Sino-German Biomedical Center, National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei Key Laboratory of Industrial Microbiology, School of Materials and Chemical Engineering, Hubei University of Technology, 430068 Wuhan, China.
Department of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, China.
Eur J Pharm Sci. 2023 Jul 1;186:106445. doi: 10.1016/j.ejps.2023.106445. Epub 2023 Apr 11.
A series of 2-Benzoxyl-Phenylpyridine derivatives were evaluated for their potential antiviral activities against EV71. The preliminary assays indicated that some of these compounds exhibited excellent antiviral effects on EV71, they could effectively inhibit virus-induced cytopathic effects (CPEs), reduce progeny viral yields, and present similar or better antiviral activities compared to the positive control drug ribavirin. Among these derivatives, compounds WY7, WY13 and WY14 showed the most potency against EV71. Investigation of the underlying mechanism of action revealed that these compounds target EV71 replication in cells post infection, they could profoundly inhibit viral RNA replication and protein synthesis, and inhibit virus-induced cell apoptosis. Further experiments demonstrated that compound WY7 potently inhibited the activity of the EV71 3C protease (3Cpro), and to some extent, it affected the activity of 3D polymerase (3Dpol), thus blocking viral replication, but not the activity of the 2A proteinase (2Apro). Modeling of the molecular binding of the 3Cpro-WY7 complex revealed that compound WY7 was predicted to insert into the substrate-binding pocket of EV71 3Cpro, blocking substrate recognition and thereby inhibiting EV71 3Cpro activity. These results indicate that these compounds might be feasible therapeutic agents against EV71 infection and that these compounds may provide promising lead scaffolds for the further design and synthesis of potential antiviral agents.
一系列 2-苯并氧苯基吡啶衍生物被评估了其对 EV71 的潜在抗病毒活性。初步试验表明，这些化合物中的一些对 EV71 表现出优异的抗病毒作用，它们能有效抑制病毒引起的细胞病变效应（CPE），降低病毒产量，并表现出与阳性对照利巴韦林相似或更好的抗病毒活性。在这些衍生物中，WY7、WY13 和 WY14 对 EV71 的抑制活性最强。作用机制的研究表明，这些化合物在感染后靶向 EV71 的细胞复制，能显著抑制病毒 RNA 复制和蛋白合成，并抑制病毒诱导的细胞凋亡。进一步的实验表明，WY7 能有效抑制 EV71 3C 蛋白酶（3Cpro）的活性，在一定程度上影响 3D 聚合酶（3Dpol）的活性，从而阻断病毒复制，但不影响 2A 蛋白酶（2Apro）的活性。3Cpro-WY7 复合物的分子结合建模表明，WY7 化合物被预测插入 EV71 3Cpro 的底物结合口袋，阻止底物识别，从而抑制 EV71 3Cpro 的活性。这些结果表明，这些化合物可能是针对 EV71 感染的可行治疗药物，这些化合物可能为进一步设计和合成潜在的抗病毒药物提供有前景的先导骨架。
