Tryptophan-galactosylamine conjugates inhibit and disaggregate amyloid fibrils of Aβ42 and hIAPP peptides while reducing their toxicity

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number484
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - 1 Dec 2020

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