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Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of M<sup>pro</sup> and Its Antiviral Activity in Cells against SARS-CoV-2
oleh: Francesca Mangiavacchi, Pawel Botwina, Elena Menichetti, Luana Bagnoli, Ornelio Rosati, Francesca Marini, Sérgio F. Fonseca, Laura Abenante, Diego Alves, Agnieszka Dabrowska, Anna Kula-Pacurar, David Ortega-Alarcon, Ana Jimenez-Alesanco, Laura Ceballos-Laita, Sonia Vega, Bruno Rizzuti, Olga Abian, Eder J. Lenardão, Adrian Velazquez-Campoy, Krzysztof Pyrc, Luca Sancineto, Claudio Santi
Format: | Article |
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Diterbitkan: | MDPI AG 2021-06-01 |
Deskripsi
The development of new antiviral drugs against SARS-CoV-2 is a valuable long-term strategy to protect the global population from the COVID-19 pandemic complementary to the vaccination. Considering this, the viral main protease (M<sup>pro</sup>) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin <b>1</b> has been recently reported to be a potent M<sup>pro</sup> inhibitor in vitro, and we explored the effect produced by the introduction of organoselenium functionalities in this scaffold. In particular, we report here a new synthetic method to prepare previously inaccessible C-8 seleno-quercetin derivatives. By screening a small library of flavonols and flavone derivatives, we observed that some compounds inhibit the protease activity in vitro. For the first time, we demonstrate that quercetin (<b>1</b>) and 8-(<i>p</i>-tolylselenyl)quercetin (<b>2d</b>) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC<sub>50</sub> of 192 μM and 8 μM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for M<sup>pro</sup> inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher M<sup>pro</sup> activity of <b>2d</b> and, as a result, its better antiviral profile.