Differential inhibition of metabolite amyloid formation by generic fibrillation-modifying polyphenols

Shira Shaham-Niv,Pavel Rehak,Lihi Adler-Abramovich,Aviad Levin,Dor Zaguri,Petr Král,Lela Vuković,Ehud Gazit

doi:10.1038/s42004-018-0025-z

Abstract

The formation of ordered amyloid fibrils by proteins and polypeptides is associated with human disorders. A recent extension of the amyloidogenic building block family includes several small metabolites, which form assemblies with structural and functional similarities to well-established amyloids. Here we investigate whether generic amyloid polyphenolic inhibitors can also restrict the formation of metabolite fibrils. We reveal that epigallocatechin gallate and tannic acid inhibit amyloid-like fibrillation of adenine, phenylalanine, and tyrosine. Moreover, the compounds reduce the cytotoxicity triggered by these assemblies. In contrast, acetylsalicylic acid, used as a control does not have an inhibitory effect. The compounds’ differential effects at various time points is consistent with molecular dynamics simulations, providing information about the inhibition mechanisms and inhibitors’ key interactions with the monomeric and subsequent crystalline fibril states. Taken together, we provide additional evidence for the fundamental similarities between protein- and metabolite-based amyloids, the inhibition process and dynamics of association.

Highlights

The formation of ordered amyloid fibrils by proteins and polypeptides is associated with human disorders
We further present the ability of generic polyphenol amyloid inhibitors to effectively reduce the formation of metabolite amyloid fibrils, as demonstrated by in vitro assays, molecular dynamics simulations and using a neuronal cell culture model
Different polyphenols can serve as universal inhibitors of the process of amyloid fibril formation regardless of the amino-acid composition of the protein and polypeptide assemblies

Summary

Introduction

The formation of ordered amyloid fibrils by proteins and polypeptides is associated with human disorders. Amyloid aggregates are well-ordered β-sheet-rich supramolecular structures, formed by the self-assembly of a wide class of proteins and polypeptides, which do not exhibit simple structural or functional similarities[1,2,3,4,5] This group of proteins and polypeptides is associated with a family of amyloid diseases, related to intra- and extra-cellular protein-misfolding processes, which result in the formation of deposits and plaques and lead to cell death. High concentrations of natural polyphenols can be found in a wide variety of plants, where they function in protection against diseases and UV light This family of molecules, which represent the first generation of amyloid-based potential therapeutic agents, cause a dramatic reduction in amyloidogenic-related cell death, as well as efficient inhibition of amyloid self-assembly in vitro. Minimal building blocks assemblies, composed of peptides as short as dipeptides, reflect some of the fundamental physical properties of full-length amyloid proteins and polypeptides (Fig. 1a)

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