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

Yang Yi; Rong Yu; Heng Xue; Zhengtong Jin; Meng Zhang; Yang-Oujie Bao; Zilong Wang; Hongping Wei; Xue Qiao; Hang Yang

doi:10.1016/j.ijantimicag.2023.107039

Chrysin 7-O-β-D-glucuronide, a dual inhibitor of SARS-CoV-2 3CL^pro and PL^pro, for the prevention and treatment of COVID-19

Int J Antimicrob Agents. 2024 Jan;63(1):107039. doi: 10.1016/j.ijantimicag.2023.107039. Epub 2023 Nov 17.

Authors

Yang Yi¹, Rong Yu², Heng Xue³, Zhengtong Jin², Meng Zhang², Yang-Oujie Bao², Zilong Wang², Hongping Wei³, Xue Qiao², Hang Yang⁴

Affiliations

¹ State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China; Yunnan Baiyao International Medical Research Centre, Peking University, Beijing, China. Electronic address: yiyang64780822@126.com.
² State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China.
³ CAS Key Laboratory of Special Pathogens and Biosafety, Centre for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
⁴ CAS Key Laboratory of Special Pathogens and Biosafety, Centre for Biosafety Mega-Science, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China; Hubei Jiangxia Laboratory, Wuhan, China. Electronic address: yangh@wh.iov.cn.

PMID: 37981073
DOI: 10.1016/j.ijantimicag.2023.107039

Abstract

The emergence of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) resulted in the coronavirus 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 baicalensis Georgi targeting the proteases 3CL^pro and PL^pro. After screening 25 flavonoids, chrysin 7-O-β-D-glucuronide was found to be a potent inhibitor of SARS-CoV-2 on Vero E6 cells, with half-maximal effective concentration of 8.72 µM. Surface plasmon resonance assay, site-directed mutagenesis and enzymatic activity measurements indicated that chrysin-7-O-β-D-glucuronide inhibits SARS-CoV-2 by binding to H41 of 3CL^pro, and K157 and E167 of PL^pro. Hydrogen-deuterium exchange mass spectrometry analysis showed that chrysin-7-O-β-D-glucuronide changes the conformation of PL^pro. Finally, chrysin 7-O-β-D-glucuronide was shown to have anti-inflammatory activity, mainly due to reduction of the levels of the pro-inflammatory cytokines interleukin (IL)-1β and IL-6.

Keywords: 3CL(pro); COVID-19; Chrysin 7-O-β-D-glucuronide; PL(pro); SARS-CoV-2.

MeSH terms

Antiviral Agents / chemistry
Antiviral Agents / pharmacology
Antiviral Agents / therapeutic use
COVID-19*
Cysteine Endopeptidases / chemistry
Flavonoids / pharmacology
Flavonoids / therapeutic use
Glucuronides / pharmacology
Humans
Molecular Docking Simulation
Protease Inhibitors / pharmacology
SARS-CoV-2

Substances

chrysin
Glucuronides
Cysteine Endopeptidases
Protease Inhibitors
Flavonoids
Antiviral Agents