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 (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.
Authors
- Andreas O. Frank (ORCID: https://orcid.org/0000-0002-2330-3974)
- Daniel Fuller (ORCID: https://orcid.org/0000-0002-8896-3746)
- Richard T. Eastman (ORCID: https://orcid.org/0000-0003-3580-380X)
- Weiping Jia (ORCID: https://orcid.org/0000-0002-6244-2168)
- Laura Tandeske
- Kristine Donahue (ORCID: https://orcid.org/0000-0003-3248-7573)
- Ryan Chan (ORCID: https://orcid.org/0000-0002-1840-3620)
- Keira Garland
- Dustin Dovala (ORCID: https://orcid.org/0000-0002-2278-5027)
- Vanessa M. Marx
- Thierry T. Diagana (ORCID: https://orcid.org/0000-0002-8520-5683)
- Matthew J. Hesse (ORCID: https://orcid.org/0000-0002-4759-5086)
- Scott A. Busby
- Frederick J. King (ORCID: https://orcid.org/0000-0001-5958-5451)
- Stephanie Moquin (ORCID: https://orcid.org/0000-0002-8696-4315)
- Heidi Carias
- Wilian A. Cortopassi (ORCID: https://orcid.org/0000-0001-8038-7847)
- Heinz E. Moser (ORCID: https://orcid.org/0000-0002-8013-2139)
- Eric Fang (ORCID: https://orcid.org/0000-0001-8850-1528)
- David T. Barkan
- Elizabeth Ornelas (ORCID: https://orcid.org/0000-0002-2629-3644)
- Christopher R. Sarko (ORCID: https://orcid.org/0000-0003-0492-908X)
- Lei Zhang (ORCID: https://orcid.org/0000-0002-5726-7449)
- Mark Knapp (ORCID: https://orcid.org/0000-0002-5770-7715)
- Nadine Jarrousse
- Zachary Nguyen
- Jenny Tang
- Yu Wang (ORCID: https://orcid.org/0000-0001-6351-6467)
Institutions
- Genomics Institute of the Novartis Research Foundation (US)
- Novartis (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-09-27
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c01404
- Citations
- 12
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 4.67
Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases