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Discovery of Polyphenolic Natural Products as SARS-CoV-2 M^pro Inhibitors for COVID-19.

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 M^pro. Several compounds were discovered to inhibit M^pro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 M^pro, 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 future COVID-19 research.

SUBMITTER: Kruger N

PROVIDER: S-EPMC9959258 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Discovery of Polyphenolic Natural Products as SARS-CoV-2 M<sup>pro</sup> Inhibitors for COVID-19.

Krüger Nadine N Kronenberger Thales T Xie Hang H Rocha Cheila C Pöhlmann Stefan S Su Haixia H Xu Yechun Y Laufer Stefan A SA Pillaiyar Thanigaimalai T

Pharmaceuticals (Basel, Switzerland) 20230128 2

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 ...[more]

PMID: 37259339

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Project description:In the past two years, the COVID-19 pandemic has caused over 5 million deaths and 250 million infections worldwide. Despite successful vaccination efforts and emergency approval of small molecule therapies, a diverse range of antivirals is still needed to combat the inevitable resistance that will arise from new SARS-CoV-2 variants. The main protease of SARS-CoV-2 (Mpro) is an attractive drug target due to the clinical success of protease inhibitors against other viruses, such as HIV and HCV. However, in order to combat resistance, various chemical scaffolds need to be identified that have the potential to be developed into potent inhibitors. To this end, we screened a high-content protease inhibitor library against Mproin vitro, in order to identify structurally diverse compounds that could be further developed into antiviral leads. Our high-content screening efforts retrieved 27 hits each with > 50% inhibition in our Mpro FRET assay. Of these, four of the top inhibitor compounds were chosen for follow-up due to their potency and drugability (Lipinski's rules of five criteria): anacardic acid, aloesin, aloeresin D, and TCID. Further analysis via dose response curves revealed IC50 values of 6.8 μM, 38.9 μM, 125.3 μM, and 138.0 μM for each compound, respectively. Molecular docking studies demonstrated that the four inhibitors bound at the catalytic active site of Mpro with varying binding energies (-7.5 to -5.6 kcal/mol). Furthermore, Mpro FRET assay kinetic studies demonstrated that Mpro catalysis is better represented by a sigmoidal Hill model than the standard Michaelis-Menten hyperbola, indicating substantial cooperativity of the active enzyme dimer. This result suggests that the dimerization interface could be an attractive target for allosteric inhibitors. In conclusion, we identified two closely-related natural product compounds from the Aloe plant (aloesin and aloeresin D) that may serve as novel scaffolds for Mpro inhibitor design and additionally confirmed the strongly cooperative kinetics of Mpro proteolysis. These results further advance our knowledge of structure-function relationships in Mpro and offer new molecular scaffolds for inhibitor design.

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Discovery of Polyphenolic Natural Products as SARS-CoV-2 M^pro Inhibitors for COVID-19.

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Discovery of Polyphenolic Natural Products as SARS-CoV-2 M<sup>pro</sup> Inhibitors for COVID-19.

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

Publications

Discovery of Polyphenolic Natural Products as SARS-CoV-2 M<sup>pro</sup> Inhibitors for COVID-19.

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OmicsDI is part of the ELIXIR infrastructure

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Discovery of Polyphenolic Natural Products as SARS-CoV-2 M^pro Inhibitors for COVID-19.