1. Seleno-Functionalization of Quercetin Improves the Non-Covalent Inhibition of M pro and Its Antiviral Activity in Cells against SARS-CoV-2.
- Author
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Mangiavacchi F, Botwina P, Menichetti E, Bagnoli L, Rosati O, Marini F, Fonseca SF, Abenante L, Alves D, Dabrowska A, Kula-Pacurar A, Ortega-Alarcon D, Jimenez-Alesanco A, Ceballos-Laita L, Vega S, Rizzuti B, Abian O, Lenardão EJ, Velazquez-Campoy A, Pyrc K, Sancineto L, and Santi C
- Subjects
- Animals, Antiviral Agents metabolism, Antiviral Agents pharmacology, Binding Sites, COVID-19 pathology, COVID-19 virology, Catalytic Domain, Chlorocebus aethiops, Humans, Hydrogen Bonding, Molecular Docking Simulation, Protease Inhibitors chemistry, Protease Inhibitors metabolism, Protease Inhibitors pharmacology, Quercetin metabolism, Quercetin pharmacology, SARS-CoV-2 isolation & purification, Selenium metabolism, Vero Cells, Viral Matrix Proteins metabolism, Virus Replication drug effects, Antiviral Agents chemistry, Quercetin chemistry, SARS-CoV-2 metabolism, Selenium chemistry, Viral Matrix Proteins antagonists & inhibitors
- Abstract
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
pro ) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin 1 has been recently reported to be a potent Mpro 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 ( 1 ) and 8-( p -tolylselenyl)quercetin ( 2d ) block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC50 of 192 μM and 8 μM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for Mpro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher Mpro activity of 2d and, as a result, its better antiviral profile.- Published
- 2021
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