Discovery of next-generation dengue NS4B inhibitors

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PROJECT 5 – ABSTRACT The goal of this project is to discover next-generation dengue NS4B inhibitors. We currently have a pan-dengue serotype NS4B inhibitor NITD-688 in phase I clinical trial. Preclinical results suggest two potential liabilities that might threaten this compound for further development. Thus, we will develop a second-generation compound to mitigate the liabilities. We will achieve the goal by pursuing three aims. (i) Optimize the next generation of dengue NS4B inhibitor. We have developed a comprehensive medicinal chemistry optimization strategy to improve the compound properties. (ii) Conduct preclinical characterization and deliver an IND-ready next-generation NS4B inhibitor. (iii) Determine the mode-of-action and resistance potential of NITD-688. NS4B is a transmembrane protein that participates in replication complex through interacting with other viral and host proteins. We will take chemo-proteomic, biochemical, and cellular approaches to define the mechanism of compound inhibition. Such knowledge can be applied to other membrane proteins for antiviral discovery.