Ghosh Arun K, Gemma Sandra, Tang Jordan
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
Neurotherapeutics. 2008 Jul;5(3):399-408. doi: 10.1016/j.nurt.2008.05.007.
beta-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-beta (Abeta), its gene deletion produces only mild phenotypes. In addition, beta-secretase is an aspartic protease whose mechanism and inhibition are well known. The development of beta-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 beta-secretase inhibitor drug. The current status of the field offers grounds for some optimism, in that beta-secretase inhibitors have been shown to reduce brain Abeta and to rescue the cognitive decline in transgenic AD mice, and an orally available beta-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.
β-分泌酶（膜天冬氨酸蛋白酶2，BACE1）是开发治疗阿尔茨海默病（AD）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β-淀粉样蛋白（Aβ）产生的途径的第一步发挥作用，而且其基因缺失仅产生轻微的表型。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已为人熟知。在过去七年中积极研发的β-分泌酶抑制剂进展缓慢，原因是难以在单个抑制剂分子中兼具所需的特性。然而，该领域的稳步进展已带来了具有许多靶向特征的抑制剂。在这篇综述中，我们描述了在β-分泌酶抑制剂药物研发中基于结构的抑制剂进化策略。该领域的现状带来了一些乐观的理由，因为β-分泌酶抑制剂已被证明可减少脑内Aβ并挽救转基因AD小鼠的认知衰退，且一种口服可用的β-分泌酶抑制剂候选药物正在进行临床试验。基于这一知识库，预计会有更多候选药物在人体中进行测试，最终可能会从这个靶点开发出成功的疾病修饰药物。
