Molecular Interactions of Tannic Acid with Proteins Associated with SARS-CoV-2 Infectivity.

Mohamed Haddad,Normand Mousseau,Roger Gaudreault,Gabriel Sasseville,Steve Bourgault,Hannah Wiebe,Charles Ramassamy,Theo Van De Ven,Phuong Trang Nguyen

doi:10.3390/ijms23052643

Abstract

The overall impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on our society is unprecedented. The identification of small natural ligands that could prevent the entry and/or replication of the coronavirus remains a pertinent approach to fight the coronavirus disease (COVID-19) pandemic. Previously, we showed that the phenolic compounds corilagin and 1,3,6-tri-O-galloyl-β-D-glucose (TGG) inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 target receptor on the cell membrane of the host organism. Building on these promising results, we now assess the effects of these phenolic ligands on two other crucial targets involved in SARS-CoV-2 cell entry and replication, respectively: transmembrane protease serine 2 (TMPRSS2) and 3-chymotrypsin like protease (3CLpro) inhibitors. Since corilagin, TGG, and tannic acid (TA) share many physicochemical and structural properties, we investigate the binding of TA to these targets. In this work, a combination of experimental methods (biochemical inhibition assays, surface plasmon resonance, and quartz crystal microbalance with dissipation monitoring) confirms the potential role of TA in the prevention of SARS-CoV-2 infectivity through the inhibition of extracellular RBD/ACE2 interactions and TMPRSS2 and 3CLpro activity. Moreover, molecular docking prediction followed by dynamic simulation and molecular mechanics Poisson–Boltzmann surface area (MMPBSA) free energy calculation also shows that TA binds to RBD, TMPRSS2, and 3CLpro with higher affinities than TGG and corilagin. Overall, these results suggest that naturally occurring TA is a promising candidate to prevent and inhibit the infectivity of SARS-CoV-2.

Highlights

We investigate experimentally the interactions between natural polyphenolic ligands— tannic acid (TA), TGG, and corilagin—with proteins involved in the relevant steps for cellular entry and replication of the virus—receptor binding domain (RBD) (N501Y), transmembrane protease serine 2 (TMPRSS2), and 3-chymotrypsin like protease (3CLpro)
Our results demonstrate that TA, TGG, and corilagin can inhibit the binding between the spike protein RBD (N501Y) and the human angiotensin-converting enzyme 2 (ACE2) receptor as well as reduce the activities of the enzymes TMPRSS2 and 3CLpro, with TA being the most potent ligand, able to reduce the binding by up to 95% and enzyme activities by 60% to 70%
Among seven promising polyphenols tested, we found that TA was the most potent natural compound to prevent the RBD (N501Y) spike protein/human ACE2 interaction, as well as to inhibit the activities of TMPRSS2 and 3CLpro

Summary

Introduction

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a zoonotic coronavirus first identified in China, has led to the worldwide coronavirus disease (COVID-19). Pandemic with more than 400 million known cases of infection and 5.8 million deaths as of February 2022. Mutated SARS-CoV-2 variants are emerging with increased infectivity, facilitating their spread [1]; e.g., the SARS-CoV-2 B.1.617.2 (Delta) variant possesses a higher replication rate and transmissibility than B.1.1.7 (Alpha) [2]. The B.1.1.529 (Omicron) variant with 30 mutations has emerged [3]. Though vaccination campaigns have been implemented in many countries, there is still an urgency to develop effective and accessible therapeutics

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