Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness
David T. Barkan, Keira Garland, Lei Zhang, Richard T. Eastman, Matthew J. Hesse, Mark Knapp, Elizabeth Ornelas, Jenny Tang, Wilian A. Cortopassi, Yu Wang, Frederick J. King, Weiping Jia, Zachary Nguyen, Andreas O. Frank, Ryan Chan, Eric Fang, Daniel Fuller, Scott A. Busby, Heidi Carias, Kristine Donahue, Laura Tandeske, Thierry T. Diagana, Nadine Jarrousse, Heinz E. Moser, Christopher R. Sarko, Dustin Dovala, Stephanie Moquin, Vanessa M. Marx
Abstract
High Resolution Image Download MS PowerPoint Slide The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (M pro ), we constructed a structurally diverse M pro panel by clustering all known coronavirus sequences by M pro active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple M pro homologues. Additionally, we solved the first X-ray cocrystal structure of M pro from the human-infecting OC43 coronavirus, providing insights into potency differences among compound–target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses.