School of Pharmaceutical Sciences, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, China; High Throughput Drug Screening Platform of Xiamen University, China.
Department of Neurosurgery, Xiamen Key Laboratory of Brain Center, The First Affiliated Hospital of Xiamen University, China.
Biochem Biophys Res Commun. 2022 Feb 5;591:118-123. doi: 10.1016/j.bbrc.2021.12.108. Epub 2021 Dec 30.
3-chyomotrypsin like protease (3CLpro) has been considered as a promising target for developing anti-SARS-CoV-2 drugs. Herein, about 6000 compounds were analyzed by high-throughput screening using enzyme activity model, and Merbromin, an antibacterial agent, was identified as a potent inhibitor of 3CLpro. Merbromin strongly inhibited the proteolytic activity of 3CLpro but not the other three proteases Proteinase K, Trypsin and Papain. Michaelis-Menten kinetic analysis showed that Merbromin was a mixed-type inhibitor of 3CLpro, due to its ability of increasing the K and decreasing the K of 3CLpro. The binding assays and molecular docking suggested that 3CLpro possessed two binding sites for Merbromin. Consistently, Merbromin showed a weak binding to the other three proteases. Together, these findings demonstrated that Merbromin is a selective inhibitor of 3CLpro and provided a scaffold to design effective inhibitors of SARS-CoV-2.
3- 糜蛋白酶样蛋白酶（3CLpro）已被认为是开发抗 SARS-CoV-2 药物的有前途的靶标。在此，使用酶活性模型对大约 6000 种化合物进行了高通量筛选，发现抗菌剂 Merbromin 是 3CLpro 的有效抑制剂。Merbromin 强烈抑制 3CLpro 的蛋白水解活性，但不抑制其他三种蛋白酶蛋白酶 K、胰蛋白酶和木瓜蛋白酶。米氏动力学分析表明，Merbromin 是 3CLpro 的混合型抑制剂，因为它能够增加 K 和降低 3CLpro 的 K。结合测定和分子对接表明，3CLpro 具有两个与 Merbromin 的结合位点。一致地，Merbromin 对其他三种蛋白酶表现出较弱的结合。总之，这些发现表明 Merbromin 是 3CLpro 的选择性抑制剂，并为设计有效的 SARS-CoV-2 抑制剂提供了一个支架。
