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Selective AAK1 and GAK Inhibitors for Combating Dengue and other Emerging Viral Infections


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Emerging viruses, such as dengue (DENV) and Ebola (EBOV), pose threats to military and global health. There are no approved drugs or vaccines available against these viruses. Our goal is to develop broad-spectrum antivirals with a high genetic barrier to resistance by targeting host proteins that are critical to the life cycle of multiple viruses. The goals of this project are to optimize selective inhibitors of AAK1 and GAK, host kinases we discovered as targets for broad-spectrum antivirals, and advance their development to a pre-IND stage. This approach would also protect against multiple other biothreat agents. During the past year we have optimized the antiviral activity of two distinct series of GAK inhibitors and a series of AAK1 inhibitors, all with excellent broad- spectrum antiviral activity (DENV, CHIKV and EBOV and SARS-CoV-2), including in human primary cells, with a high barrier to resistance. We have also demonstrated target modulation with representative compounds and determined key in vitro ADME parameters. We have submitted a proposal for an expansion award whose goal is to advance these imporved compounds to animal studies.



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