Flavonoids Derived from the Roots of <i>Lespedeza bicolor</i> Inhibit the Activity of SARS-CoV Papain-like Protease.

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 <i>Lespedeza bicolor</i>. The compounds were identified as erythrabyssin II (<b>1</b>), lespebuergine G4 (<b>2</b>), 1-methoxyerythrabyssin II (<b>3</b>), bicolosin A (<b>4</b>), bicolosin B (<b>5</b>), bicolosin (<b>6</b>), xanthoangelol (<b>7</b>), (±)-lespeol (<b>8</b>), and parvisoflavanone (<b>9</b>). Most compounds (<b>1</b>-<b>4</b> and <b>6</b>-<b>8</b>) inhibited SARS-CoV PLpro activity in a dose-dependent manner, with their <i>K</i>_is ranging from 5.56 to 75.37 μM. The structure-activity analysis of pterocarpans (<b>1</b>-<b>6</b>) showed that activity was enhanced by C1-OCH₃, but it was reduced by C8-CH₃. 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.