• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

内质网氨基肽酶（ERAP）抑制剂在自身免疫和免疫肿瘤学中的作用：药物化学研究进展。

ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.

机构信息

U1177 - Drugs and Molecules for Living Systems, Univ. Lille, Inserm, Institut Pasteur de Lille, F-59000 Lille, France.

European Genomic Institute for Diabetes, EGID, University of Lille, F-59000 Lille, France.

出版信息

J Med Chem. 2024 Jul 25;67(14):11597-11621. doi: 10.1021/acs.jmedchem.4c00840. Epub 2024 Jul 16.

DOI:10.1021/acs.jmedchem.4c00840
PMID:39011823
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11284793/
Abstract

Endoplasmic reticulum aminopeptidases ERAP1 and 2 are intracellular aminopeptidases that trim antigenic precursors and generate antigens presented by major histocompatibility complex class I (MHC-I) molecules. They thus modulate the antigenic repertoire and drive the adaptive immune response. ERAPs are considered as emerging targets for precision immuno-oncology or for the treatment of autoimmune diseases, in particular MHC-I-opathies. This perspective covers the structural and biological characterization of ERAP, their relevance to these diseases and the ongoing research on small-molecule inhibitors. We describe the chemical and pharmacological space explored by medicinal chemists to exploit the potential of these targets given their localization, biological functions, and family depth. Specific emphasis is put on the binding mode, potency, selectivity, and physchem properties of inhibitors featuring diverse scaffolds. The discussion provides valuable insights for the future development of ERAP inhibitors and analysis of persisting challenges for the translation for clinical applications.

摘要

内质网氨基肽酶 ERAP1 和 2 是细胞内氨基肽酶，可修剪抗原前体并产生主要组织相容性复合体 I 类 (MHC-I) 分子呈递的抗原。因此，它们调节抗原库并驱动适应性免疫反应。ERAP 被认为是精准免疫肿瘤学或治疗自身免疫性疾病（特别是 MHC-I 相关疾病）的新兴靶点。本观点涵盖了 ERAP 的结构和生物学特征、它们与这些疾病的相关性以及针对小分子抑制剂的正在进行的研究。我们描述了药物化学家探索的化学和药理学空间，以利用这些靶点的潜力，因为它们的定位、生物学功能和家族深度。特别强调了具有不同骨架的抑制剂的结合模式、效力、选择性和物理化学性质。讨论为 ERAP 抑制剂的未来发展以及分析转化为临床应用中持续存在的挑战提供了有价值的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/076b0ef5f6fb/jm4c00840_0022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/d8f2e48a2327/jm4c00840_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/86ad85630971/jm4c00840_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/595acba186e7/jm4c00840_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/43979e83e2ec/jm4c00840_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/12a7539e55e5/jm4c00840_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/3962e3be9de3/jm4c00840_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/380852b58a0b/jm4c00840_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/33ede6a14755/jm4c00840_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/0dd72dc63d35/jm4c00840_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/ec4768ea5b3e/jm4c00840_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/518f8cef6485/jm4c00840_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/6d168637047b/jm4c00840_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/461402769145/jm4c00840_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/1c91548d85e4/jm4c00840_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/1ebbc010ed1e/jm4c00840_0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/006a162c8d52/jm4c00840_0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/7b50ed72c567/jm4c00840_0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/c8bcc9d99f29/jm4c00840_0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/4964e3714e93/jm4c00840_0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/649b329ce820/jm4c00840_0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/7e3719f30cfb/jm4c00840_0021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/076b0ef5f6fb/jm4c00840_0022.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/d8f2e48a2327/jm4c00840_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/86ad85630971/jm4c00840_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/595acba186e7/jm4c00840_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/43979e83e2ec/jm4c00840_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/12a7539e55e5/jm4c00840_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/3962e3be9de3/jm4c00840_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/380852b58a0b/jm4c00840_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/33ede6a14755/jm4c00840_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/0dd72dc63d35/jm4c00840_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/ec4768ea5b3e/jm4c00840_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/518f8cef6485/jm4c00840_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/6d168637047b/jm4c00840_0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/461402769145/jm4c00840_0013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/1c91548d85e4/jm4c00840_0014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/1ebbc010ed1e/jm4c00840_0015.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/006a162c8d52/jm4c00840_0016.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/7b50ed72c567/jm4c00840_0017.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/c8bcc9d99f29/jm4c00840_0018.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/4964e3714e93/jm4c00840_0019.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/649b329ce820/jm4c00840_0020.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/7e3719f30cfb/jm4c00840_0021.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/103e/11284793/076b0ef5f6fb/jm4c00840_0022.jpg

