选择性免疫蛋白酶体抑制剂研究进展

doi:10.3785/j.issn.1008-9292.2019.12.15

浙江大学学报（医学版）

2019, Vol. 48

Issue (6): 688-694 DOI: 10.3785/j.issn.1008-9292.2019.12.15

综述

选择性免疫蛋白酶体抑制剂研究进展

孔丽敏¹(

),陆婧怡²,祝华建²,张建康^2,*(

)

1. 浙江大学医学院附属第一医院药学部, 浙江杭州 310003
2. 浙江大学城市学院医学院, 浙江杭州 310015

Research progress on selective immunoproteasome inhibitors

KONG Limin¹(

),LU Jingyi²,ZHU Huajian²,ZHANG Jiankang^2,*(

)

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

全文: PDF(2094 KB)

HTML( 11 )

摘要：

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

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 words: Proteasomeinhibitors/analysis Multienzyme complexes Structure-activity relationship Autoimmune diseases Proteasome inhibitors/therapy Bortezomib Review

收稿日期: 2019-01-30 出版日期: 2020-01-19

R94

基金资助: 国家自然科学基金(81803432);浙江省基础公益研究计划(LGF18H300001)

通讯作者: 张建康 E-mail: liminkong@zju.edu.cn;zhang_jk@zucc.edu.cn

作者简介: 孔丽敏(1987-), 女, 硕士, 主管药师, 主要从事医院药学研究; E-mail:liminkong@zju.edu.cn; https://orcid.org/000-0002-0912-1074

	服务
	把本文推荐给朋友
	加入引用管理器
	E-mail Alert
	RSS
	作者相关文章
	孔丽敏
	陆婧怡
	祝华建
	张建康

引用本文:

孔丽敏,陆婧怡,祝华建,张建康. 选择性免疫蛋白酶体抑制剂研究进展[J]. 浙江大学学报（医学版）, 2019, 48(6): 688-694.

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

链接本文:

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

图 1 主要环氧酮肽类选择性免疫蛋白酶体抑制剂的结构式

表 1 KZR-504及衍生物的蛋白酶体抑制活性及选择性[15]

图 2 ONX-0914与不同蛋白酶体共晶结合模式图

表 2 ONX-0914及衍生物的蛋白酶体抑制活性及选择性[12, 18]

图 3 其他短肽类选择性免疫蛋白酶体抑制剂的结构式

表 3 磺酰氟类与相应的环氧酮类化合物的蛋白酶体抑制活性及选择性[27]

