文献类型：期刊文献

英文题名：Drug Repurposing of Histone Deacetylase Inhibitors That Alleviate Neutrophilic Inflammation in Acute Lung Injury and Idiopathic Pulmonary Fibrosis via Inhibiting Leukotriene A4 Hydrolase and Blocking LTB4 Biosynthesis

作者：Lu, Weiqiang[1,2,3];Yao, Xue[1];Ouyang, Ping[1];Dong, Ningnin[1];Wu, Dang[1];Jiang, Xingwu[2,3];Wu, Zengrui[1];Zhang, Chen[1];Xu, Zhongyu[1];Tang, Yun[1];Zou, Shien[4];Liu, Mingyao[2,3];Li, Jian[1];Zeng, Minghua[5];Lin, Ping[6,7];Cheng, Feixiong[6,7,8,9,10];Huang, Jin[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[2]East China Normal Univ, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China;[3]East China Normal Univ, Sch Life Sci, Shanghai 200241, Peoples R China;[4]Fudan Univ, Obstet & Gynecol Hosp, Dept Gynecol, Shanghai 200011, Peoples R China;[5]Guangxi Normal Univ, Sch Chem & Chem Engn, Minist Educ, Key Lab Chem & Mol Engn Med Resources, Guilin 541004, Peoples R China;[6]Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Sichuan, Peoples R China;[7]Collaborat Innovat Ctr Biotherapy, Chengdu 610041, Sichuan, Peoples R China;[8]Northeastern Univ, Ctr Complex Networks Res, Boston, MA 02115 USA;[9]Harvard Med Sch, Ctr Canc Syst Biol, Boston, MA 02215 USA;[10]Harvard Med Sch, Dept Canc Biol, Dana Farber Canc Inst, Boston, MA 02215 USA

年份：2017

卷号：60

期号：5

起止页码：1817

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000396296100014)】；

基金：We thank Michaela S. Fooksa and Prof. Donald H. Rubin at Vanderbilt University School of Medicine for improving the English of the manuscript. We thank the staff at SSRF beamline BL17U for assistance with data collection. We thank Prof. Colin D. Funk (Department of Biochemistry, Queen's University, Canada) for pCDNA3-5-LOX, pCDNA3-p-12LOX, and pCDNA3-15-LOX-1 and Prof. Marcia E. Newcomer (Department of Biological Sciences, Louisiana State University) for stable 5 -LOX. Supported by grants from the National Natural Science Foundation of China (grants 81402482, 21222211, 91313303, 81573020), the Shanghai Committee of Science and Technology (grants 14ZR1411100, 15431902000), China Postdoctoral Science Foundation grant (2014M551361, 2015T80415), BAGUI scholar program (2014A001), Guangxi Committee of Science and Technology (2014GXNSFFA118003), and the Project of Talents Highland of Guangxi Province.

语种：英文

摘要：Acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF) are both serious public health problems with high incidence and mortality rate in adults, and with few drugs available for the efficient treatment in clinic. In this study, we identified that two known histone deacetylase (HDAC) inhibitors, suberanilohydroxamic acid (SAHA, 1) and its analogue 4(dimethylamino)-N-[7-(hydroxyamino)-7-oxoheptyl]benzamide (2), are effective inhibitors of Leukotriene A4 hydrolase (LTA4H), a key enzyme in the biosynthesis of leukotriene B4 (LTB4), across a panel of 18 HDAC inhibitors, using enzymatic assay, thermofluor assay, and X-ray crystallographic investigation. Importantly, both Land 2 markedly diminish early neutrophilic inflammation in mouse models of ALI and IPF under a clinical safety dose. Detailed mechanisms of down-regulation of proinflammatory cytokines by 1 or 2 were determined in vivo. Collectively, 1 and 2 would provide promising agents with wellknown clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.