相似文献

1
ERAP Inhibitors in Autoimmunity and Immuno-Oncology: Medicinal Chemistry Insights.内质网氨基肽酶（ERAP）抑制剂在自身免疫和免疫肿瘤学中的作用：药物化学研究进展。
J Med Chem. 2024 Jul 25;67(14):11597-11621. doi: 10.1021/acs.jmedchem.4c00840. Epub 2024 Jul 16.
2
ERAP1-dependent extreme antigen processing efficacy can govern MHC class I expression hierarchy.内质网氨肽酶1（ERAP1）依赖的极端抗原加工效能可调控MHC I类分子的表达层级。
J Immunol. 2025 Jun 1;214(6):1147-1159. doi: 10.1093/jimmun/vkaf013.
3
Targeting the aminopeptidase ERAP enhances antitumor immunity by disrupting the NKG2A-HLA-E inhibitory checkpoint.靶向氨肽酶ERAP可通过破坏NKG2A-HLA-E抑制性检查点增强抗肿瘤免疫力。
Immunity. 2024 Dec 10;57(12):2863-2878.e12. doi: 10.1016/j.immuni.2024.10.013. Epub 2024 Nov 18.
4
Prescription of Controlled Substances: Benefits and Risks管制药品的处方：益处与风险
5
Epistasis of ERAP1 With 4 Major Histocompatibility Complex Class I Alleles in Frontal Fibrosing Alopecia: A Genome-Wide Association Study Meta-Analysis.前额纤维性秃发中ERAP1与4种主要组织相容性复合体I类等位基因的上位性：一项全基因组关联研究的荟萃分析
JAMA Dermatol. 2025 Mar 1;161(3):310-314. doi: 10.1001/jamadermatol.2024.6434.
6
Updates on Intrinsic Medicinal Chemistry of 1,4-dihydropyridines, Perspectives on Synthesis and Pharmacokinetics of Novel 1,4-dihydropyrimidines as Calcium Channel Blockers: Clinical Pharmacology.1,4 - 二氢吡啶的内在药物化学进展，新型1,4 - 二氢嘧啶作为钙通道阻滞剂的合成与药代动力学展望：临床药理学
Curr Top Med Chem. 2025 Jan 1. doi: 10.2174/0115680266323908241114064318.
7
T-bet expressing Tr1 cells driven by dietary signals dominate the small intestinal immune landscape.由饮食信号驱动的表达T-bet的Tr1细胞主导小肠免疫格局。
bioRxiv. 2025 Jul 4:2025.06.30.662190. doi: 10.1101/2025.06.30.662190.
8
Systemic treatments for metastatic cutaneous melanoma.转移性皮肤黑色素瘤的全身治疗
Cochrane Database Syst Rev. 2018 Feb 6;2(2):CD011123. doi: 10.1002/14651858.CD011123.pub2.
9
Small-molecule inhibitors in psoriasis: medicinal chemistry insights.银屑病中的小分子抑制剂：药物化学见解
Expert Opin Drug Discov. 2025 Jul;20(7):891-912. doi: 10.1080/17460441.2025.2507767. Epub 2025 May 20.
10
B cell antigens: A key to optimizing CAR-T cell therapy.B细胞抗原：优化嵌合抗原受体T细胞疗法的关键
Int Rev Immunol. 2025 Jun 19:1-28. doi: 10.1080/08830185.2025.2515839.

引用本文的文献

1
Unveiling the impact of ERAP1 and ERAP2 on migration, angiogenesis and ER stress response.揭示内质网氨肽酶1（ERAP1）和内质网氨肽酶2（ERAP2）对迁移、血管生成和内质网应激反应的影响。
Front Cell Dev Biol. 2025 Mar 28;13:1564649. doi: 10.3389/fcell.2025.1564649. eCollection 2025.
2
ERAP1 Activity Modulates the Immunopeptidome but Also Affects the Proteome, Metabolism, and Stress Responses in Cancer Cells.内质网氨肽酶1（ERAP1）的活性调节免疫肽组，但也影响癌细胞中的蛋白质组、代谢和应激反应。
Mol Cell Proteomics. 2025 May;24(5):100964. doi: 10.1016/j.mcpro.2025.100964. Epub 2025 Apr 4.
3
Deleterious KOs in the HLA Class I Antigen Processing and Presentation Machinery Induce Distinct Changes in the Immunopeptidome.

