Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation.
Development of novel NEMO-binding domain mimetics for inhibiting IKK/NF-κB activation.
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DOI：
10.1371/journal.pbio.2004663
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发表时间：
2018-06
期刊：
影响因子：
9.8
通讯作者：
Robbins PD
中科院分区：
文献类型：
--
作者：
Zhao J;Zhang L;Mu X;Doebelin C;Nguyen W;Wallace C;Reay DP;McGowan SJ;Corbo L;Clemens PR;Wilson GM;Watkins SC;Solt LA;Cameron MD;Huard J;Niedernhofer LJ;Kamenecka TM;Robbins PD
核因子κB（NF-κB）是一种重要的转录因子，在调节先天性免疫和适应性免疫、细胞增殖、凋亡和衰老中起重要作用。NF-κB及其上游调节因子IκB激酶（IKK）的失调导致多种炎症和退行性疾病以及癌症的发病机制。一种含有NF-κB必需调节因子（NEMO）结合结构域（NBD）的11个氨基酸的肽，其来源于IKK β亚基的C-末端，通过破坏IKKβ和IKKγ亚基NEMO的结合而作为IKK复合物的高度选择性抑制剂发挥功能。开发了基于结构的药效团模型，通过计算机筛选鉴定NBD模拟物。两种优化的NBD模拟物SR 12343和SR 12460通过阻断IKKβ和NEMO之间的相互作用抑制肿瘤坏死因子α（TNF-α）和脂多糖（LPS）诱导的NF-κB活化，并抑制LPS诱导的小鼠急性肺部炎症。用SR 12343和SR 12460长期治疗杜氏肌营养不良症（DMD）小鼠模型减弱了炎性浸润、坏死和肌肉变性，表明这些小分子NBD模拟物是炎性和退行性疾病的潜在治疗剂。转录因子核因子κB（NF-κB）和调节NF-κB的IκB激酶（IKK）的异常上调与人类多种炎症和退行性疾病（包括衰老）相关。因此，开发能够降低IKK/NF-κB活性的有效且特异的药物具有显著的治疗潜力。在这项研究中，结构衍生的计算方法被用来筛选IKK复合物的IKK β和IKKγ亚基之间的蛋白质-蛋白质相互作用的小分子抑制剂。我们鉴定并开发了一类新的小分子，其通过解离IKK复合物选择性抑制IKK/NF-κB活化，而不影响c-Jun N-末端激酶（JNK）/p38-丝裂原活化蛋白激酶（MAPK）信号传导。这些新型分子减少了脂多糖（LPS）诱导的小鼠急性炎症，并改善了杜氏肌营养不良症（DMD）mdx小鼠模型的肌肉病理学，表明它们具有潜在的临床实用性。
Nuclear factor κB (NF-κB) is a transcription factor important for regulating innate and adaptive immunity, cellular proliferation, apoptosis, and senescence. Dysregulation of NF-κB and its upstream regulator IκB kinase (IKK) contributes to the pathogenesis of multiple inflammatory and degenerative diseases as well as cancer. An 11–amino acid peptide containing the NF-κB essential modulator (NEMO)-binding domain (NBD) derived from the C-terminus of β subunit of IKK, functions as a highly selective inhibitor of the IKK complex by disrupting the association of IKKβ and the IKKγ subunit NEMO. A structure-based pharmacophore model was developed to identify NBD mimetics by in silico screening. Two optimized lead NBD mimetics, SR12343 and SR12460, inhibited tumor necrosis factor α (TNF-α)- and lipopolysaccharide (LPS)-induced NF-κB activation by blocking the interaction between IKKβ and NEMO and suppressed LPS-induced acute pulmonary inflammation in mice. Chronic treatment of a mouse model of Duchenne muscular dystrophy (DMD) with SR12343 and SR12460 attenuated inflammatory infiltration, necrosis and muscle degeneration, demonstrating that these small-molecule NBD mimetics are potential therapeutics for inflammatory and degenerative diseases. Aberrant up-regulation of the transcription factor nuclear factor κB (NF-κB) and the IκB kinase (IKK) that regulates NF-κB is associated with a variety of inflammatory and degenerative diseases in humans, including aging. Thus, development of effective and specific drugs able to decrease IKK/NF-κB activity has significant therapeutic potential. In this study, a structure-derived computational approach was used to screen for small-molecule inhibitors of the protein–protein interaction between the IKKß and IKKγ subunits of the IKK complex. We identified and developed a novel class of small molecules that selectively inhibit IKK/NF-κB activation by dissociating the IKK complex without affecting c-Jun N-terminal kinase (JNK)/p38-mitogen-activated protein kinase (MAPK) signaling. These novel molecules reduce lipopolysaccharide (LPS)-induced acute inflammation in mice and improve muscle pathology in the mdx mouse model of Duchenne muscular dystrophy (DMD), suggesting that they would have potential clinical utility.
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影响因子：
15
作者：
Golden, Mary S.;Cote, Shaun M.;Sayeg, Marianna;Zerbe, Brandon S.;Villar, Elizabeth A.;Beglov, Dmitri;Sazinsky, Stephen L.;Georgiadis, Rosina M.;Vajda, Sandor;Kozakov, Dima;Whitty, Adrian
通讯作者：
Whitty, Adrian
DOI：
10.1074/jbc.m109.099895
发表时间：
2010-04-30
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Baima ET;Guzova JA;Mathialagan S;Nagiec EE;Hardy MM;Song LR;Bonar SL;Weinberg RA;Selness SR;Woodard SS;Chrencik J;Hood WF;Schindler JF;Kishore N;Mbalaviele G
通讯作者：
Mbalaviele G
影响因子：
8.2
作者：
Oguiza, Ainhoa;Recio, Carlota;Gomez-Guerrero, Carmen
通讯作者：
Gomez-Guerrero, Carmen
影响因子：
15.9
作者：
Tilstra, Jeremy S.;Robinson, Andria R.;Robbins, Paul D.
通讯作者：
Robbins, Paul D.
影响因子：
3.5
作者：
Jain, AN
通讯作者：
Jain, AN