有机铂取代的多金属氧酸对淀粉样蛋白纤维化的抑制作用
发布时间：2019-06-26 22:11
【摘要】：淀粉样疾病是由于蛋白质错误折叠聚集成为淀粉样纤维,从而丧失了原本的生理活性,其形成的纤维沉积在人体的组织和器官中,对细胞产生毒性。这种细胞毒性是造成一系列淀粉样疾病发病的主要机制之一,如老年痴呆症(医学上称为阿尔兹海默病)中的β淀粉样蛋白和肾功能衰竭中的溶菌酶。淀粉样疾病患者数量正在逐年增加,然而目前仅有少数几个药物可用于一些神经退行性疾病,因而开发新型淀粉样蛋白抑制剂的研究已成为研究热点之一。多金属氧酸(Polyoxometalates,缩写POMs)是过渡金属(主要是钒,钼和钨)离子通过氧连接而成的金属-氧纳米团簇,带有负电荷。由于多金属氧酸种类、结构繁多,可有多达70种元素掺入多金属氧酸盐的骨架中,因此其物理化学可调。前期研究已经证明多金属氧酸化合物可以抑制β淀粉样蛋白的纤维化,但其主要缺点是毒副作用较大,体内稳定性差且靶向性较差。由于多金属氧酸化合物的有机和有机金属衍生物不仅能够提供具有高的底物选择性与反应活性的多功能催化材料,而且有机或有机金属基团与多金属氧酸阴离子键合后,可改变阴离子表面氧原子的电荷密度,提高与目标生物分子作用的活性,从而提高其对药物的有效性,可以用于研制具有靶向功能的多酸药物。因此本论文研究了有机铂取代的Keggin结构多金属氧酸化合物对β淀粉样蛋白和溶菌酶聚集的抑制作用和细胞保护作用。本课题通过硫磺素T(Th T)荧光光谱法、非变性聚丙烯酰胺凝胶电泳(Native-Page)分别研究出有机铂取代的Keggin结构多金属氧酸化合物对β淀粉样蛋白和溶菌酶的纤维化程度的影响,利用场发射透射电镜(TEM)观察β淀粉样蛋白和溶菌酶纤维化过程中形态的变化,采用圆二色谱法(CD)研究了β淀粉样蛋白和溶菌酶聚集过程中的二级结构变化,研究表明有机铂取代的Keggin结构多金属氧酸化合物对β淀粉样蛋白和溶菌酶的聚集具有浓度依赖性的抑制作用,并且可以溶解所形成的淀粉样纤维。并采用等温滴定量热法(ITC)研究有机铂取代的Keggin结构多金属氧酸化合物与β淀粉样蛋白和溶菌酶的相互作用机制,研究表明该化合物可以通过氢键和疏水作用与β淀粉样蛋白和溶菌酶相互作用,从而抑制淀粉样蛋白的聚集和溶解其聚集产物。细胞毒性实验(MTT)研究出有机铂取代的Keggin结构多金属氧酸对神经细胞以及正常细胞几乎没有毒性。上述研究结果表明有机铂取代的Keggin结构多金属氧酸可以作为淀粉样蛋白的新型抑制剂。
[Abstract]:Starch-like disease is due to the misfolding and aggregation of proteins into starch-like fibers, thus losing its original physiological activity. The fibers formed by starch-like diseases are deposited in human tissues and organs and are toxic to cells. This cytotoxicity is one of the main mechanisms of a series of starch-like diseases, such as Alzheimer's disease (clinically called Alzheimer's disease) and lysozyme in renal failure. The number of patients with amyloidosis is increasing year by year. However, at present, only a few drugs can be used in some neurodegenerative diseases, so the development of new amyloidin inhibitors has become one of the research hotspots. Polyoxometallic acid (Polyoxometalates, acronym POMs) is a metal-oxygen nanocluster formed by oxygen bonding of transition metal (mainly vanadium, Mo and W) ions with negative charge. Because of the variety and structure of polyoxometallic acid, as many as 70 kinds of elements can be mixed into the skeleton of polyoxometalate, so its physicochemistry can be adjusted. Previous studies have shown that polyoxometalic acid compounds can inhibit the fibrosis of 尾-starch protein, but its main disadvantages are large toxic and side effects, poor stability in vivo and poor targeting. Because the organic and organometallic derivatives of polyoxometallic compounds can not only provide multifunctional catalytic materials with high substrate selectivity and reaction activity, but also the charge density of oxygen atoms on the anion surface can be changed and the activity of interacting with the target biomolecules can be improved by bonding organic or organometallic groups with polyoxometallic acid anions, thus improving their effectiveness to drugs. It can be used to develop polyacid drugs with targeted function. Therefore, the inhibitory and cellular protective effects of organic platinum-substituted Keggin polyoxometalic acid compounds on the aggregation of 尾-amylase and lysozyme were studied in this paper. In this paper, the effects of organoplatinum substituted Keggin polyoxometalates on the fibrosis degree of 尾-starch protein and lysozyme were studied by thiosulfon T (Th T) fluorescence spectroscopy and non-denatured polyacrylamide gel electrophoresis (Native-Page). The morphological changes of 尾-starch protein and lysozyme during fibrosis were observed by field emission transmission electron microscope (TEM). The secondary structure changes of 尾-starch protein and lysozyme during aggregation were studied by circular dichroism (CD). The results showed that organic platinum-substituted Keggin polyoxometalic acid compounds could inhibit the aggregation of 尾-starch protein and lysozyme in a concentration-dependent manner, and could dissolve the formed starch fibers. The interaction mechanism of organoplatinum substituted Keggin polyoxometalic acid compounds with 尾-starch protein and lysozyme was studied by isotherm titration (ITC). The results showed that the compound could interact with 尾-starch protein and lysozyme through hydrogen bond and hydrophobic interaction, thus inhibiting the aggregation of starch-like protein and dissolving its aggregation products. The cytotoxicity test (MTT) showed that organoplatinum substituted Keggin polyoxometalic acid had little toxicity to nerve cells and normal cells. These results suggest that organoplatinum substituted Keggin polyoxometalic acid can be used as a new inhibitor of starch protein.
