Na Chan Hyun, Jeon Sang Hee, Zhang Guangtao, Olson Gary L, Chae Chi-Bom
Department of Life Science, Division of Molecular and Life Sciences, Pohang University of Science and Technology, Pohang, Korea.
J Neurochem. 2007 Jun;101(6):1583-95. doi: 10.1111/j.1471-4159.2006.04441.x.
Amyloid beta-peptide (Abeta) is implicated as the major causative agent in Alzheimer's disease (AD). Abeta is produced by the processing of the amyloid precursor protein (APP) by BACE1 (beta-secretase) and gamma-secretase. Many inhibitors have been developed for the secretases. However, the inhibitors will interfere with the processing of not only APP but also of other secretase substrates. In this study, we describe the development of inhibitors that prevent production of Abeta by specific binding to the beta-cleavage site of APP. We used the hydropathic complementarity (HC) approach for the design of short peptide inhibitors. Some of the HC peptides were bound to the substrate peptide (Sub W) corresponding to the beta-cleavage site of APP and blocked its cleavage by recombinant human BACE1 (rhBACE1) in vitro. In addition, HC peptides specifically inhibited the cleavage of Sub W, and not affecting other BACE1 substrates. Chemical modification allowed an HC peptide (CIQIHF) to inhibit the processing of APP as well as the production of Abeta in the treated cells. Such novel APP-specific inhibitors will provide opportunity for the development of drugs that can be used for the prevention and treatment of AD with minimal side effects.
淀粉样β肽（Aβ）被认为是阿尔茨海默病（AD）的主要致病因子。Aβ是由淀粉样前体蛋白（APP）经β-分泌酶1（BACE1）和γ-分泌酶加工产生的。已经开发了许多针对这些分泌酶的抑制剂。然而，这些抑制剂不仅会干扰APP的加工，还会干扰其他分泌酶底物的加工。在本研究中，我们描述了通过与APP的β-切割位点特异性结合来阻止Aβ产生的抑制剂的开发。我们使用亲水性互补（HC）方法设计短肽抑制剂。一些HC肽与对应于APPβ-切割位点的底物肽（Sub W）结合，并在体外阻断其被重组人BACE1（rhBACE1）切割。此外，HC肽特异性抑制Sub W的切割，而不影响其他BACE1底物。化学修饰使一种HC肽（CIQIHF）能够抑制处理细胞中APP的加工以及Aβ的产生。这种新型的APP特异性抑制剂将为开发可用于预防和治疗AD且副作用最小的药物提供机会。
