Dynamic-Inspired Perspective on the Molecular Inhibitor of Tau Aggregation by Glucose Gallates Based on Human Neurons
Dynamic-Inspired Perspective on the Molecular Inhibitor of Tau Aggregation by Glucose Gallates Based on Human Neurons
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基于人类神经元的葡萄糖没食子酸盐 Tau 聚集分子抑制剂的动态启发视角
DOI：
10.1021/acschemneuro.1c00554
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发表时间：
2021-10-15
影响因子：
5
通讯作者：
Yao, Tianming
中科院分区：
文献类型：
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作者：
Hu, Yuan;Yang, Danjing;Yao, Tianming
tau蛋白聚集的分子抑制剂为阿尔茨海默病的疾病修饰治疗提供了有吸引力的治疗可能性。然而，由于对抑制机制的认识不够深入，导致药物的无效和伴随毒性，阻碍了药物的开发。筛选药物配体的传统方法依赖于与蛋白质受体明确结构的兼容对接。因此，tau蛋白的非结构化、高度动态特性不可避免地阻碍了tau聚集抑制剂的设计。本文提出了一种通过动态构象异构化过程减少tau聚集的新策略。选择一组没食子酸葡萄糖衍生物作为tau聚集抑制剂。这些星形分子具有生物相容性的葡萄糖核心，周围环绕着几个没食子酸多酚臂，可以通过氢键和p-p堆叠在不同的位点与肽链结合。从理论上讲，没食子葡萄糖酸酯通过提高蛋白质势能面（PES）的鞍点，即肽异构化动态通路中的屏障，通过动态机制有效抑制tau聚集。构建了基于人类神经元的tau细胞模型。我们首次证实了分子配体与tau肽链的适度热力学结合不仅可以防止肽链异构化导致聚集，还可以避免因tau与微管解离而产生的毒性。
A molecular inhibitor of tau protein aggregation offers an attractive therapeutic possibility as disease-modifying treatment of Alzheimer's disease. However, the ineffectiveness as well as adjoint toxicity due to superficial understanding of the inhibition mechanism has hindered drug development. Conventional approaches for screening drug ligands rely on compatible docking with the well-defined structure of a protein receptor. Therefore, the design of tau aggregation inhibitors has been inevitably hindered by the unstructured, highly dynamic nature of the tau protein. This paper suggested a new strategy for reducing tau aggregation through a dynamic process of conformational isomerization. A group of glucose gallate derivatives were selected as tau aggregation inhibitors. These star-shaped molecules have a biocompatible glucose core surrounded by several gallic acid polyphenol arms, which can bind to peptide chains at different sites, probably through hydrogen bonds and p-p stacking. Theoretically, by elevating the saddle point on the potential energy surfaces (PES) of proteins, the barrier in the dynamic pathway of peptide isomerization, glucose gallates effectively inhibit tau aggregation through a dynamic mechanism. A tau cell model based on human neurons was constructed. For the first time, we confirmed that the moderate thermodynamic binding of the molecular ligand to the tau peptide chain can not only prevent the isomerization of the peptide chain leading to aggregation but also avoid toxicity resulting from the dissociation of tau from microtubules.