Reactive Amphiphilic Conjugated Polymers for Inhibiting Amyloid β Assembly

Abstract

Protein misfolding and aberrant aggregations are associated with multiple prevalent and intractable diseases. Inhibition of amyloid assembly is apromising strategy for the treatment of amyloidosis.R eported here is the design and synthesis of areactive conjugated polymer,apoly(p-phenylene vinylene) derivative,f unctionalizedw ith p-nitrophenyl esters (PPV-NP) and it inhibits the assembly of amyloid proteins, degrades preformed fibrils,a nd reduces the cytotoxicity of amyloid aggregations in living cells.PPV-NP is attached to the proteins through hydrophobic interactions and irreversible covalent linkage.P PV-NP also exhibited the capacity to eliminate Ab plaques in brain slices in ex vivo assays.T his work represents an innovative attempt to inhibit protein pathogenic aggregates,and may offer insights into the development of therapeutic strategies for amyloidosis.Proteins are one of the most important basic bio-macromolecules in organisms.T he aberrant assembly of proteins into insoluble amyloid aggregates would disrupt their biological functions and result in the generation of toxic intermediates and amyloidosis,w hich are relevant to ar ange of intractable human disorders such as Alzheimersd isease, Parkinsonsd isease,d ialysis-related amyloidosis,a nd type-2 diabetes. [1][2][3][4][5][6][7] On this account, numerous approaches to inhibit amyloid assembly have emerged, ranging from synthetic and natural small-molecule compounds, [4,8,9] peptides, [10,11] antibodies, [12] and nanoparticles [13,14] to artificial chaperones, [15] which make certain achievements to the inhibition of pathogenic aggregates.H owever,t od ate,t he pharmacological treatments for these diseases are still unsatisfactory. [16] Rational chemical designs to effectively inhibit and disrupt the amyloid assembly are still of great significance.In fact, most previous inhibitors functioned through noncovalent interactions,s uch as hydrophobic interactions, p-p stacking,e lectrostatic interactions,a nd hydrogen bonding. These interactions are intrinsically weak and susceptible to the surrounding environment. [17] Thef luctuation of either pH or temperature may induce the disassembly of inhibitor/ protein complexes,and would make the inhibitors invalid. In contrast, covalent interactions are more chemically stable and not susceptible to the fluctuation of surrounding environment. Reactions between inhibitors and proteins are usually irreversible,and inhibitors could remain attached to proteins for long time.T hus,d eveloping new inhibiting materials for amyloid assembly with acovalent-linking strategy is expected to lead to prolonged duration of inhibition and improved efficiency.T he amphiphilic conjugated polymers are considered pioneering materials in the biomedical field owing to their unique photoelectrical properties. [18][19][20][21][22][23][24] Here,w e designed and synthesized ar eactive conjugated polymer, ap oly(p-phenylene vinylene) derivative,f unctionalized with p-nitrophenyl active esters (PPV-NP) to inhibit protein assembly and disru...

Self-triggered click reaction in an Alzheimer's disease model:in situbifunctional drug synthesis catalyzed by neurotoxic copper accumulated in amyloid-β plaques

“…S9 and S10, † a click reaction was promoted in a Cu-treated AD model of CL2006 worms aer 12 h. Organotypic brain slice cultures largely preserve brain architecture and possess major disease features, providing a practical platform for direct medication and real-time monitoring therapeutic effects. 38,39 Therefore, this technology is widely used for studying neurodegenerative diseases. In addition, it has been observed that copper levels are elevated in senile plaques, the hippocampus, and cortex of AD model mice.…”

“…S26 †). 39 We next investigated whether Ab40-Cu aggregates could act as a catalyst for the in situ synthesis of the bifunctional drug 6 in cells. It has been proven that silica nanoparticles can penetrate the blood-brain barrier (BBB) by inducing tight junction loss and cytoskeleton arrangement.…”

Robust and Tumor-Environment-Activated DNA Cross-Linker Driving Nanoparticle Accumulation for Enhanced Therapeutics

“…1 Nanotechnology has been widely used in the field of tumor theranostics. 2 The nanoparticle sizes play an essential role in the enrichment of nanoparticles at the tumor sites. 3 Compared with large-sized nanoparticles, small-sized nanoparticles show advantages of deep tissue penetration and long circulation lifetimes.…”

Naphthalene monoimide derivative ameliorates amyloid burden and cognitive decline in a transgenic mouse model of Alzheimer’s disease

“…The synaptic dysfunction impairs the synaptic plasticity and hippocampal LTP formation causing neuronal damage, memory loss and cognitive decline under AD pathogenesis (4). Contemporary studies have shown that Aβ aggregation species interact with the plasma membrane and promote the internalization of misfolded Aβ peptides by punch holes through the membrane (5,28,29). These results motivated us to evaluate the anti-AD properties of TGR63 in an APP/PS1 double transgenic AD mouse model.…”