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Antiviral Res. 2015 Dec;124:20-9. doi: 10.1016/j.antiviral.2015.10.018. Epub 2015 Oct 26.

Identification of novel anti-hepatitis C virus agents by a quantitative high throughput screen in a cell-based infection assay.

Author information

1
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
2
National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA.
3
Department of Molecular and Cellular Biochemistry, Indiana University, 212 S Hawthorne St, Bloomington, IN 47405, USA.
4
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jliang@nih.gov.

Abstract

Hepatitis C virus (HCV) poses a major health threat to the world. The recent development of direct-acting antivirals (DAAs) against HCV has markedly improved the response rate of HCV and reduced the side effects in comparison to the interferon-based therapy. Despite this therapeutic advance, there is still a need to develop new inhibitors that target different stages of the HCV life cycle because of various limitations of the current regimens. In this study, we performed a quantitative high throughput screening of the Molecular Libraries Small Molecule Repository (MLSMR) of ∼350,000 chemicals for novel HCV inhibitors using our previously developed cell-based HCV infection assay. Following confirmation and structural clustering analysis, we narrowed down to 158 compounds from the initial ∼3000 molecules that showed inhibitory activity for further structural and functional analyses. We were able to assign the majority of these compounds to specific stage(s) in the HCV life cycle. Three of them are direct inhibitors of NS3/4A protease. Most of the compounds appear to act on novel targets in HCV life cycle. Four compounds with novel structure and excellent drug-like properties, three targeting HCV entry and one targeting HCV assembly/secretion, were advanced for further development as lead hits. These compounds represent diverse chemotypes that are potential lead compounds for further optimization and may offer promising candidates for the development of novel therapeutics against HCV infection. In addition, they represent novel molecular probes to explore the complex interactions between HCV and the cells.

KEYWORDS:

Antiviral; Cell-based assay; HCV inhibitors; High throughput screening; Viral life cycle

PMID:
26515788
PMCID:
PMC4684727
DOI:
10.1016/j.antiviral.2015.10.018
[Indexed for MEDLINE]
Free PMC Article

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