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High-throughput Screening for Broad-spectrum Chemical Inhibitors of RNA Viruses
Published on: May 5, 2014
Optimized high-throughput screen for hepatitis C virus translation inhibitors
Katherine E Berry1, Betty Peng, David Koditek
1Department of Chemistry, University of California, Berkeley, CA, USA.
Journal of Biomolecular Screening
|February 8, 2011
Summary
Researchers sought selective Hepatitis C virus (HCV) translation inhibitors. Despite screening over 430,000 compounds, no selective inhibitors were found, highlighting challenges in RNA-specific drug discovery.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Hepatitis C virus (HCV) poses a significant global health challenge.
- Novel therapeutic strategies targeting HCV are urgently required.
- Translation initiation via the HCV internal ribosome entry site (IRES) is a potential therapeutic target.
Purpose of the Study:
- To develop and implement a high-throughput screening assay for identifying selective inhibitors of HCV IRES-dependent translation initiation.
- To screen a large chemical library to discover compounds that specifically block HCV IRES function.
Main Methods:
- Optimization of in vitro translation systems using rabbit reticulocyte lysate.
- Development of a high-throughput assay comparing HCV IRES-driven translation to 5' capped mRNA control.
- Screening of approximately 430,000 small molecules for IRES inhibitory activity.
- Secondary counterscreening to validate and eliminate false positives.
Main Results:
- Initial screening identified approximately 1700 potential hits.
- Counterscreening revealed that most hits were non-specific inhibitors of general translation or luciferase.
- No selective inhibitors of HCV IRES-dependent translation were identified.
- A novel scaffold of general translation inhibitors was discovered.
Conclusions:
- Developing selective RNA-specific inhibitors presents significant challenges, often complicated by off-target effects.
- The study underscores the difficulties in high-throughput screening for specific RNA elements.
- Further research is needed to overcome hurdles in discovering targeted antiviral therapies for HCV.
