Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of A\u03b242 and hIAPP peptides while reducing their toxicity

Ashim Paul,Moran Frenkel-Pinter,Daniel Segal,Ehud Gazit,Giulia Milordini,Daniela Escobar Alvarez,Elsa Zacco

doi:10.1038/s42003-020-01216-5

Ashim Paul, Moran Frenkel-Pinter + Show 5 more

Open Access

https://doi.org/10.1038/s42003-020-01216-5

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Abstract

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer’s disease (AD) and Type-2 diabetes Mellitus (T2DM). Aggregation of specific peptides, like Aβ42 in AD and hIAPP in T2DM, causes cellular dysfunction resulting in the respective pathology. While these amyloidogenic proteins lack sequence homology, they all contain aromatic amino acids in their hydrophobic core that play a major role in their self-assembly. Targeting these aromatic residues by small molecules may be an attractive approach for inhibiting amyloid aggregation. Here, various biochemical and biophysical techniques revealed that a panel of tryptophan-galactosylamine conjugates significantly inhibit fibril formation of Aβ42 and hIAPP, and disassemble their pre-formed fibrils in a dose-dependent manner. They are also not toxic to mammalian cells and can reduce the cytotoxicity induced by Aβ42 and hIAPP aggregates. These tryptophan-galactosylamine conjugates can therefore serve as a scaffold for the development of therapeutics towards AD and T2DM.

Highlights

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer’s disease (AD) and Type-2 diabetes Mellitus (T2DM)
By means of Thioflavin T (ThT)-binding assay, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM) and Congo red birefringence, we show that the presence of galactose is key for the improved efficiency of tryptophan as amyloid inhibitor
To examine the possibility of combining an amino acid and a glycan into a potentially improved amyloid inhibitor, we conjugated tryptophan to the N-glycoside 1-amino-1-deoxy-β-Dgalactose and to its variants derived from the substitution of the OH on C2 with NH2 and NAc groups

Summary

Introduction

Self-assembly of proteins into amyloid fibrils is a hallmark of various diseases, including Alzheimer’s disease (AD) and Type-2 diabetes Mellitus (T2DM). Considering the untreated Aβ42 plateau value as 100% aggregation, in the presence of 5-fold molar excess of WGal, WGalNH2 and WGalNAc the level of amyloid fibrils was reduced by ~50%, ~57%, and ~70%, respectively (Fig. 2a, b).

Results

Conclusion