Golde Todd E, Koo Edward H, Felsenstein Kevin M, Osborne Barbara A, Miele Lucio
Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Biochim Biophys Acta. 2013 Dec;1828(12):2898-907. doi: 10.1016/j.bbamem.2013.06.005. Epub 2013 Jun 17.
γ-Secretase is a fascinating, multi-subunit, intramembrane cleaving protease that is now being considered as a therapeutic target for a number of diseases. Potent, orally bioavailable γ-secretase inhibitors (GSIs) have been developed and tested in humans with Alzheimer's disease (AD) and cancer. Preclinical studies also suggest the therapeutic potential for GSIs in other disease conditions. However, due to inherent mechanism based-toxicity of non-selective inhibition of γ-secretase, clinical development of GSIs will require empirical testing with careful evaluation of benefit versus risk. In addition to GSIs, compounds referred to as γ-secretase modulators (GSMs) remain in development as AD therapeutics. GSMs do not inhibit γ-secretase, but modulate γ-secretase processivity and thereby shift the profile of the secreted amyloid β peptides (Aβ) peptides produced. Although GSMs are thought to have an inherently safe mechanism of action, their effects on substrates other than the amyloid β protein precursor (APP) have not been extensively investigated. Herein, we will review the current state of development of GSIs and GSMs and explore pertinent biological and pharmacological questions pertaining to the use of these agents for select indications. This article is part of a Special Issue entitled: Intramembrane Proteases.
γ-分泌酶是一种迷人的多亚基膜内裂解蛋白酶，目前正被视为多种疾病的治疗靶点。强效的、口服生物可利用的γ-分泌酶抑制剂（GSIs）已被开发并在患有阿尔茨海默病（AD）和癌症的人类患者中进行了测试。临床前研究还表明GSIs在其他疾病状况下具有治疗潜力。然而，由于γ-分泌酶非选择性抑制的固有基于机制的毒性，GSIs的临床开发将需要进行经验性测试，并仔细评估益处与风险。除了GSIs之外，被称为γ-分泌酶调节剂（GSMs）的化合物仍在作为AD治疗药物进行研发。GSMs并不抑制γ-分泌酶，而是调节γ-分泌酶的持续加工能力，从而改变所分泌的淀粉样β肽（Aβ）的肽谱。尽管GSMs被认为具有本质上安全的作用机制，但其对淀粉样β蛋白前体（APP）以外的底物的影响尚未得到广泛研究。在此，我们将综述GSIs和GSMs的当前开发状态，并探讨与这些药物用于特定适应症相关的生物学和药理学问题。本文是名为“膜内蛋白酶”的特刊的一部分。
