Evaluation of polyphenols from Broussonetia papyrifera as coronavirus protease inhibitors

The current study was designed to assess the inhibitory activity of Broussonetia papyrifera-derived polyphenols against 3-chymotrypsin-like and papain-like coronavirus cysteine proteases. The isolated compounds were broussochalcone B (1), broussochalcone A (2), 4-hydroxyisolonchocarpin (3), papyriflavonol A (4), 3′-(3-methylbut-2-enyl)-3′,4,7-trihydroxyflavane (5), kazinol A (6), kazinol B (7), broussoflavan A (8), kazinol F (9), and kazinol J (10). All polyphenols were more potent against papain-like protease (PL pro ) than against 3-chymotripsin-like protease (3CL pro ); therefore, we investigated their structural features that were responsible for this selectivity. Compound 4 was the most potent inhibitor of PL pro with an IC 50 value of 3.7 μM. The active compounds displayed kinetic behaviors, and the binding constants of their interaction with PL pro were determined from surface plasmon resonance analysis. Our results suggest B. papyrifera constituents as promising candidates for development into potential anti-coronaviral agents.