图 4 非共价结合肽类选择性免疫蛋白酶体抑制剂的结构式

1	ZHANG J , WU P , HU Y . Clinical and marketed proteasome inhibitors for cancer treatment[J]. Curr Med Chem, 2013, 20 (20): 2537- 2551 doi: 10.2174/09298673113209990122
2	CIECHANOVER A . The ubiquitin-proteasome pathway:on protein death and cell life[J]. EMBO J, 1998, 17 (24): 7151- 7160 doi: 10.1093/emboj/17.24.7151
3	SOAVE C L , GUERIN T , LIU J et al. Targeting the ubiquitin-proteasome system for cancer treatment:discovering novel inhibitors from nature and drug repurposing[J]. Cancer Metastasis Rev, 2017, 36 (4): 717- 736 doi: 10.1007/s10555-017-9705-x
4	MEINERS S , EVANKOVICH J , MALLAMPALLI R K . The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis[J]. Transl Res, 2018, 198 17- 28 doi: 10.1016/j.trsl.2018.03.003
5	CROMM P M , CREWS C M . The proteasome in modern drug discovery:second life of a highly valuable drug target[J]. ACS Cent Sci, 2017, 3 (8): 830- 838 doi: 10.1021/acscentsci.7b00252
6	VERBRUGGE S E , SCHEPER R J , LEMS W F et al. Proteasome inhibitors as experimental therapeutics of autoimmune diseases[J]. Arthritis Res Ther, 2015, 17 17 doi: 10.1186/s13075-015-0529-1
7	ZHENG Q , HUANG T , ZHANG L et al. Dysregulation of ubiquitin-proteasome system in neurodegenerative diseases[J]. Front Aging Neurosci, 2016, 8 303
8	LIP P Z , DEMASI M , BONATTO D . The role of the ubiquitin proteasome system in the memory process[J]. Neurochem Int, 2017, 102 57- 65 doi: 10.1016/j.neuint.2016.11.013
9	VISEKRUNA A , SLAVOVA N , DULLAT S et al. Expression of catalytic proteasome subunits in the gut of patients with Crohn's disease[J]. Int J Colorectal Dis, 2009, 24 (10): 1133- 1139 doi: 10.1007/s00384-009-0679-1
10	BASLER M , DAJEE M , MOLL C et al. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome[J]. J Immunol, 2010, 185 (1): 634- 641 doi: 10.4049/jimmunol.0903182
11	OH I S, TEXTORIS-TAUBE K, SUNG P S, et al. Immunoproteasome induction is suppressed in hepatitis C virus-infected cells in a protein kinase R-dependent manner[J/OL]. Exp Mol Med, 2016, 48(11): e270.
12	HUBER E M , BASLER M , SCHWAB R et al. Immuno-and constitutive proteasome crystal structures reveal differences in substrate and inhibitor specificity[J]. Cell, 2012, 148 (4): 727- 738 doi: 10.1016/j.cell.2011.12.030
13	GUIMAR?ES G , GOMES M , CAMPOS P C et al. Immunoproteasome subunits are required for CD8+ T Cell function and host resistance to brucella abortus infection in mice[J]. Infect Immun, 2018, 86 (3):
14	JOHNSON H , LOWE E , ANDERL J L et al. Required immunoproteasome subunit inhibition profile for anti-inflammatory efficacy and clinical candidate KZR-616((2 S, 3 R)-N-((S)-3-(Cyclopent-1-en-1-yl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)-3-hydroxy-3-(4-methoxyphenyl)-2-((S)-2-(2-morpholinoacetamido)propanamido)propenamide)[J]. J Med Chem, 2018, 61 (24): 11127- 11143 doi: 10.1021/acs.jmedchem.8b01201
15	JOHNSON H , ANDERL J L , BRADLEY E K et al. Discovery of highly selective inhibitors of the immunoproteasome low molecular mass polypeptide 2(LMP2) subunit[J]. ACS Med Chem Lett, 2017, 8 (4): 413- 417 doi: 10.1021/acsmedchemlett.6b00496
16	HO Y K , BARGAGNA-MOHAN P , WEHENKEL M et al. LMP2-specific inhibitors:chemical genetic tools for proteasome biology[J]. Chem Biol, 2007, 14 (4): 419- 430 doi: 10.1016/j.chembiol.2007.03.008
17	MUCHAMUEL T , BASLER M , AUJAY M A et al. A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis[J]. Nat Med, 2009, 15 (7): 781- 787 doi: 10.1038/nm.1978
18	DE BRUIN G , HUBER E M , XIN B T et al. Structure-based design of β1i or β5i specific inhibitors of human immunoproteasomes[J]. J Med Chem, 2014, 57 (14): 6197- 6209 doi: 10.1021/jm500716s
19	MYUNG J , KIM K B , LINDSTEN K et al. Lack of proteasome active site allostery as revealed by subunit-specific inhibitors[J]. Mol Cell, 2001, 7 (2): 411- 420 doi: 10.1016/S1097-2765(01)00188-5
20	BASLER M , LAUER C , MOEBIUS J et al. Why the structure but not the activity of the immunoproteasome subunit low molecular mass polypeptide 2 rescues antigen presentation[J]. J Immunol, 2012, 189 (4): 1868- 1877 doi: 10.4049/jimmunol.1103592
21	KUHN D J , HUNSUCKER S A , CHEN Q et al. Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors[J]. Blood, 2009, 113 (19): 4667- 4676 doi: 10.1182/blood-2008-07-171637
22	DUBIELLA C , CUI H , GERSCH M et al. Selective inhibition of the immunoproteasome by ligand-induced crosslinking of the active site[J]. Angew Chem Int Ed Engl, 2014, 53 (44): 11969- 11973 doi: 10.1002/anie.201406964
23	DUBIELLA C , BAUR R , CUI H et al. Selective inhibition of the immunoproteasome by structure-based targeting of a non-catalytic cysteine[J]. Angew Chem Int Ed Engl, 2015, 54 (52): 15888- 15891 doi: 10.1002/anie.201506631
24	SINGH P K , FAN H , JIANG X et al. Immunoproteasome β5i-selective dipeptidomimetic inhibitors[J]. Chem Med Chem, 2016, 11 (19): 2127- 2131 doi: 10.1002/cmdc.201600384

