Identification of hepatitis C virus inhibitors targeting different aspects of infection using a cell-based assay Journal Article

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Authors: Yu, X.; Sainz, B., Jr; Petukhov, P. A.; Uprichard, S. L.
Article Title: Identification of hepatitis C virus inhibitors targeting different aspects of infection using a cell-based assay
Abstract: With 2 to 3% of the worldwide population chronically infected, hepatitis C virus (HCV) infection continues to be a major health care burden. Unfortunately, current interferon-based treatment options are not effective in all patients and are associated with significant side effects. Consequently, there is an ongoing need to identify and develop new anti-HCV therapies. Toward this goal, we previously developed a cell-based HCV infection assay for antiviral compound screening based on a low-multiplicity-of-infection approach that uniquely allows for the identification of antiviral compounds that target cell culture-derived HCV (HCVcc) at any step of the viral infection cycle. Using this assay, here we report the screening of the NCI Diversity Set II library, containing 1,974 synthesized chemical compounds, and the identification of compounds with specific anti-HCV activity. In combination with toxicity counterscreening, we identified 30 hits from the compound library, 13 of which showed reproducible and dose-dependent inhibition of HCV with mean therapeutic indices (50% cytotoxic concentration [CC(50)]/50% effective concentration [EC(50)]) of greater than 6. Using HCV pseudotype and replicon systems of multiple HCV genotypes, as well as infectious HCVcc-based assembly and secretion analysis, we determined that different compounds within this group of candidate inhibitors target different steps of viral infection. The compounds identified not only will serve as biological probes to study and further dissect the biology of viral infection but also should facilitate the development of new anti-HCV therapeutic treatments.
Journal Title: Antimicrobial Agents and Chemotherapy
Volume: 56
Issue: 12
ISSN: 1098-6596; 0066-4804
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 6109
End Page: 6120
Language: eng
DOI/URL:

10.1128/AAC.01413-12

10.1128/AAC.01413-12
Notes: LR: 20130712; GR: R01 AI070827/AI/NIAID NIH HHS/United States; GR: R01 AI078881/AI/NIAID NIH HHS/United States; GR: R01-AI070827/AI/NIAID NIH HHS/United States; GR: R03 AI085226/AI/NIAID NIH HHS/United States; GR: R03-AI085226/AI/NIAID NIH HHS/United States; GR: R21 CA133266/CA/NCI NIH HHS/United States; GR: R21-CA133266/CA/NCI NIH HHS/United States; GR: R56/R01-AI078881/AI/NIAID NIH HHS/United States; JID: 0315061; 0 (Antiviral Agents); 0 (Indicators and Reagents); 0 (RNA, Viral); 0 (Small Molecule Libraries); OID: NLM: PMC3497158; 2012/09/04 [aheadofprint]; ppublish