Dataset Information

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

ABSTRACT: The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (M^pro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent M^pro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in M^pro via high resolution co-crystallography and investigated their chemical reactivity via mass spectrometry. Stronger M^pro inhibition than ebselen and potent ability to rescue infected cells were observed for a number of derivatives. A free selenium atom bound with cysteine of catalytic dyad has been revealed in crystallographic structures of M^pro with ebselen and MR6-31-2 suggesting hydrolysis of the enzyme bound organoselenium covalent adduct and formation of a phenolic by-product, confirmed by mass spectrometry. The target engagement with selenation mechanism of inhibition suggests wider therapeutic applications of these compounds against SARS-CoV-2 and other zoonotic beta-corona viruses.

SUBMITTER: Amporndanai K

PROVIDER: S-EPMC8144557 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

Amporndanai Kangsa K Meng Xiaoli X Shang Weijuan W Jin Zhenmig Z Rogers Michael M Zhao Yao Y Rao Zihe Z Liu Zhi-Jie ZJ Yang Haitao H Zhang Leike L O'Neill Paul M PM Samar Hasnain S S

Nature communications 20210524 1

The SARS-CoV-2 pandemic has triggered global efforts to develop therapeutics. The main protease of SARS-CoV-2 (Mpro), critical for viral replication, is a key target for therapeutic development. An organoselenium drug called ebselen has been demonstrated to have potent Mpro inhibition and antiviral activity. We have examined the binding modes of ebselen and its derivative in Mpro via high resolution co-crystallography and investigated their chemical reactivity vi ...[more]

PMID: 34031399

Similar Datasets

Project description:There is an urgent need for vaccines and antiviral drugs to combat the COVID-19 pandemic. Encouraging progress has been made in developing antivirals targeting SARS-CoV-2, the etiological agent of COVID-19. Among the drug targets being investigated, the viral main protease (M pro ) is one of the most extensively studied drug targets. M pro is a cysteine protease that hydrolyzes the viral polyprotein at more than 11 sites and it is highly conserved among coronaviruses. In addition, M pro has a unique substrate preference for glutamine in the P1 position. Taken together, it appears that M pro inhibitors can achieve both broad-spectrum antiviral activity and a high selectivity index. Structurally diverse compounds have been reported as M pro inhibitors, with several of which also showed antiviral activity in cell culture. In this study, we investigated the mechanism of action of six previously reported M pro 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 M pro by these six compounds is non-specific and the inhibition is abolished or greatly reduced with the addition of reducing reagent DTT. In the absence of DTT, these six compounds not only inhibit M pro , but also a panel of viral cysteine proteases including SARS-CoV-2 papain-like protease, the 2A pro and 3C pro from enterovirus A71 (EV-A71) and EV-D68. However, none of the compounds inhibits the viral replication of EV-A71 or EV-D68, suggesting that the enzymatic inhibition potency IC 50 values obtained in the absence of DTT cannot be used to faithfully predict their cellular antiviral activity. Overall, we provide compelling evidence suggesting that ebselen, disulfiram, tideglusib, carmofur, shikonin, and PX-12 are non-specific SARS-CoV-2 M pro inhibitors, and urge the scientific community to be stringent with hit validation.

Dataset Information

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

Publications

Inhibition mechanism of SARS-CoV-2 main protease by ebselen and its derivatives.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets