Regulation Of Pentapeptides And PNMA Modified Gold Nanoclusters On HIAPP Fibrosis

Type 2 diabetes（T2D）is a protein conformational disease,mainly influence the metabolic system of human.There isn’t any specific medicine for T2D due to its complex inducement.Several hypnoses raised for the inducement of T2D,and the toxicity of the aggregation of h IAPP is the most accepted and researched inducement.Development of h IAPP aggregation inhibitor is regarded as the most potential treatment for T2D.Our group have done so much work on the synthesis of gold nanoclusters and the inhibition the aggregation of h IAPP.According to the previous works,this thesis designed and synthesized two kinds of gold nanoclusters modified by peptides and an artificial chaperone—poly-NIPAm-co-Methyl-Arginine（PNMA）modified gold nanocluster.Further,we explored and analyzed the dynamic processing of h IAPP by materials above and the corresponding mechanism.There are three section in the thesis:In the first chapter,the thesis reviewed T2D and the hypnosis of its inducements,analyzed the inducements and some pathway of T2D.Then we reviewed the application of nanomaterials in the neurogenerative disease in both inhibition and reversion of fibrillation.The work of this thesis is summarized in the end.In chapter 2,we designed and synthesized two gold nanoclusters modified by DEVD derivative peptides sequence（CDEVD&Ac-DEVDC）,which is the recognition sequence of caspase-3.The CD-Au NCs and DC-Au NCs were designed to aim at multi pathway therapy of T2D.The h IAPP dynamic assay showed that the CD-Au NCs and DC-Au NCs could inhibit the fibrillation of h IAPP efficiently.And the T-AOC kit result of the materials indicated that both CD-Au NCs and DC-Au NCs showed strong potential in ROS pathway.In the meanwhile,CD-Au NCs showed some effect in inhibition the activity of caspase-3.The two Au NCs basically achieved the target of in vitro application of multi-targeting against T2D pathways,indicating that it is feasible to modify gold nanocluster with functional peptide ligands to achieve multi-targeting against neurodegenerative diseases.In chapter 3,we designed and synthesized an artificial molecular chaperone PNMA-Au NCs that mimics the molecular chaperone.This material is a polymer modified gold nanocluster,the polymer was made by copolymerizing 20%??acryl arginine methyl ester and 80%isopropylacrylamide as monomers.The material has a certain hydrophobic structure at 37°C,with a large number of positively charged domains in the structure,which is similar to the structural characteristics of molecular chaperones.PNMA-Au NCs can effectively inhibit the fibrillation of h IAPP at low concentrations(10 mg·L^-1),and can protect INS cells from the toxic effects of h IAPP aggregation.PNMA-Au NCs have also been shown to be able to effectively reverse the mature h IAPP fiber structure and restore its original conformation,indicating that the material basically fulfills the function of a molecular chaperone,and illustrates a solution to functionalize a flexible polymer to mimic protein functions.It has practical value and significance,and provides a new direction for the development of new drugs for protein conformational disease.In summary,this thesis designed three nanomaterials for the fibrillation hypothesis of h IAPP,basically achieving the design purpose from the perspective of multi-targeting and maintaining the natural protein conformation of h IAPP.It provides new ideas and research directions for the development of new drugs for type2 diabetes and drugs for protein conformational disease.