Abstract
Despite the now infamous coronavirus disease outbreaks caused by severe acute respiratory syndrome coronavirus (SARS-CoV), this virus continues to be a threat to the global population. Although a huge research effort has targeted SARS-CoV, no report exists regarding natural small molecules targeting one of its key enzymes, papain-like protease (PLpro). In this study, nine flavonoids displaying SARS-CoV PLpro inhibitory activity were isolated from the root bark of Lespedeza bicolor. The compounds were identified as erythrabyssin II (1), lespebuergine G4 (2), 1-methoxyerythrabyssin II (3), bicolosin A (4), bicolosin B (5), bicolosin (6), xanthoangelol (7), (±)-lespeol (8), and parvisoflavanone (9). Most compounds (1-4 and 6-8) inhibited SARS-CoV PLpro activity in a dose-dependent manner, with their K(i)s ranging from 5.56 to 75.37 μM. The structure-activity analysis of pterocarpans (1-6) showed that activity was enhanced by C1-OCH(3), but it was reduced by C8-CH(3). A mechanistic analysis revealed that all inhibitors were noncompetitive. Some of the key compounds isolated in this study are pterocarpans, which are abundantly present in the Leguminosae family. Overall, a rich source of SARS-CoV papain-like protease inhibitors was identified in this study.