Barkan, Dave, Garland, Keira, Zhang, Lei, Eastman, Rich, Hesse, Matthew, Knapp, Mark, Ornelas, Elizabeth, Tang, Jenny, Cortopassi, Wilian, Wang, Yvonne, King, Frederick, Jia, Weiping, Nguyen, Zachary, Chan, Ryan, Fang, Eric, Fuller, Daniel, Busby, Scott, Carias, Heidi, Donahue, Kristine, Tandeske, Laura, Jarrousse Coscoy, Nadine, Moser, Heinz, Sarko, Christopher, Diagana, Thierry, Dovala, Dustin, Moquin, Stephanie and Marx, Vanessa (2024) Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness. Journal of medicinal chemistry, 67 (19). pp. 17454-17471. ISSN 1520-4804

Abstract

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 (Mpro), we constructed a structurally diverse Mpro panel by clustering all known coronavirus sequences by Mpro 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 Mpro homologues. Additionally, we solved the first X-ray cocrystal structure of Mpro 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.

Item Type:	Article
Keywords:	Humans SARS-CoV-2 Coronavirus 3C Proteases Antiviral Agents Crystallography, X-Ray COVID-19 Drug Treatment Structure-Activity Relationship COVID-19 Coronavirus Protease Inhibitors Coronavirus OC43, Human Catalytic Domain Models, Molecular Protease Inhibitors Pandemics Pandemic Preparedness
Date Deposited:	26 Nov 2024 00:45
Last Modified:	26 Nov 2024 00:45
URI:	https://oak.novartis.com/id/eprint/53535