Yan Wenzhong, Qing Jie, Mei Hanbing, Nong Junxiu, Huang Jin, Zhu Jin, Jiang Hualiang, Liu Lei, Zhang Linqi, Li Jian
Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China; School of Medicine, Tsinghua University, Beijing 100084, China.
Bioorg Med Chem Lett. 2015 Dec 15;25(24):5682-6. doi: 10.1016/j.bmcl.2015.11.002. Epub 2015 Nov 2.
In this work, the relationship between cyclophilin A (CypA) and EV71 prompted us to screen a series of small molecular CypA inhibitors which were previously reported by our group. Among them, compounds 1 and 2 were discovered as non-immunosuppressive anti-EV71 agents with an EC50 values of 1.07±0.17μM and 3.36±0.45μM in virus assay, respectively, which were desirably for the further study. The subsequent chemical modifications derived a novel class of molecules, among which compound 11 demonstrated the most potent anti-EV71 activity in virus assay (EC50=0.37±0.17μM), and low cytotoxicity (CC50>25μM). The following CypA enzyme inhibition studies indicated that there was not only the enzyme inhibition activity, undoubtedly important, functioning in the antiviral process, but also some unknown mechanisms worked in combination, and the further study is underway in our laboratory. Nevertheless, to the best of our knowledge, compound 11 was probably the most potent small molecular anti-EV71 agent via CypA inhibitory mechanism to date. Consequently, our study provided a new potential small molecule for curing EV71 infection.
在本研究中，亲环素A（CypA）与肠道病毒71型（EV71）之间的关系促使我们筛选了一系列先前由我们小组报道的小分子CypA抑制剂。其中，化合物1和2被发现为非免疫抑制性抗EV71药物，在病毒试验中的半数有效浓度（EC50）值分别为1.07±0.17μM和3.36±0.45μM，适合进一步研究。随后的化学修饰产生了一类新型分子，其中化合物11在病毒试验中表现出最强的抗EV71活性（EC50 = 0.37±0.17μM），且细胞毒性较低（半数细胞毒性浓度CC50>25μM）。接下来的CypA酶抑制研究表明，在抗病毒过程中不仅存在无疑很重要的酶抑制活性，而且还有一些未知机制共同起作用，我们实验室正在进行进一步研究。然而，据我们所知，化合物11可能是迄今为止通过CypA抑制机制最有效的小分子抗EV71药物。因此，我们的研究为治疗EV71感染提供了一种新的潜在小分子药物。
