tetano
Editor, Senior Moderator
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[SUP] 1 [/SUP], Keira Garland[SUP] 2 [/SUP], Lei Zhang[SUP] 2 [/SUP], Richard T Eastman[SUP] 3 [/SUP], Matthew Hesse[SUP] 2 [/SUP], Mark Knapp[SUP] 4 [/SUP], Elizabeth Ornelas[SUP] 4 [/SUP], Jenny Tang[SUP] 4 [/SUP], Wilian Augusto Cortopassi[SUP] 2 [/SUP], Yu Wang[SUP] 5 [/SUP], Frederick King[SUP] 5 [/SUP], Weiping Jia[SUP] 2 [/SUP], Zachary Nguyen[SUP] 1 [/SUP], Andreas O Frank[SUP] 2 [/SUP], Ryan Chan[SUP] 3 [/SUP], Eric Fang[SUP] 4 [/SUP], Daniel Fuller[SUP] 1 [/SUP], Scott Busby[SUP] 1 [/SUP], Heidi Carias[SUP] 4 [/SUP], Kristine Donahue[SUP] 4 [/SUP], Laura Tandeske[SUP] 4 [/SUP], Thierry T Diagana[SUP] 3 [/SUP], Nadine Jarrousse[SUP] 3 [/SUP], Heinz Moser[SUP] 2 [/SUP], Christopher Sarko[SUP] 2 [/SUP], Dustin Dovala[SUP] 4 [/SUP], Stephanie Moquin[SUP] 3 [/SUP], Vanessa M Marx[SUP] 2 [/SUP]
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 (M[SUP]pro[/SUP]), we constructed a structurally diverse M[SUP]pro[/SUP] panel by clustering all known coronavirus sequences by M[SUP]pro[/SUP] 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[SUP]pro[/SUP] homologues. Additionally, we solved the first X-ray cocrystal structure of M[SUP]pro[/SUP] 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[SUP] 1 [/SUP], Keira Garland[SUP] 2 [/SUP], Lei Zhang[SUP] 2 [/SUP], Richard T Eastman[SUP] 3 [/SUP], Matthew Hesse[SUP] 2 [/SUP], Mark Knapp[SUP] 4 [/SUP], Elizabeth Ornelas[SUP] 4 [/SUP], Jenny Tang[SUP] 4 [/SUP], Wilian Augusto Cortopassi[SUP] 2 [/SUP], Yu Wang[SUP] 5 [/SUP], Frederick King[SUP] 5 [/SUP], Weiping Jia[SUP] 2 [/SUP], Zachary Nguyen[SUP] 1 [/SUP], Andreas O Frank[SUP] 2 [/SUP], Ryan Chan[SUP] 3 [/SUP], Eric Fang[SUP] 4 [/SUP], Daniel Fuller[SUP] 1 [/SUP], Scott Busby[SUP] 1 [/SUP], Heidi Carias[SUP] 4 [/SUP], Kristine Donahue[SUP] 4 [/SUP], Laura Tandeske[SUP] 4 [/SUP], Thierry T Diagana[SUP] 3 [/SUP], Nadine Jarrousse[SUP] 3 [/SUP], Heinz Moser[SUP] 2 [/SUP], Christopher Sarko[SUP] 2 [/SUP], Dustin Dovala[SUP] 4 [/SUP], Stephanie Moquin[SUP] 3 [/SUP], Vanessa M Marx[SUP] 2 [/SUP]
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 (M[SUP]pro[/SUP]), we constructed a structurally diverse M[SUP]pro[/SUP] panel by clustering all known coronavirus sequences by M[SUP]pro[/SUP] 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[SUP]pro[/SUP] homologues. Additionally, we solved the first X-ray cocrystal structure of M[SUP]pro[/SUP] 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.