Seleno-functionalization of quercetin improves the non-covalent inhibition of mpro and its antiviral activity in cells against sars-cov-2

Mangiavacchi 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. (Universidad de Zaragoza) ; Jimenez-Alesanco A. (Universidad de Zaragoza) ; Ceballos-Laita L. ; Vega S. ; Rizzuti B. ; Abian O. (Universidad de Zaragoza) ; Lenardão E.J. ; Velazquez-Campoy A. (Universidad de Zaragoza) ; Pyrc K. ; Sancineto L. ; Santi C.

Resumen: 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.

Idioma: Inglés

DOI: 10.3390/ijms22137048

Año: 2021

Publicado en: International Journal of Molecular Sciences 22, 13 (2021), 22137048[20 pp]
ISSN: 1661-6596

Factor impacto JCR: 6.208 (2021)

Categ. JCR: BIOCHEMISTRY & MOLECULAR BIOLOGY rank: 69 / 297 = 0.232 (2021) - Q1 - T1
Categ. JCR: CHEMISTRY, MULTIDISCIPLINARY rank: 50 / 180 = 0.278 (2021) - Q2 - T1

Factor impacto CITESCORE: 6.9 - Computer Science (Q1) - Chemical Engineering (Q1) - Medicine (Q1) - Biochemistry, Genetics and Molecular Biology (Q2)

Factor impacto SCIMAGO: 1.176 - Computer Science Applications (Q1) - Inorganic Chemistry (Q1) - Spectroscopy (Q1) - Organic Chemistry (Q1) - Physical and Theoretical Chemistry (Q1) - Molecular Biology (Q1)

Financiación: info:eu-repo/grantAgreement/ES/DGA/E45-17R
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/CPII13-00017
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-FIS/PI18-00349
Financiación: info:eu-repo/grantAgreement/ES/MCIU-AEI-FEDER/BES-2017-080739
Financiación: info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P

Tipo y forma: Article (Published version)

Área (Departamento): Área Bioquímica y Biolog.Mole. (Dpto. Bioq.Biolog.Mol. Celular)