Chrysin 7-O-fi-D-glucuronide, a dual inhibitor of SARS-CoV-2 3CLpro and PLpro, for the prevention and treatment of COVID-19

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in the coro-navirus disease 2019 (COVID-19) pandemic. Given the advent of subvariants, there is an urgent need to develop novel drugs. The aim of this study was to find SARS-CoV-2 inhibitors from Scutellaria baicalen-sis Georgi targeting the proteases 3CLpro and PLpro. After screening 25 flavonoids, chrysin 7-O -fi-D-glucuronide was found to be a potent inhibitor of SARS-CoV-2 on Vero E6 cells, with half-maximal ef-fective concentration of 8.72 mu M. Surface plasmon resonance assay, site-directed mutagenesis and enzy-matic activity measurements indicated that chrysin-7-O -fi-D-glucuronide inhibits SARS-CoV-2 by binding to H41 of 3CLpro, and K157 and E167 of PLpro. Hydrogen-deuterium exchange mass spectrometry analysis showed that chrysin-7-O -fi-D-glucuronide changes the conformation of PLpro. Finally, chrysin 7-O -fi-D-glucuronide was shown to have anti-inflammatory activity, mainly due to reduction of the levels of the pro-inflammatory cytokines interleukin (IL)-1fi and IL-6.(c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )