Turning the tide on Alzheimer's disease: modulation of γ-secretase.
Turning the tide on Alzheimer's disease: modulation of γ-secretase.
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DOI：
10.1186/s13578-021-00738-7
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发表时间：
2022-01-04
影响因子：
7.5
通讯作者：
Li YM
中科院分区：
文献类型：
--
作者：
Luo JE;Li YM
阿尔茨海默病（AD）是最常见的神经退行性疾病。淀粉样蛋白-β（Aβ）斑块是“淀粉样蛋白假说”不可或缺的一部分，该假说认为Aβ肽的积累触发了一系列病理事件，导致神经变性并最终导致AD。虽然FDA批准了aducanumab，这是第一种Aβ靶向治疗，但需要多种安全有效的治疗方法来靶向AD的复杂病理。γ-分泌酶是一种对Aβ肽的生成至关重要的膜内乙酰基蛋白酶。γ-分泌酶的活性和特异性受专性亚基和调节蛋白的共同调控。由于γ-分泌酶的结构和功能复杂以及pan抑制剂的早期临床失败，γ-分泌酶一直是AD的具有挑战性的药物靶标。然而，γ-分泌酶调节剂已经显著改变了靶向γ-分泌酶的方法。在这里，我们回顾γ-分泌酶和小分子调节剂，从最初的非甾体抗炎药的子集的特点，最新的临床候选人。我们还讨论了γ-分泌酶的化学生物学，在高分辨率结构研究出现之前，小分子探针使γ-分泌酶的结构和功能得以深入了解。最后，我们讨论了最近的γ-分泌酶的晶体结构，这为底物识别和小分子的分子机制提供了有价值的前景。我们得出结论，γ-分泌酶的调节将成为AD治疗新浪潮的一部分。
Alzheimer’s disease (AD) is the most common type of neurodegenerative disorder. Amyloid-beta (Aβ) plaques are integral to the “amyloid hypothesis,” which states that the accumulation of Aβ peptides triggers a cascade of pathological events leading to neurodegeneration and ultimately AD. While the FDA approved aducanumab, the first Aβ-targeted therapy, multiple safe and effective treatments will be needed to target the complex pathologies of AD. γ-Secretase is an intramembrane aspartyl protease that is critical for the generation of Aβ peptides. Activity and specificity of γ-secretase are regulated by both obligatory subunits and modulatory proteins. Due to its complex structure and function and early clinical failures with pan inhibitors, γ-secretase has been a challenging drug target for AD. γ-secretase modulators, however, have dramatically shifted the approach to targeting γ-secretase. Here we review γ-secretase and small molecule modulators, from the initial characterization of a subset of NSAIDs to the most recent clinical candidates. We also discuss the chemical biology of γ-secretase, in which small molecule probes enabled structural and functional insights into γ-secretase before the emergence of high-resolution structural studies. Finally, we discuss the recent crystal structures of γ-secretase, which have provided valuable perspectives on substrate recognition and molecular mechanisms of small molecules. We conclude that modulation of γ-secretase will be part of a new wave of AD therapeutics.
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影响因子：
4.2
作者：
Boy, Kenneth M.;Guernon, Jason M.;Macor, John E.
通讯作者：
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影响因子：
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作者：
Fouladi, Maryam;Stewart, Clinton F.;Gilbertson, Richard J.
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DOI：
10.1124/jpet.112.199356
发表时间：
2013-03-01
影响因子：
3.5
作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.8
作者：
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通讯作者：
Li YM