TY - JOUR
T1 - Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2
AU - Drayman, Nir
AU - DeMarco, Jennifer K
AU - Jones, Krysten A
AU - Azizi, Saara-Anne
AU - Froggatt, Heather M
AU - Tan, Kemin
AU - Maltseva, Natalia Ivanovna
AU - Chen, Siquan
AU - Nicolaescu, Vlad
AU - Dvorkin, Steve
AU - Furlong, Kevin
AU - Kathayat, Rahul S
AU - Firpo, Mason R
AU - Mastrodomenico, Vincent
AU - Bruce, Emily A
AU - Schmidt, Madaline M
AU - Jedrzejczak, Robert
AU - Muñoz-Alía, Miguel Á
AU - Schuster, Brooke
AU - Nair, Vishnu
AU - Han, Kyu-Yeon
AU - O'Brien, Amornrat
AU - Tomatsidou, Anastasia
AU - Meyer, Bjoern
AU - Vignuzzi, Marco
AU - Missiakas, Dominique
AU - Botten, Jason W
AU - Brooke, Christopher B
AU - Lee, Hyun
AU - Baker, Susan C
AU - Mounce, Bryan C
AU - Heaton, Nicholas S
AU - Severson, William E
AU - Palmer, Kenneth E
AU - Dickinson, Bryan C
AU - Joachimiak, Andrzej
AU - Randall, Glenn
AU - Tay, Savaş
N1 - Funding: ND is a recipient of the Human Frontiers Science Program (HFSP) post-doctoral fellowship. Funding for this project was provided in part by federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract HHSN272201700060C (to AJ) and by the DOE Office of Science through the National Virtual Biotechnology Laboratory, a consortium of DOE national laboratories focused on response to COVID-19, with funding provided by the Coronavirus CARES Act (to AJ). EAB acknowledges funding by NIH P20GM125498 (UVM Translational Global Infectious Disease Research Center) and NIH P30GM118228-04 (UVM Center for Immunology and Infectious Disease). JWB acknowledges funding from the Office of the Vice President for Research at the University of Vermont and NIH grants R41AI132047, R21AI154198, and U01AI1141997. BM acknowledges the NIGMS grant R35GM138199. The use of SBC beamlines at the Advanced Photon Source is supported by the U.S. Department of Energy (DOE) Office of Science and operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357. BD acknowledges funding from the National Institute of General Medical Sciences (R35 GM119840). KP acknowledges funding from the NIH grant P20 GM125504. SCB acknowledges funding from NIH grant R01 AI085089. ST acknowledges funding support by the Pritzker School of Molecular Engineering at The University of Chicago.
PY - 2021/8/20
Y1 - 2021/8/20
N2 - 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).
AB - 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).
KW - COVID-19
KW - severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
UR - http://www.scopus.com/inward/record.url?scp=85113296822&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85113296822&partnerID=8YFLogxK
U2 - 10.1126/science.abg5827
DO - 10.1126/science.abg5827
M3 - Article
C2 - 34285133
SN - 0036-8075
VL - 373
SP - 931
EP - 936
JO - Science
JF - Science
IS - 6557
M1 - eabg5827
ER -