RT Journal Article
SR Electronic
T1 Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 729392
DO 10.1101/729392
A1 Gabriella T. Heller
A1 Francesco A. Aprile
A1 Thomas C. T. Michaels
A1 Ryan Limbocker
A1 Michele Perni
A1 Francesco Simone Ruggeri
A1 Benedetta Mannini
A1 Thomas Löhr
A1 Massimiliano Bonomi
A1 Carlo Camilloni
A1 Alfonso De Simone
A1 Isabella C. Felli
A1 Roberta Pierattelli
A1 Tuomas P. J. Knowles
A1 Christopher M. Dobson
A1 Michele Vendruscolo
YR 2020
UL http://biorxiv.org/content/early/2020/05/20/729392.abstract
AB Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that has been shown to modify the properties of their monomeric states. Here, we identify a small molecule, called 10074-G5, capable of binding and sequestering the intrinsically disordered amyloid-β peptide (Aβ) in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and 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. We observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. 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.Teaser A small molecule binds to a disordered protein in its monomeric form, preventing its aggregation linked to Alzheimer’s disease.Competing Interest StatementThe authors have declared no competing interest.