Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Discovery of Polyphenolic Natural Products as SARS-CoV-2 Mpro Inhibitors for COVID-19

Nadine Krüger
ORCID logo ,
Thales Kronenberger
ORCID logo ,
Hang Xie
,
Cheila Rocha
,
Stefan Pöhlmann
ORCID logo ,
Haixia Su
,
Yechun Xu
* ,
Stefan A. Laufer
ORCID logo ,
Thanigaimalai Pillaiyar
* ORCID logo
Version 1 : Received: 24 November 2022 / Approved: 28 November 2022 / Online: 28 November 2022 (13:40:01 CET)

A peer-reviewed article of this Preprint also exists.

Krüger, N.; Kronenberger, T.; Xie, H.; Rocha, C.; Pöhlmann, S.; Su, H.; Xu, Y.; Laufer, S.A.; Pillaiyar, T. Discovery of Polyphenolic Natural Products as SARS-CoV-2 Mpro Inhibitors for COVID-19. Pharmaceuticals 2023, 16, 190. Krüger, N.; Kronenberger, T.; Xie, H.; Rocha, C.; Pöhlmann, S.; Su, H.; Xu, Y.; Laufer, S.A.; Pillaiyar, T. Discovery of Polyphenolic Natural Products as SARS-CoV-2 Mpro Inhibitors for COVID-19. Pharmaceuticals 2023, 16, 190.

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 Mpro. Several compounds were discovered to inhibit the Mpro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 Mpro, and the X-ray structure revealed covalent interaction with the protease's catalytic Cys145 site. Selected potent molecules also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for COVID-19 research.

Keywords

Antivirals; coronavirus; COVID-19; covalent drugs; dynamic light scattering; inhibitors; main protease; natural products

Subject

Chemistry and Materials Science, Medicinal Chemistry

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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