Department of Chemistry, Duke University, P.O. Box 90346, Durham, North Carolina 27708, USA.
J Am Chem Soc. 2010 Apr 14;132(14):4994-5. doi: 10.1021/ja100943r.
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.
淀粉样蛋白级联假说与金属离子在阿尔茨海默病进展中的作用的交集，激发了人们使用金属结合化合物作为潜在治疗剂的兴趣。在本工作中，我们描述了一种前螯合剂 SWH，它可被β-分泌酶酶促激活，生成高亲和性铜螯合剂 CP。由于β-分泌酶负责淀粉样前体蛋白的淀粉样形成加工，因此这种前螯合剂策略赋予了针对铜螯合的疾病特异性，这是一般金属螯合剂所不可能实现的。此外，一旦被激活，CP 就能够有效地从淀粉样蛋白-β中螯合铜，阻止并分解铜诱导的淀粉样蛋白-β聚集，并减少铜促进的活性氧形成。
