药学学报, 2021, 56(4): 1063-1069
引用本文:
陈贝贝, 蒋露莹, 郭芳妍, 屈莉莉, 汪文倩, 金成华, 刘夫锋. 托卡朋衍生物PCDNA抑制Aβ42纤维化并降低其细胞毒性[J]. 药学学报, 2021, 56(4): 1063-1069.
CHEN Bei-bei, JIANG Lu-ying, GUO Fang-yan, QU Li-li, WANG Wen-qian, JIN Cheng-hua, LIU Fu-feng. Tolcapone derivative PCDNA inhibits Aβ42 fibrillogenesis and reduces its cytotoxicity[J]. Acta Pharmaceutica Sinica, 2021, 56(4): 1063-1069.

托卡朋衍生物PCDNA抑制Aβ42纤维化并降低其细胞毒性
陈贝贝1, 蒋露莹1, 郭芳妍2, 屈莉莉1, 汪文倩1, 金成华2*, 刘夫锋1*
1. 天津科技大学生物工程学院, 天津 300457;
2. 延边大学药学院, 吉林 延吉 133002
摘要:
淀粉样β蛋白(amyloid-β protein,Aβ)在脑内的异常聚集是诱发阿尔茨海默症(Alzheimer's disease,AD)的重要原因,因此开发抑制Aβ聚集的药物是治疗AD的重要手段之一。前期研究发现托卡朋能抑制Aβ42聚集并降低Aβ42聚集物诱导的细胞毒性,但临床研究发现托卡朋有很强的肝毒性。为了降低托卡朋的肝毒性,对其侧链结构进行改造并获得其衍生物苯乙基(E)-2-氰基-3-(3,4二羟基-5-硝基苯)-丙烯酸酯(PCDNA)。通过硫磺素T(thioflavin T,ThT)和原子力显微镜(atomic force microscopy,AFM)实验研究了PCDNA对Aβ42纤维化的抑制作用;通过细胞毒性实验研究了PCDNA对Aβ42聚集物诱导的细胞毒性作用;并研究了PCDNA对成熟Aβ42纤维的解聚作用。最后,通过分子对接实验研究了PCDNA与Aβ42五聚体之间的相互作用。这些实验结果为研究托卡朋结构类似物作为Aβ抑制剂奠定了基础。
关键词:    阿尔茨海默症      淀粉样β蛋白      抑制剂      托卡朋衍生物      纤维化      分子对接     
Tolcapone derivative PCDNA inhibits Aβ42 fibrillogenesis and reduces its cytotoxicity
CHEN Bei-bei1, JIANG Lu-ying1, GUO Fang-yan2, QU Li-li1, WANG Wen-qian1, JIN Cheng-hua2*, LIU Fu-feng1*
1. College of Biotechnology, Tianjin University of Science and Technology, Tianjin 300457, China;
2. College of Pharmacy, Yanbian University, Yanji 133002, China
Abstract:
Abnormal aggregation of amyloid-β protein (Aβ) in brain plays a vital role in the occurrence of Alzheimer's disease (AD). Hence, inhibiting Aβ aggregation is one major tactic for therapy of AD. Previous studies have found that tolcapone can inhibit Aβ42 aggregation and reduce the cytotoxicity induced by Aβ42 aggregates, but clinical studies have found that tolcapone has strong liver toxicity. To reduce the liver toxicity of tolcapone, its side chain structure was modified to obtain its derivative phenethyl (E)-2-cyano-3-(3,4 dihydroxy-5-nitrobenzene)-acrylate (PCDNA). Thioflavin T (ThT) and atomic force microscopy (AFM) assays were used to explore the inhibitory effect of PCDNA on Aβ42 fibrillogenesis. The cytotoxicity assays were used to explore the inhibitory effect of PCDNA against the cytotoxicity induced by Aβ42 aggregates. In addition, the depolymerization effect of PCDNA on mature Aβ42 fibrils was also explored. Finally, molecular docking was used to explore the interaction between PCDNA and Aβ42 pentamer. These results lay the foundation for the study of the structural analogues of tolcapone as Aβ inhibitors.
Key words:    Alzheimer's disease    amyloid-β protein    inhibitor    tolcapone derivative    fibrillogenesis    molecular docking   
收稿日期: 2020-12-03
DOI: 10.16438/j.0513-4870.2020-1853
基金项目: 国家自然科学基金资助项目(21878234,81560557);天津市自然科学基金资助项目(18JCZDJC33000).
通讯作者: 刘夫锋,Tel:86-22-60602717,E-mail:fufengliu@tust.edu.cn;金成华,Tel:86-433-2436942,E-mail:jinchenghua@ybu.edu.cn
Email: fufengliu@tust.edu.cn;jinchenghua@ybu.edu.cn
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