Background and Significance: Approximately 3.2 million people in the United States are currently living with hepatitis C virus (HCV). As a positive-sense RNA virus, HCV is prone to mutations, which makes it difficult to design drugs that can target either the viral proteins or the genome itself. It has been discovered that a small section of the 5’ non-coding RNA, called the internal ribosome entry site (IRES) subdomain IIa acts as a molecular switch. The IRES recruits human ribosomes to bind, which causes a conformational change in the subdomain IIa, and allows for the ribosome to translate the RNA into viral proteins. Notably, this small section of RNA is highly conserved; as previously discovered, the virus showed only two point mutations in the subdomain IIa. Due to this high degree of conservation, it is an invaluable target for drug design that mimics the natural ligand and forces the IRES into a conformation that will not recruit ribosomes, rendering the virus unable to reproduce. Methods: We have created an improved, efficient synthesis of diverse methylsulfoximine molecules using novel techniques developed in our laboratory. We have initiated synthesizing new analogs designed to improve affinity of the targets for the HCV RNA. We plan to conduct rapid assays of the new compounds against the IRES-IIa subdomain, allowing us to iteratively refine SAR and leverage our new synthetic route toward obtaining compounds with increased potency. Results: It has been shown that precise shape complementarity based solely on hydrophobic interactions can significantly improve ligand binding even in hydrophilic target sites such as RNA. We have focused on synthesizing heterocyclic methylsulfoximine derivatives of the natural HCV IRES ligand that will take advantage of these space-filling interactions. The initial scaffold has been synthesized and tested on the RNA construct. We are currently working on modifying the scaffold to be more like the native ligand to further improve binding to the IRES. Conclusions: The efficient new synthetic route we have developed has made it practical to obtain enough material to optimize for inhibition, replication and favorable pharmacokinetics and bioavailability, thus advancing the prospects of this class of compounds as potential anti-HCV medications.

Synthesis of new hepatitis C virus translation inhibitors

2019 Fall National Meeting

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