Inhibition of Amyloid Fibril Formation by Polyphenols: Structural Similarity and Aromatic Interactions as a Common Inhibition Mechanism

Abstract

The formation of well-ordered fibrillar protein deposits is common to a large group of amyloidassociated 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.Key words: Aromatic Interactions, pi-pi interactions, polyphenols, protein misfolding, self-assembly. Received 4 October 2005, revised and accepted for publication 21 October 2005Amyloidogenic diseases are characterized by conformational changes that are followed by aggregation of proteins inside or outside cells. This self-assembly into well-ordered supramolecular assemblies and eventually deposits (also termed plaques in neurodegenerative diseases) is associated with major human diseases and has key medical importance. A partial list of more than 20 amyloid-related diseases includes Alzheimer's disease, Parkinson's disease, Huntington's disease, prion diseases, familial amyloidosis, and type II diabetes (1-13).In spite of the fact that various amyloid-forming proteins and polypeptides do not reveal any simple sequence homology, all amyloid assemblies share similar ultrastructural and physiochemical properties. All amyloid fibrils have a characteristic, elongated fibrillar morphology with a diameter of 5-15 nm, a b-sheet-rich structure (14-16), and typical X-ray fiber diffraction with a reflection of 4.6-4.8 in the meridian (17,18). Another well-known characteristic of all amyloid fibrils is their interaction with specific dyes such as Congo red and thioflavin T, which results in definite optical behavior such as birefringence and fluorescence, respectively (19,20).In this article, we will describe the up-to-date knowledge on the molecular interactions that lead to amyloid fibril formation and the therapeutic approaches to amyloidogenic diseases, and will focus on a small molecular family ...

Synthesis and Multitarget Biological Profiling of a Novel Family of Rhein Derivatives As Disease-Modifying Anti-Alzheimer Agents

“…These results are also important in the context of the treatment of amyloidoses in general, insofar as they support the increasingly accepted notion that all diseases that involve the pathological aggregation of a particular protein might share common mechanisms and common therapeutic interventions. 75,76 Indeed, other examples of compounds able to inhibit the aggregation of several amyloidogenic proteins have been reported. 40,75,77 Protection Against the Synaptic Failure Induced by Aβ Oligomers in Hippocampal Slices of C57bl6 Mice.…”

“…75,76 Indeed, other examples of compounds able to inhibit the aggregation of several amyloidogenic proteins have been reported. 40,75,77 Protection Against the Synaptic Failure Induced by Aβ Oligomers in Hippocampal Slices of C57bl6 Mice. In the light of the outstanding multi-target pharmacological profile found in vitro and in E. coli cells for the enantiopure rhein-huprine hybrids (+)-and (-)-7e, involving the modulation of crucial targets of the pathological network of AD, these compounds were selected as leads for further pharmacological characterization.…”

Myricetin Prevents Fibrillogenesis of Hen Egg White Lysozyme

“…7,8 Among the most promising small-molecule inhibitors, the naturally occurring polyphenols show the most effective antiamyloidogenic activity. 9 A group of polyphenols found in green tea (GTPs) including (−)-epigallocatechin (EGC), (−)-epicatechin gallate (ECG), and (−)-epigallocatechin gallate (EGCG) have been reported as effective inhibitors of alkali-saltinduced fibrillogenesis of hen egg white lysozyme (HEWL) with ECG as the most potent polyphenol. 10 A previous report demonstrated that curcumin can also inhibit the aggregation and formation of amyloid fibrillation of HEWL at pH 2.0 in a dosedependent manner.…”

Aβ(1-42) Assembly in the Presence of scyllo-Inositol Derivatives: Identification of an Oxime Linkage as Important for the Development of Assembly Inhibitors

“…26,27 Previous polyphenol studies have shown that a minimum of two aryl rings are required for Aβ(1-42) binding, with one ring being a phenolic group which contains at least one hydroxyl substitution and the length of the linker is critical for activity. 27 We therefore synthesized a series of compounds with increasing number and positioning of hydroxyl groups around the phenyl-scyllo-inositol backbone with an oxime linkage, compounds 6−11.…”