Group of Catalysis, Synthesis and Organic Green Chemistry, Department of Pharmaceutical Sciences, University of Perugia Via del Liceo 1, 06100 Perugia, Italy.
Virogenetics Laboratory of Virology, Malopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7a, 30-387 Krakow, Poland.
Int J Mol Sci. 2021 Jun 30;22(13):7048. doi: 10.3390/ijms22137048.
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) is among the most promising molecular targets in light of its importance during the viral replication cycle. The natural flavonoid quercetin has been recently reported to be a potent M 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 () and 8-(-tolylselenyl)quercetin () block SARS-CoV-2 replication in infected cells at non-toxic concentrations, with an IC of 192 μM and 8 μM, respectively. Based on docking experiments driven by experimental evidence, we propose a non-covalent mechanism for M inhibition in which a hydrogen bond between the selenium atom and Gln189 residue in the catalytic pocket could explain the higher M activity of and, as a result, its better antiviral profile.
开发针对 SARS-CoV-2 的新型抗病毒药物是保护全球人口免受 COVID-19 大流行的宝贵长期策略，与疫苗接种相辅相成。有鉴于此，鉴于其在病毒复制周期中的重要性，病毒主蛋白酶（M）是最有前途的分子靶标之一。天然类黄酮槲皮素最近被报道为体外有效的 M 抑制剂，我们探索了在该支架中引入有机硒官能团所产生的效果。特别是，我们在这里报告了一种新的合成方法来制备以前无法获得的 C-8 硒代槲皮素衍生物。通过筛选黄酮醇和黄酮衍生物的小文库，我们观察到一些化合物在体外抑制蛋白酶活性。我们首次证明，槲皮素（）和 8-（-甲苯基硒基）槲皮素（）以非毒性浓度阻断感染细胞中的 SARS-CoV-2 复制，IC 分别为 192 μM 和 8 μM。基于实验证据驱动的对接实验，我们提出了 M 抑制的非共价机制，其中催化口袋中硒原子和 Gln189 残基之间的氢键可以解释 M 活性更高的和，因此其更好的抗病毒特性。
