112027 20230519145547.0 doi 10.3390/ijms22137048 sideral 127107 ART-2021-127107 eng Mangiavacchi F. Seleno-functionalization of quercetin improves the non-covalent inhibition of mpro and its antiviral activity in cells against sars-cov-2 2021 Access copy available to the general public Unrestricted 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 (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. info:eu-repo/grantAgreement/ES/DGA/E45-17R info:eu-repo/grantAgreement/ES/ISCIII/CPII13-00017 info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349 info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739 info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P info:eu-repo/semantics/openAccess by http://creativecommons.org/licenses/by/3.0/es/ 6.208 2021 BIOCHEMISTRY & MOLECULAR BIOLOGY 69 / 297 = 0.232 2021 Q1 T1 CHEMISTRY, MULTIDISCIPLINARY 50 / 180 = 0.278 2021 Q2 T1 1.176 2021 Computer Science Applications 2021 Q1 Inorganic Chemistry 2021 Q1 Spectroscopy 2021 Q1 Organic Chemistry 2021 Q1 Physical and Theoretical Chemistry 2021 Q1 Molecular Biology 2021 Q1 6.9 2021 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion 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. Universidad de Zaragoza (orcid)0000-0003-1885-4365 Jimenez-Alesanco A. Universidad de Zaragoza (orcid)0000-0003-4726-7821 Ceballos-Laita L. (orcid)0000-0003-1892-5063 Vega S. (orcid)0000-0002-1232-6310 Rizzuti B. Abian O. Universidad de Zaragoza (orcid)0000-0001-5664-1729 Lenardão E.J. Velazquez-Campoy A. Universidad de Zaragoza (orcid)0000-0001-5702-4538 Pyrc K. Sancineto L. Santi C. 1002 060 Universidad de Zaragoza Dpto. Bioq.Biolog.Mol. Celular Área Bioquímica y Biolog.Mole. 22, 13 (2021), 22137048[20 pp] Int. j. mol. sci. International Journal of Molecular Sciences 1661-6596 2925097 http://zaguan.unizar.es/record/112027/files/texto_completo.pdf Versión publicada 2921021 http://zaguan.unizar.es/record/112027/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:112027 articulos driver 2023-05-18-15:46:28 ARTICLE