It is estimated that over 170 million people are infected by HCV worldwide. Currently, there are limited therapeutic agents and no vaccine available for HCV infection. Thus, it is necessary to develop new anti-HCV drugs. The HCV is a member of the family Flaviviridae. The HCV genome contains a long, single open reading frame mRNA that encodes the viral proteins. An internal ribosome entry site (IRES)cis-acting element was identified in the 5' untranslated region of the HCV RNA, which directs translation initiation of the viral proteins. The HCV IRES has conserved primary sequences, unique secondary and tertiary structures, and a distinct interaction mode with cellular initiation factors. Based on the applicant's expertise in drug discovery, i.e. targeting post-transcriptional control, the investigators are pursuing HCV IRES-mediated translation initiation against HCV infection. Using HCV IRES translation assays established at PTC Therapeutics, Inc., the applicants have identified low molecular weight compounds that are active against HCV IRES-mediated translation. The goal of the proposed research is to further assess compound selectivity to cap-dependent translation, the cytotoxicity profiles of the HCV IRES hits and their efficacy in a self-replicating subgenomic HCV system. A successful outcome of the proposed studies will be the identification of lead candidates that act on HCV IRES-facilitated translation initiation.
