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© Research
Publication : bioRxiv

Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in bioRxiv - 29 Jul 2019

G. T. Heller, F. A. Aprile, T. C. T. Michaels, R. Limbocker, M. Perni, F. S. Ruggeri, B. Mannini, T. Löhr, M. Bonomi, A. De Simone, I. C. Felli, R. Pierattelli, T. P. J. Knowles, C. M. Dobson, M. Vendruscolo

bioRxiv (2019)

Disordered proteins are challenging therapeutic targets, and no drug is currently in use that can modify the properties of their monomeric states. Here, we identify a small molecule capable of binding and sequestering the amyloid-β peptide (Aβ) in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and, in this manner, inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterise this interaction using biophysical experiments and integrative structural ensemble determination methods. Furthermore, we show that this small molecule rescues a Caenorhabditis elegans model of Aβ-associated toxicity in a manner consistent with the mechanism of action identified from the in silico and in vitro studies. These results provide an illustration of the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behaviour for therapeutic purposes.

https://doi.org/10.1101/729392