Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness.

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 (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. Additionall

SUBMITTER: Barkan DT 

PROVIDER: S-EPMC11472307 | biostudies-literature | 2024 Oct

REPOSITORIES: biostudies-literature