Among common strategies for amyloid fibrillation inhibition, the use of naturally occurring polyphenols as an efficient therapeutic approach has attracted a growing body of attention. However, the poor water solubility and low bioavailability of these compounds have greatly restricted their clinical application in amyloid-related diseases. Thus, different types of formulations have been developed to overcome these limitations; among them, nanonization appears to be one of the most notable approaches. Herein, we show that the polyphenolic fraction of propolis (PFP), in the nanosheet form (PFP nanosheet), exhibits an improved capacity for amyloid fibrillation inhibition as well as clearance of preformed fibrils of bovine insulin. This increased efficiency is suggested to be related to the aqueous solubility and surface area enhancement as well as surface modifications upon undergoing the nanonization process, which can lead to strong binding with and trapping of protein at the surface of the nanosheets. On the basis of thioflavin T results, it is suggested that although PFP may modulate the fibrillation process via shortening of the lag phase, prolongation of the nucleation phase through interaction with and stabilizing monomeric species is the mechanism of action of PFP nanosheets. We propose that nanonization of natural small molecules can be considered as a powerful approach to improve their anti-amyloidogenic properties and overcome obstacles originating from poor water solubility and low bioavailability of drug candidates relating to neurodegenerative diseases. Taken together, the obtained results may suggest PFP nanosheets as a potential candidate for use against neurological disorders.
Natural
compounds with anti-aggregation capacity are increasingly
recognized as viable candidates against neurodegenerative diseases.
Recently, the polyphenolic fraction of propolis (PFP), a complex bee
product, has been shown to inhibit amyloid aggregation of a model
protein especially in the nanosheet form. Here, we examine the aggregation-modulating
effects of the PFP nanosheets on α-synuclein (α-syn),
an intrinsically disordered protein involved in the pathogenesis of
Parkinson’s disease. Based on a range of biophysical data including
intrinsic and extrinsic fluorescence, circular dichroism (CD) data,
and nuclear magnetic resonance spectroscopy, we propose a model for
the interaction of α-syn with PFP nanosheets, where the positively
charged N-terminal and the middle non-amyloid component regions of
α-syn act as the main binding sites with the negatively charged
PFP nanosheets. The Thioflavin T (ThT) fluorescence, Congo red absorbance,
and CD data reveal a prominent dose-dependent inhibitory effect of
PFP nanosheets on α-syn amyloid aggregation, and the microscopy
images and MTT assay data suggest that the PFP nanosheets redirect
α-syn aggregation toward nontoxic off-pathway oligomers. When
preformed α-syn amyloid fibrils are present, fluorescence images
show co-localization of PFP nanosheets and ThT, further confirming
the binding of PFP nanosheets with α-syn amyloid fibrils. Taken
together, our results demonstrate the binding and anti-aggregation
activity of PFP nanosheets in a disease-related protein system and
propose them as potential nature-based tools for probing and targeting
pathological protein aggregates in neurodegenerative diseases.
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