茶多酚功能化柱芳烃超分子自组装体的构建及其对β-淀粉样蛋白纤维化的抑制作用

阿尔兹海默症（AD）是一种严重危害人类健康的疾病。大脑中β-淀粉样蛋白（Aβ）的错误折叠而致的纤维化与AD直接相关，因而抑制Aβ纤维化是治疗AD的一种方法。研究表明葫芦脲等大环超分子以及茶多酚均具有抑制Aβ纤维化的能力。与传统的大环超分子相比，柱芳烃彰显了许多性能上的优点，而且它可以在水溶液中形成自组装体有利于进入细胞。然而，柱芳烃及其自组装体对Aβ纤维化抑制的研究还未见报道。我们前期成功合成柱[5]芳烃，并发现其对Aβ纤维化的抑制能力是葫芦脲7的约500倍。为此，本项目拟合成茶多酚功能化的两亲性柱[5]芳烃并制备其自组装体，研究其在体外和细胞内对Aβ纤维化的抑制作用，考察茶多酚和柱芳烃对蛋白纤维化的双重抑制作用。同时，结合主客体分子模拟研究，揭示自组装体对蛋白纤维化的抑制机理。研究结果为Aβ纤维化高效抑制剂的研发提供理论依据，为AD药物的研发提供新思路。同时可拓宽柱芳烃在生物领域的应用。

Alzheimer disease (AD) is a kind of disease that seriously affects human health. The misfolding of the beta-amyloid protein (Aβ) could result in the fibrillation, which is considered to be directly correlated to AD. Therefore, inhibition of the fibrillation of Aβ is considered to be one of the useful herapeutic methods for AD. It has been indicated that macrocyclic supramolecules (e.g. cucurbituril) and tea polyphenol both have the ability of inhibiting the formation of beta-amyloid protein fibrillation. Comparing with the typical macrocyclic supramolecules, pillararene has some merits. Furthermore, pillararene has the potential to form supramolecular self-assemblies, which may easily enter into cell. However, the inhibition ability of the fibrillation by pillararene or pillararene-based self-assembly has not been reported. In our preparatory experiment, we successfully synthesized pilla[5]rarene and found that the Aβ(1-40) fibrillation inhibition ability of pilla[5]rarene was appropriately 500 folds higher than that of cucur[7]bituril. Therefore, in the present project, we will propose to synthesize the tea polyphenol (EGCG)-functionalized amphipathic pilla[5]rarene (EGCG-AP5) and prepare EGCG-AP5 self-assembly, then investigate the inhibition ability of the fibrillation by EGCG-AP5 self-assembly using Aβ(1-40) and Aβ(1-42) as model amyloid proteins. Furthermore, we will reveal the inhibition mechanism of fibrillation by EGCG-AP5 self-assembly by using the results of host-guest molecular docking. The constructed self-assembly is expected to play double roles of EGCG and pillararene in inhibiting fibrillation of beta-amyloid protein by EGCG-AP5. The results will provide new thoughts and theoretical foundation for the research and development of efficient fibrillation inhibitor. Furthermore, the results may also provide helpful insights into prevention and treatment of AD, which may broaden the applications of pillararene in the biological field.