Repurposing Halicin as a potent covalent inhibitor for the SARS-CoV-2 main protease

The rapid spread of COVID-19 has caused a worldwide public health crisis. For prompt and effective development of antivirals for SARS-CoV-2, the pathogen of COVID-19, drug repurposing has been broadly conducted by targeting the main protease (M(Pro)), a key enzyme responsible for the replication of virus inside the host. In this study, we evaluate the inhibition potency of a nitrothiazole-containing drug, halicin, and reveal its reaction and interaction mechanism with M(Pro). The in vitro potency test shows that halicin inhibits the activity of M(Pro) an IC(50) of 181.7 ​nM. Native mass spectrometry and X-ray crystallography studies clearly indicate that the nitrothiazole fragment of halicin covalently binds to the catalytic cysteine C145 of M(Pro). Interaction and conformational changes inside the active site of M(Pro) suggest a favorable nucleophilic aromatic substitution reaction mechanism between M(Pro) C145 and halicin, explaining the high inhibition potency of halicin towards M(Pro).