Department of Chemical Biology and Bioimaging, Wroclaw University of Science and Technology, Wroclaw, Poland.
Institute of Molecular Medicine, University of Lübeck, Lübeck, Germany.
Protein Sci. 2024 Sep;33(9):e5139. doi: 10.1002/pro.5139.
The main protease from coronaviruses and the 3C protease from enteroviruses play a crucial role in processing viral polyproteins, making them attractive targets for the development of antiviral agents. In this study, we employed a combinatorial chemistry approach-HyCoSuL-to compare the substrate specificity profiles of the main and 3C proteases from alphacoronaviruses, betacoronaviruses, and enteroviruses. The obtained data demonstrate that coronavirus Ms exhibit overlapping substrate specificity in all binding pockets, whereas the 3C from enterovirus displays slightly different preferences toward natural and unnatural amino acids at the P4-P2 positions. However, chemical tools such as substrates, inhibitors, and activity-based probes developed for SARS-CoV-2 M can be successfully applied to investigate the activity of the M from other coronaviruses as well as the 3C from enteroviruses. Our study provides a structural framework for the development of broad-spectrum antiviral compounds.
冠状病毒的主要蛋白酶和肠道病毒的 3C 蛋白酶在病毒多蛋白的加工中起着至关重要的作用，因此成为开发抗病毒药物的有吸引力的靶标。在这项研究中，我们采用组合化学方法-HyCoSuL-来比较甲型冠状病毒、乙型冠状病毒和肠道病毒的主要蛋白酶和 3C 蛋白酶的底物特异性谱。获得的数据表明，冠状病毒 Ms 在所有结合口袋中表现出重叠的底物特异性，而肠道病毒的 3C 对 P4-P2 位置的天然和非天然氨基酸表现出略有不同的偏好。然而，为 SARS-CoV-2 M 开发的化学工具，如底物、抑制剂和基于活性的探针，可以成功地应用于研究其他冠状病毒的 M 以及肠道病毒的 3C 的活性。我们的研究为开发广谱抗病毒化合物提供了结构框架。
