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

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).

SUBMITTER: Drayman N

PROVIDER: S-EPMC8809056 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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

Drayman Nir N DeMarco Jennifer K JK Jones Krysten A KA Azizi Saara-Anne SA Froggatt Heather M HM Tan Kemin K Maltseva Natalia Ivanovna NI Chen Siquan S Nicolaescu Vlad V Dvorkin Steve S Furlong Kevin K Kathayat Rahul S RS Firpo Mason R MR Mastrodomenico Vincent V Bruce Emily A EA Schmidt Madaline M MM Jedrzejczak Robert R Muñoz-Alía Miguel Á MÁ Schuster Brooke B Nair Vishnu V Han Kyu-Yeon KY O'Brien Amornrat A Tomatsidou Anastasia A Meyer Bjoern B Vignuzzi Marco M Missiakas Dominique D Botten Jason W JW Brooke Christopher B CB Lee Hyun H Baker Susan C SC Mounce Bryan C BC Heaton Nicholas S NS Severson William E WE Palmer Kenneth E KE Dickinson Bryan C BC Joachimiak Andrzej A Randall Glenn G Tay Savaş S

Science (New York, N.Y.) 20210720 6557

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 mas ...[more]

PMID: 34285133

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Project description:Pathogenic coronaviruses are a major threat to global public health. Here, using a recombinant reporter virus-based compound screening approach, we identified small-molecule inhibitors that potently block the replication of severe acute respiratory syndrome virus 2 (SARS-CoV-2). Among them, JIB-04 inhibited SARS-CoV-2 replication in Vero E6 cells with a 50% effective concentration of 695 nM, with a specificity index of greater than 1,000. JIB-04 showed in vitro antiviral activity in multiple cell types, including primary human bronchial epithelial cells, against several DNA and RNA viruses, including porcine coronavirus transmissible gastroenteritis virus. In an in vivo porcine model of coronavirus infection, administration of JIB-04 reduced virus infection and associated tissue pathology, which resulted in improved weight gain and survival. These results highlight the potential utility of JIB-04 as an antiviral agent against SARS-CoV-2 and other viral pathogens. IMPORTANCE The coronavirus disease 2019 (COVID-19), the disease caused by SARS-CoV-2 infection, is an ongoing public health disaster worldwide. Although several vaccines are available as a preventive measure and the FDA approval of an orally bioavailable drug is on the horizon, there remains a need for developing antivirals against SARS-CoV-2 that could work on the early course of infection. By using infectious reporter viruses, we screened small-molecule inhibitors for antiviral activity against SARS-CoV-2. Among the top hits was JIB-04, a compound previously studied for its anticancer activity. Here, we showed that JIB-04 inhibits the replication of SARS-CoV-2 as well as different DNA and RNA viruses. Furthermore, JIB-04 conferred protection in a porcine model of coronavirus infection, although to a lesser extent when given as therapeutic rather than prophylactic doses. Our findings indicate a limited but still promising utility of JIB-04 as an antiviral agent in the combat against COVID-19 and potentially other viral diseases.

Dataset Information

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

Publications

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

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