Stimuli-Chromic Oxazolidine Derivatives as Highly Efficient Molecular Probes for Monitoring Fibrillation Kinetics and Intracellular Detection of Amyloid Fibrils.
The authors report two membrane-permeable, aggregation-induced-emission oxazolidine probes (OX1/OX2) that turn on red fluorescence upon binding amyloid fibrils, detect intracellular α-synuclein and insulin aggregates, and — per docking—show stronger fibril binding (OX2) than ThT.
What the AI sees
The authors report two membrane-permeable, aggregation-induced-emission oxazolidine probes (OX1/OX2) that turn on red fluorescence upon binding amyloid fibrils, detect intracellular α-synuclein and insulin aggregates, and — per docking—show stronger fibril binding (OX2) than ThT.
Research significance
By enabling sensitive intracellular and red-shifted detection of α-synuclein assemblies with low cytotoxicity, these probes are valuable tools for studying aggregation kinetics, cellular pathology, and for screening or validating therapeutics and biomarkers relevant to Parkinson's disease.
Source abstract
Misfolding and aggregation of proteins into amyloid fibrils is a main pathological hallmark of neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Thus, development of probes with the potential to cross biological membranes and detect intracellular aggregates is an area of intense research. In the present study, we have reported the synthesis of two new stimuli-chromic oxazolidine derivatives (OX1 and OX2), with aggregation-induced emission (AIE) characteristics, for monitoring fibrillation kinetics and intracellular detection of amyloid fibrils. Although both probes are nonfluorescent in the presence of monomers and soluble oligomers, their binding to amyloid fibrils is accompanied by considerable red fluorescence. We suggest that changes in the polarity of the amyloid fibril microenvironment, caused by structural changes and exposure of hydrophobic regions during the fibrillation process, promote the selective binding and aggregation of these compounds on the surface of amyloid fibrils, leading to their considerable fluorescence emission. Cellular experiments indicate that both dyes are membrane-permeable without any significant cytotoxicity and can detect intracellular fibrils of α-synuclein and human insulin. Molecular docking studies suggest stronger binding affinity of OX2 than that of ThT for monomers and amyloid fibrils. In summary, we believe that properties such as intracellular detection of amyloid fibrils, red fluorescence without any significant interference with autofluorescence, and solid-state solvatochromic and AIE characteristics may distinguish OX1/OX2 from ThT and previously reported probes, making these compounds more suitable candidates for the detection of amyloid aggregates both in vitro and in vivo.