阿尔兹海默症（AD）严重影响人类生命健康，至今仍无有效临床治疗药物。β-淀粉样蛋白（Aβ）是引发AD的重要因子，主流针对其中部或C端的聚集抑制策略存在不足，至今未有突破。如何有效阻断Aβ病理功能，急需创新的药物设计思维。高度柔性的AβN端与多种AD病理过程密切相关，屏蔽其病理功能可产生多重抗AD药理效应，但如何实现对其特异性捕获仍然是尚未解决的科学难点。本课题首次提出基于“主－客”体作用模式的分子设计策略，已在天然环肽结构基础上，设计、发现了能特异性捕获AβN端的先导分子，并证实了其具有同时抑制Aβ早期聚集、解聚Aβ聚集体、降低Aβ毒性以及清除模型鼠脑部Aβ斑块等功能。进一步研究将从先导分子的关键基团、环结构、以及拟肽化改造等多方面入手，对其进行结构优化；系统研究优先分子对AβN端病理功能的影响，解析其作用的分子机制与构效关系；为研发基于AβN端功能调控创新机制的抗AD药物提供重要基础。

Alzheimer's disease (AD) is a progressive neurodegenerative disease contributing to the serious deterioration of human health, and there is no efficient clinical drug available so far. Amyloid-β (Aβ) species contributed the main cause of AD pathogenesis though most of the clinical trial targeting Aβ failed in recent years. Hydrophobic central or C - terminus targeted drug design remain deficient and novel strategies of blocking the Aβ pathological function is urgently needed. The hydrophilic amyloid-β (Aβ) N-terminus is deeply involved in AD pathogenesis，masking the N-terminus will generate multiple positive pharmacological effects. Unfortunately, the flexibility of N-terminus render it hardly to be targeted, and how to capture the N-terminus of Aβ remains a key scientific concerns. In this project, we raised a strategy based on a "Host-Guest" capturing manner, and in preliminary work, designed and discovered active cyclopeptides which are capable of blocking N-terminus, inhibiting the early oligomerization of monomeric Aβ, reversing the preformed fibrillar Aβ to monomer, dissolving the plaque and sequentially decreasing the toxicity of Aβ. Further works will focus on the structure optimization of the lead cyclopeptide via ring/residue improvement and peptide-mimics based modification, and evaluation of the effects of lead cyclopeptide on the pathological functions of Aβ to illustrate the molecular mechanism. This project will offer a key basis for the novel drug design based on the regulation of N-terminus of Aβ, for AD therapy.