淀粉样疾病是由蛋白错误折叠发生聚集引起，抑制蛋白毒性聚集是防治该类疾病的难题和关键。申请人前期发现咖啡酸等小分子能抑制淀粉样蛋白毒性聚集，但特异性不足、对多种蛋白折叠均有作用，影响蛋白正常功能。研究表明源自蛋白聚集核心区域的六肽是能特异性结合母肽的最短多肽，所以本课题将针对小分子抑制剂特异性的不足，以帕金森病为模型，其淀粉样蛋白alpha-synuclein为研究对象，通过AGGRESCAN、TANGO和REMD 方法从synuclein聚集核心区域筛高特异性六肽；利用end capping、特殊氨基酸反应等方法，将咖啡酸及其类似物分别与筛选出的六肽连接，形成新的六肽-小分子缀合物。结合体外、细胞和线虫模型实验，研究缀合物对synuclein聚集的特异性、抑制性及机制，并比较缀合物之间i的作用差异，确定最优六肽及咖啡酸的构效关系，为特异性聚集抑制剂作为防治淀粉样疾病药物提供新思路和基础。

Amyloid diseases is a series diseases which caused by proteins misfolding. Inhibiting the aggregation of amyloidogenic proteins is regarding as an effective therapy for amyloid diseases. Our previous results have shown a series small compounds as caffeic acid can inhibit the toxic aggregation of amyloidgenic proteins, but with poor specificity which can also affect parts of natural proteins. Hexapeptide derived from the hot domain of amyloidogenic proteins has shown specificity and is the minimum peptide which has specificity. Thus, in order to solve the lack specificity of small molecular inhibitors, this program plans to design series of hexapeptide from alpha-synuclein, which is an amyloidogenic protein in Parkinson’s diseases through the Aggrescan、TANGO Program and REMD molecular dynamics. By using end capping synthesis methods, we plan to connect caffeic acid and its analogues with designed hexapeptide together to form new conjugates. Combining biophysics、molecular biology methods and C. elegans model, we will study the specificity and inhibitory effect of new conjugates for the toxicity aggregation of alpha-synuclein, and compared the effect of caffeic acid and its analogues to confirm the structure activity relationship of caffeic acid and it analogues, which to gather new evidence for the research on anti-amyloid drugs.