A prochelator activated by beta-secretase inhibits Abeta aggregation and suppresses copper-induced reactive oxygen species formation.
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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.
SubjectAmyloid Precursor Protein Secretases
Reactive Oxygen Species
Published Version (Please cite this version)10.1021/ja100943r
Publication InfoFolk, Drew S; & Franz, Katherine J (2010). A prochelator activated by beta-secretase inhibits Abeta aggregation and suppresses copper-induced reactive oxygen species formation. J Am Chem Soc, 132(14). pp. 4994-4995. 10.1021/ja100943r. Retrieved from https://hdl.handle.net/10161/4038.
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Member of the Duke Cancer Institute
Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use