2. Academic Validation
  3. Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness

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

  • J Med Chem. 2024 Oct 10;67(19):17454-17471. doi: 10.1021/acs.jmedchem.4c01404.
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

Affiliations

  • 1 Discovery Sciences, Novartis Biomedical Research, Cambridge, Massachusetts 02139, United States.
  • 2 Global Discovery Chemistry, Novartis Biomedical Research, Emeryville, California 94608, United States.
  • 3 Global Health, Novartis Biomedical Research, Emeryville, California 94608, United States.
  • 4 Discovery Sciences, Novartis Biomedical Research, Emeryville, California 94608, United States.
  • 5 Discovery Sciences, Novartis Biomedical Research, La Jolla, California 92121, United States.
PMID: 39332817 DOI: 10.1021/acs.jmedchem.4c01404
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 (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.

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