基于聚金属氧酸盐对Amyloid蛋白的定点化学修饰及其在阿尔茨海默症治疗中的应用

阿尔茨海默症（AD）是现代社会中人类健康的第四大杀手。过量β-淀粉样蛋白Amyloid (Aβ)的产生和聚集在发病过程中起着核心作用。尽管目前已报道了大量的抑制剂用于抑制Aβ的聚集，但是抑制剂只能改变未聚集与聚集蛋白之间的比例，不能从根本上减少病变蛋白的总量。而在生物体内，蛋白质的功能可以通过翻译后修饰（PTM）迅速改变。与使用抑制剂相比，PTM可以在不改变氨基酸序列的情况下影响蛋白质的聚集。受此启发，如果可以将Aβ靶向抑制剂利用特定的化学方法定点修饰在Aβ蛋白指定氨基酸上，模拟蛋白的翻译后修饰，那么就可以实现对Aβ蛋白聚集的有效抑制。基于此，本项目拟利用Aβ抑制剂，聚金属氧酸盐（POMs），在保持POMs原有的优异性基础上，改造其结构，理性设计、合成系列对Aβ蛋白具有特定氨基酸位点修饰功能的新型AD治疗试剂，为有效抑制Aβ蛋白聚集提供新途径。

Alzheimer’s disease (AD) is the most common form of dementia, which affects more than 24 million people worldwide. Although the molecular mechanisms of AD pathogenesis are not clearly understood owing to its complexity, recent advances have demonstrated that the polymerization of amyloid β-peptides (Aβ) into amyloid fibrils is crucial. As a therapeutic strategy to alleviate Aβ-induced neurotoxicity, the first step was to decrease the amount of Aβ assembly in the brain. One way to decrease the amount of Aβ assembly is by Aβ inhibitors. However, the use of inhibitors is just a “passive treatment”, which can just change the ratio between Aβ monomers and Aβ aggregates, not decrease the amount of total Aβ. When Aβ is over expressed in AD patients, the requirement of inhibitor is increasing consecutively, which may cause other unpredictable symptoms. In organisms, the functions of proteins can be changed rapidly through posttranslational modification (PTM), which has unique advantages in the field of disease treatment. Comparing to the use of inhibitors, changing PTM can quickly shut down the pathogenic function of proteins without changing the amino acids sequences. Inspired by the natural PTM, the widely reported Aβ inhibitor, polyoxometalates (POMs), will be taken as the research object. On the basis of maintaining the original excellent properties of POMs, we will rationally design and synthesize a series of Aβ specific "chemical post translation modifiers", which will hopefully obtain better therapeutic effect of AD. At the same time, it also provides a new way for the research of using inorganic compounds to regulate the function of biomolecules.