Development and mechanism of γ-secretase modulators for Alzheimer's disease.
Development and mechanism of γ-secretase modulators for Alzheimer's disease.
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DOI：
10.1021/bi400377p
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发表时间：
2013-05-14
期刊：
影响因子：
2.9
通讯作者：
Li, Yue-Ming
中科院分区：
文献类型：
--
作者：
Crump, Christina J.;Johnson, Douglas S.;Li, Yue-Ming
γ-分泌酶是一种由早老素、Nicastrin、Aph 1和Pen 2组成的γ-酰基膜内蛋白酶，具有19个跨膜结构域。γ-分泌酶裂解淀粉样前体蛋白（APP）释放Aβ肽，可能在阿尔茨海默病（AD）的发病机制中发挥作用。此外，γ-分泌酶切割Notch和其他I型膜蛋白。γ-分泌酶抑制剂（GSI）已被开发并用于临床研究。然而，临床试验显示GSI的不良反应可能与Notch信号传导、总体APP加工和其他底物裂解的非歧视性抑制有关。因此，这些发现要求开发靶向γ-分泌酶活性的疾病调节剂，以降低Aβ42的产生，而不阻断γ-分泌酶底物的整体加工。γ-分泌酶调节剂（GSMs）最初来源于非甾体抗炎药（NSAIDs），具有这些特性，是本文的重点。然而，第一代GSM由于效力低和不期望的神经药代动力学特性而具有有限的潜力。这代GSM被认为与APP底物、γ-分泌酶或两者相互作用。为了提高效力和脑可用性，已经开发了第二代GSM，包括NSAID衍生的羧酸和非NSAID衍生的杂环化学型以及天然产物衍生的GSM。这一代GSM的动物研究显示了令人鼓舞的临床前概况。此外，使用有效的GSM光亲和探针，多项研究明确表明，羧酸和杂环GSM都特异性靶向早老素，γ-分泌酶的催化亚基。此外，两种类型的GSM在γ-分泌酶复合物内具有不同的结合位点，并表现出不同的Aβ谱。GSMs诱导γ-分泌酶的构象变化以实现调节。提出并讨论了各种模型。尽管GSM研究取得了进展，但仍有许多悬而未决的问题有待研究，以实现开发GSM作为有效的AD治疗方法的最终目标。
γ-Secretase is an aspartyl intramembranal protease composed of presenilin, Nicastrin, Aph1 and Pen2 with 19 transmembrane domains. γ-Secretase cleaves the amyloid precursor proteins (APP) to release Aβ peptides that likely play a causative role in the pathogenesis of Alzheimer disease (AD). In addition, γ-secretase cleaves Notch and other type I membrane proteins. γ-Secretase inhibitors (GSIs) have been developed and used for clinical studies. However, clinical trials have shown adverse effects of GSIs that are potentially linked with non-discriminatory inhibition of Notch signaling, overall APP processing and other substrate cleavages. Therefore, these findings call for the development of disease modifying agents that target γ-secretase activity to lower Aβ42 production without blocking the overall processing of γ-secretase substrates. γ-Secretase modulators (GSMs) originally derived from non-steroidal anti-inflammatory drugs (NSAIDs) display such characteristics and are the focus of this review. However, first generation GSMs have limited potential due to low potency and undesired neuropharmacokinetic properties. This generation of GSMs has been suggested to interact with the APP substrate, γ-secretase or both. To improve the potency and brain availability, second generation GSMs including NSAID-derived carboxylic acid and non-NSAID-derived heterocyclic chemotypes as well as natural product-derived GSMs have been developed. Animal studies of this generation of GSMs have shown encouraging preclinical profiles. Moreover, using potent GSM photoaffinity probes, multiple studies unambiguously have showed that both carboxylic acid and heterocyclic GSMs specifically target presenilin, the catalytic subunit of γ-secretase. In addition, two types of GSMs have distinct binding sites within the γ-secretase complex and exhibit different Aβ profiles. GSMs induce a conformational change of γ-secretase to achieve modulation. Various models are proposed and discussed. Despite the progress of GSM research, many outstanding issues remain to be investigated to achieve the ultimate goal of developing GSMs as effective AD therapies.
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