Ebselen, Disulfiram, Carmofur, PX-12, Tideglusib, and Shikonin Are Nonspecific Promiscuous SARS-CoV-2 Main Protease Inhibitors.

ACS Pharmacology & Translational Science
Chunlong MaJun Wang

Abstract

Among the drug targets being investigated for SARS-CoV-2, the viral main protease (Mpro) is one of the most extensively studied. Mpro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites. It is highly conserved and has a unique substrate preference for glutamine in the P1 position. Therefore, Mpro inhibitors are expected to have broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as Mpro inhibitors. In this study, we investigated the mechanism of action of six previously reported Mpro inhibitors, ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12, using a consortium of techniques including FRET-based enzymatic assay, thermal shift assay, native mass spectrometry, cellular antiviral assays, and molecular dynamics simulations. Collectively, the results showed that the inhibition of Mpro by these six compounds is nonspecific and that the inhibition is abolished or greatly reduced with the addition of reducing reagent 1,4-dithiothreitol (DTT). Without DTT, these six compounds inhibit not only Mpro but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease and 2Apro and 3Cpro from enterovirus A71 (EV-A7...Continue Reading

Citations

Jan 12, 2021·Expert Review of Clinical Pharmacology·Chiranjib ChakrabortyGovindasamy Agoramoorthy
Jan 25, 2021·Journal of Ethnopharmacology·Zhonglei Wang, Liyan Yang
Feb 12, 2021·ACS Infectious Diseases·Kas SteutenMatthew Bogyo
Feb 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Chunlong Ma, Jun Wang
Mar 20, 2021·Journal of Molecular Graphics & Modelling·Sheng GuoZhili Zuo
Apr 2, 2021·Archives of Toxicology·Cristina W NogueiraJoão B T Rocha
Apr 24, 2021·Journal of Medicinal Chemistry·Naoya KitamuraJun Wang
Apr 22, 2021·Advances and Applications in Bioinformatics and Chemistry : AABC·Bruno O VilloutreixPhilippe Beaune
May 22, 2021·Molecular Informatics·Pablo Andrei NogaraJoão Batista Teixeira Rocha
May 26, 2021·Nature Communications·Kangsa AmporndanaiS Samar Hasnain
Jun 1, 2021·Frontiers in Molecular Biosciences·Miao Mei, Xu Tan
Jun 12, 2021·SLAS Discovery·Kathryn M Nelson, Michael A Walters
Jun 19, 2021·Biomedit︠s︡inskai︠a︡ khimii︠a︡·A V SulimovV B Sulimov

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Datasets Mentioned

BETA
MF973167

Methods Mentioned

BETA
X-ray
enzymatic assay
FRET
thermal shift
Assay
PCR

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