Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia.
Biol Chem. 2010 Aug;391(8):849-59. doi: 10.1515/BC.2010.089.
Alzheimer's disease (AD) is characterized by the extracellular deposition of the beta-amyloid protein (Abeta). Abeta is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by beta-secretase and gamma-secretase liberates Abeta from APP. The aspartyl protease BACE1 (beta-site APP-cleaving enzyme 1) catalyses the rate-limiting step in the production of Abeta, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.
阿尔茨海默病（AD）的特征是β-淀粉样蛋白（Abeta）的细胞外沉积。Abeta 是一种更大的前体蛋白——淀粉样前体蛋白（APP）的片段。β-分泌酶和γ-分泌酶对 APP 进行顺序蛋白水解切割，将 Abeta 从 APP 中释放出来。天冬氨酸蛋白酶 BACE1（β-位点 APP 切割酶 1）催化 Abeta 产生的限速步骤，因此它被认为是阿尔茨海默病药物开发的主要靶点。然而，BACE1 抑制剂治疗的发展存在两个问题。首先，BACE1 具有重要的生理作用。因此，抑制该酶可能会产生毒性后果。其次，BACE1 的活性部位相对较大，许多需要抑制 BACE1 活性的大型化合物都不太可能穿过血脑屏障。这篇综述重点介绍了 BACE1 的结构、基于开发活性位点抑制剂的当前治疗策略，以及涉及靶向 BACE1 表达或翻译后调控的新治疗方法。
