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
  • 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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