Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.
Chemical Biology, Molecular Mechanism and Clinical Perspective of γ-Secretase Modulators in Alzheimer's Disease.
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DOI：
10.2174/157015911798376352
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发表时间：
2011-12
影响因子：
5.3
通讯作者：
Weggen S
中科院分区：
文献类型：
--
作者：
Bulic B;Ness J;Hahn S;Rennhack A;Jumpertz T;Weggen S
大量证据表明，脑内淀粉样蛋白Aβ42肽的寡聚和积聚在家族性和散发性阿尔茨海默病的发病机制中起着至关重要的作用。影像研究表明，Aβ的积聚在临床症状出现前许多年就开始了，随后的神经变性和认知能力下降可能独立于Aβ而进行。这意味着有必要对认知正常的人进行早期干预，采用优先考虑安全性的治疗策略。天冬氨酸蛋白酶γ-分泌酶催化细胞产生Aβ42肽的最后一步，是抗淀粉样变干预策略的主要靶点。由于γ-分泌酶在Noch信号通路中的重要作用，第一代γ-分泌酶抑制剂已经观察到明显的基于机制的毒性，这种方法的安全性受到质疑。然而，两类新的小分子，γ分泌酶调节剂(GSM)和缺口保留的γ分泌酶抑制剂，使γ分泌酶重新成为AD的药物靶点。β是一种小分子，会导致产物从GSM 42转向更短、毒性更低的抗体多肽。重要的是，GSM没有其他生理上重要的γ-分泌酶复合体底物，如Noch。最近，已经描述了具有纳米分子效力和良好的体内性质的GSM。本文综述了γ-分泌酶的特殊蛋白分解活性，以及以γ-分泌酶复合体为靶点的化合物的化学生物学、分子机制和临床应用前景，重点介绍了GSM。
Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.