Research Group Chemical Biology of Neurodegenerative Diseases, Center of Advanced European Studies and Research, D-53175 Bonn, Germany.
Curr Neuropharmacol. 2011 Dec;9(4):598-622. doi: 10.2174/157015911798376352.
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.
有充分的证据表明，淀粉样蛋白 Aβ42 肽的寡聚化和积累在家族性和散发性阿尔茨海默病的发病机制中至关重要。影像学研究表明，Aβ 的积累在临床症状出现前多年就开始了，随后的神经退行性变和认知能力下降可能与 Aβ 无关。这意味着需要在认知正常的个体中进行早期干预，采用以安全性为优先的治疗策略。天冬氨酸蛋白酶 γ-分泌酶催化 Aβ42 肽在细胞内生成的最后一步，是抗淀粉样蛋白形成干预策略的主要靶点。由于 γ-分泌酶在 NOTCH 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，因此该方法的安全性受到质疑。然而，两种新的小分子类别，γ-分泌酶调节剂（GSM）和 NOTCH 节约型 γ-分泌酶抑制剂，使 γ-分泌酶重新成为 AD 的药物靶点。GSM 是一种小分子，可使产物从 Aβ42 向较短且毒性较小的 Ab 肽转移。重要的是，GSM 可使 NOTCH 等 γ-分泌酶复合物的其他生理上重要的底物免受影响。最近，已经描述了具有纳摩尔效力和良好体内特性的 GSM。在这篇综述中，我们总结了关于 γ-分泌酶异常蛋白水解活性的知识，以及靶向 γ-分泌酶复合物的化合物的化学生物学、分子机制和临床观点，特别关注 GSM。
