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J Zhejiang Univ (Med Sci)  2019, Vol. 48 Issue (6): 688-694    DOI: 10.3785/j.issn.1008-9292.2019.12.15
    
Research progress on selective immunoproteasome inhibitors
KONG Limin1(),LU Jingyi2,ZHU Huajian2,ZHANG Jiankang2,*()
1. Department of Pharmacy, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
2. School of Medicine, Zhejiang University City College, Hangzhou 310015, China
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Abstract  

Immunoproteasome is associated with various diseases such as hematologic malignancies, inflammatory, autoimmune and central nervous system diseases, and over expression of immunoproteasome is observed in all of these diseases. Immunoproteasome inhibitors can reduce the expression of immunoproteasome by inhibiting the production of related cell-inducing factors and the activity of T lymphocyte for treating related diseases. In order to achieve good efficacy and reduce the toxic effects, key for development of selective immunoproteasome inhibitors is the high selectivity and potent activity of the three active subunits of the proteasome. This review summarizes the structure and functions of immunoproteasome and the associated diseases. Besides, structure, activity and status of selective immunoproteasome inhibitors are also been highlighted.



Key wordsProteasomeinhibitors/analysis      Multienzyme complexes      Structure-activity relationship      Autoimmune diseases      Proteasome inhibitors/therapy      Bortezomib      Review     
Received: 30 January 2019      Published: 19 January 2020
CLC:  R94  
  R967  
Corresponding Authors: ZHANG Jiankang     E-mail: liminkong@zju.edu.cn;zhang_jk@zucc.edu.cn
Cite this article:

KONG Limin,LU Jingyi,ZHU Huajian,ZHANG Jiankang. Research progress on selective immunoproteasome inhibitors. J Zhejiang Univ (Med Sci), 2019, 48(6): 688-694.

URL:

http://www.zjujournals.com/med/10.3785/j.issn.1008-9292.2019.12.15     OR     http://www.zjujournals.com/med/Y2019/V48/I6/688


选择性免疫蛋白酶体抑制剂研究进展

免疫蛋白酶体与血液肿瘤、感染性疾病、自身免疫性疾病、中枢神经系统疾病等密切相关,这些疾病均呈现免疫蛋白酶体高表达。免疫蛋白酶体抑制剂可通过抑制相关细胞诱导因子的生成和自身反应性T细胞的活性来阻断免疫蛋白酶体的表达,从而治疗相关疾病。选择性免疫蛋白酶体抑制剂研发的关键是针对免疫型蛋白酶体的高度选择性,兼顾蛋白酶体上三个活性亚基的活性水平,才能在达到良好疗效的同时减少不良反应。本文介绍了免疫蛋白酶体的结构、功能,以及与多种疾病之间的关系,针对目前已报道的环氧酮肽类共价结合、其他短肽类共价结合、短肽类非共价结合选择性免疫蛋白酶体抑制剂的结构、活性及发展现状作一综述。


关键词: 半胱氨酸内肽酶类/分析,  多酶复合物,  构效关系,  自身免疫疾病,  蛋白酶体抑制剂/治疗,  硼替佐米,  综述 
Fig 1 Structures of selective epoxyketone peptidyl immunoproteasome inhibitors
化合物 蛋白酶体抑制活性(IC50) 选择性(β1c/β1i)
β1i β1c
IC50:半抑制浓度.
KZR-504 0.05 46.35 927
类似物1 0.11 >222 >2000
类似物2 0.14 91.07 651
Tab 1 Proteasome inhibitory activities and selectivities of KZR-504 and its derivatives[15]  (μmol/L)
Fig 2 Binding modes of ONX-0914 with immunoproteasome and constitutive proteasome
化合物 蛋白酶体抑制活性(IC50) 选择性(β5c/β5i)
β1i β1c β2i β2c β5i β5c
ONX-0914 460 >104 590 1100 5.7 54 9
PR-924 1840 >104 >104 >104 2.5 227 91
LU-005i 300 >104 410 2500 6.6 287 43
LU-025i >104 >104 >104 >104 36 1900 53
LU-045i >104 >104 >104 >104 32 827 26
LU-015i 7100 >104 >104 >104 8.3 4600 553
Tab 2 Proteasome inhibitory activities and selectivities of ONX-0914 and its derivatives[12, 18]  (nmol/L)
Fig 3 Structures of other peptidyl covalent selective immunoproteasome inhibitors
化合物 蛋白酶体抑制活性(IC50) 选择性(β5c/β5i)
β5i β5c
ONX-0914 0.06 0.51 9
化合物3 1.13 28.46 25
卡非佐米 0.02 0.005 0.3
化合物4 0.05 0.03 0.6
Tab 3 Proteasome inhibitory activities and selectivities of sulfonyl fluoride and corresponding epoxyketone derivatives[27] (μmol/L)
Fig 4 Structures of non-covalent peptidyl selective immunoproteasome inhibitors
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