Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors.
Discovery and characterization of 2-aminobenzimidazole derivatives as selective NOD1 inhibitors.
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DOI：
10.1016/j.chembiol.2011.06.009
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发表时间：
2011-07-29
影响因子：
--
通讯作者：
Reed JC
中科院分区：
文献类型：
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作者：
Correa RG;Khan PM;Askari N;Zhai D;Gerlic M;Brown B;Magnuson G;Spreafico R;Albani S;Sergienko E;Diaz PW;Roth GP;Reed JC
NLR 家族蛋白在先天免疫反应中发挥着重要作用。 NOD1 (NLRC1) 响应细菌配体激活各种信号通路，包括 NF-κB。 NOD1 基因的遗传性多态性与哮喘、炎症性肠病和其他疾病有关。使用高通量筛选 (HTS) 测定法测量 NOD1 诱导的 NF-κB 报告基因活性，然后进行多次下游反筛选，消除影响其他 NF-κB 途径的化合物，鉴定出选择性抑制 NOD1 的 2-氨基苯并咪唑化合物。对原型化合物 Nodinitib-1（ML130；CID-1088438）的机理研究表明，这些小分子在体外引起 NOD1 构象变化，并改变细胞中 NOD1 的亚细胞靶向。总而言之，这一类首创的抑制剂为研究 NOD1 活性调节机制提供了化学探针，并为探索 NOD1 在各种感染和炎症性疾病中的作用提供了工具。
NLR family proteins play important roles in innate immune response. NOD1 (NLRC1) activates various signaling pathways including NF-κB in response to bacterial ligands. Hereditary polymorphisms in the NOD1 gene are associated with asthma, inflammatory bowel disease, and other disorders. Using a high throughput screening (HTS) assay measuring NOD1-induced NF-κB reporter gene activity, followed by multiple downstream counter-screens that eliminated compounds impacting other NF-κB pathways, 2-aminobenzimidazole compounds were identified that selectively inhibit NOD1. Mechanistic studies of a prototypical compound, Nodinitib-1 (ML130; CID-1088438), suggest these small molecules cause conformational changes of NOD1 in vitro and alter NOD1 subcellular targeting in cells. Altogether, this inaugural class of inhibitors provides chemical probes for interrogating mechanisms regulating NOD1 activity and tools for exploring the roles of NOD1 in various infectious and inflammatory diseases.