Inhibition of HEWL fibril formation by taxifolin: Mechanism of action

Among therapeutic approaches for amyloid-related diseases, attention has recently turned to the use of natural products as effective anti-aggregation compounds. Although a wealth of in vitro and in vivo evidence indicates some common inhibitory activity of these compounds, they don't generally...

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Bibliographic Details
Published in:PloS one 2017-11, Vol.12 (11), p.e0187841
Main Authors: Mahdavimehr, Mohsen, Meratan, Ali Akbar, Ghobeh, Maryam, Ghasemi, Atiyeh, Saboury, Ali Akbar, Nemat-Gorgani, Mohsen
Format: Article
Language:English
Subjects:
Agglomeration
Aggregates
Amyloid
Amyloidosis
Binding
Biochemistry
Biocompatibility
Biology and Life Sciences
Biopharmaceutics
Biophysics
Chains
Drug therapy
Experiments
Fibrillogenesis
Fluorescence
Food
Genetic aspects
Hydrophobicity
Medicine and Health Sciences
Molecular structure
Natural products
Physical Sciences
Polyphenols
Protein interaction
Proteins
Spectrum analysis
Toxicity
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Summary:Among therapeutic approaches for amyloid-related diseases, attention has recently turned to the use of natural products as effective anti-aggregation compounds. Although a wealth of in vitro and in vivo evidence indicates some common inhibitory activity of these compounds, they don't generally suggest the same mechanism of action. Here, we show that taxifolin, a ubiquitous bioactive constituent of foods and herbs, inhibits formation of HEWL amyloid fibrils and their related toxicity by causing formation of very large globular, chain-like aggregates. A range of amyloid-specific techniques were employed to characterize this process. We found that taxifolin exerts its effect by binding to HEWL prefibrillar species, rather than by stabilizing the molecule in its native-like state. Furthermore, it's binding results in diverting the amyloid pathway toward formation of very large globular, chain-like aggregates with low β-sheet content and reduced solvent-exposed hydrophobic patches. ThT fluorescence measurements show that the binding capacity of taxifolin is significantly reduced, upon generation of large protofibrillar aggregates at the end of growth phase. We believe these results may help design promising inhibitors of protein aggregation for amyloid-related diseases.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0187841