【摘要】：淀粉樣疾病是由于蛋白質(zhì)錯(cuò)誤折疊聚集成為淀粉樣纖維,從而喪失了原本的生理活性,其形成的纖維沉積在人體的組織和器官中,對細(xì)胞產(chǎn)生毒性。這種細(xì)胞毒性是造成一系列淀粉樣疾病發(fā)病的主要機(jī)制之一,如老年癡呆癥(醫(yī)學(xué)上稱為阿爾茲海默病)中的β淀粉樣蛋白和腎功能衰竭中的溶菌酶。淀粉樣疾病患者數(shù)量正在逐年增加,然而目前僅有少數(shù)幾個(gè)藥物可用于一些神經(jīng)退行性疾病,因而開發(fā)新型淀粉樣蛋白抑制劑的研究已成為研究熱點(diǎn)之一。多金屬氧酸(Polyoxometalates,縮寫POMs)是過渡金屬(主要是釩,鉬和鎢)離子通過氧連接而成的金屬-氧納米團(tuán)簇,帶有負(fù)電荷。由于多金屬氧酸種類、結(jié)構(gòu)繁多,可有多達(dá)70種元素?fù)饺攵嘟饘傺跛猁}的骨架中,因此其物理化學(xué)可調(diào)。前期研究已經(jīng)證明多金屬氧酸化合物可以抑制β淀粉樣蛋白的纖維化,但其主要缺點(diǎn)是毒副作用較大,體內(nèi)穩(wěn)定性差且靶向性較差。由于多金屬氧酸化合物的有機(jī)和有機(jī)金屬衍生物不僅能夠提供具有高的底物選擇性與反應(yīng)活性的多功能催化材料,而且有機(jī)或有機(jī)金屬基團(tuán)與多金屬氧酸陰離子鍵合后,可改變陰離子表面氧原子的電荷密度,提高與目標(biāo)生物分子作用的活性,從而提高其對藥物的有效性,可以用于研制具有靶向功能的多酸藥物。因此本論文研究了有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸化合物對β淀粉樣蛋白和溶菌酶聚集的抑制作用和細(xì)胞保護(hù)作用。本課題通過硫磺素T(Th T)熒光光譜法、非變性聚丙烯酰胺凝膠電泳(Native-Page)分別研究出有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸化合物對β淀粉樣蛋白和溶菌酶的纖維化程度的影響,利用場發(fā)射透射電鏡(TEM)觀察β淀粉樣蛋白和溶菌酶纖維化過程中形態(tài)的變化,采用圓二色譜法(CD)研究了β淀粉樣蛋白和溶菌酶聚集過程中的二級結(jié)構(gòu)變化,研究表明有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸化合物對β淀粉樣蛋白和溶菌酶的聚集具有濃度依賴性的抑制作用,并且可以溶解所形成的淀粉樣纖維。并采用等溫滴定量熱法(ITC)研究有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸化合物與β淀粉樣蛋白和溶菌酶的相互作用機(jī)制,研究表明該化合物可以通過氫鍵和疏水作用與β淀粉樣蛋白和溶菌酶相互作用,從而抑制淀粉樣蛋白的聚集和溶解其聚集產(chǎn)物。細(xì)胞毒性實(shí)驗(yàn)(MTT)研究出有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸對神經(jīng)細(xì)胞以及正常細(xì)胞幾乎沒有毒性。上述研究結(jié)果表明有機(jī)鉑取代的Keggin結(jié)構(gòu)多金屬氧酸可以作為淀粉樣蛋白的新型抑制劑。
[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.
【學(xué)位授予單位】：哈爾濱工業(yè)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R597.2

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