Investigation on Small Molecules Targeting Cu(I) Preventing Copper-Mediated Neurotoxicity

doi:10.6023/A14120892

Acta Chim. Sinica ›› 2015, Vol. 73 ›› Issue (8): 799-807.DOI: 10.6023/A14120892 Previous Articles Next Articles

Article

阻断铜离子介导神经毒性的小分子抑制剂研究

赵德胜^a, 陈媚莎^a, 吴为辉^a, 郭莹^a, 陈永湘^a, 赵玉芬^a, 李艳梅^a,b

a 清华大学化学系生命有机磷化学及化学生物学教育部重点实验室北京 100084;
b 北京脑重大疾病研究院帕金森病研究所北京 100069

投稿日期:2015-04-16 发布日期:2015-05-13
通讯作者: 李艳梅, 陈永湘 E-mail:liym@tsinghua.edu.cn;chen-yx@mail.tsinghua.edu.cn
基金资助:
项目受国家重点基础研究发展计划(973项目)(Nos. 2013CB910700和2012CB821600)和国家自然科学基金(Nos. 21472109和21261130090)资助.

Investigation on Small Molecules Targeting Cu(I) Preventing Copper-Mediated Neurotoxicity

Zhao Desheng^a, Chen Meisha^a, Wu Weihui^a, Guo Ying^a, Chen Yongxiang^a, Zhao Yufen^a, Li Yanmei^a,b

a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084;
b China Beijing Institute for Brain Disorders Center of Parkinson's Disease, Beijing 100069

Received:2015-04-16 Published:2015-05-13
Supported by:
Project supported by the National Basic Research Program of China (973 program) (Nos. 2013CB910700 and 2012CB821600) and the National Natural Science Foundation of China (Nos. 21472109 and 21261130090).

1. Investigation on Small Molecules Targeting Cu(I) Preventing Copper-Mediated Neurotoxicity.PDF(4920KB)

Abstract

In this work, we designed small molecules YG-1 and YG-2 derived from molecule Thioflavin-T (ThT) containing structural moieties targeting Cu(I). To realize the purpose of Cu(I) binding, we eliminate the methyl group of ThT molecule and incorporate a nitrogen atom instead of sulfur atom. The imine in benzimidole is expected to coordinate Cu(I) effectively. This strategy is aiming at inhibiting the toxicity redox cycle and protecting cells. Using UV absorption spectroscopy, we find that YG-1 can interact with Cu(I) effectively, but not with Cu(II). ESI-MS further characterized the interactions between YG-1/2 and Cu(I) in forms of YG-1/2-Cu(I)-YG-1/2 and YG-1/2-Cu(I)-YG-1/2-Cu(I)-YG-1/2. Focusing on the peaks of complexes observed from the ESI-MS results, we calculate the binding motifs of Cu(I) to YG-1/2 by MD simulation. In particular, we study all the five possible symmetric modes of YG-1 and YG-2 respectively, which are supposed to be more stable than asymmetric modes. The simulation results show that the mode with Cu(I) binding to the imine in benzimidole of YG-1/2 in a linear geometry is the most stable structure with the lowest energy (-0.229 and -0.232 Hartree for YG-1 and YG-2 respectively). As reducing the production of ROS is an important pathway to alleviate the copper-induced Aβ1-40 cytotoxicity, we test the effects of YG-1/2 on eliminating ROS production using 3-coumarin carboxylic acid (3-CCA) fluorescence spectroscopy, and find that YG-1/2 can block ROS production almost completely. Finally, we examine the cellular protective effects of YG-1 and YG-2 against the toxicity of Aβ1-40-Cu(I) by 3-(4,5-dimethyl-2-thiaz-oyl)-2,5-diphenyl-tetrazolium bromide(MTT) assay. Experimental results show that YG-1/2 can alleviate the Cu(I)-induced Aβ1-40 toxicity and increase cell viability. Up until now, researchers have devoted many efforts to prevent copper-mediated ROS toxicity. However, few attempts have been made to treat protein-misfolding diseases by targeting Cu(I) and blocking the copper redox cycle. The designed molecules YG-1/2 in this work are able to capture Cu(I) from participating further reactions in the protein-copper redox cycle and prohibit the generation of ROS. This finding may lead to a new therapeutic strategy for treating copper-mediated protein misfolding diseases.

Key words: Cu(I), β-amyloid, small molecule, reactive oxygen species, neurotoxicity

Cite this article

Zhao Desheng, Chen Meisha, Wu Weihui, Guo Ying, Chen Yongxiang, Zhao Yufen, Li Yanmei. Investigation on Small Molecules Targeting Cu(I) Preventing Copper-Mediated Neurotoxicity[J]. Acta Chim. Sinica, 2015, 73(8): 799-807.

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阻断铜离子介导神经毒性的小分子抑制剂研究

Investigation on Small Molecules Targeting Cu(I) Preventing Copper-Mediated Neurotoxicity

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