Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues

Weglarz-Tomczak Ewelina; Vassiliou Stamatia; Mucha Artur

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Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues

机译：通过筛选含磷氨基酸和二肽类似物的文库，发现人氨肽酶ERAP1和ERAP2的有效和选择性抑制剂

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A collection of fifty phosphonic and phosphinic acids was screened for inhibition of ERAP1 and ERAP2, the human endoplasmic reticulum aminopeptidases. The cooperative action of these enzymes is manifested by trimming a variety of antigenic precursors to be presented on the cell surface by major histocompatibility class I. The SAR studies revealed several potent compounds, particularly among the phosphinic dipeptide analogues, that were strong inhibitors of ERAP2 (K-i = 100-350 nM). A wide structural diversity of the applied organophosphorus compounds, predominantly non-proteinogenic analogues, allowed identification of representatives selective toward only one form of ERAP. For example, N'-substituted alpha,beta-diaminophosphonates and phosphinates exhibited potency only toward ERAP2, which is in agreement with the P1 basic substrate-oriented specificity. Such discriminating ligands are invaluable tools for elucidating the precise role of a particular aminopeptidase in the concerted function of antigen processing and in human diseases. (C) 2016 Elsevier Ltd. All rights reserved.

机译：筛选了五十种膦酸和次膦酸的集合以抑制ERAP1和ERAP2（人内质网氨基肽酶）的抑制。这些酶的协同作用表现为通过主要的组织相容性I类修剪要在细胞表面呈递的多种抗原前体。SAR研究表明，有几种有效的化合物，尤其是次膦酸二肽类似物，是ERAP2的强抑制剂（ Ki = 100-350 nM）。所应用的有机磷化合物（主要为非蛋白类似物）的结构差异很大，从而可以鉴定仅对一种形式的ERAP有选择性的代表。例如，N′-取代的α，β-二氨基膦酸酯和次膦酸酯仅对ERAP2表现出效力，这与P1基本的底物定向特异性一致。此类区分性配体是阐明特定氨基肽酶在抗原加工和人类疾病的协同功能中的确切作用的宝贵工具。（C）2016 Elsevier Ltd.保留所有权利。

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《Bioorganic and Medicinal Chemistry Letters》 |2016年第16期|共5页
作者
Weglarz-Tomczak Ewelina; Vassiliou Stamatia; Mucha Artur;
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正文语种 eng
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Metalloaminopeptidases; Antigenic peptide processing; Organophosphorus inhibitors; SAR studies;

机译：金属氨基肽酶;抗原肽加工;有机磷抑制剂;SAR研究;

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1. Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues [J] . Weglarz-Tomczak Ewelina, Vassiliou Stamatia, Mucha Artur Bioorganic and Medicinal Chemistry Letters . 2016,第16期

机译：通过筛选含磷氨基酸和二肽类似物的文库，发现人氨肽酶ERAP1和ERAP2的有效和选择性抑制剂
2. Discovery of an exceptionally potent and selective class of fatty acid amide hydrolase inhibitors enlisting proteome-wide selectivity screening: concurrent optimization of enzyme inhibitor potency and selectivity. [J] . Leung D, Du W, Hardouin C, Bioorganic and Medicinal Chemistry Letters . 2005,第5期

机译：发现了一种特别有效和选择性的脂肪酸酰胺水解酶抑制剂，可进行蛋白质组范围的选择性筛选：同时优化酶抑制剂的效能和选择性。
3. Identification of Potent and Selective Inhibitors of the Plasmodium falciparum M18 Aspartyl Aminopeptidase (PfM18AAP) of Human Malaria via High-Throughput Screening [J] . Timothy Spicer, Virneliz Fernandez-Vega, Louis Scampavia, Journal of biomolecular screening: The official journal of the Society for Biomolecular Screening . 2014,第7期

机译：通过高通量筛选鉴定恶性疟原虫M18天冬氨酰氨肽酶（PfM18AAP）的有效和选择性抑制剂
4. 2-Oxoamides Based on Amino Acids and Dipeptides as Selective Phospholipase A_2 Inhibitors Presenting Anti-inflammatory Activity [C] . George Kokotos Chinese International Peptide Symposium . 2013

机译：基于氨基酸和二肽作为选择性磷脂酶A_2抑制剂呈现抗炎活性的2-氧氧酰胺
5. Part one. Synthesis of phosphorus-containing amino acid analogues derived from trans-4-hydroxyproline and the study of their bioactivity in the glutamate excitatory neurotransmitter system. Part two. Synthesis, structural modifications and in vitro pharmacology of quinoline-2,4-dicarboxylic acids as proposed inhibitors of the glutamate vesicular transporter. [D] . Carrigan, Christina Nicole. 2000

机译：第一部分。反式-4-羟基脯氨酸衍生的含磷氨基酸类似物的合成及其在谷氨酸兴奋性神经递质系统中的生物活性的研究。第二部分。喹啉-2,4-二羧酸作为谷氨酸囊泡转运蛋白的抑制剂的合成，结构修饰和体外药理作用。
6. P1′ Residue-Oriented Virtual Screening for Potent and Selective Phosphinic (Dehydro) Dipeptide Inhibitors of Metallo-Aminopeptidases [O] . Michał Talma, Artur Mucha 2020

机译：面向P1残基的金属-氨基肽酶有效和选择性膦（脱氢）二肽抑制剂的虚拟筛选
7. Concerted in vitro trimming of viral HLA-B27-restricted ligands by human ERAP1 and ERAP2 aminopeptidases. [O] . Elena Lorente, Alejandro Barriga, Carolina Johnstone, 2013

机译：通过人ERap1和ERap2氨肽酶协同体外修剪病毒HLa-B27限制性配体。

Discovery of potent and selective inhibitors of human aminopeptidases ERAP1 and ERAP2 by screening libraries of phosphorus-containing amino acid and dipeptide analogues

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