ArticleAntimicrobial agents and chemotherapy2008
Discovery and characterization of substituted diphenyl heterocyclic compounds as potent and selective inhibitors of hepatitis C virus replication.
Article in Antimicrobial agents and chemotherapy, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
3 citing papers in PubMed.
- De novo polymerase activity and oligomerization of hepatitis C virus RNA-dependent RNA-polymerases from genotypes 1 to 5.PloS one · 2011Article
- A cell protection screen reveals potent inhibitors of multiple stages of the hepatitis C virus life cycle.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Development of a cell-based hepatitis C virus infection fluorescent resonance energy transfer assay for high-throughput antiviral compound screening.Antimicrobial agents and chemotherapy · 2009Article
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Authors and funding
21 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A novel small-molecule inhibitor, referred to here as R706, was discovered in a high-throughput screen of chemical libraries against Huh-7-derived replicon cells carrying autonomously replicating subgenomic RNA of hepatitis C virus (HCV). R706 was highly potent in blocking HCV RNA replication as measured by real-time reverse transcription-PCR and Western blotting of R706-treated replicon cells. Structure-activity iterations of the R706 series yielded a lead compound, R803, that was more potent and highly specific for HCV replication, with no significant inhibitory activity against a panel of HCV-related positive-stranded RNA viruses. Furthermore, HCV genotype 1 replicons displayed markedly higher sensitivity to R803 treatment than a genotype 2a-derived replicon. In addition, R803 was tested by a panel of biochemical and cell-based assays for on-target and off-target activities, and the data suggested that the compound had a therapeutic window close to 100-fold, while its exact mechanism of action remained elusive. We found that R803 was more effective than alpha interferon (IFN-alpha) at blocking HCV RNA replication in the replicon model. In combination studies, R803 showed a weak synergistic effect with IFN-alpha/ribavirin but only additive effects with a protease inhibitor and an allosteric inhibitor of RNA-dependent RNA polymerase (20). We conclude that R803 and related heterocyclic compounds constitute a new class of HCV-specific inhibitors that could potentially be developed as a treatment for HCV infection.
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