水溶性金属卟啉拮抗hIAPP毒性的机理及构效关系研究

人胰岛淀粉样蛋白(hIAPP)聚集和氧化/硝化应激，是2型糖尿病(T2D)的重要病理特征。抑制聚集和减少氧化/硝化应激药物能够防治T2D。最近我们发现铁卟啉可以有效抑制hIAPP的聚集，但因其具有细胞毒性而无法用于治疗T2D。一些水溶性金属卟啉可以安全用于动物体内的过氧亚硝酸根(ONOO-)清除，能够减轻体内氧化/硝化应激。我们推测这些水溶性金属卟啉可以作为具有抑制hIAPP聚集和清除ONOO-的双功能药物。本项目拟选择不同衍生基团和不同金属中心的水溶性金属卟啉，通过多种现代分析测试手段，研究不同的衍生基团和不同的金属中心对金属卟啉抑制hIAPP聚集能力和抑制hIAPP损伤生物膜的能力差异，然后在胰岛β细胞上研究并验证这些金属卟啉是否具有抑制外源性和内源性hIAPP导致的细胞功能丧失和死亡。本研究可阐明金属卟啉抑制hIAPP聚集和细胞毒性的构效关系，为寻找新的防治T2D的药物提供科学依据。

Human islet amyloid polypeptide (hIAPP) aggregation and oxidative stress, as well as nitrative stress, are important pathology features of type 2 diabetes (T2D), and anti-aggregation compounds are thought to be beneficial to inhibit T2D. Recently we found that iron porphyrin inhibited hIAPP aggregation effectively, but iron porphyrin is toxic to islet -cells. Some metal porphyrin water-soluble derivatives, which had been found to be active peroxynitrite (ONOO-) decomposers, had been safely used as ONOO- scavengers in vivo. Considering the similar structure with iron porphyrin, we hypothesis that these metal porphyrin water-soluble derivatives could be used to inhibit hIAPP aggregation. Besides, with the ONOO- scavenging activity, these water-soluble metalloporphyrins may act as duel function compounds to inhibit hIAPP aggregation and ONOO- caused oxidation and protein tyrosine nitration. Thus, these water-soluble metalloporphyrins may be ideal candidates for preventing T2D. To confirm our hypothesis, we’ll: (1) study the binding properties between hIAPP and metal porphyrins, as well as their structure-active relationship on scavenging ONOO-; (2) study their structure-active relationship on inhibiting hIAPP aggregation; (3) study their structure-active relationship on inhibiting hIAPP caused membrane damage; (4) study the roles of the interaction between hIAPP and metal porphyrins in mitochondrion function, protein oxidation and nitration on rat insulinoma INS-1 cell. These studies will not only provide structure-activity of metal porphyrin water-soluble derivatives on inhibiting hIAPP aggregation and its cytotoxicity, but also are important for providing scientific basis and new therapeutic agents for preventing and curing of T2D.