Masitinib is a Broad Coronavirus 3CL Inhibitor that Blocks Replication of SARS-CoV-2

Journal Article · Thu Aug 19 04:00:00 EDT 2021 · Science

DOI:https://doi.org/10.1126/science.abg5827· OSTI ID:1819318

Drayman, Nir ^[1]; DeMarco, Jennifer K. ^[2]; Jones, Krysten A. ^[3]; Azizi, Saara-Anne ^[4]; Froggatt, Heather M. ^[5]; Tan, Kemin ^[6]; Maltseva, Natalia Ivanovna ^[7]; Chen, Siquan ^[8]; Nicolaescu, Vlad ^[9]; Dvorkin, Steve ^[9]; Furlong, Kevin ^[9]; Kathayat, Rahul S. ^[3]; Firpo, Mason R. ^[10]; Mastrodomenico, Vincent ^[11]; Bruce, Emily A. ^[12]; Schmidt, Madaline M. ^[13]; Jedrzejczak, Robert ^[14]; Muñoz-Alía, Miguel Á. ^[15]; Schuster, Brooke ^[16]; Nair, Vishnu ^[16] ; Han, Kyu-yeon ^[17]; O’Brien, Amornrat ^[18]; Tomatsidou, Anastasia ^[19]; Meyer, Bjoern ^[20]; Vignuzzi, Marco ^[21]; Missiakas, Dominique ^[9]; Botten, Jason W. ^[22]; Brooke, Christopher B. ^[23]; Lee, Hyun ^[24]; Baker, Susan C. ^[25]; Mounce, Bryan C. ^[26]; Heaton, Nicholas S. ^[5]; Severson, William E. ^[27]; Palmer, Kenneth E. ^[28]; Dickinson, Bryan C. ^[3]; Joachimiak, Andrzej ^[29]; Randall, Glenn ^[30]; Tay, Savaş ^[16]

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1. Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
2. Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.
3. Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
4. Department of Chemistry, The University of Chicago, Chicago, IL, USA.; Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
5. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.; Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
6. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
7. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
8. Cellular Screening Center, The University of Chicago, Chicago, IL, USA.; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
9. Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
10. Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
11. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
12. Cellular Screening Center, The University of Chicago, Chicago, IL, USA.; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
13. Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
14. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.
15. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
16. Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
17. Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.; Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
18. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, Biophysics Core at Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA.
19. Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
20. Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
21. Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.; Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
22. Cellular Screening Center, The University of Chicago, Chicago, IL, USA.; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
23. Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
24. Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT, USA.; Department of Pharmaceutical Sciences, College of Pharmacy, Biophysics Core at Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA.
25. Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.; Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
26. Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.; Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
27. Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.; Department of Chemistry, The University of Chicago, Chicago, IL, USA.
28. Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.; Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
29. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
30. Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

There is an urgent need for antiviral agents that treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We screened a library of 1900 clinically safe drugs against OC43, a human beta coronavirus that causes the common cold, and evaluated the top hits against SARS-CoV-2. Twenty drugs significantly inhibited replication of both viruses in cultured human cells. Eight of these drugs inhibited the activity of the SARS-CoV-2 main protease, 3CLpro, with the most potent being masitinib, an orally bioavailable tyrosine kinase inhibitor. X-ray crystallography and biochemistry show that masitinib acts as a competitive inhibitor of 3CLpro. Mice infected with SARS-CoV-2 and then treated with masitinib showed >200-fold reduction in viral titers in the lungs and nose, as well as reduced lung inflammation. Masitinib was also effective in vitro against all tested variants of concern.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: USDOE Office of Science (SC)
• DOE Contract Number: AC02-06CH11357
• OSTI ID: 1819318
• Journal Information: Science, Journal Name: Science Journal Issue: 6557 Vol. 373; ISSN 0036-8075
• Publisher: AAAS
• Country of Publication: United States
• Language: ENGLISH