tetano
Editor, Senior Moderator
Science
. 2021 Jul 20;eabg5827.
doi: 10.1126/science.abg5827. Online ahead of print.
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2
Nir Drayman[SUP] 1 [/SUP], Jennifer K DeMarco[SUP] 2 3 [/SUP], Krysten A Jones[SUP] 4 5 [/SUP], Saara-Anne Azizi[SUP] 6 5 [/SUP], Heather M Froggatt[SUP] 7 8 [/SUP], Kemin Tan[SUP] 9 8 10 11 [/SUP], Natalia Ivanovna Maltseva[SUP] 4 8 10 11 [/SUP], Siquan Chen[SUP] 4 12 [/SUP], Vlad Nicolaescu[SUP] 4 [/SUP], Steve Dvorkin[SUP] 4 4 [/SUP], Kevin Furlong[SUP] 4 [/SUP], Rahul S Kathayat[SUP] 4 5 [/SUP], Mason R Firpo[SUP] 13 2 [/SUP], Vincent Mastrodomenico[SUP] 2 [/SUP], Emily A Bruce[SUP] 12 9 14 [/SUP], Madaline M Schmidt[SUP] 9 14 [/SUP], Robert Jedrzejczak[SUP] 8 10 11 [/SUP], Miguel Á Muñoz-Alía[SUP] 15 15 [/SUP], Brooke Schuster[SUP] 4 13 [/SUP], Vishnu Nair[SUP] 4 13 [/SUP], Kyu-Yeon Han[SUP] 3 6 [/SUP], Amornrat O'Brien[SUP] 16 2 [/SUP], Anastasia Tomatsidou[SUP] 9 4 [/SUP], Bjoern Meyer[SUP] 7 [/SUP], Marco Vignuzzi[SUP] 11 7 [/SUP], Dominique Missiakas[SUP] 4 4 [/SUP], Jason W Botten[SUP] 12 9 14 17 [/SUP], Christopher B Brooke[SUP] 14 18 19 [/SUP], Hyun Lee[SUP] 17 16 [/SUP], Susan C Baker[SUP] 7 13 2 [/SUP], Bryan C Mounce[SUP] 7 20 2 [/SUP], Nicholas S Heaton[SUP] 7 8 [/SUP], William E Severson[SUP] 5 3 [/SUP], Kenneth E Palmer[SUP] 18 3 [/SUP], Bryan C Dickinson[SUP] 4 5 [/SUP], Andrzej Joachimiak[SUP] 8 19 10 11 20 [/SUP], Glenn Randall[SUP] 19 4 [/SUP], Savaş Tay[SUP] 21 13 [/SUP]
Affiliations
Abstract
There is an urgent need for antiviral agents that treat SARS-CoV-2 infection. We screened a library of 1,900 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 vitro. 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).
. 2021 Jul 20;eabg5827.
doi: 10.1126/science.abg5827. Online ahead of print.
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2
Nir Drayman[SUP] 1 [/SUP], Jennifer K DeMarco[SUP] 2 3 [/SUP], Krysten A Jones[SUP] 4 5 [/SUP], Saara-Anne Azizi[SUP] 6 5 [/SUP], Heather M Froggatt[SUP] 7 8 [/SUP], Kemin Tan[SUP] 9 8 10 11 [/SUP], Natalia Ivanovna Maltseva[SUP] 4 8 10 11 [/SUP], Siquan Chen[SUP] 4 12 [/SUP], Vlad Nicolaescu[SUP] 4 [/SUP], Steve Dvorkin[SUP] 4 4 [/SUP], Kevin Furlong[SUP] 4 [/SUP], Rahul S Kathayat[SUP] 4 5 [/SUP], Mason R Firpo[SUP] 13 2 [/SUP], Vincent Mastrodomenico[SUP] 2 [/SUP], Emily A Bruce[SUP] 12 9 14 [/SUP], Madaline M Schmidt[SUP] 9 14 [/SUP], Robert Jedrzejczak[SUP] 8 10 11 [/SUP], Miguel Á Muñoz-Alía[SUP] 15 15 [/SUP], Brooke Schuster[SUP] 4 13 [/SUP], Vishnu Nair[SUP] 4 13 [/SUP], Kyu-Yeon Han[SUP] 3 6 [/SUP], Amornrat O'Brien[SUP] 16 2 [/SUP], Anastasia Tomatsidou[SUP] 9 4 [/SUP], Bjoern Meyer[SUP] 7 [/SUP], Marco Vignuzzi[SUP] 11 7 [/SUP], Dominique Missiakas[SUP] 4 4 [/SUP], Jason W Botten[SUP] 12 9 14 17 [/SUP], Christopher B Brooke[SUP] 14 18 19 [/SUP], Hyun Lee[SUP] 17 16 [/SUP], Susan C Baker[SUP] 7 13 2 [/SUP], Bryan C Mounce[SUP] 7 20 2 [/SUP], Nicholas S Heaton[SUP] 7 8 [/SUP], William E Severson[SUP] 5 3 [/SUP], Kenneth E Palmer[SUP] 18 3 [/SUP], Bryan C Dickinson[SUP] 4 5 [/SUP], Andrzej Joachimiak[SUP] 8 19 10 11 20 [/SUP], Glenn Randall[SUP] 19 4 [/SUP], Savaş Tay[SUP] 21 13 [/SUP]
Affiliations
- PMID: 34285133
- DOI: 10.1126/science.abg5827
Abstract
There is an urgent need for antiviral agents that treat SARS-CoV-2 infection. We screened a library of 1,900 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 vitro. 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).