title: Systematic development of small molecules to inhibit specific microscopic steps of Aβ42 aggregation in Alzheimer's disease.
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.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Johnny
authors.initials: J
authors.lastname: Habchi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Sean
authors.initials: S
authors.lastname: Chia
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Ryan
authors.initials: R
authors.lastname: Limbocker
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mannini
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Minkoo
authors.initials: M
authors.lastname: Ahn
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Michele
authors.initials: M
authors.lastname: Perni
authors.affiliation: Department of Clinical Sciences, Lund University, 221 00 Lund, Sweden.|Memory Clinic, Skåne University Hospital, 205 02 Malmo, Sweden.
authors.forename: Oskar
authors.initials: O
authors.lastname: Hansson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Janet R
authors.initials: JR
authors.lastname: Kumita
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Pavan Kumar
authors.initials: PK
authors.lastname: Challa
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom.
authors.forename: Samuel I A
authors.initials: SI
authors.lastname: Cohen
authors.affiliation: Department of Biochemistry & Structural Biology, Center for Molecular Protein Science, Lund University, 221 00 Lund, Sweden.
authors.forename: Sara
authors.identifier: 0000-0001-9629-7109
authors.initials: S
authors.lastname: Linse
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk tpjk2@cam.ac.uk cmd44@cam.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk tpjk2@cam.ac.uk cmd44@cam.ac.uk.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; mv245@cam.ac.uk tpjk2@cam.ac.uk cmd44@cam.ac.uk.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D017173:Caenorhabditis elegans; D002555:Cerebrospinal Fluid / Q000737:chemistry; D055808:Drug Discovery; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D054852:Small Molecule Libraries; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; amyloid-β peptide; drug discovery; protein aggregation; protein misfolding