tetano
Editor, Senior Moderator
Sci Rep
. 2024 Oct 21;14(1):24751.
doi: 10.1038/s41598-024-75519-6. New insights in the mechanism of the SARS-CoV-2 M[SUP]pro[/SUP] inhibition by benzisoselenazolones and diselenides
Luca Sancineto[SUP] 1 [/SUP], Francesca Mangiavacchi[SUP] 1 [/SUP], Agnieszka Dabrowska[SUP] 2 3 [/SUP], Agata J Pacuła-Miszewska[SUP] 4 [/SUP], Magdalena Obieziurska-Fabisiak[SUP] 4 [/SUP], Cecilia Scimmi[SUP] 1 [/SUP], Veronica Ceccucci[SUP] 1 [/SUP], Juan Kong[SUP] 5 [/SUP], Yao Zhao[SUP] 5 [/SUP], Gianluca Ciancaleoni[SUP] 6 [/SUP], Vanessa Nascimento[SUP] 7 [/SUP], Bruno Rizzuti[SUP] 8 9 [/SUP], Marco Bortoli[SUP] 10 [/SUP], Laura Orian[SUP] 11 [/SUP], Anna Kula-Pacurar[SUP] 2 [/SUP], Haitao Yang[SUP] 5 [/SUP], Jacek Ścianowski[SUP] 4 [/SUP], Ying Lei[SUP] 12 [/SUP], Krzysztof Pyrc[SUP] 13 [/SUP], Claudio Santi[SUP] 14 [/SUP]
Affiliations
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 (M[SUP]pro[/SUP]). Here, a series of benzisoselenazolones and diselenides were tested for their ability to inhibit M[SUP]pro[/SUP]; 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 M[SUP]pro[/SUP].
Keywords: Benzisoselenazolones; Diselenides; Ebselen; Glutathione; SARS-CoV-2 main protease inhibitors.
. 2024 Oct 21;14(1):24751.
doi: 10.1038/s41598-024-75519-6. New insights in the mechanism of the SARS-CoV-2 M[SUP]pro[/SUP] inhibition by benzisoselenazolones and diselenides
Luca Sancineto[SUP] 1 [/SUP], Francesca Mangiavacchi[SUP] 1 [/SUP], Agnieszka Dabrowska[SUP] 2 3 [/SUP], Agata J Pacuła-Miszewska[SUP] 4 [/SUP], Magdalena Obieziurska-Fabisiak[SUP] 4 [/SUP], Cecilia Scimmi[SUP] 1 [/SUP], Veronica Ceccucci[SUP] 1 [/SUP], Juan Kong[SUP] 5 [/SUP], Yao Zhao[SUP] 5 [/SUP], Gianluca Ciancaleoni[SUP] 6 [/SUP], Vanessa Nascimento[SUP] 7 [/SUP], Bruno Rizzuti[SUP] 8 9 [/SUP], Marco Bortoli[SUP] 10 [/SUP], Laura Orian[SUP] 11 [/SUP], Anna Kula-Pacurar[SUP] 2 [/SUP], Haitao Yang[SUP] 5 [/SUP], Jacek Ścianowski[SUP] 4 [/SUP], Ying Lei[SUP] 12 [/SUP], Krzysztof Pyrc[SUP] 13 [/SUP], Claudio Santi[SUP] 14 [/SUP]
Affiliations
- PMID: 39433805
- DOI: 10.1038/s41598-024-75519-6
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 (M[SUP]pro[/SUP]). Here, a series of benzisoselenazolones and diselenides were tested for their ability to inhibit M[SUP]pro[/SUP]; 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 M[SUP]pro[/SUP].
Keywords: Benzisoselenazolones; Diselenides; Ebselen; Glutathione; SARS-CoV-2 main protease inhibitors.