Tea Catechins in Green Tea Inhibit the Activity of SARS-CoV-2 Main Protease via Covalent Adduction

We herein examined the inhibitory effects of tea catechins on the SARS-CoV-2 main protease (M^pro). Among the catechins analyzed, epigallocatechin 3-(3″-<i>O</i>-methyl)gallate, epigallocatechin gallate (EGCG), gallocatechin, gallocatechin gallate, and epigallocatechin inhibited recombinant M^pro in a dose-dependent manner. Peptide mapping revealed that catechins preferentially formed covalent bonds with five sequences with the strongest activity at the C145 active site. Fragmentation analysis indicated 184 cleavages from peptides containing C145, corresponding to the D ring, suggesting that the B ring was attached to C145. When 10 bottled teas were incubated with M^pro, four green teas inhibited the enzyme by over 80%, whereas the blended and barley teas showed no effect. EGCG reacted covalently with SARS-CoV-2 M^pro within cells when incubated with cultured cells expressing M^pro. This is the first study to report direct covalent binding between tea catechins and M^pro in cells. This suggests that catechins from green tea can inhibit M^pro in infected cells.