多功能金属螯合剂的设计及其治疗阿尔茨海默病的分子机制

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that badly affects the life of senior citizens. Existing drugs can only alleviate the symptoms, but cannot terminate the pathogenic processes of the disease. Therefore, further development of anti-AD drugs has great practical significance. The pathological hallmark of AD is the aggregation of amyloid β-peptides (Aβ) in the hippocampus area of the cortex in the brain. Thus, the inhibition of Aβ aggregation is crucial to the therapy of AD. The increase in the content of zinc and copper ions in the brain plays a major role in the pathogenesis of AD. These ions not only induce the Aβ aggregation, but also elicit the production of hydroxyl free radicals, causing oxidative damage to brain tissues. The main metal binding sites locate at His-6, -13, -14 and Met-35 amino acid residues in Aβ. Acetylcholinesterase is the enzyme responsible for hydrolyzing the neurotransmitter acetylcholine, thereby facilitating the termination of impulse transmission and leading to cognitive dysfunction. Consequently, the inhibitor of this enzyme can improve the cognitive function of AD patients. In this project, we will design and construct a series of multifunctional metal chelators. At least two functional units are included in these chelators: a macrocyclic amine responsible for zinc- or copper-chelating, and a lipophilic platinum or palladium complex with planar aromatic ligand responsible for specific His- and Met-binding. Two moieties are connected by an appropriate linker to form a multifunctional molecular unity. Such chelators are supposed to possess simultaneously the properties of metal chelators, Aβ function modulators, enzyme inhibitors, and so on, and can be a class of potential multi-target-directed anti-AD agents.

阿尔茨海默病（AD）严重影响老年人的生活质量，现有药物只能缓解症状不能终止病程，所以研制抗AD药物具有重大的现实意义。大脑皮层和海马区神经细胞外β-淀粉样蛋白（Aβ）聚集是AD的病理特征，因此抑制Aβ聚集是治疗AD的关键。大脑内锌、铜离子含量升高是诱发AD的主要因素之一，它们不仅诱导Aβ聚集，还与之结合诱导产生羟基自由基，对脑组织造成氧化损伤。His-6、-13、-14和Met-35是Aβ结合金属离子的主要位点。乙酰胆碱酯酶能水解神经递质乙酰胆碱，终止冲动传递，导致认知功能障碍，因此抑制其活性亦可改善认知功能。本项目拟设计合成一类多功能螯合剂，其中一个功能单元是螯合锌、铜离子的大环多胺，另一个功能单元是对His和Met残基有特异性结合能力的脂溶性平面芳香铂、钯配合物，两者通过连接体相联形成复合多功能分子，它们同时具备金属螯合剂、Aβ性能调控剂和酶抑制剂等性质，是一类潜在的多靶点AD治疗剂。

阿尔茨海默病（AD）严重影响老年人的生活质量，现有药物只能缓解症状不能终止病程，所以研制抗 AD 药物具有重大的现实意义。大脑皮层和海马区神经细胞外β-淀粉样蛋白（Aβ）聚集是 AD 的病理特征，因此抑制 Aβ聚集是治疗 AD 的关键。大脑内锌、铜离子含量升高是诱发 AD 的主要因素之一，它们不仅诱导 Aβ聚集，还与之结合诱导产生羟基自由基，对脑组织造成氧化损伤。本项目设计合成了一类多功能荧光螯合剂来特异性靶向与金属相关的Aβ聚集体和捕获金属离子以及时检测Aβ斑块并促使其解聚。该类化合物同时具备金属螯合剂、Aβ性能调控剂和Aβ斑检测剂的性质，可以抑制金属离子诱导或自发的Aβ聚集，并通过荧光变化对AD小鼠脑匀浆进行同步实时监测，是一类潜在的多靶点AD治疗诊断剂。此外，本项目还设计合成了一类多金属氧酸盐，得到了新颖的Aβ构象调节剂，为治疗包括AD在内的蛋白错误折叠疾病开辟了新思路。

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