doi:10.3390/ijms22137048engMangiavacchi F.Botwina P.Menichetti E.Bagnoli L.Rosati O.Marini F.Fonseca S.F.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 E.J.Velazquez-Campoy A.Pyrc K.Sancineto L.Santi C.Seleno-functionalization of quercetin improves the non-covalent inhibition of mpro and its antiviral activity in cells against sars-cov-2ART-2021-127107The 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 (Mpro ) 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.2021http://zaguan.unizar.es/record/11202710.3390/ijms22137048http://zaguan.unizar.es/record/112027oai:zaguan.unizar.es:112027info:eu-repo/grantAgreement/ES/DGA/E45-17Rinfo:eu-repo/grantAgreement/ES/ISCIII/CPII13-00017info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-PInternational Journal of Molecular Sciences 22, 13 (2021), 22137048[20 pp]byhttp://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccess