ABSTRACT
Amyloid ß peptide (Aß) plays a crucial role in the pathogenesis of Alzheimer's disease (AD). Currently, decreasing Aß production and preventing Aß aggregation are thought to be important strategies in anti-AD therapy. However, inhibiting Aß production or aggregation in isolation is not sufficient to reverse the neurodegenerative process of AD patients in clinical testing. Here, a self-assembly molecular chaperone (SAMC) consisting of γ-secretase inhibitor DAPT and mixed-shell polymeric micelles is devised, serving as a bifunctional suppressor of AD. This two-in-one combinational system can simultaneously inhibit Aß production and aggregation, which would contribute to enhancing the therapeutic effect by decreasing Aß levels. Decorating a neuron-specific RVG29 peptide onto the surface, the DAPT-incorporated SAMC can specifically target neuronal cells and, thus, will relieve the strong side effect of DAPT on normal cells. Therefore, this combination strategy holds great potential to open up an avenue for AD treatment.
ABSTRACT
By combining KLVFF peptide and self-assembly chaperone we fabricate a new system to achieve the synchronization between Aß fibril disaggregation and reducing toxicity of Aß fragments (monomers or oligomers) that consequently formed. When the KLVFF peptides disaggregate fibrils into fragments, the hydrophobic domains of self-assembly chaperones promptly bind them at the same time. This binding blocks the re-aggregation of the fragments and their interaction with cells, and hence reduces the toxicity of these dangerous fragments.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/toxicity , Amyloid/chemistry , Amyloid/metabolism , Molecular Chaperones/pharmacology , Oligopeptides/pharmacology , Protein Aggregation, Pathological/drug therapy , Amyloid beta-Peptides/chemistry , Drug Synergism , Hydrophobic and Hydrophilic Interactions , Micelles , Molecular Chaperones/chemical synthesis , Molecular Chaperones/chemistry , Oligopeptides/chemistry , Particle Size , Protein Aggregates/drug effects , Surface PropertiesABSTRACT
Artificial chaperones are of great interest in fighting protein misfolding and aggregation for the protection of protein bioactivity. A comprehensive understanding of the interaction between artificial chaperones and proteins is critical for the effective utilization of these materials in biomedicine. In this work, we fabricated three kinds of artificial chaperones with different surface charges based on mixed-shell polymeric micelles (MSPMs), and investigated their protective effect for lysozymes under thermal stress. It was found that MSPMs with different surface charges showed distinct chaperone-like behavior, and the neutral MSPM with PEG shell and PMEO2MA hydrophobic domain at high temperature is superior to the negatively and positively charged one, because of the excessive electrostatic interactions between the protein and charged MSPMs. The results may benefit to optimize this kind of artificial chaperone with enhanced properties and expand their application in the future.
Subject(s)
Avian Proteins/chemistry , Micelles , Molecular Chaperones/chemistry , Muramidase/chemistry , Polyethylene Glycols/chemistry , Protein Refolding , Animals , Chickens , Hot Temperature , Humans , Protein DenaturationABSTRACT
Inspired by delicate structures and multiple functions of natural multiple enzyme architectures such as peroxisomes, we constructed an artificial multiple enzyme system by coencapsulation of glucose oxidases (GOx) and artificial peroxidases in a supramolecular hydrogel. The artificial peroxidase was a functional complex micelle, which was prepared by the self-assembly of diblock copolymer and hemin. Compared with catalase or horseradish peroxidase (HRP), the functional micelle exhibited comparable activity and better stability, which provided more advantages in constructing a multienzyme with a proper oxidase. The hydrogel containing the two catalytic centers was further used as a catalyst for green oxidation of glucose, which was a typical cascade reaction. Glucose was oxidized by oxygen (O2) via the GOx-mediated reaction, producing toxic intermediate hydrogen peroxide (H2O2). The produced H2O2 further oxidized peroxidase substrates catalyzed by hemin-micelles. By regulating the diffusion modes of the enzymes and substrates, the artificial multienzyme based on hydrogel could successfully activate the cascade reaction, which the soluble enzyme mixture could not achieve. The hydrogel, just like a protective covering, protected oxidases and micelles from inactivation via toxic intermediates and environmental changes. The artificial multienzyme could efficiently achieve the oxidation task along with effectively eliminating the toxic intermediates. In this way, this system possesses great potentials for glucose detection and green oxidation of a series of substrates related to biological processes.
Subject(s)
Hydrogels/chemistry , Macromolecular Substances/chemical synthesis , Multienzyme Complexes/chemistry , Oxidoreductases/chemistry , Peroxidases/chemistry , Catalysis , Enzyme Activation , Enzyme Stability , Enzymes, Immobilized/chemistry , Materials TestingABSTRACT
The disruption of Aß homeostasis, which results in the accumulation of neurotoxic amyloids, is the fundamental cause of Alzheimer's disease (AD). Molecular chaperones play a critical role in controlling undesired protein misfolding and maintaining intricate proteostasis inâ vivo. Inspired by a natural molecular chaperone, an artificial chaperone consisting of mixed-shell polymeric micelles (MSPMs) has been devised with tunable surface properties, serving as a suppressor of AD. Taking advantage of biocompatibility, selectivity toward aberrant proteins, and long blood circulation, these MSPM-based chaperones can maintain Aß homeostasis by a combination of inhibiting Aß fibrillation and facilitating Aß aggregate clearance and simultaneously reducing Aß-mediated neurotoxicity. The balance of hydrophilic/hydrophobic moieties on the surface of MSPMs is important for their enhanced therapeutic effect.
