription-PCR and detection of viral protein. Sequencing of multiple independent replicon clones revealed the presence of additional nonsynonymous mutations. Interestingly, all potentially adaptive mutations mapped to the NS3 protein. These mutations, when introduced back into original constructs, substantially increased colony formation efficiency. To make these replicons useful for high-throughput screening and evaluation of antiviral compounds, they were modified to express a chimeric fusion protein of firefly luciferase and neomycin phosphotransferase to yield stable replicon-expressing cells. Using these constructs, the inhibitory effects of beta interferon (IFN-β), an NS3 protease inhibitor, and an NS5B nucleoside polymerase inhibitor were readily detected by monitoring luciferase activity. In conclusion, we have established functional replicons for HCV genotypes 3a and 4a, important new additions to the armamentarium required to develop inhibitors with a pan-genotype activity.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.