Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.

TitleStructure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42.
Publication TypeJournal Article
Year of Publication2014
AuthorsMcKoy, AF, Chen, J, Schüpbach, T, Hecht, MH
JournalChem Biol Drug Des
Volume84
Issue5
Pagination505-12
Date Published2014 Nov
ISSN1747-0285
KeywordsAging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Animals, Genetically Modified, Drosophila melanogaster, High-Throughput Screening Assays, Humans, Male, Peptide Fragments, Rats, Small Molecule Libraries, Structure-Activity Relationship, Toxicity Tests
Abstract

<p>Inhibiting aggregation of the amyloid-beta (Aβ) peptide may be an effective strategy for combating Alzheimer's disease. As the high-resolution structure of the toxic Aβ aggregate is unknown, rational design of small molecule inhibitors is not possible, and inhibitors are best isolated by high-throughput screening. We applied high-throughput screening to a collection of 65,000 compounds to identify compound D737 as an inhibitor of Aβ aggregation. D737 diminished the formation of oligomers and fibrils, and reduced Aβ42-induced cytotoxicity. Most importantly, D737 increased the life span and locomotive ability of transgenic flies in a Drosophila melanogaster model of Alzheimer's disease (J Biol Chem, 287, 2012, 38992). To explore the chemical features that make D737 an effective inhibitor of Aβ42 aggregation and toxicity, we tested a small collection of eleven analogues of D737. Overall, the ability of a compound to inhibit Aβ aggregation was a good predictor of its efficacy in prolonging the life span and locomotive ability of transgenic flies expressing human Aβ42 in the central nervous system. Two compounds (D744 and D830) with fluorine substitutions on an aromatic ring were effective inhibitors of Aβ42 aggregation and increased the longevity of transgenic flies beyond that observed for the parent compound, D737.</p>

DOI10.1111/cbdd.12341
Alternate JournalChem Biol Drug Des
PubMed ID24751138
PubMed Central IDPMC4197064
Grant ListR21 AG028462 / AG / NIA NIH HHS / United States
5R21AG028462 / AG / NIA NIH HHS / United States
/ / Howard Hughes Medical Institute / United States