title: A novel inhibitor of amyloid β (Aβ) peptide aggregation: from high throughput screening to efficacy in an animal model of Alzheimer disease.
abstract: Compelling evidence indicates that aggregation of the amyloid β (Aβ) peptide is a major underlying molecular culprit in Alzheimer disease. Specifically, soluble oligomers of the 42-residue peptide (Aβ42) lead to a series of events that cause cellular dysfunction and neuronal death. Therefore, inhibiting Aβ42 aggregation may be an effective strategy for the prevention and/or treatment of disease. We describe the implementation of a high throughput screen for inhibitors of Aβ42 aggregation on a collection of 65,000 small molecules. Among several novel inhibitors isolated by the screen, compound D737 was most effective in inhibiting Aβ42 aggregation and reducing Aβ42-induced toxicity in cell culture. The protective activity of D737 was most significant in reducing the toxicity of high molecular weight oligomers of Aβ42. The ability of D737 to prevent Aβ42 aggregation protects against cellular dysfunction and reduces the production/accumulation of reactive oxygen species. Most importantly, treatment with D737 increases the life span and locomotive ability of flies in a Drosophila melanogaster model of Alzheimer disease.
authors.affiliation: Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
authors.forename: Angela Fortner
authors.initials: AF
authors.lastname: McKoy
authors.forename: Jermont
authors.initials: J
authors.lastname: Chen
authors.forename: Trudi
authors.initials: T
authors.lastname: Schupbach
authors.forename: Michael H
authors.initials: MH
authors.lastname: Hecht
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000818:Animals; D030801:Animals, Genetically Modified; D052160:Benzothiazoles; D002626:Chemistry, Pharmaceutical / Q000379:methods; D004331:Drosophila melanogaster; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008956:Models, Chemical; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry; D010455:Peptides / Q000737:chemistry; D017382:Reactive Oxygen Species; D013844:Thiazoles / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; C577860:D737 compound; D007211:Indoles; D010446:Peptide Fragments; D010455:Peptides; D017382:Reactive Oxygen Species; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); D049452:Green Fluorescent Proteins; C009462:thioflavin T