2. Academic Validation
  3. Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models

Discovery of Coronavirus Main Protease Inhibitors with Enhanced Brain Exposure and Potent Oral Efficacy in SARS-CoV-2 and MERS Infection Models

  • J Med Chem. 2026 Jan 22;69(2):1530-1551. doi: 10.1021/acs.jmedchem.5c03015.
Luca Lizzadro 1,  Jiapeng Li 1,  Taha Y Taha 2 3,  Gilles Degotte 1,  Tyler C Detomasi 1,  Francisco J Zapatero-Belinchon 2,  Eric R Hantz 1,  Sijie Huang 1,  Yusuke Matsui 2,  Will R Henderson 1,  Jack T McCann 1,  Mauricio Montano 2,  Julia Rosecrans 2,  Daniel F Torres Pomares 1,  Briana L McGovern 4 5,  Randy Diaz-Tapia 4 5,  Jared Benjamin 4 5,  Mary E Gordon 4 5,  Isidora D Suazo 4 5,  Nicholas S Settineri 6,  Amy Diallo 7,  Nevan J Krogan 8 9,  Brian K Shoichet 1 9,  Kliment A Verba 7 9,  Randy Albrecht 4 5,  Adolfo García-Sastre 4 5 10 11 12 13,  Kris M White 4 5,  Melanie Ott 2 14 15,  Charles S Craik 1 9,  Adam R Renslo 1 9
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
  • 2 Gladstone Infectious Disease Institute, Gladstone Institutes, San Francisco, California 94158, United States.
  • 3 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California 94158, United States.
  • 4 Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 5 Global Health Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 6 Advanced Light Source, Lawrence Berkeley National Laboratory, Berkeley, California 94720, United States.
  • 7 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
  • 8 Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
  • 9 Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, California 94158, United States.
  • 10 Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 11 The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 12 Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 13 The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.
  • 14 Department of Medicine, University of California, San Francisco, California 94158, United States.
  • 15 Chan Zuckerberg Biohub - San Francisco, San Francisco, California, United Stateshttps://biohub.org/.
PMID: 41490206 DOI: 10.1021/acs.jmedchem.5c03015
Abstract

The main proteases (MPro) of coronaviruses are clinically validated targets for Antiviral discovery. Herein, we detail the in vivo optimization of uracil-core MPro 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 MPro 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 (M)-AVI-4773 (5-(5,6-difluoro-1H-benzo[d][1,2,3]triazol-1-yl)-3-((M)-isoquinolin-4-yl)-6-methyl-1-(prop-2-yn-1-yl)pyrimidine-2,4(1H,3H)-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.

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