• Li Jun Yang, Rui Hong Chen, Sami Hamdoun, Paolo Coghi, Jerome P L Ng, David Wei Zhang, Xiaoling Guo, Chenglai Xia, Betty Yuen Kwan Law, and Vincent Kam Wai Wong.
• Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China.
• Phytomedicine. 2021 Jul 1; 87: 153591.

BackgroundThe outbreak of coronavirus (SARS-CoV-2) disease caused more than 100,000,000 people get infected and over 2,200,000 people being killed worldwide. However, the current developed vaccines or drugs may be not effective in preventing the pandemic of COVID-19 due to the mutations of coronavirus and the severe side effects of the newly developed vaccines. Chinese herbal medicines and their active components play important antiviral activities. Corilagin exhibited antiviral effect on human immunodeficiency virus (HIV), hepatitis C virus (HCV) and Epstein-Barr virus (EBV). However, whether it blocks the interaction between SARS-CoV-2 RBD and hACE2 has not been elucidated.PurposeTo characterize an active compound, corilagin derived from Phyllanthus urinaria as potential SARS-CoV-2 entry inhibitors for its possible preventive application in daily anti-virus hygienic products.MethodsComputational docking coupled with bio-layer interferometry, BLI were adopted to screen more than 1800 natural compounds for the identification of SARS-CoV-2 spike-RBD inhibitors. Corilagin was confirmed to have a strong binding affinity with SARS-CoV-2-RBD or human ACE2 (hACE2) protein by the BLI, ELISA and immunocytochemistry (ICC) assay. Furthermore, the inhibitory effect of viral infection of corilagin was assessed by in vitro pseudovirus system. Finally, the toxicity of corilagin was examined by using MTT assay and maximal tolerated dose (MTD) studies in C57BL/6 mice.ResultsCorilagin preferentially binds to a pocket that contains residues Cys 336 to Phe 374 of spike-RBD with a relatively low binding energy of -9.4 kcal/mol. BLI assay further confirmed that corilagin exhibits a relatively strong binding affinity to SARS-CoV-2-RBD and hACE2 protein. In addition, corilagin dose-dependently blocks SARS-CoV-2-RBD binding and abolishes the infectious property of RBD-pseudotyped lentivirus in hACE2 overexpressing HEK293 cells, which mimicked the entry of SARS-CoV-2 virus in human host cells. Finally, in vivo studies revealed that up to 300 mg/kg/day of corilagin was safe in C57BL/6 mice. Our findings suggest that corilagin could be a safe and potential antiviral agent against the COVID-19 acting through the blockade of the fusion of SARS-CoV-2 spike-RBD to hACE2 receptors.ConclusionCorilagin could be considered as a safe and environmental friendly anti-SARS-CoV-2 agent for its potential preventive application in daily anti-virus hygienic products.Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.

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