肝素寡糖抑制Aβ淀粉样蛋白细胞毒性的构效关系研究

项目名称： 肝素寡糖抑制Aβ淀粉样蛋白细胞毒性的构效关系研究

项目编号： No.21302113

项目类型： 青年科学基金项目

立项/批准年度： 2014

项目学科： 数理科学和化学

项目作者： 靳岚

作者单位： 山东大学

项目金额： 25万元

中文摘要： 本项目拟以肝素酶I酶解所得的肝素四糖、六糖、八糖、十糖和Aβ40为研究对象，通过MTT法检测肝素寡糖影响体外神经细胞存活率来表明肝素寡糖可以抑制Aβ40的细胞毒性，通过预保护和损伤修复模型验证肝素寡糖对神经细胞具有保护作用。利用液相NMR技术结合分子对接计算的方法，研究肝素寡糖与Aβ40间的相互作用，辅助ITC技术获得热力学参数，从分子水平上确定肝素寡糖与Aβ40相互作用的差异性，进而确定其细微结构的构效关系，明确其与Aβ40结合所必须的最小活性结构的独特性，为将明确活性中心的肝素寡糖作为有效治疗AD的药物提供良好的理论基础。

中文关键词： β淀粉样蛋白；肝素寡糖；氢氘交换质谱；核磁共振波谱；构效关系

英文摘要： Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in elderly people. Pathological researches indicate that the mechanism is associated with the prodcution and misfolding of β-amyloid peptide (Aβ). Low molecular weight heparin can inhibit Aβ's misorientation through binding to Aβ. The shortest effective binding fragment is tetrasaccharides (dp4s). Heparin can bind to more than 100 different kinds of proteins and exhibit different bioactivities. This is due to its structural complexity including different monosaccharide components, degree of polymorization, sulfation degrees and different subsituents and so on. Therefore, study of the relationship between structure and activity of heparin is important for heparin's usage in medicine. This project is planned to study the interactions between heparin dp4s and Aβ mainly using NMR and docking techniques. ITC will also be used for the collection of thermodynamic parameters to give quantitative results. Difference of binding effects of the three dp4s will be compared to show the structre and activity relationship. The effective binding domain will be determined.

英文关键词： β-amyloid peptide；heparin oligosaccharide；hydrogen-deuterium exchange MS；NMR；structure-activity relationship