Identification, synthesis and pharmacological evaluation of novel anti-EV71 agents via cyclophilin A inhibition

Bioorg Med Chem Lett. 2015 Dec 15;25(24):5682-6. doi: 10.1016/j.bmcl.2015.11.002.

Wenzhong Yan ¹, Jie Qing ², Hanbing Mei ¹, Junxiu Nong ³, Jin Huang ¹, Jin Zhu ¹, Hualiang Jiang ¹, Lei Liu ⁴, Linqi Zhang ⁵, Jian Li ⁶

Affiliations

1 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
2 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.
3 School of Medicine, Tsinghua University, Beijing 100084, China.
4 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. Electronic address: lliu@mail.tsinghua.edu.cn.
5 School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: zhanglinqi@biomed.tsinghua.edu.cn.
6 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. Electronic address: jianli@ecust.edu.cn.

PMID: 26564266 DOI: 10.1016/j.bmcl.2015.11.002

Abstract

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.

Keywords

Cyclophilin A; EV71; HFMD; Small molecule inhibitor.

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