Inhibitors of the immunoproteasome: current status and future directions.
Inhibitors of the immunoproteasome: current status and future directions.
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DOI：
10.2174/1381612811319220018
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发表时间：
2013
影响因子：
3.1
通讯作者：
Lee W
中科院分区：
文献类型：
--
作者：
Miller Z;Ao L;Kim KB;Lee W
泛素-蛋白酶体系统(UPS)在维持蛋白质动态平衡和调节多种细胞过程中起着重要作用。蛋白酶体是一种多酶复合体，是UPS的关键成分，已被FDA批准为Bortezomib和carfilzomib的治疗靶点。这些蛋白酶体抑制剂药物显著改善了血液系统恶性肿瘤患者的预后，目前正在研究其他类型的癌症以及其他几种疾病。这些已被批准的蛋白酶体抑制剂不分青红皂白地针对结构性蛋白酶体和免疫蛋白酶体的催化活性，它们对正常细胞中结构性蛋白酶体的抑制作用被认为是导致不良副作用的原因之一。此外，选择性免疫蛋白酶体抑制被认为对其他疾病有独特的作用，包括那些涉及免疫功能异常的疾病。免疫蛋白酶体最初被认为在获得性免疫反应中发挥作用，但在炎症性疾病和癌症等疾病状态下经常上调，提示其功能超出了抗原提呈。为了探索免疫蛋白酶体作为治疗这些疾病的潜在靶点，免疫蛋白酶体特异性抑制剂的开发已成为最近研究的焦点。由于学术和工业团体的大量努力，免疫蛋白酶体选择性抑制剂现在已经被识别出来，并在几种疾病模型上进行了测试。这些抑制剂也为研究免疫蛋白酶体的生物学功能提供了一套有价值的化学工具。在这篇综述中，我们将重点介绍免疫蛋白酶体选择性抑制剂的最新进展。
The ubiquitin-proteasome system (UPS) plays a vital role in maintaining protein homeostasis and regulating numerous cellular processes. The proteasome, a multi-protease complex, is the key component of the UPS and has been validated as a therapeutic target by the FDA's approval of bortezomib and carfilzomib. These proteasome inhibitor drugs have substantially improved outcomes in patients with hematological malignancies and are currently being investigated for other types of cancer as well as several other diseases. These approved proteasome inhibitors target the catalytic activity of both the constitutive proteasome and the immunoproteasome indiscriminately, and their inhibitory effects on the constitutive proteasome in normal cells are believed to contribute to unwanted side effects. In addition, selective immunoproteasome inhibition has been proposed to have unique effects on other diseases, including those involving aberrant immune function. Initially recognized for its role in the adaptive immune response, the immunoproteasome is often upregulated in disease states such as inflammatory diseases and cancer, suggesting functions beyond antigen presentation. In an effort to explore the immunoproteasome as a potential therapeutic target in these diseases, the development of immunoproteasome-specific inhibitors has become the focus of recent studies. Owing to considerable efforts by both academic and industry groups, immunoproteasome-selective inhibitors have now been identified and tested against several disease models. These inhibitors also provide a valuable set of chemical tools for investigating the biological function of the immunoproteasome. In this review, we will focus on the recent efforts towards the development of immunoproteasome-selective inhibitors.
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影响因子：
3.1
作者：
Angeles, Arkhjamil;Fung, Gabriel;Luo, Honglin
通讯作者：
Luo, Honglin
影响因子：
5.2
作者：
Atkinson, Stuart P.;Collin, Joseph;Armstrong, Lyle
通讯作者：
Armstrong, Lyle
影响因子：
9
作者：
Bossola, M;Muscaritoli, M;Baccino, FM
通讯作者：
Baccino, FM
影响因子：
3.7
作者：
Díaz-Hernández, M;Martín-Aparicio, E;Lucas, JJ
通讯作者：
Lucas, JJ
影响因子：
16.6
作者：
Feling, RH;Buchanan, GO;Fenical, W
通讯作者：
Fenical, W