Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer’s disease


Type
Article
Change log
Authors
Abstract

The aggregation of the 42-residue form of the amyloid-β peptide (Aβ42) is a pivotal event in Alzheimer’s disease (AD). The use of chemical kinetics has recently enabled highly accurate quantifications of the effects of small molecules on specific microscopic steps in Aβ42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against Aβ42 aggregation that uses as a read-out the changes in the nucleation and elongation rate constants caused by candidate small molecules. We thus identify a pool of compounds that target specific microscopic steps in Aβ42 aggregation. We then test further these small molecules in human cerebrospinal fluid and in a Caenorhabditis elegans model of AD. Our results show that this strategy represents a powerful approach to identify systematically small molecule lead compounds, thus offering an appealing opportunity to reduce the attrition problem in drug discovery.

Description
Keywords
Alzheimer’s disease, amyloid-β peptide, drug discovery, protein aggregation, protein misfolding, Alzheimer Disease, Amyloid beta-Peptides, Animals, Caenorhabditis elegans, Cerebrospinal Fluid, Drug Discovery, Humans, Peptide Fragments, Small Molecule Libraries
Journal Title
Proceedings of the National Academy of Sciences
Conference Name
Journal ISSN
0027-8424
1091-6490
Volume Title
Publisher
Proceedings of the National Academy of Sciences
Sponsorship
Engineering and Physical Sciences Research Council (EP/K039520/1)