本文引用的文献

1
Endoplasmic reticulum aminopeptidase 2 regulates CD4 T cells pyroptosis in rheumatoid arthritis.内质网氨肽酶2调节类风湿关节炎中CD4 T细胞的焦亡。
Arthritis Res Ther. 2024 Jan 25;26(1):36. doi: 10.1186/s13075-024-03271-3.
2
Small molecule inhibitors for cancer immunotherapy and associated biomarkers - the current status.小分子抑制剂在癌症免疫治疗及相关生物标志物中的应用现状。
Front Immunol. 2023 Oct 31;14:1297175. doi: 10.3389/fimmu.2023.1297175. eCollection 2023.
3
Evolutionary immuno-genetics of endoplasmic reticulum aminopeptidase II (ERAP2).
HLA I类抗原加工与呈递机制中的有害基因敲除会导致免疫肽组发生明显变化。
Mol Cell Proteomics. 2025 Mar 18;24(5):100951. doi: 10.1016/j.mcpro.2025.100951.
4
Discovery of New Nanomolar Selective IRAP Inhibitors.新型纳摩尔级选择性IRAP抑制剂的发现。
J Med Chem. 2025 Feb 27;68(4):4168-4195. doi: 10.1021/acs.jmedchem.4c01744. Epub 2025 Feb 7.
5
Optimization of Potent and Selective Cyclohexyl Acid ERAP1 Inhibitors Using Structure- and Property-Based Drug Design.利用基于结构和性质的药物设计优化强效和选择性环己基酸ERAP1抑制剂
ACS Med Chem Lett. 2024 Nov 6;15(12):2107-2114. doi: 10.1021/acsmedchemlett.4c00401. eCollection 2024 Dec 12.
内质网氨肽酶 II（ERAP2）的进化免疫遗传学。
Genes Immun. 2023 Dec;24(6):295-302. doi: 10.1038/s41435-023-00225-8. Epub 2023 Nov 4.
4
M1-aminopeptidase family - beyond antigen-trimming activities.M1 氨肽酶家族 - 超越抗原修剪活动。
Curr Opin Immunol. 2023 Aug;83:102337. doi: 10.1016/j.coi.2023.102337. Epub 2023 May 20.
5
Distinct modulation of cellular immunopeptidome by the allosteric regulatory site of ER aminopeptidase 1.别构调节位点对 ER 氨肽酶 1 的细胞免疫肽组的独特调节作用。
Eur J Immunol. 2023 Aug;53(8):e2350449. doi: 10.1002/eji.202350449. Epub 2023 May 15.
6
EULAR study group on 'MHC-I-opathy': identifying disease-overarching mechanisms across disciplines and borders.EULAR 研究小组关于“MHC-I 病”：在学科和边界内识别疾病普遍存在的机制。
Ann Rheum Dis. 2023 Jul;82(7):887-896. doi: 10.1136/ard-2022-222852. Epub 2023 Mar 27.
7
Cell-Specific and Variant-Linked Alterations in Expression of ERAP1, ERAP2, and LNPEP Aminopeptidases in Psoriasis.银屑病中 ERAP1、ERAP2 和 LNPEP 氨肽酶表达的细胞特异性和变体相关性改变。
J Invest Dermatol. 2023 Jul;143(7):1157-1167.e10. doi: 10.1016/j.jid.2023.01.012. Epub 2023 Jan 28.
8
An orally available small molecule that targets soluble TNF to deliver anti-TNF biologic-like efficacy in rheumatoid arthritis.一种口服可用的小分子，其靶向可溶性肿瘤坏死因子（TNF），以在类风湿性关节炎中发挥类似抗TNF生物制剂的疗效。
Front Pharmacol. 2022 Nov 16;13:1037983. doi: 10.3389/fphar.2022.1037983. eCollection 2022.
9
Targeting the antigen processing and presentation pathway to overcome resistance to immune checkpoint therapy.针对抗原加工和呈递途径克服免疫检查点治疗耐药性。
Front Immunol. 2022 Jul 22;13:948297. doi: 10.3389/fimmu.2022.948297. eCollection 2022.
10
Discovery of the First Selective Nanomolar Inhibitors of ERAP2 by Kinetic Target-Guided Synthesis.通过动力学靶向合成发现 ERAP2 的首个选择性纳摩尔抑制剂。
Angew Chem Int Ed Engl. 2022 Sep 26;61(39):e202203560. doi: 10.1002/anie.202203560. Epub 2022 Aug 19.