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

A549 Cells Animals Antiviral Agents / chemistry Benzamides COVID-19 / virology Catalytic Domain Coronavirus 3C Proteases / antagonists & inhibitors Coronavirus OC43, Human / drug effects Cysteine Proteinase Inhibitors / chemistry HEK293 Cells Humans Inhibitory Concentration 50 Mice Mice, Transgenic Microbial Sensitivity Tests Piperidines Pyridines SARS-CoV-2 / drug effects Thiazoles / chemistry Viral Load / drug effects Virus Replication / drug effects COVID-19 Drug Treatment

Journal

Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511

Informations de publication

Date de publication:
20 08 2021
Historique:
received: 14 01 2021
accepted: 14 07 2021
pubmed: 22 7 2021
medline: 28 8 2021
entrez: 21 7 2021
Statut: ppublish

Résumé

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).

Identifiants

DOI: 10.1126/science.abg5827 PMID: 34285133 PMC: PMC8809056
pubmed: 34285133
pii: science.abg5827
doi: 10.1126/science.abg5827
pmc: PMC8809056
mid: NIHMS1770213
doi:

Substances chimiques

Antiviral Agents 0
Benzamides 0
Cysteine Proteinase Inhibitors 0
Piperidines 0
Pyridines 0
Thiazoles 0
3C-like proteinase, SARS-CoV-2 EC 3.4.22.-
Coronavirus 3C Proteases EC 3.4.22.28
masitinib M59NC4E26P

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

931-936

Subventions

Organisme : NIGMS NIH HHS
ID : R35 GM119840
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM138199
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI085089
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM125498
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI139246
Pays : United States
Organisme : NIGMS NIH HHS
ID : P30 GM118228
Pays : United States
Organisme : NIAID NIH HHS
ID : HHSN272201700060C
Pays : United States
Organisme : NIAID NIH HHS
ID : U01 AI141997
Pays : United States
Organisme : NIGMS NIH HHS
ID : P20 GM125504
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI154198
Pays : United States
Organisme : NIAID NIH HHS
ID : R41 AI132047
Pays : United States

Commentaires et corrections

Type : UpdateOf

Informations de copyright

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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Auteurs

Nir Drayman (N)

Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA. tays@uchicago.edu nirdra@uchicago.edu.
ORCID: 0000-0003-4460-9558

Jennifer K DeMarco (JK)

Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.
ORCID: 0000-0003-4807-6250

Krysten A Jones (KA)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0003-0711-5516

Saara-Anne Azizi (SA)

Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-9226-9917

Heather M Froggatt (HM)

Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
ORCID: 0000-0001-7785-0976

Kemin Tan (K)

Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
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.
ORCID: 0000-0002-4003-7903

Natalia Ivanovna Maltseva (NI)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
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.
ORCID: 0000-0002-2871-465X

Siquan Chen (S)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Cellular Screening Center, The University of Chicago, Chicago, IL, USA.

Vlad Nicolaescu (V)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-6347-0232

Steve Dvorkin (S)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.

Kevin Furlong (K)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.

Rahul S Kathayat (RS)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-9159-2413

Mason R Firpo (MR)

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.

Vincent Mastrodomenico (V)

Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.

Emily A Bruce (EA)

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.
ORCID: 0000-0001-8391-370X

Madaline M Schmidt (MM)

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.
ORCID: 0000-0003-3893-3466

Robert Jedrzejczak (R)

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.
ORCID: 0000-0001-6375-7199

Miguel Á Muñoz-Alía (MÁ)

Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA.
ORCID: 0000-0002-6217-9451

Brooke Schuster (B)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-7070-6143

Vishnu Nair (V)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-7321-1170

Kyu-Yeon Han (KY)

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.
ORCID: 0000-0002-2561-8187

Amornrat O'Brien (A)

Department of Pharmaceutical Sciences, College of Pharmacy, Biophysics Core at Research Resources Center, University of Illinois at Chicago, Chicago, IL, USA.
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.

Anastasia Tomatsidou (A)

Department of Medicine, Division of Immunobiology, Larner College of Medicine, University of Vermont, Burlington, VT, USA.
Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.

Bjoern Meyer (B)

Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
ORCID: 0000-0002-7903-5710

Marco Vignuzzi (M)

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.
ORCID: 0000-0002-4400-771X

Dominique Missiakas (D)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.

Jason W Botten (JW)

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.
ORCID: 0000-0001-6839-0306

Christopher B Brooke (CB)

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.
ORCID: 0000-0002-6815-1193

Hyun Lee (H)

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.
ORCID: 0000-0003-2570-8120

Susan C Baker (SC)

Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
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.
ORCID: 0000-0001-6485-8143

Bryan C Mounce (BC)

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.
Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA.
ORCID: 0000-0003-1710-5362

Nicholas S Heaton (NS)

Institut Pasteur, Viral Populations and Pathogenesis Unit, Centre National de la Recherche Scientifique UMR 3569, Paris, France.
Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
ORCID: 0000-0002-5307-3428

William E Severson (WE)

Department of Chemistry, The University of Chicago, Chicago, IL, USA.
Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.

Kenneth E Palmer (KE)

Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY, USA.

Bryan C Dickinson (BC)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
Department of Chemistry, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-9616-1911

Andrzej Joachimiak (A)

Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA.
Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, 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 Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0003-2535-6209

Glenn Randall (G)

Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA.
ORCID: 0000-0001-7417-3615

Savaş Tay (S)

Department of Microbiology, Ricketts Laboratory, University of Chicago, Chicago, IL, USA. tays@uchicago.edu nirdra@uchicago.edu.
Pritzker School for Molecular Engineering, The University of Chicago, Chicago, IL, USA.
ORCID: 0000-0002-1912-6020

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules A549 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Eucaryotes › Animaux › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Anti-infectieux › Antiviraux › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Composés chimiques organiques › Hydrocarbures › Hydrocarbures cycliques › Hydrocarbures aromatiques › Dérivés du benzène › Benzoates › Benzamides › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Maladies de l'appareil respiratoire › Infections de l'appareil respiratoire › Pneumopathie infectieuse › Pneumopathie virale › COVID-19 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Domaine catalytique › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines virales › Protéines virales non structurales › Protéases virales › Protéases virales 3C › Protéases 3C des coronavirus › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Betacoronavirus-1 › Coronavirus humain OC43 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Inhibiteurs de protéases › Inhibiteurs de la cystéine protéinase › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Cellules › Cellules épithéliales › Cellules HEK293 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes toxicologiques › Concentration inhibitrice 50 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de sensibilité microbienne › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pipéridines › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Pyridines › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Virus › Virus à ARN › Virus à ARN à brin positif › Nidovirales › Coronaviridae › Coronavirus › Betacoronavirus › Virus du SRAS › SARS-CoV-2 › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azoles › Thiazoles › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Charge virale › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Phénomènes microbiologiques › Phénomènes physiologiques viraux › Réplication virale › Masitinib is a broad coronavirus 3CL inhibitor...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Traitements médicamenteux de la COVID-19 › Masitinib is a broad coronavirus 3CL inhibitor...