Functional Gallic Acid-Based Dendrimers as Synthetic Nanotools to Remodel Amyloid-β-42 into Noncytotoxic Forms.

Ana R Araújo,Ricardo A Pires,Rui L Reis,Juan Correa,Eduardo Fernandez-Megia,Vicente Dominguez-Arca

doi:10.1021/acsami.1c17823

Abstract

The self-assembly of amyloid-β (Aβ) generates cytotoxic oligomers linked to the onset and progression of Alzheimer’s disease (AD). As many fundamental molecular pathways that control Aβ aggregation are yet to be unraveled, an important strategy to control Aβ cytotoxicity is the development of bioactive synthetic nanotools capable of interacting with the heterogeneous ensemble of Aβ species and remodel them into noncytotoxic forms. Herein, the synthesis of nanosized, functional gallic acid (Ga)-based dendrimers with a precise number of Ga at their surface is described. It is shown that these Ga-terminated dendrimers interact by H-bonding with monomeric/oligomeric Aβ species at their Glu, Ala, and Asp residues, promoting their remodeling into noncytotoxic aggregates in a process controlled by the Ga units. The multivalent presentation of Ga on the dendrimer surface enhances their ability to interact with Aβ, inhibiting the primary and secondary nucleation of Aβ fibrillization and disrupting the Aβ preformed fibrils.

Highlights

Pathological protein/peptide aggregation is on the basis of several neurodegenerative processes, such as the ones leading to Alzheimer’s disease (AD).[1]
For the preparation of dendrimers functionalized with Ga units on the periphery, we selected dendritic scaffolds of the gallic acid− triethylene glycol (GATG) family[14,20] with terminal amine groups
To generate a dendrimer of higher Ga valency, the same strategy was applied to a 3G1 dendrimer, leading to 3G1-GaOH (9 Ga units)

Summary

Introduction

Pathological protein/peptide aggregation is on the basis of several neurodegenerative processes, such as the ones leading to Alzheimer’s disease (AD).[1] In AD, amyloid-β (Aβ) peptides of different lengths (between 38 and 43 amino acids) are at the onset and progression of the disease. These amyloidogenic Aβ species are highly prone to aggregate into a diverse set of supramolecular assemblies that range from short oligomers to long fibrils. These supramolecular assemblies are typically maintained through H-bonding between the backbones of nearby peptide monomers, as well as by π−π stacking between aromatic amino acid residues, making them key targets for the inhibition of the Aβ supramolecular assembly.[8]

Methods

Results

Conclusion