Department of Experimental Pathology, University of Bologna, via S. Giacomo 12, 40126 Bologna, Italy.
Curr Pharm Des. 2013;19(4):702-18.
Immunoproteasome is an emerging biological target that constitutes a key element not only in antigen presentation but also in T cell and cytokine regulation as well as cellular homeostasis. Respect to standard proteasome, the inducible expression and different sensitivity towards activity modulators of immunoproteasome render it a potential therapeutic target for tumours and central nervous system diseases. In this review we report the cutting edge studies for understanding when immunoproteasome expression is induced and how it regulates pivotal pathways involved in tumours and neuropathologies, including apoptosis and inflammation. We emphasize its role as a new pharmacological target by describing the recent medicinal chemistry efforts aimed at design selective small-molecule modulators of both standard- and immuno-proteasome forms. Finally, we also present an in silico model of the human immunoproteasome structure by the major molecular differences with the 20S standard proteasome and discuss the perspective for the design of novel specific smallmolecule modulators for the different proteasome isoforms.
免疫蛋白酶体是一个新兴的生物靶点，它不仅是抗原呈递的关键因素，而且在 T 细胞和细胞因子调节以及细胞内稳态中也起着关键作用。与标准蛋白酶体相比，免疫蛋白酶体的诱导表达和对活性调节剂的不同敏感性使其成为肿瘤和中枢神经系统疾病的潜在治疗靶点。在这篇综述中，我们报告了为理解免疫蛋白酶体表达何时被诱导以及它如何调节肿瘤和神经病理学中涉及凋亡和炎症的关键途径的最新研究进展。我们通过描述旨在设计标准和免疫蛋白酶体形式的选择性小分子调节剂的最新药物化学研究，强调了它作为一个新的药理学靶点的作用。最后，我们还通过主要分子差异介绍了人免疫蛋白酶体结构的计算模型与 20S 标准蛋白酶体，并讨论了为不同蛋白酶体同工型设计新型特异性小分子调节剂的前景。
