beta-Secretase as a therapeutic target for Alzheimer's disease.
beta-Secretase as a therapeutic target for Alzheimer's disease.
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DOI：
10.1016/j.nurt.2008.05.007
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发表时间：
2008-07
期刊：
影响因子：
--
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Ghosh AK;Gemma S;Tang J
β分泌酶(Memapsin 2，BACE1)是开发治疗阿尔茨海默病(AD)的抑制剂药物的一个有吸引力的靶点。这种蛋白酶不仅在导致淀粉样蛋白-β(Aβ)产生的第一步起作用，而且其基因缺失只产生轻微的表型。此外，β-分泌酶是一种天冬氨酸蛋白酶，其作用机制和抑制作用是众所周知的。在过去的七年里，β分泌酶抑制剂的发展一直很缓慢，因为很难将所需的性质结合到一个单一的抑制剂分子中。然而，这一领域的稳步发展带来了包含许多靶向特征的抑制剂。本文就β-分泌酶抑制剂药物开发中基于结构的抑制剂进化策略作一综述。该领域的现状提供了一些乐观的理由，因为β分泌酶抑制剂已经被证明可以减少脑Aβ，并挽救转基因AD小鼠的认知能力下降，而且一种口服β分泌酶抑制剂候选药物正在进行临床试验。有了这个知识基础，似乎有理由期待更多的候选药物将在人体上进行测试，然后最终可能会从这个目标中产生成功的疾病修改药物。
β-Secretase (memapsin 2, BACE1) is an attractive target for the development of inhibitor drugs to treat Alzheimer’s disease (AD). Not only does this protease function at the first step in the pathway leading to the production of amyloid-β (Aβ), its gene deletion produces only mild phenotypes. In addition, β-secretase is an aspartic protease whose mechanism and inhibition are well known. The development of β-secretase inhibitors, actively pursued over the last seven years, has been slow, due to the difficulty in combining the required properties in a single inhibitor molecule. Steady progress in this field, however, has brought about inhibitors that contain many targeted characteristics. In this review, we describe the strategy of structure-based inhibitor evolution in the development of β-secretase inhibitor drug. The current status of the field offers grounds for some optimism, in that β-secretase inhibitors have been shown to reduce brain Aβ and to rescue the cognitive decline in transgenic AD mice, and an orally available β-secretase inhibitor drug candidate is in clinical trial. With this knowledge base, it seems reasonable to expect that more drug candidates will be tested in human, and then successful disease-modifying drugs may ultimately emerge from this target.
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