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 M pro 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 IC 50 of 192 μM and 8 μM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for M pro inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher M pro activity of 2d and, as a result, its better antiviral profile.
【저자키워드】 SARS-CoV-2, main protease, Selenium, flavanols, 【초록키워드】 vaccination, Antiviral, COVID-19 pandemic, quercetin, protease, in vitro, antiviral drug, viral replication, inhibitor, SARS-CoV-2 replication, mechanism, Protease activity, Hydrogen bond, complementary, residue, Compound, M pro, molecular target, flavonol, infected cell, experimental evidence, derivatives, concentrations, docking experiment, GLN189, non-toxic, PROTECT, produced, reported, inhibit, driven by, explain, catalytic, inaccessible, 【제목키워드】 inhibition, activity, M pro,