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.
Mesh Terms:
Antiviral Agents, COVID-19, COVID-19 Drug Treatment, Catalytic Domain, Coronavirus 3C Proteases, Coronavirus OC43, Human, Coronavirus Protease Inhibitors, Crystallography, X-Ray, Humans, Models, Molecular, Pandemic Preparedness, Pandemics, Protease Inhibitors, SARS-CoV-2, Structure-Activity Relationship
Antiviral Agents, COVID-19, COVID-19 Drug Treatment, Catalytic Domain, Coronavirus 3C Proteases, Coronavirus OC43, Human, Coronavirus Protease Inhibitors, Crystallography, X-Ray, Humans, Models, Molecular, Pandemic Preparedness, Pandemics, Protease Inhibitors, SARS-CoV-2, Structure-Activity Relationship
J Med Chem
Date: Oct. 10, 2024
PubMed ID: 39332817
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