Inhibition of γ-Secretase Activity by Helical β-Peptide Foldamers
Inhibition of γ-Secretase Activity by Helical β-Peptide Foldamers
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DOI：
10.1021/ja9001458
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发表时间：
2009-06-03
影响因子：
15
通讯作者：
Higuchi, Tsunehiko
中科院分区：
文献类型：
--
作者：
Imamura, Yuki;Watanabe, Naoto;Higuchi, Tsunehiko
阿尔茨海默病（Alzheimer's disease，AD）是一种神经退行性疾病，其病理特征是淀粉样β（A β）肽在细胞外大量沉积形成老年斑，γ-分泌酶抑制淀粉样前体蛋白（amyloidogenic amyloid precursor protein，APP）的加工是AD预防和治疗的重要策略。在这里，我们表明，β-肽折叠体设计采用12-螺旋构象在溶液中是有效的和特异性的γ-分泌酶抑制剂。破坏螺旋性的细微修饰大大降低了抑制效力，表明螺旋构象对于有效抑制至关重要。这些β-肽与螺旋肽型抑制剂竞争，表明它们与γ-分泌酶的底物结合位点相互作用。在纳摩尔浓度下具有抑制活性的β-肽应该是用于开发γ-分泌酶特异性抑制剂和分子工具以探索膜内蛋白酶的底物识别的有用的先导化合物。
Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by extensive extracellular deposition of amyloid-beta (A beta) peptides as senile plaques, and inhibition of "amyloidogenic" amyloid precursor protein (APP) processing by gamma-secretase is an important strategy for prevention and treatment of AD. Here we show that beta-peptide foldamers designed to adopt a 12-helical conformation in solution are potent and specific inhibitors of gamma-secretase. Subtle modifications that disrupt helicity substantially reduce inhibitory potency, suggesting that helical conformation is critical for effective inhibition. These beta-peptides competed with helical peptide-type inhibitor, suggesting that they interact with the substrate binding site of gamma-secretase. The beta-peptide with inhibitory activity at nanomolar concentration should be a useful lead compound for development of gamma-secretase-specific inhibitors and molecular tools to explore substrate recognition by intramembrane proteases.