【学位授予单位】：哈尔滨工业大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R597.2
本文编号：2506540
[Abstract]:Starch-like disease is due to the misfolding and aggregation of proteins into starch-like fibers, thus losing its original physiological activity. The fibers formed by starch-like diseases are deposited in human tissues and organs and are toxic to cells. This cytotoxicity is one of the main mechanisms of a series of starch-like diseases, such as Alzheimer's disease (clinically called Alzheimer's disease) and lysozyme in renal failure. The number of patients with amyloidosis is increasing year by year. However, at present, only a few drugs can be used in some neurodegenerative diseases, so the development of new amyloidin inhibitors has become one of the research hotspots. Polyoxometallic acid (Polyoxometalates, acronym POMs) is a metal-oxygen nanocluster formed by oxygen bonding of transition metal (mainly vanadium, Mo and W) ions with negative charge. Because of the variety and structure of polyoxometallic acid, as many as 70 kinds of elements can be mixed into the skeleton of polyoxometalate, so its physicochemistry can be adjusted. Previous studies have shown that polyoxometalic acid compounds can inhibit the fibrosis of 尾-starch protein, but its main disadvantages are large toxic and side effects, poor stability in vivo and poor targeting. Because the organic and organometallic derivatives of polyoxometallic compounds can not only provide multifunctional catalytic materials with high substrate selectivity and reaction activity, but also the charge density of oxygen atoms on the anion surface can be changed and the activity of interacting with the target biomolecules can be improved by bonding organic or organometallic groups with polyoxometallic acid anions, thus improving their effectiveness to drugs. It can be used to develop polyacid drugs with targeted function. Therefore, the inhibitory and cellular protective effects of organic platinum-substituted Keggin polyoxometalic acid compounds on the aggregation of 尾-amylase and lysozyme were studied in this paper. In this paper, the effects of organoplatinum substituted Keggin polyoxometalates on the fibrosis degree of 尾-starch protein and lysozyme were studied by thiosulfon T (Th T) fluorescence spectroscopy and non-denatured polyacrylamide gel electrophoresis (Native-Page). The morphological changes of 尾-starch protein and lysozyme during fibrosis were observed by field emission transmission electron microscope (TEM). The secondary structure changes of 尾-starch protein and lysozyme during aggregation were studied by circular dichroism (CD). The results showed that organic platinum-substituted Keggin polyoxometalic acid compounds could inhibit the aggregation of 尾-starch protein and lysozyme in a concentration-dependent manner, and could dissolve the formed starch fibers. The interaction mechanism of organoplatinum substituted Keggin polyoxometalic acid compounds with 尾-starch protein and lysozyme was studied by isotherm titration (ITC). The results showed that the compound could interact with 尾-starch protein and lysozyme through hydrogen bond and hydrophobic interaction, thus inhibiting the aggregation of starch-like protein and dissolving its aggregation products. The cytotoxicity test (MTT) showed that organoplatinum substituted Keggin polyoxometalic acid had little toxicity to nerve cells and normal cells. These results suggest that organoplatinum substituted Keggin polyoxometalic acid can be used as a new inhibitor of starch protein.
【学位授予单位】：哈尔滨工业大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R597.2
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