UC San Diego

Hepatitis C Virus (HCV) contains an Internal Ribosome Entry Site (IRES), which is a 5’ region of noncoding RNA that allows for the viral genome to initiate cap independent translation, inserting itself into the 40S subunit. It then hijacks the ribosome to translate the viral genome. This process of IRES driven translation is mediated by a conformational switch, known as an RNA switch, which allows the IRES to attach itself to the 40S subunit, but also to detach once the process of translation has been initiated by the viral genome. Both conformations are necessary for the IRES driven translation initiation. This RNA switch region is highly conserved, and therefore was an interesting target for research. The RNA switch is mediated by a ligand binding mechanism, where a native ligand binds into a pocket in the RNA and locks it into the configuration that allows for the release of the IRES. In this work, we have used structure-guided synthesis to analyze the binding pocket and attempt to explore binding interactions of portions of the pocket that have not been previously well understood. We have synthesized a variety of compounds with different functional groups and functionality that provide us with a better understanding of this binding pocket and will allow for further study of RNA switch binding pockets as potential small molecule drug targets.