Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2

Journal Article · Fri Aug 20 00:00:00 EDT 2021 · Science

DOI:https://doi.org/10.1126/science.abg5827· OSTI ID:1820458

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.

Targeting the main protease of SARS-CoV-2 Inside host cells, the RNA genome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is translated into two polyproteins that are cleaved to give the individual viral proteins. The main viral protease, known as Mpro or 3CLpro, plays a key role in these cleavages, making it an important drug target. Drayman et al. identified eight drugs that target 3CLpro from a library of 1900 clinically safe drugs. Because of the challenge of working with SARS-CoV-2, they started by screening for drugs that inhibit the replication of a human coronavirus that causes the common cold. They then evaluated the top hits for inhibiting SARS-CoV-2 replication and for inhibiting 3CLpro. Masitinib, a broad antiviral, inhibited the main proteases of coronaviruses and picornaviruses and was effective in reducing SARS-CoV-2 replication in mice.

• Research Organization: Argonne National Laboratory (ANL), Argonne, IL (United States)
• Sponsoring Organization: U.S. Department of Energy
• DOE Contract Number: AC02-06CH11357
• OSTI ID: 1820458
• Journal Information: Science, Journal Name: Science Journal Issue: 6557 Vol. 373; ISSN 0036-8075
• Publisher: AAAS
• Country of Publication: United States
• Language: ENGLISH