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

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.