Systematic development of small molecules to inhibit specific microscopic steps of A[Beta]42 aggregation in Alzheimer's disease

• Published in: Proceedings of the National Academy of Sciences - PNAS 2017-01, Vol.114 (2), p.E200
• Main Authors: Habchi, Johnny, Chia, Sean, Limbocker, Ryan, Mannini, Benedetta, Ahn, Minkoo, Perni, Michele, Hansson, Oskar, Arosio, Paolo, Kumita, Janet R, Challa, Pavan Kumar, Cohen, Samuel IA, Linse, Sara, Dobson, Christopher M, Knowles, Tuomas PJ, Vendruscolo, Michele
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Kinetics; Microscopy; Molecules
• ISSN: 0027-8424; 1091-6490

The aggregation of the 42-residue form of the amyloid-... peptide (A...42) 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 A...42 aggregation. Here, we exploit this approach to develop a rational drug discovery strategy against A...42 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 A...42 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. (ProQuest: ... denotes formulae/symbols omitted.)