Therapeutic Targeting of HCV Internal Ribosomal Entry Site RNA

Abstract

HCV infection is a significant human disease, leading to liver cirrhosis and cancer, and killing >10,000 people in the US annually. Translation of the viral RNA genome is initiated by ribosomal binding to a highly structured RNA element, the internal ribosomal entry site (IRES), which presents a novel target for therapeutic intervention. We will first discuss studies of oligonucleotide therapeutics targeting various regions of the 340-nucleotide IRES, many of which have effectively blocked IRES function in vitro and are active against virus replication in cell culture. Although low nanomolar potencies have been obtained for DNA- and RNA-based molecules, stability and drug delivery challenges remain to be addressed for these particular HCV compounds. Several classes of small molecule inhibitors have been identified from screening protocols or designed from established RNA therapeutic scaffolds. In particular, small molecule IRES inhibitors based on a benzimidazole scaffold bind specifically to the IRES, and inhibit viral replication in cell culture at micromolar concentrations with low toxicity. The structure of the RNA target in complex with a representative member of these small molecule inhibitors demonstrates that a large RNA conformational change occurs upon inhibitor binding. The RNA complex shows how the inhibitor alters the global RNA structure and provides a framework for structure-based drug design of novel HCV therapeutics.