The World Health Organization estimates there are 71 million people currently living with hepatitis C virus (HCV), with 15-30% of those infected developing advanced liver diseases such as cirrhosis or liver cancer. While current treatments can be very effective, they are extremely cost prohibitive, limiting access to many individuals. Another issue is most of these treatments target the same viral protein, non-structural protein 5B (NS5B), an RNA dependent RNA polymerase. With an anticipated mutation in NS5B, these therapeutics may ultimately be rendered ineffective.<br/>Although most small-molecule drugs target proteins, and most drugs that target RNA target ribosomal RNA, non-coding regions of viral genomes have become an interesting target for anti-viral therapeutics. Certain viruses, such as HCV, have an internal ribosome entry site (IRES) located in the 5’ region of their non-coding RNA. IRESs are used to hijack ribosomal production of proteins in cells even without eukaryotic transcription factors. The HCV IRES allows for cap-independent translation of viral genes, rendering the recruitment of many host initiation factors unnecessary. While many viruses contain IRESs with varied structures, our lab has discovered a highly conserved internal loop in the HCV IRES which works as a molecular switch. Due to its importance in translation, as well as the segment being highly conserved, the HCV IRES is an interesting target for new anti-viral drugs.<br/>We have shown that precise shape complementarity based solely on hydrophobic interactions can significantly improve ligand binding in the IRES, even though it’s a hydrophilic RNA pocket.  We have focused on synthesizing heterocyclic derivatives of the natural HCV IRES ligand that will take advantage of these space-filling interactions.  Multiple scaffolds have been tested against the IRES construct, and we are currently designing and synthesizing new derivatives based on these results.

Design and synthesis of new hepatitis C virus translation inhibitors

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.