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

Angela F. McKoy, Jermont Chen, Trudi Schupbach, Michael H. Hecht

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)505-512
Number of pages8
JournalChemical Biology and Drug Design
Volume84
Issue number5
DOIs
StatePublished - Nov 1 2014

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Keywords

  • Amyloid-beta aggregation inhibitors
  • Biologic screening
  • Chemical biology
  • Chemical structure
  • Drug discovery

Fingerprint Dive into the research topics of 'Structure-activity relationships for a series of compounds that inhibit aggregation of the Alzheimer's peptide, Aβ42'. Together they form a unique fingerprint.

  • Cite this