抑制剂作用的人胰岛淀粉样肽热力学性质与聚集机制探究

项目名称： 抑制剂作用的人胰岛淀粉样肽热力学性质与聚集机制探究

项目编号： No.21473251

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 数理科学和化学

项目作者： 杜为红

作者单位： 中国人民大学

项目金额： 86万元

中文摘要： II型糖尿病是严重威胁人类健康的一种疾病，人胰岛淀粉样多肽(hIAPP)通过二级结构改变产生β-折叠构象并进一步聚集纤维化，导致细胞膜破损、细胞膜通透性增大与氧化压力，以及胰岛β细胞功能丧失，是II型糖尿病重要的致病因素，因而抑制hIAPP聚集对II型糖尿病的治疗意义重大。金属钌和钒的配合物因其较低的细胞毒性已被用作潜在的抗癌及降糖药物，但它们对淀粉样多肽的聚集抑制鲜有报道。本课题组拟通过差示扫描量热、荧光光谱、电喷雾质谱、等温滴定量热法、细胞毒性检测等手段研究不同构型钌、钒金属配合物与hIAPP相互作用的热力学性质，揭示金属配合物与hIAPP的结合亲和性与结合方式，探索不同构型配体对hIAPP自身聚集热稳定性及动力学行为的影响，形成对hIAPP金属抑制剂结构功能关系的规律性认识，阐明金属配合物对多肽聚集纤维化的抑制机理，研究工作对设计和发展针对II型糖尿病的潜在金属药物具有重要意义。

中文关键词： 人胰岛淀粉样肽；热力学性质；抑制剂；相互作用；聚集体

英文摘要： Type II diabetes is a kind of disease which seriously threaten human being's health. Human islet amyloid polypetide(hIAPP) may transfer its conformation from normal secondary structure to an abnormal β-sheet component, and induce the peptide to selfaggregate and further fibrillate. It results in the damage of cell membrane, the increasing of membrance permeability and oxidative stress, and the dysfunction of islet β-cell which is a crucial factor in the pathogenic mechanism of type II diabets. Therefore, inhibiting the aggregation of hIAPP is of great value to treat this kind of disease. Metal complexes based on ruthenium and vanadium cations are widely used as potential antiancer and antidiabetic drugs due to their lower cytotoxicity. However, those compounds are rarely reported to inhibit the aggregation of hIAPP. In this project, we'd like to investigate the thermodynamic properties of the interactions between hIAPP and metal complexes base on ruthenium and vanadium cations, by different biophysical methods such as differencial scanning calorimetry, fluorescence spectroscopy, ESI-MS, isothermal titration calorimetry and detection of related cytotoxicity. The studies will explain the different binding affinity and binding mode between them, explore the effects of various ligands on the thermal stability and selfaggregation kinetics of hIAPP, and reveal the rules of metal inhibitors in their structure-activity relationship. It may also indicate the inhibition mechanism of metal complexes on peptide fibrillation. The work will be significant for designing and developing potential metallodrugs against type II diabetes.

英文关键词： Human islet amyloid polypeptide;thermodynamic property;inhibitors;interaction;aggregation