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J Am Chem Soc. 2010 Apr 14;132(14):4994-5. doi: 10.1021/ja100943r.

A prochelator activated by beta-secretase inhibits Abeta aggregation and suppresses copper-induced reactive oxygen species formation.

Author information

1
Department of Chemistry, Duke University, P.O. Box 90346, Durham, North Carolina 27708, USA.

Abstract

The intersection of the amyloid cascade hypothesis and the implication of metal ions in Alzheimer's disease progression has sparked an interest in using metal-binding compounds as potential therapeutic agents. In the present work, we describe a prochelator SWH that is enzymatically activated by beta-secretase to produce a high affinity copper chelator CP. Because beta-secretase is responsible for the amyloidogenic processing of the amyloid precursor protein, this prochelator strategy imparts disease specificity toward copper chelation not possible with general metal chelators. Furthermore, once activated, CP efficiently sequesters copper from amyloid-beta, prevents and disassembles copper-induced amyloid-beta aggregation, and diminishes copper-promoted reactive oxygen species formation.

PMID:
20297791
PMCID:
PMC2860781
DOI:
10.1021/ja100943r
[Indexed for MEDLINE]
Free PMC Article

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