Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins.

Vladimir I Muronetz,Irina Sevostyanova,Pavel Semenyuk,Aleksandra Melnikova,Kseniya Barinova,Sofia Kudryavtseva,Maria Medvedeva,Yulia Stroylova,Matej Sova

doi:10.3390/molecules25204647

Abstract

This review presents the main properties of hydroxycinnamic acid (HCA) derivatives and their potential application as agents for the prevention and treatment of neurodegenerative diseases. It is partially focused on the successful use of these compounds as inhibitors of amyloidogenic transformation of proteins. Firstly, the prerequisites for the emergence of interest in HCA derivatives, including natural compounds, are described. A separate section is devoted to synthesis and properties of HCA derivatives. Then, the results of molecular modeling of HCA derivatives with prion protein as well as with α-synuclein fibrils are summarized, followed by detailed analysis of the experiments on the effect of natural and synthetic HCA derivatives, as well as structurally similar phenylacetic and benzoic acid derivatives, on the pathological transformation of prion protein and α-synuclein. The ability of HCA derivatives to prevent amyloid transformation of some amyloidogenic proteins, and their presence not only in food products but also as natural metabolites in human blood and tissues, makes them promising for the prevention and treatment of neurodegenerative diseases of amyloid nature.

Highlights

Such socially significant diseases as Alzheimer’s, Parkinson’s, Huntington’s, prion diseases of humans and other mammals, and other neurodegenerative diseases, are associated with aggregation of disease-specific proteins, which leads to the formation of amyloid oligomers and fibrils [1,2]
In case of prion protein, interest in hydroxycinnamic acid (HCA) derivatives as anti-amyloid compounds stems from their structural similarity to a “half” of the curcumin molecule
Using in vitro experiments on various mutant forms of α-synuclein, it has been shown that the binding of curcumin to the protein occurs in a hydrophobic non-amyloid-β component region 60–100, in which 15 aliphatic amino acids, tryptophan in position 94 or 3 alanines in position 89–91 may serve as possible binding sites [171], which correlates with the results of molecular docking for HCA derivatives carried out using fibril structures [118]

Summary

Introduction

Such socially significant diseases as Alzheimer’s, Parkinson’s, Huntington’s, prion diseases of humans and other mammals, and other neurodegenerative diseases, are associated with aggregation of disease-specific proteins, which leads to the formation of amyloid oligomers and fibrils [1,2]. These protein species are thought to be toxic to cells through a myriad of mechanisms, including active cell-to-cell spreading [3,4,5]. In case of prion protein, interest in HCA derivatives as anti-amyloid compounds stems from their structural similarity to a “half” of the curcumin molecule. The main focus of the discussion will be on the influence of HCA derivatives and structurally close compounds on the amyloid transformation of PrP and α-synuclein

Naturally Occurring Hydroxycinnamic Acids and Their Derivatives

Findings

Conclusions