Abstract The antineoplastic drug Carmofur was shown to inhibit SARS-CoV-2 main protease (M pro ). Here the X-ray crystal structure of M pro in complex with Carmofur reveals that the carbonyl reactive group of Carmofur is covalently bound to catalytic Cys145, whereas its fatty acid tail occupies the hydrophobic S2 subsite. Carmofur inhibits viral replication in cells (EC 50 = 24.30 μM) and it is a promising lead compound to develop new antiviral treatment for COVID-19.

Structural basis for the inhibition of SARS-CoV-2 main protease by antineoplastic drug Carmofur