Assessment of targeted protein degradation as a strategy for potent antivirals with high barriers to resistance

There is a major need for antivirals to combat the diverse viral pathogens causing human disease. Drugs that potently inhibit one or more related viruses with high natural barriers to resistance remain a much-desired but elusive goal. “Degronimids” represent a new class of inhibitors that induce degradation of their targets through recruitment of the E3 ubiquitin ligase cereblon. This inhibitory strategy can alleviate the need for stoichiometric target engagement and also suppress drug resistance. Recent examples in cancer biology demonstrate that degronimids against kinases and transcriptional enzymes deplete their requisite targets and have superior efficacy and resistance profiles relative to the parental compounds. Here, we propose to develop and evaluate degronimids that inhibit hepatitis C virus and dengue virus through inhibition and targeted degradation of specific viral targets. The goal of this work is to provide proof of concept that degronimid antivirals have superior antiviral potency and resistance profile when compared to the parental compounds. Viral targets and parent inhibitors have been judiciously selected to allow synthesis and characterization of antiviral degronimids on a relatively short time scale by leveraging our virological tools and expertise as well as by taking advantage of resistance mutations that have already been well-documented in the literature.