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

Abstract

A crystal structure of SARS-CoV-2 with inhibitor carmofur reveals the mechanism of action of this compound and opens the way to develop more potent drugs. The antineoplastic drug carmofur is shown to inhibit the 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 (EC50 = 24.30 mu M) and is a promising lead compound to develop new antiviral treatment for COVID-19.