Organic Platinum Subsitituted Polyoxometalates As Inhibitors Of Amyloid Protein

Amyloid disease is due to the protein misfolding. The protein can be gathered as amyloid fiber by misfolding and lost their original physiological activity. The amyloid fiber can induce cytoxicity by depositing in tissues and organs of the human body. The cytotoxicity is the main pathological mechanisms of amyloid disease, such as βAmyloid peptide in Alzheimer’s disease and lysozyme in kidney failure. The population of Amyloid disease patient is increasing year after year. However, there are only few drugs can be used in some neurodegenerative diseases, so it is become important to develop new amyloid protein inhibitors.Polyoxometalates(POMs) is nano clusters composed of negatively charged transition metal(mainly vanadium, molybdenum and tungsten) and oxygen. The physical chemistry of POMs is adjustable because about 70 kinds of elements can be inserted in the skeleton of the POMs and the variety and structure of POMs is great.Previous research has shown that POMs could inhibit the aggregation of β amyloid peptides, but it has too many drawback, such as the higher cytoxicity, the poor stability and no targeting property. The derivatization of POMs with organic and organic-metal groups can not only provide high substrate selectivity and reactivity of multi-functional catalytic materials, but also change the surface charge density of the oxygen anion and improve the activity to the target biological molecules, thus improves the effectiveness of the drug and can be used in developing more targeted drugs. In this dissertation, we studied the inhibition of the organic platinum-substituted Keggin-type structure POMs the aggregation of β amyloid protein and lysozyme and the cellular protection.Thioflavin T(Th T) fluorescence assay and Native-Page had been used to investigate the influence of organic platinum-substituted Keggin-type POMs on the aggregation of βamyloid protein and lysozyme. TEM was used to observe the morphologic change of the β amyloid protein and lysozyme in the process of the aggregation. CD was carried out to study the change of the secondary structure of the β amyloid protein and lysozyme in the process of the aggregation. It was found that organic platinumsubstituted Keggin-type POMs shows concentration-dependent inhibitory behavior toward the aggregation of the β amyloid protein and lysozyme. Most importantly, the organic platinum-substituted Keggin-type POMs can dissolve the amyloid fibers as well.ITC results disclosed that the organic platinum-substituted Keggin-type POMs can interact with the β amyloid protein and lysozyme via the hydrogen bonding and hydrophobic effect and thus inhibit the aggregation of the β amyloid protein and lysozyme and dissolve the amyloid fibers. MTT results demonstrated that the organic platinum-substituted Keggin-type POMs has no cytoxicity toward the HUVEC and PC12 cell lines. Above research shows that the organic platinum-substituted Keggin-type POMs is a potential inhibitor for amyloid protein.