阿尔茨海默病是当今威胁老年人群健康的社会性热点问题之一，其发病的一个重要机制是神经元内Tau蛋白自聚集形成神经纤维性缠结。设计构建Tau蛋白聚集高效抑制剂，是寻找先导化合物、研发药物的关键。本课题基于先期Tau聚集分子机制研究成果，提出双端识别、发卡型对接的抑制剂分子设计策略。不同于文献报道的单端识别（只有1个生物效应团）小分子抑制剂，只对Tau蛋白肽链上1个位置识别结合，本课题设计构建的双端识别（含2个生物效应团）抑制剂能同时在肽链上2个位置识别结合，能与肽链形成发卡结构，通过抑制剂分子夹住Tau蛋白肽链，限制其折叠、盘绕、靠近堆积的自由度，加强其结合力，提高其选择性，达到高效抑制Tau聚集的目的。利用电镜、荧光探针等实验方法观察抑制效果，结合分子对接等计算机辅助手段，通过化学合成、天然分子的筛选、改造，获得更为高效的Tau蛋白自聚集抑制剂，为阿尔茨海默病药物的研发提供先导物和理论依据。

Alzheimer's disease is a major threats on the health of aging population, and becomes a hot social issues today. One of the important pathological mechanism of this disease is the abnormal aggregation of Tau protein within neurons, to deposite as neuro-fibrillary tangles. Therefore, design of Tau protein aggregation inhibitors, is the key step for searching lead compounds, and developing AD drugs. This project is based on the early research progress on aggregation mechanism of Tau protein; A strategy for the design of two-side recognition, hairpin type inhibitor on Tau aggregation has been suggested. Different from the single-side recognition inhibitors reported earlier (only one biophore within one inhibitor molecule), which can bind to Tau peptide chain only at one site, the two-side recognition inhibitors (two biophores within one inhibitor molecule ) in this research, can bind to Tau peptide chain at two-sites, forming a hairpin-like structure. By Cliping peptide chain, the inhibitor molecules eliminate the freedom of folding, coiling, approaching and accumulating of Tau protein, strengthen its binding force, improve its selectivity, and achieve the goal of effective inhibition of Tau aggregation. The inhibitory effect will be investigated by electron microscope, fluorescent probe, combined with computer methods such as molecular docking and simulation. By screening natural organic molecules, together with chemical synthesis of new compounds, more inhibitors with higher efficiency and specificity on Tau aggregation should be obtained. The new type inhibitors will provide lead compounds and theoretical preparation for drug development of Alzheimer's disease.