Functional Regulation Of Covalent Organic Frameworks For Inhibiting β-amyloid Protein Aggregation

Covalent organic framework(COFs)materials have been at the forefront of the research of porous materials in recent years.They have potential applications in the fields of chemical catalysis,drug loading and charge transport due to the advantages of predesign,diverse structure,adjustable pore size and chemical regulation.However,the application of COFs in the biological field needs to overcome the disadvantages of poor solvent dispersion,large size and low specificity.Therefore,it is of great significance for the application of COFs materials to reasonably select building blocks,chemical functional modification and multifunctional synergies.In this thesis,based on the functional regulation of COFs materials,the strategies of pre-designing the monomer construction of COFs,regulating the synthesis process and functionalization after synthesis were adopted.COFs films with high photoelectrochemical response performance and COFs nanospheres targeted functionalization of β-amyloid(Aβ)protein were prepared to inhibit Aβ protein aggregation.The research work of this thesis mainly includes the following three parts:(1)2D COFs films with energy transfer and charge transfer synergiesIn this chapter,a unique two-dimensional organic covalent frameworks(2D COFs)film with high photoelectrochemical response of donor(D)-acceptor(A)heterostructure was designed and synthesized.Based on the solubility differences of5-oxo-2,3-dihydro-5H-thiazolo [3,2-a] pyridine-3,7-dicarboxylic acid(TPA)and 5,10,15,20-tetrakis(4-aminophenyl)porphyrin(TAPP)and their highly overlapping spectral properties,a resonance energy transfer(RET)system with TPA as energy donor and TAPP as energy acceptor was designed in advance.The results also showed a charge transfer(CT)process in the system with TAPP as electron donor and TPA as electron acceptor.An amide reaction between hydrophilic TPA and hydrophobic TAPP at the water/oil(dichloromethane)interface yielded RET and CT synergistic D-A heterostructural ultra-thin 2D COFs TPA@TAPP films.The structure,morphology,optical properties and photoelectric response of 2D COFs films were characterized,and the mechanism of resonant energy transfer and charge transfer was investigated.The results showed that 2D COFs TPA@TAPP thin films have high photoelectrical conversion efficiency,which has a unique advantage in the field of organic photovoltaic.(2)Sodium phosphate functionalized COFs nanospheres for inhibition ofβ-amyloid protein aggregationIn this chapter,sodium phosphate(SP)functionalized COFs nanospheres were synthesized at room temperature and successfully used to inhibit β-amyloid(Aβ)protein aggregation.First,TD-COFs nanospheres were synthesized with 1,3,5-tri(4-aminophenyl)benzene(TPB)and 2,5-dihydroxyterephthaldeyde(DHTP)as monomers by adjusting the amount of catalyst at room temperature.Then,the hydroxyl groups on DHTP further reacted with phosphorus trichloride to prepare SP-COFs nanospheres functionalized with sodium phosphate.SP groups played a dual role as functional groups targeting Aβ protein and improving the water dispersion of SP-COFs nanospheres.The morphology,size,crystal structure,surface area and pore size of SP-COFs nanospheres were studied by electron microscopy,X-ray diffraction.The inhibition mechanism of SP-COFs nanospheres on Aβ protein aggregation was studied by circular dichroism,isothermal titration and molecular dynamics simulation.This study is the first exploration of COFs-based nanomaterials as inhibitors of Aβprotein aggregation,which has important guiding implications for the inhibition of Aβprotein fibrillation for Alzheimer’s disease(AD)prevention.(3)Targeted peptide functionalized COFs nanospheres for inhibition β-amyloid monomers aggregation and dissociation of β-amyloid fibrilsBased on the study in the previous chapter,we further synthesized KD8-COFs nanospheres with photothermal response using TAPP and DHTP as monomers,and KLVFFAED(KD8)peptide as competing agents of TAPP.Due to the targeting effect for Aβ protein of KD8 and the photothermal properties of TAPP,the nanospheres showed a strong affinity for Aβ protein,and could bind specifically to Aβ protein,which inhibited the fibrillation of Aβ protein,and directly decomposed Aβ protein fibrils on 808 nm laser irradiation.In addition,the morphology,size,crystal structure,surface area and pore size of KD8-COFs nanospheres were also characterized,as well as the inhibition effect on Aβ protein aggregation and the dissociation effect on Aβfibrils.This study demonstrated that the COFs-based nanomaterials against amyloid aggregation can not only inhibit Aβ protein fibrillation,but also effectively dissociate the formed Aβ protein fibrils,which has potential value in the treatment of AD patients.