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

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

  • Sci Rep. 2024 Oct 21;14(1):24751. doi: 10.1038/s41598-024-75519-6.
Luca Sancineto 1,  Francesca Mangiavacchi 1,  Agnieszka Dabrowska 2 3,  Agata J Pacuła-Miszewska 4,  Magdalena Obieziurska-Fabisiak 4,  Cecilia Scimmi 1,  Veronica Ceccucci 1,  Juan Kong 5,  Yao Zhao 5,  Gianluca Ciancaleoni 6,  Vanessa Nascimento 7,  Bruno Rizzuti 8 9,  Marco Bortoli 10,  Laura Orian 11,  Anna Kula-Pacurar 2,  Haitao Yang 5,  Jacek Ścianowski 4,  Ying Lei 12,  Krzysztof Pyrc 13,  Claudio Santi 14
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, Perugia, 06100, PG, Italy.
  • 2 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, Krakow, 30-387, Poland.
  • 3 Microbiology Department, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, Krakow, 30-387, Poland.
  • 4 Department of Organic Chemistry, Faculty of Chemistry, Nicolaus Copernicus University, 7 Gagarin Street, Torun, Poland.
  • 5 Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China.
  • 6 Dipartimento di Chimica e Chimica Industriale (DCCI), Università di Pisa, Via Giuseppe Moruzzi, 13, Pisa, 56124, Italy.
  • 7 Departamento de Quımica Organica, Laboratorio de Sintese e Aplicaçao de Substancias Supramoleculares e Organocalcogenios (SupraSelen), Universidade Federal Fluminense, Outeiro Sao Joao Batista s/n, Niteroi, 24020-141, RJ, Brazil.
  • 8 Department of Physics, CNR-NANOTEC, SS Rende, University of Calabria, Rende, 87036, CS, Italy.
  • 9 Institute of Biocomputation and Physics of Complex Systems, Joint Unit GBsC-CSIC-BIFI, University of Zaragoza, Zaragoza, 50018, Spain.
  • 10 Department of Chemistry and Hylleraas Centre for Quantum Molecular Sciences, University of Oslo, Oslo, 0315, Norway.
  • 11 Dipartimento di Scienze Chimiche, Università degli Studi di Padova, Padova, 35131, Italy.
  • 12 Shanghai Institute for Advanced Immunochemical Studies, School of Life Science and Technology, ShanghaiTech University, Shanghai, China. leiying@shanghaitech.edu.cn.
  • 13 Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, Krakow, 30-387, Poland. k.a.pyrc@uj.edu.pl.
  • 14 Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, Perugia, 06100, PG, Italy. claudio.santi@unipg.it.
PMID: 39433805 DOI: 10.1038/s41598-024-75519-6
Abstract

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.

Keywords

Benzisoselenazolones; Diselenides; Ebselen; Glutathione; SARS-CoV-2 main protease inhibitors.

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