Active components in Ephedra sinica stapf disrupt the interaction between ACE2 and SARS-CoV-2 RBD: Potent COVID-19 therapeutic agents

Ephedra sinica Stapf is a widely used folk medicine in Asia to treat lung diseases, such as cold, cough and asthma. Many efforts have revealed that some traditional Chinese medicine (TCM) prescriptions containing Ephedra sinica could effectively alleviate the symptoms and prevent the fatal deteriora...

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Published in:Journal of ethnopharmacology 2021-10, Vol.278, p.114303-114303, Article 114303
Main Authors: Mei, Jie, Zhou, Yatong, Yang, Xinping, Zhang, Fan, Liu, Xiufeng, Yu, Boyang
Format: Article
Language:English
Subjects:
ACE2
Angiotensin-Converting Enzyme 2 - chemistry
Angiotensin-Converting Enzyme 2 - metabolism
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Cell Line
COVID-19
COVID-19 - prevention & control
COVID-19 - virology
COVID-19 Drug Treatment
Ephedra sinica
Ephedra sinica - chemistry
Humans
Models, Molecular
Molecular Docking Simulation
Plant Extracts - chemistry
Plant Extracts - pharmacology
Plant Stems
PPI inhibitor
Protein Binding
Protein Conformation
Protein Domains
Quinoline-2-carboxylic acid
Receptors, Cell Surface
SARS-CoV-2
Spike Glycoprotein, Coronavirus
Virus Internalization - drug effects
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Summary:Ephedra sinica Stapf is a widely used folk medicine in Asia to treat lung diseases, such as cold, cough and asthma. Many efforts have revealed that some traditional Chinese medicine (TCM) prescriptions containing Ephedra sinica could effectively alleviate the symptoms and prevent the fatal deterioration of COVID-19. The present study aims to discover active compounds in Ephedra sinica disrupting the interaction between angiotensin-converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein receptor-binding domain (SARS-CoV-2 RBD) to inhibit SARS-CoV-2 virus infection. The ethanol extracts of Ephedra sinica were prepared. Activity guided isolation of constituents was carried out by measuring the inhibitory activity on ACE2-RBD interaction. The structures of active compounds were identified by HPLC-Q-TOF-MS/MS and NMR. To testify the contribution of main components for the inhibitory activity, different samples were prepared by components knock-out strategy. The mechanism of compounds inhibiting protein-protein interaction (PPI) was explored by competition inhibition assays, surface plasmon resonance (SPR) assays and molecular docking. SARS-CoV-2 S protein-pseudoviruses were used to observe the viropexis effect in cells. Ephedra sinica extracts (ESE) could effectively inhibit the interaction between ACE2 and SARS-CoV-2 RBD (IC50 = 95.01 μg/mL). Three active compounds, 4,6-dihydroxyquinoline-2-carboxylic acid, 4-hydroxyquinoline-2-carboxylic acid and 4-hydroxy-6-methoxyquinoline-2-carboxylic acid were identified to inhibit ACE2-RBD interaction (IC50 = 0.58 μM, 0.07 μM and 0.15 μM respectively). And knock-out the three components could eliminate the inhibitory activity of ESE. Molecular docking calculations indicated that the hydrogen bond was the major intermolecular force. Finally, our results also showed that these compounds could inhibit the infectivity of SARS-CoV-2 S protein-pseudoviruses to 293T-ACE2 (IC50 = 0.44–1.09 μM) and Calu-3 cells. These findings suggested that quinoline-2-carboxylic acids in Ephedra sinica could be considered as potential therapeutic agents for COVID-19. Further, this study provided some justification for the ethnomedicinal use of Ephedra sinica for COVID-19. [Display omitted] •Quinoline-2-carboxylic acids in Ephedra sinica disrupt ACE2-RBD interaction.•Quinoline-2-carboxylic acids abolish the infectivity of SARS-CoV-2 pseudoviruses.•Ephedra sinica and quinoline-2-carboxylic acids may be COVID-19 therapeutic agents.
ISSN:0378-8741
1872-7573
DOI:10.1016/j.jep.2021.114303