Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation
Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation
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DOI：
10.1021/acs.jmedchem.9b02123
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发表时间：
2020-03-26
影响因子：
7.3
通讯作者：
Stratikos, Efstratios
中科院分区：
文献类型：
--
作者：
Liddle, John;Hutchinson, Jonathan P.;Stratikos, Efstratios
内质网氨基肽酶1 （ERAP1）是一种产生抗原肽的细胞内酶，是癌症免疫治疗和自身免疫控制的新兴靶点。先前描述的ERAP1抑制剂靶向活性位点，选择性有限，使其临床潜力最小化。为了解决这个问题，我们使用高通量筛选靶向ERAP1的调控位点，并发现了一个对ERAP1具有高选择性的小分子撞击。（4aR,5S,6R,8S,8aR）-5-（2-（呋喃-3-基）乙基）-8-羟基-5,6,8 -a -三甲基-3,4,4a,5,6,7,8,8 -a -八氢萘-1-羧酸是一种天然产物，是一种亚微摩尔、高选择性和细胞活性的ERAP1调节剂。虽然该化合物可以激活小模型底物的水解，但它是生理上相关的长肽的竞争性抑制剂。晶体分析证实，该化合物靶向酶的调控位点，该酶通常结合肽底物的c端。我们的发现为选择性ERAP1调节剂的开发提供了一个新的起点，这些调节剂具有进一步临床开发的潜力。
ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates antigenic peptides and is an emerging target for cancer immunotherapy and the control of autoimmunity. ERAP1 inhibitors described previously target the active site and are limited in selectivity, minimizing their clinical potential. To address this, we targeted the regulatory site of ERAP1 using a high-throughput screen and discovered a small molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active modulator of ERAP1. Although the compound activates hydrolysis of small model substrates, it is a competitive inhibitor for physiologically relevant longer peptides. Crystallographic analysis confirmed that the compound targets the regulatory site of the enzyme that normally binds the C-terminus of the peptide substrate. Our findings constitute a novel starting point for the development of selective ERAP1 modulators that have potential for further clinical development.