Looking for a generic inhibitor of amyloid-like fibril formation among flavone derivatives

Abstract

A range of diseases is associated with amyloid fibril formation. Despite different proteins being responsible for each disease, all of them share similar features including beta-sheet-rich secondary structure and fibril-like protein aggregates. A number of proteins can form amyloid-like fibrils in vitro, resembling structural features of disease-related amyloids. Given these generic structural properties of amyloid and amyloid-like fibrils, generic inhibitors of fibril formation would be of interest for treatment of amyloid diseases. Recently, we identified five outstanding inhibitors of insulin amyloid-like fibril formation among the pool of 265 commercially available flavone derivatives. Here we report testing of these five compounds and of epi-gallocatechine-3-gallate (EGCG) on aggregation of alpha-synuclein and beta-amyloid. We used a Thioflavin T (ThT) fluorescence assay, relying on halftimes of aggregation as the measure of inhibition. This method avoids large numbers of false positive results. Our data indicate that four of the five flavones and EGCG inhibit alpha-synuclein aggregation in a concentration-dependent manner. However none of these derivatives were able to increase halftimes of aggregation of beta-amyloid.

Epigallocatechin-3-gallate preferentially induces aggregation of amyloidogenic immunoglobulin light chains

“…It has been found recently that EGCG did not inhibit fibril formation according to ThT and TEM using the patient-derived λ-V L sequence Mcg 29 . We would like to mention that similar controversies were also reported for Aβ and EGCG 56 . We speculate that this is related to a potentially lower amyloidogenicity of Mcg.…”

The Environment Is a Key Factor in Determining the Anti-Amyloid Efficacy of EGCG

“…The effects of potential inhibitor compounds on the process of amyloid fibril formation are often determined by analysing the kinetics of aggregation [15,29,30,32,33,[63][64][65][66][67][68] and/or the maximum ThT intensity [29,30,32,33,65,[67][68][69][70][71] in the absence and presence of the compound. The effects of EGCG and EGCG ox on the process of amyloid fibril formation by both insulin and α-synuclein performed under distinct environmental conditions were assessed using both aforementioned approaches (Figures 1 and S7), and the conclusions are presented in (Table 1).…”

Inhibition of Amyloid-like Fibril Formation of Trypsin by Red Wines

“…Resveratrol, a polyphenolic red wine constituent, inhibits Aβ42 fibril formation and islet amyloid polypeptide aggregation in a dose-dependent manner [9][10]. The inhibitory effect of flavone derivatives is dependent on the number and position of hydroxyl groups around the flavone backbone [11]. The position of phenolic hydroxyl moieties on the aromatic rings is a major determinant of the potent anti-aggregation effect, while the number of hydroxyl groups is less important [12].…”