Inhibition of the SARS-CoV-2 3CLpro main protease by plant polyphenols

Miha Bahun; Marko Jukić; Domen Oblak; Luka Kranjc; Gregor Bajc; Matej Butala; Krištof Bozovičar; Tomaž Bratkovič; Črtomir Podlipnik; Nataša Poklar Ulrih

doi:10.1016/j.foodchem.2021.131594

Inhibition of the SARS-CoV-2 3CL^pro main protease by plant polyphenols

Food Chem. 2022 Mar 30;373(Pt B):131594. doi: 10.1016/j.foodchem.2021.131594. Epub 2021 Nov 14.

Authors

Affiliations

¹ Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
² Laboratory of Physical Chemistry and Chemical Thermodynamics, Faculty of Chemistry and Chemical Engineering, University of Maribor, SI-2000 Maribor, Slovenia; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, SI-6000 Koper, Slovenia.
³ Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
⁴ Department of Biology, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
⁵ Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana, SI-1000 Ljubljana, Slovenia.
⁶ Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia. Electronic address: crtomir.podlipnik@fkkt.uni-lj.si.
⁷ Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, SI-1000 Ljubljana, Slovenia; Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins (CIPKeBiP), SI-1000 Ljubljana, Slovenia. Electronic address: natasa.poklar@bf.uni-lj.si.

Abstract

The abundance of polyphenols in edible plants makes them an important component of human nutrition. Considering the ongoing COVID-19 pandemic, a number of studies have investigated polyphenols as bioactive constituents. We applied in-silico molecular docking as well as molecular dynamics supported by in-vitro assays to determine the inhibitory potential of various plant polyphenols against an important SARS-CoV-2 therapeutic target, the protease 3CL^pro. Of the polyphenols in initial in-vitro screening, quercetin, ellagic acid, curcumin, epigallocatechin gallate and resveratrol showed IC₅₀ values of 11.8 µM to 23.4 µM. In-silico molecular dynamics simulations indicated stable interactions with the 3CL^pro active site over 100 ns production runs. Moreover, surface plasmon resonance spectroscopy was used to measure the binding of polyphenols to 3CL^pro in real time. Therefore, we provide evidence for inhibition of SARS-CoV-2 3CL^pro by natural plant polyphenols, and suggest further research into the development of these novel 3CL^pro inhibitors or biochemical probes.

Keywords: 3CL(pro); 4-hydroxy-3-nitrophenylacetic acid (PubChem CID: 447364); COVID-19; Edible plants; Polyphenols; Protease inhibitor; SARS-CoV-2; caffeic acid (PubChem CID: 689043); chlorogenic acid (PubChem CID: 1794427); curcumin (PubChem CID: 969516); ellagic acid (PubChem CID: 5281855); epigallocatechin gallate (PubChem CID: 65064); ferulic acid (PubChem CID: 445858); galangin (PubChem CID: 5281616); isorhamnetin (PubChem CID: 5281654); kaempferol (PubChem CID: 5280863); kaempferol-rutinoside (PubChem CID:5318767); phlorizin (PubChem CID: 6072); protocatechuic acid (PubChem CID: 72); quercetin (PubChem CID: 5280343); quinic acid (PubChem CID: 6508); resveratrol (PubChem CID: 445154); sinapic acid (PubChem CID: 637775); syringic acid (PubChem CID: 10742); umbellic acid (PubChem CID: 446611).

MeSH terms

Coronavirus 3C Proteases / antagonists & inhibitors*
Molecular Docking Simulation
Peptide Hydrolases
Polyphenols* / pharmacology
SARS-CoV-2 / drug effects*

Substances

Polyphenols
Peptide Hydrolases
3C-like proteinase, SARS-CoV-2
Coronavirus 3C Proteases