ANTIVIRAL STRATEGY DIRECTED TOWARD HCV RNA TRANSLATION

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Hepatitis C virus (HCV) infects 0,5-1.5% of the world population. It causes acute and chronic hepatitis and cirrhosis and is highly associated with hepatocellular carcinoma. We have proposed an anti-HCV strategy that relies on the unique property of HCV RNA translation, which is directed by the internal ribosomal entry site (IRES) located in the HCV 5' untranslated region. The goal of this strategy is to identify antiviral compounds that specifically inhibit HCV translation without affecting cap- dependent translation of cellular mRNA. In phase I, we have successfully established a stable cell line expressing a dual-reporter construct, CAT- IRES-Fluci, and have screened in our automated facilities 73,000 fungal extracts and compounds against this cell line for activities that inhibit the firefly luciferase (Fluci) signal under the translational control of IRES. This screen results in identification of 21 hits that show difference between Fluci inhibition and MTT inhibition (a cytotoxic indicator), which are now being investigated in follow-up. In phase II, we will complete screening of a total of 75,000 fungal extracts and 55,000 compounds. Hits that score and are reconfirmed in high throughput screening will be prioritized with respect to potency, selectivity, cytotoxicity, and antiviral activity. Active compounds in fungal extracts will be purified and their chemical structure determined. Anti-HCV drugs will be developed with our collaborative partner, Biochem Pharma, in phase III. PROPOSED COMMERCIAL APPLICATION: HCV infects 0.5-1.5% of the world population and poses a major health problem since there is no effective prevention or treatment available. Compounds and natural products that inhibit HCV RNA translation can be developed into novel antiviral drugs with enormous commercial potential.