The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease

Wei-Chung Chiou; Jui-Chieh Chen; Yun-Ti Chen; Jinn-Moon Yang; Lih-Hwa Hwang; Yi-Shuan Lyu; Hsin-Yi Yang; Cheng Huang

doi:10.1016/j.bbrc.2020.12.106

The inhibitory effects of PGG and EGCG against the SARS-CoV-2 3C-like protease

Biochem Biophys Res Commun. 2022 Feb 5:591:130-136. doi: 10.1016/j.bbrc.2020.12.106. Epub 2021 Jan 6.

Authors

Wei-Chung Chiou¹, Jui-Chieh Chen², Yun-Ti Chen³, Jinn-Moon Yang⁴, Lih-Hwa Hwang⁵, Yi-Shuan Lyu¹, Hsin-Yi Yang¹, Cheng Huang⁶

Affiliations

¹ Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan.
² Department of Biochemical Science and Technology, National Chiayi University, Chiayi, Taiwan.
³ Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan.
⁴ Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan; Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan; Center for Intelligent Drug Systems and Smart Bio-devices, National Chiao Tung University, Hsinchu, Taiwan; Faculty of Internal Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung City, Taiwan; Hepatobiliary Division, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung City, Taiwan.
⁵ Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
⁶ Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan. Electronic address: chengh@ym.edu.tw.

Abstract

The coronavirus disease (COVID-19) pandemic, resulting from human-to-human transmission of a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has led to a global health crisis. Given that the 3 chymotrypsin-like protease (3CLpro) of SARS-CoV-2 plays an indispensable role in viral polyprotein processing, its successful inhibition halts viral replication and thus constrains virus spread. Therefore, developing an effective SARS-CoV-2 3CLpro inhibitor to treat COVID-19 is imperative. A fluorescence resonance energy transfer (FRET)-based method was used to assess the proteolytic activity of SARS-CoV-2 3CLpro using intramolecularly quenched fluorogenic peptide substrates corresponding to the cleavage sequence of SARS-CoV-2 3CLpro. Molecular modeling with GEMDOCK was used to simulate the molecular interactions between drugs and the binding pocket of SARS-CoV-2 3CLpro. This study revealed that the V_max of SARS-CoV-2 3CLpro was about 2-fold higher than that of SARS-CoV 3CLpro. Interestingly, the proteolytic activity of SARS-CoV-2 3CLpro is slightly more efficient than that of SARS-CoV 3CLpro. Meanwhile, natural compounds PGG and EGCG showed remarkable inhibitory activity against SARS-CoV-2 3CLpro than against SARS-CoV 3CLpro. In molecular docking, PGG and EGCG strongly interacted with the substrate binding pocket of SARS-CoV-2 3CLpro, forming hydrogen bonds with multiple residues, including the catalytic residues C145 and H41. The activities of PGG and EGCG against SARS-CoV-2 3CLpro demonstrate their inhibition of viral protease activity and highlight their therapeutic potentials for treating SARS-CoV-2 infection.

Keywords: 3CL protease (3CLpro); COVID-19; EGCG; PGG; SARS-CoV-2.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
COVID-19 / epidemiology
COVID-19 / prevention & control
COVID-19 / virology
Catechin / analogs & derivatives*
Catechin / chemistry
Catechin / metabolism
Catechin / pharmacology
Coronavirus 3C Proteases / antagonists & inhibitors*
Coronavirus 3C Proteases / chemistry
Coronavirus 3C Proteases / metabolism
Drug Evaluation, Preclinical / methods
Humans
Hydrolyzable Tannins / chemistry
Hydrolyzable Tannins / metabolism
Hydrolyzable Tannins / pharmacology*
Kinetics
Models, Molecular
Molecular Docking Simulation*
Molecular Structure
Pandemics
Protease Inhibitors / chemistry
Protease Inhibitors / metabolism
Protease Inhibitors / pharmacology
Protein Binding
Protein Domains
SARS-CoV-2 / drug effects*
SARS-CoV-2 / enzymology
SARS-CoV-2 / physiology
Virus Replication / drug effects

Substances

Hydrolyzable Tannins
Protease Inhibitors
pentagalloylglucose
Catechin
epigallocatechin gallate
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases