A small molecule binding HMGB1 and HMGB2 inhibits microglia-mediated neuroinflammation

被引：110

作者：

Lee, Sanghee ^{[1
]}

Nam, Youngpyo ^{[2
]}

Koo, Ja Young ^{[1
]}

Lim, Donghyun ^{[3
]}

Park, Jongmin ^{[1
]}

Ock, Jiyeon ^{[2
]}

Kim, Jaehong ^{[2
]}

Suk, Kyoungho ^{[2
]}

Park, Seung Bum ^{[1
,3
]}

机构：

[1] Seoul Natl Univ, Dept Chem, Seoul, South Korea

[2] Kyungpook Natl Univ, Sch Med, Plus KNU Biomed Convergence Program BK21, Dept Pharmacol,Brain Sci & Engn Inst, Taegu, South Korea

[3] Seoul Natl Univ, Dept Biophys & Chem Biol, N Bio Inst, Seoul, South Korea

来源：

NATURE CHEMICAL BIOLOGY | 2014年 / 10卷 / 12期

基金：

新加坡国家研究基金会;

关键词：

MOBILITY GROUP BOX-1; CHROMATIN PROTEIN HMGB1; TARGET IDENTIFICATION; INFLAMMATION; DISCOVERY; TRIGGERS; RELEASE;

D O I：

10.1038/nchembio.1669

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Because of the critical role of neuroinflammation in various neurological diseases, there are continuous efforts to identify new therapeutic targets as well as new therapeutic agents to treat neuroinflammatory diseases. Here we report the discovery of inflachromene (ICM), a microglial inhibitor with anti-inflammatory effects. Using the convergent strategy of phenotypic screening with early stage target identification, we show that the direct binding target of ICM is the high mobility group box (HMGB) proteins. Mode-of-action studies demonstrate that ICM blocks the sequential processes of cytoplasmic localization and extracellular release of HMGBs by perturbing its post-translational modification. In addition, ICM effectively downregulates proinflammatory functions of HMGB and reduces neuronal damage in vivo. Our study reveals that ICM suppresses microglia-mediated inflammation and exerts a neuroprotective effect, demonstrating the therapeutic potential of ICM in neuroinflammatory diseases.

引用

页码：1055 / +

页数：9

共 29 条

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