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J Am Chem Soc DOI:10.1021/ja107552s

Small molecule microarrays enable the discovery of compounds that bind the Alzheimer's Aβ peptide and reduce its cytotoxicity.

Publication TypeJournal Article
Year of Publication2010
AuthorsChen, J, Armstrong, AH, Koehler, AN, Hecht, MH
JournalJ Am Chem Soc
Volume132
Issue47
Pages17015-22
Date Published2010 Dec 01
ISSN1520-5126
KeywordsAlzheimer Disease, Amyloid beta-Peptides, Animals, Cell Survival, Cytotoxins, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, High-Throughput Screening Assays, Microarray Analysis, PC12 Cells, Peptide Fragments, Protein Binding, Rats, Reproducibility of Results, Small Molecule Libraries
Abstract

The amyloid-β (Aβ) aggregation pathway is a key target in efforts to discover therapeutics that prevent or delay the onset of Alzheimer's disease. Efforts at rational drug design, however, are hampered by uncertainties about the precise nature of the toxic aggregate. In contrast, high-throughput screening of compound libraries does not require a detailed understanding of the structure of the toxic species, and can provide an unbiased method for the discovery of small molecules that may lead to effective therapeutics. Here, we show that small molecule microarrays (SMMs) represent a particularly promising tool for identifying compounds that bind the Aβ peptide. Microarray slides with thousands of compounds immobilized on their surface were screened for binding to fluorescently labeled Aβ. Seventy-nine compounds were identified by the SMM screen, and then assayed for their ability to inhibit the Aβ-induced killing of PC12 cells. Further experiments focused on exploring the mechanism of rescue for one of these compounds: Electron microscopy and Congo red binding showed that the compound enhances fibril formation, and suggest that it may rescue cells by accelerating Aβ aggregation past an early toxic oligomer. These findings demonstrate that the SMM screen for binding to Aβ is effective at identifying compounds that reduce Aβ toxicity, and can reveal potential therapeutic leads without the biases inherent in methods that focus on inhibitors of aggregation.

URLhttp://dx.doi.org/10.1021/ja107552s
DOI10.1021/ja107552s
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/21062056?dopt=Abstract

Alternate JournalJ. Am. Chem. Soc.
PubMed ID21062056
PubMed Central IDPMC3063105
Grant ListR21 AG028462 / AG / NIA NIH HHS / United States
5R21AG028462 / AG / NIA NIH HHS / United States
R21 AG028462-02 / AG / NIA NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States