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Inhibition of Amyloid Fibril Formation by Polyphenols: Structural Similarity and Aromatic Interactions as a Common Inhibition Mechanism
Author(s) -
Porat Yair,
Abramowitz Adel,
Gazit Ehud
Publication year - 2006
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2005.00318.x
Subject(s) - chemistry , amyloid (mycology) , polyphenol , small molecule , fibril , mechanism (biology) , in vitro , biochemistry , mechanism of action , cytotoxicity , amyloid disease , protein aggregation , biophysics , structure–activity relationship , amyloid fibril , pharmacology , biology , amyloid β , disease , antioxidant , medicine , inorganic chemistry , philosophy , epistemology , pathology
The formation of well‐ordered fibrillar protein deposits is common to a large group of amyloid‐associated disorders. This group consists of several major human diseases such as Alzheimer's disease, Parkinson's disease, prion diseases, and type II diabetes. Currently, there is no approved therapeutic agent directed towards the formation of fibrillar assemblies, which have been recently shown to have a key role in the cytotoxic nature of amyloidogenic proteins. One important approach in the development of therapeutic agents is the use of small molecules that specifically and efficiently inhibit the aggregation process. Several small polyphenol molecules have been demonstrated to remarkably inhibit the formation of fibrillar assemblies in vitro and their associated cytotoxicity. Yet, the inhibition mechanism was mostly attributed to the antioxidative properties of these polyphenol compounds. Based on several observations demonstrating that polyphenols are capable of inhibiting amyloid fibril formation in vitro , regardless of oxidative conditions, and in view of their structural similarities we suggest an additional mechanism of action. This mechanism is assuming structural constraints and specific aromatic interactions, which direct polyphenol inhibitors to the amyloidogenic core. This proposed mechanism is highly relevant for future de novo inhibitors‘ design as therapeutic agents for the treatment of amyloid‐associated diseases.