[1]	杜啸添,欧阳宏伟. 组蛋白甲基化水平与骨关节炎病理发展的关联性[J]. 浙江大学学报（医学版）, 2019, 48(6): 682-687.
[2]	李雪,李文斌,封士兰,王荣. 血红蛋白在高原低氧适应中的机制研究进展[J]. 浙江大学学报（医学版）, 2019, 48(6): 674-681.
[3]	丁怡丹,李文斌,王荣,张建春. 高原低氧对血脑屏障结构及其药物通透性影响的研究进展[J]. 浙江大学学报（医学版）, 2019, 48(6): 668-673.
[4]	徐佳俊,舒强. 三维打印技术在先天性心脏病中的应用[J]. 浙江大学学报（医学版）, 2019, 48(5): 573-579.
[5]	张军浩,金静华,杨巍. 自噬调控血管平滑肌细胞功能在颅内动脉瘤形成和破裂中的作用[J]. 浙江大学学报（医学版）, 2019, 48(5): 552-559.
[6]	陈钿雨,祁鸣. 单亲二体及其在癌症中的作用研究进展[J]. 浙江大学学报（医学版）, 2019, 48(5): 560-566.
[7]	林静,陈志敏. 儿童重症腺病毒肺炎早期识别的研究进展[J]. 浙江大学学报（医学版）, 2019, 48(5): 567-572.
[8]	黄淑敏,赵正言. 重症联合免疫缺陷病新生儿筛查及免疫系统重建研究进展[J]. 浙江大学学报（医学版）, 2019, 48(4): 351-357.
[9]	陈光杰,王晓豪,唐达星. 性别发育异常的评估、诊断和治疗研究进展[J]. 浙江大学学报（医学版）, 2019, 48(4): 358-366.
[10]	张建民. 缺血性脑血管疾病手术治疗新进展[J]. 浙江大学学报（医学版）, 2019, 48(3): 233-240.
[11]	吴雨星, 张世红, 陈忠. 缰核及其神经环路在神经精神疾病中的作用研究进展[J]. 浙江大学学报（医学版）, 2019, 48(3): 310-317.
[12]	张韵竹, 朱春鹏, 陆新良. 胃癌早期诊断的血清生物学标志物研究进展[J]. 浙江大学学报（医学版）, 2019, 48(3): 326-333.
[13]	朱紫菱, 谈静, 邓红. 肿瘤细胞膜/质蛋白转位入核研究进展[J]. 浙江大学学报（医学版）, 2019, 48(3): 318-325.
[14]	BabooKalianee Devi,陈正云,张信美. 子宫腺肌病患者药物治疗进展[J]. 浙江大学学报（医学版）, 2019, 48(2): 142-147.
[15]	吴彬彬,杨毅. 心脏手术相关急性肾损伤早期生物学标志物研究进展[J]. 浙江大学学报（医学版）, 2019, 48(2): 224-229.

Viewed

Full text

Abstract

Cited

Shared

Discussed