Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models
The main proteases (M<sup>Pro</sup>) of coronaviruses are clinically validated targets for antiviral discovery. Herein, we detail the in vivo optimization of uracil-core M<sup>Pro</sup> inhibitors derived from AVI-4516, an in vivo active lead bearing an unactivated propargyl warhead. To expand the anticoronaviral spectrum, we introduced diverse C6 substitution to target the S1' pocket in M<sup>Pro</sup> and observed enhanced cellular activity against various nirmatrelvir-resistant mutants. Pharmacokinetic profiling of 12 analogs revealed overall inferior exposure of the C6 aryl analogs. However, PK profiling across three species identified the improved atropisomeric lead (<i>M</i>)-AVI-4773 (5-(5,6-difluoro-1<i>H</i>-benzo[<i>d</i>][1,2,3]triazol-1-yl)-3-((<i>M</i>)-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1<i>H</i>,3<i>H</i>)-dione), which exhibits rapid-onset oral efficacy in both SARS-CoV-2 and Middle East respiratory syndrome (MERS) mouse models, highlighting a promising chemotype with the potential to deliver anticoronaviral development candidates.
Authors
- Adolfo Garcı́a-Sastre (ORCID: https://orcid.org/0000-0002-6551-1827)
- Briana L McGovern (ORCID: https://orcid.org/0000-0002-0492-9904)
- Randy A. Albrecht (ORCID: https://orcid.org/0000-0003-4008-503X)
- Tyler C. Detomasi (ORCID: https://orcid.org/0000-0003-4390-108X)
- Amy Diallo (ORCID: https://orcid.org/0000-0001-9843-2255)
- Kris M. White (ORCID: https://orcid.org/0000-0003-0889-0506)
- Mauricio Montaño (ORCID: https://orcid.org/0000-0002-0353-0037)
- Gilles Degotte (ORCID: https://orcid.org/0000-0001-6318-4626)
- Taha Y. Taha (ORCID: https://orcid.org/0000-0002-7344-7490)
- Isidora D. Suazo (ORCID: https://orcid.org/0000-0001-8274-7471)
- Kliment A. Verba (ORCID: https://orcid.org/0000-0002-2238-8590)
- W H Henderson
- Nicholas S. Settineri (ORCID: https://orcid.org/0000-0003-0272-454X)
- M. Trenholme Gordon
- Randy Diaz-Tapia
- Mélanie Ott (ORCID: https://orcid.org/0000-0002-5697-1274)
- Yusuke Matsui (ORCID: https://orcid.org/0000-0002-6016-2867)
- Luca Lizzadro
- Eric R. Hantz (ORCID: https://orcid.org/0000-0002-2588-7619)
- Charles S. Craik (ORCID: https://orcid.org/0000-0001-7704-9185)
- Daniel F. Torres Pomares
- Julia Rosecrans (ORCID: https://orcid.org/0009-0000-3111-5933)
- Zapatero-Belinchon Francisco J
- Adam R Renslo
- Jared Benjamin
- Jiapeng Li
- Nevan J. Krogan
- Sijie Huang
- Jack T. McCann
- Brian K. Shoichet
Institutions
- Gladstone Institutes (US)
- Lawrence Berkeley National Laboratory (US)
- University of California, San Francisco (US)
- University of California System (US)
- Quantitative BioSciences (US)
- Office of Infectious Diseases (US)
- Chan Zuckerberg Initiative (United States) (US)
- Advanced Light Source
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-01-05
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03015
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00