7L5D

The crystal structure of SARS-CoV-2 Main Protease in complex with demethylated analog of masitinib

Summary for 7L5D

• Entry DOI: 10.2210/pdb7l5d/pdb
• Descriptor: 3C-like proteinase, N-(4-methyl-3-{[4-(pyridin-3-yl)-1,3-thiazol-2-yl]amino}phenyl)-4-[(piperazin-1-yl)methyl]benzamide, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: sars-cov-2, covid-19, 3cl, main protease, masitinib, demethylation, analog, structural genomics, center for structural genomics of infectious diseases, csgid, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 34991.07

Authors

Tan, K.,Maltseva, N.I.,Jedrzejczak, R.P.,Joachimiak, A.,Center for Structural Genomics of Infectious Diseases (CSGID) (deposition date: 2020-12-21, release date: 2020-12-30, Last modification date: 2023-10-18)

Primary citation

Drayman, N.,DeMarco, J.K.,Jones, K.A.,Azizi, S.A.,Froggatt, H.M.,Tan, K.,Maltseva, N.I.,Chen, S.,Nicolaescu, V.,Dvorkin, S.,Furlong, K.,Kathayat, R.S.,Firpo, M.R.,Mastrodomenico, V.,Bruce, E.A.,Schmidt, M.M.,Jedrzejczak, R.,Munoz-Alia, M.A.,Schuster, B.,Nair, V.,Han, K.Y.,O'Brien, A.,Tomatsidou, A.,Meyer, B.,Vignuzzi, M.,Missiakas, D.,Botten, J.W.,Brooke, C.B.,Lee, H.,Baker, S.C.,Mounce, B.C.,Heaton, N.S.,Severson, W.E.,Palmer, K.E.,Dickinson, B.C.,Joachimiak, A.,Randall, G.,Tay, S.
Masitinib is a broad coronavirus 3CL inhibitor that blocks replication of SARS-CoV-2.
Science, 373:931-936, 2021

PubMed 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).

PubMed: 34285133
DOI: 10.1126/science.abg5827

Experimental method

X-RAY DIFFRACTION (1.58 Å)