New insights in the mechanism of the SARS-CoV-2 Mpro inhibition by benzisoselenazolones and diselenides

Although global vaccination campaigns alleviated the SARS-CoV-2 pandemic in terms of morbidity and mortality, the ability of the virus to originate mutants may reduce the efficacy of vaccines, posing a serious risk of a renewed pandemic. There is therefore a need to develop small molecules capable o...

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Bibliographic Details
Authors: Sancineto, Luca, Mangiavacchi, Francesca, Dabrowska, Agnieszka, Pacuła-Miszewska, Agata J., Obieziurska-Fabisiak, Magdalena, Scimmi, Cecilia, Ceccucci, Veronica, Kong, Juan, Zhao, Yao, Ciancaleoni, Gianluca, Nascimento, Vanessa, Rizzuti, Bruno, Bortoli, Marco, Orian, Laura, Kula-Pacurar, Anna, Yang, Haitao, Ścianowski, Jacek, Lei, Ying, Pyrc, Krzysztof, Santi, Claudio
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/371114
Online Access:http://hdl.handle.net/10261/371114
https://api.elsevier.com/content/abstract/scopus_id/85206968480
Access Level:Open access
Keyword:Benzisoselenazolones
Diselenides
Ebselen
Glutathione
SARS-CoV-2 main protease inhibitors
Description
Summary:Although global vaccination campaigns alleviated the SARS-CoV-2 pandemic in terms of morbidity and mortality, the ability of the virus to originate mutants may reduce the efficacy of vaccines, posing a serious risk of a renewed pandemic. There is therefore a need to develop small molecules capable of targeting conserved viral targets, such as the main protease (Mpro). Here, a series of benzisoselenazolones and diselenides were tested for their ability to inhibit Mpro; then the most potent compounds were measured for antiviral activity in vitro, and the mechanism of action was investigated. Density functional theory calculations, molecular docking and molecular dynamics simulations were also used to elucidate the protein/drug interaction. Finally, a bio-organic model was established to study the reaction between selenorganic compounds and biologically relevant thiols to unveil possible metabolic pathways of such compounds. The overall results contribute to the identification of a series of novel Se-containing molecules active against SARS-CoV-2 and to the clarification of some important aspects in the mechanisms of action of such inhibitors targeting SARS-CoV-2 Mpro.

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