The mission of Project 5 is to develop orally available direct-acting clinical candidates to prevent or treat the significant morbidity and mortality associated with enterovirus infections. It is estimated that enteroviruses are responsible for ~20 million infections in the U.S. and more than one billion worldwide each year. There are currently no effective antiviral therapeutics available to prevent or treat non-poliovirus enterovirus infections. This project will fully characterize orally-available ribonucleosides with potent inhibitory activity against clinically relevant enteroviruses and determine the efficacy of these compounds in physiologically relevant in vitro and in vivo models. Studies of enterovirus antiviral therapeutics have been limited by the lack of suitable models that recapitulate the unique cellular and immunologic features of the cells and tissues targeted by these viruses in vivo. The studies proposed in this project will utilize physiologically relevant in vitro human and in vivo mouse models developed by the lead of this project. These models include primary human airway cultures, primary stem cell-derived human enteroid models, human cerebral organoids, and mouse models that recapitulate many aspects of enterovirus clinical disease. Given that these studies will utilize physiologically relevant models, the compounds identified will be highly significant and clinically optimized, as our systems will model enterovirus infections of highly relevant tissue types in vitro and in vivo. This project will directly synergize with multiple AC/DC Cores and Projects. AC/DC Cores will direct the identification of lead compounds that will be rigorously tested for anti-enterovirus activity in the in vitro and in vivo models described above. The findings from this project will also directly influence these Cores, which will work with data generated by this project to further identify leads. As many of these same leads will be tested by other projects against other RNA viruses, this built-in synergy will allow for direct integration of leads across diverse viral families. The studies proposed in Project 5 thus contribute directly to the Center’s mission of generating applicable clinical candidates to address RNA viruses of major pandemic potential.
