Krüger Nadine, Kronenberger Thales, Xie Hang, Rocha Cheila, Pöhlmann Stefan, Su Haixia, Xu Yechun, Laufer Stefan A, Pillaiyar Thanigaimalai
Infection Biology Unit, German Primate Center, Leibniz Institute for Primate Research Göttingen, Kellnerweg 4, 37077 Göttingen, Germany.
Institute of Pharmacy, Pharmaceutical/Medicinal Chemistry and Tübingen Center for Academic Drug Discovery, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
Pharmaceuticals (Basel). 2023 Jan 28;16(2):190. doi: 10.3390/ph16020190.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 M. Several compounds were discovered to inhibit M at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 M, and the X-ray structure revealed covalent interaction with the protease's catalytic Cys145 site. Selected potent molecules also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for future COVID-19 research.
由于2019年冠状病毒病（COVID-19）大流行，严重急性呼吸综合征冠状病毒2（SARS-CoV-2）促使了直接作用抗病毒药物的研发。SARS-CoV-2的主要蛋白酶是一种关键酶，可分解从病毒RNA合成的多聚蛋白，使其成为SARS-CoV-2治疗药物研发的有效靶点。新的化学表型经常在天然产物中被发现。在本研究中，我们使用荧光测定法测试了多种天然产物抑制SARS-CoV-2 M的能力。发现几种化合物在低微摩尔浓度下就能抑制M。可以将刺槐素与SARS-CoV-2 M一起结晶，X射线结构显示其与蛋白酶的催化半胱氨酸145位点存在共价相互作用。选定的强效分子也表现出抗病毒特性且无细胞毒性。其中一些强效抑制剂可能会被用作未来COVID-19研究的先导化合物。
