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Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.
Drayman, Nir; DeMarco, Jennifer K; Jones, Krysten A; Azizi, Saara-Anne; Froggatt, Heather M; Tan, Kemin; Maltseva, Natalia Ivanovna; Chen, Siquan; Nicolaescu, Vlad; Dvorkin, Steve; Furlong, Kevin; Kathayat, Rahul S; Firpo, Mason R; Mastrodomenico, Vincent; Bruce, Emily A; Schmidt, Madaline M; Jedrzejczak, Robert; Muñoz-Alía, Miguel Á; Schuster, Brooke; Nair, Vishnu; Han, Kyu-Yeon; O'Brien, Amornrat; Tomatsidou, Anastasia; Meyer, Bjoern; Vignuzzi, Marco; Missiakas, Dominique; Botten, Jason W; Brooke, Christopher B; Lee, Hyun; Baker, Susan C; Mounce, Bryan C; Heaton, Nicholas S; Severson, William E; Palmer, Kenneth E; Dickinson, Bryan C; Joachimiak, Andrzej; Randall, Glenn; Tay, Savas.
  • Drayman N; Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA. tays@uchicago.edu nirdra@uchicago.edu.
  • DeMarco JK; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.
  • Jones KA; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Azizi SA; Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • Froggatt HM; Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
  • Tan K; Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • Maltseva NI; Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
  • Chen S; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
  • Nicolaescu V; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Dvorkin S; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
  • Furlong K; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.
  • Kathayat RS; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.
  • Firpo MR; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Mastrodomenico V; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
  • Bruce EA; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.
  • Schmidt MM; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.
  • Jedrzejczak R; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Muñoz-Alía MÁ; Cellular Screening Center, The University of Chicago, Chicago, IL, USA.
  • Schuster B; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Nair V; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Han KY; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • O'Brien A; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Tomatsidou A; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
  • Meyer B; Department of Chemistry, The University of Chicago, Chicago, IL, USA.
  • Vignuzzi M; Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
  • Missiakas D; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
  • Botten JW; Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
  • Brooke CB; Cellular Screening Center, The University of Chicago, Chicago, IL, USA.
  • Lee H; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Baker SC; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Mounce BC; Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Heaton NS; Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
  • Severson WE; Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
  • Palmer KE; Center for Structural Genomics of Infectious Diseases, Consortium for Advanced Science and Engineering, University of Chicago, Chicago, IL, USA.
  • Dickinson BC; Structural Biology Center, X-ray Science Division, Argonne National Laboratory, Argonne, IL, USA.
  • Joachimiak A; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
  • Randall G; Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
  • Tay S; Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Science ; 373(6557): 931-936, 2021 08 20.
Article in English | MEDLINE | ID: covidwho-1319369
ABSTRACT
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 (B.1.1.7, B.1.351, and P.1).
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Thiazoles / Cysteine Proteinase Inhibitors / Coronavirus OC43, Human / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Science Year: 2021 Document Type: Article

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Thiazoles / Cysteine Proteinase Inhibitors / Coronavirus OC43, Human / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Prognostic study Topics: Variants Limits: Animals / Humans Language: English Journal: Science Year: 2021 Document Type: Article