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

Although global vaccination campaigns relieved the SARS-CoV-2 pandemic in terms of morbidity and mortality, the capability of the virus to originate mutants may reduce vaccines efficiency, posing a serious risk to fall into the pandemic again. As a result, there is the need to develop small molecules able to tackle 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, for the most potent compounds, the antiviral activity was measured in vitro, and the mechanism of action was investigated. Density functional theory and molecular docking procedures were also implemented to shed a light into the protein/compound interaction. Finally, a bioorganic model was set up to investigate the reaction between selenorganic compounds and biologically relevant thiols, to unravel possible metabolic pathways of such compounds. The overall results contribute to identify a series of novel compounds active against SARS-CoV-2, and to clarify some important aspects in the mechanisms of action of Se-containing inhibitors targeting the SARS-CoV-2 main protease (Mpro).