新型抗阿尔茨海默病的多靶向配体的设计、合成和生物活性研究

项目名称： 新型抗阿尔茨海默病的多靶向配体的设计、合成和生物活性研究

项目编号： No.21202098

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 有机化学

项目作者： 郑伟

作者单位： 上海市计划生育科学研究所

项目金额： 25万元

中文摘要： 由于阿尔茨海默病(AD)的多因子发病机制，多靶向配体（MTDLs）成为最有前景的AD治疗药物研究领域。Aβ异常聚集和氧化应激是AD 的两个关键病理标志，它们相互影响与促进, 是产生一系列神经毒性作用的根本原因。本项目我们以自主开发的ZQ309为先导物展开，主要内容包括（1）以AD最核心的病理因子为靶标，设计新型MTDLs；（2）经分子对接和ADME/T预测虚拟筛选，选择预测活性高、类药的新化合物进行合成和生物活性测试，包括抗Aβ聚集、AChE酶动力学、抗氧化等；（3）利用高内涵细胞分析、行为学检测和mAPPTg转基因小鼠模型对最优的侯选药物进行整体评价。通过本研究有望获得具有AChE抑制、抗Aβ聚集、抗氧化和神经保护多重作用的MTDLs类候选药物，多靶点调控AD病程；并有助于进一步阐明AChE、Aβ聚集沉积和氧化应激的互作机制，为此类药物研发提供新的化学线索。

中文关键词： 阿尔茨海默病；多靶向配体；分子对接；抗氧化；Aβ聚集

英文摘要： The multifactorial pathogenesis of Alzheimer's disease (AD) strongly suggests that the strategy of multi-target-directed ligands may represent a promising direction for the treatment of AD. Aβ aggregation and oxidative stress are prominent neuropathological hallmarks of AD, which promoted and interacted with each other, playing crucial roles in the neurotoxic cascade . In this project, starting with lead compound ZQ309, we designed novel MTDLs capable of hitting crucial pathogenesis, and virtual screened these new compounds through molecular docking and ADME/T properties prediction. Then, promising compounds are chosen for synthesis and pharmacological studies, including Aβ aggregation inhibition, AChE inhibition and antioxidative activity. We will evaluate the potent drug candidates using high content screening (HCS ) assay, behavioral test and mAPPTg transgenic mouse model. The aim of this project is to achieve MTDLs with AChE inhibition activity, anti-Aβ aggregation, and antioxidative activity, as drug candidates for AD therapy, and further elucidate the interaction mechanism of AChE or oxidative stress with Aβ aggregation and deposition, providing new theory basis and chemical cues for drug development.

英文关键词： Alzheimer's disease；multi-target-directed ligands；molecular docking；antioxidants；Aβ aggregation