Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits.
Ebselen and congeners inhibit NADPH oxidase 2-dependent superoxide generation by interrupting the binding of regulatory subunits.
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Ebselen 和同类物通过中断调节亚基的结合来抑制 NADPH 氧化酶 2 依赖性超氧化物的产生。
DOI：
10.1016/j.chembiol.2012.04.015
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发表时间：
2012
影响因子：
--
通讯作者：
Lambeth,JDavid
中科院分区：
文献类型：
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作者：
Smith,SusanME;Min,Jaeki;Ganesh,Thota;Diebold,Becky;Kawahara,Tsukasa;Zhu,Yerun;McCoy,James;Sun,Aiming;Snyder,JamesP;Fu,Haian;Du,Yuhong;Lewis,Iestyn;Lambeth,JDavid
NADPH氧化酶（Nox）是活性氧（ROS）的主要来源，其在正常生理学中起作用，并且当过度产生时，在病理生理学中起作用。最近使用Nox 2缺陷小鼠的研究将这种同种型鉴定为对抗Nox 2相关炎症性疾病的新靶标。Nox 2的激活依赖于其异二聚体伴侣p22 phox的富含脯氨酸的结构域与p47 phox的结合。通过荧光偏振监测这种相互作用的高通量筛选确定了依布硒啉及其几种类似物作为抑制剂。进行药物化学以探索结构-活性关系并优化效力。Ebselen和类似物有效抑制Nox 1和Nox 2活性，但对其他亚型的有效性较低。依布硒啉还阻断p47 phoxto中性粒细胞膜的易位。因此，依布硒啉及其类似物代表一类通过中断Nox 2活化调节亚基的组装来抑制ROS产生的化合物。
NADPH oxidases (Nox) are a primary source of reactive oxygen species (ROS), which function in normal physiology and, when overproduced, in pathophysiology. Recent studies using mice deficient in Nox2 identify this isoform as a novel target against Nox2-implicated inflammatory diseases. Nox2 activation depends on the binding of the proline-rich domain of its heterodimeric partner p22phoxto p47phox. A high-throughput screen that monitored this interaction via fluorescence polarization identified ebselen and several of its analogs as inhibitors. Medicinal chemistry was performed to explore structure-activity relationships and to optimize potency. Ebselen and analogs potently inhibited Nox1 and Nox2 activity but were less effective against other isoforms. Ebselen also blocked translocation of p47phoxto neutrophil membranes. Thus, ebselen and its analogs represent a class of compounds that inhibit ROS generation by interrupting the assembly of Nox2-activating regulatory subunits.