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J Med Chem
. 2024 Sep 27.
doi: 10.1021/acs.jmedchem.4c01404. Online ahead of print. Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness
David T Barkan 1 , Keira Garland 2 , Lei Zhang 2 , Richard T Eastman 3 , Matthew Hesse 2 , Mark Knapp 4 , Elizabeth Ornelas 4 , Jenny Tang 4 , Wilian Augusto Cortopassi 2 , Yu Wang 5 , Frederick King 5 , Weiping Jia 2 , Zachary Nguyen 1 , Andreas O Frank 2 , Ryan Chan 3 , Eric Fang 4 , Daniel Fuller 1 , Scott Busby 1 , Heidi Carias 4 , Kristine Donahue 4 , Laura Tandeske 4 , Thierry T Diagana 3 , Nadine Jarrousse 3 , Heinz Moser 2 , Christopher Sarko 2 , Dustin Dovala 4 , Stephanie Moquin 3 , Vanessa M Marx 2
Affiliations
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.
. 2024 Sep 27.
doi: 10.1021/acs.jmedchem.4c01404. Online ahead of print. Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness
David T Barkan 1 , Keira Garland 2 , Lei Zhang 2 , Richard T Eastman 3 , Matthew Hesse 2 , Mark Knapp 4 , Elizabeth Ornelas 4 , Jenny Tang 4 , Wilian Augusto Cortopassi 2 , Yu Wang 5 , Frederick King 5 , Weiping Jia 2 , Zachary Nguyen 1 , Andreas O Frank 2 , Ryan Chan 3 , Eric Fang 4 , Daniel Fuller 1 , Scott Busby 1 , Heidi Carias 4 , Kristine Donahue 4 , Laura Tandeske 4 , Thierry T Diagana 3 , Nadine Jarrousse 3 , Heinz Moser 2 , Christopher Sarko 2 , Dustin Dovala 4 , Stephanie Moquin 3 , Vanessa M Marx 2
Affiliations
- PMID: 39332817
- DOI: 10.1021/acs.jmedchem.4c01404
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.