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
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
复制标题
组蛋白脱乙酰酶抑制剂的药物再利用，通过抑制白三烯 A4 水解酶和阻断 LTB4 生物合成来减轻急性肺损伤和特发性肺纤维化中的中性粒细胞炎症
DOI：
10.1021/acs.jmedchem.6b01507
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发表时间：
2017-03-09
影响因子：
7.3
通讯作者：
Huang, Jin
中科院分区：
文献类型：
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作者：
Lu, Weiqiang;Yao, Xue;Huang, Jin
急性肺损伤（acute lung injury，ALI）和特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）是严重的公共卫生问题，在成人中发病率和死亡率高，临床上有效治疗药物较少。在本研究中，我们鉴定了两种已知的组蛋白去乙酰化酶（HDAC）抑制剂，辛二酰异羟肟酸（SAHA，1）及其类似物4（二甲氨基）-N-[7-（羟基氨基）-7-氧代庚基]苯甲酰胺（2），是白三烯A4水解酶（LTA 4 H）的有效抑制剂，白三烯A4水解酶是白三烯B4（LTB 4）生物合成中的关键酶，在一组18种HDAC抑制剂中，热荧光分析和X射线晶体学研究。重要的是，在临床安全剂量下，Land 2均显著减少ALI和IPF小鼠模型中的早期嗜酸性炎症。在体内确定了1或2下调促炎细胞因子的详细机制。总的来说，1和2将提供具有众所周知的临床安全性的有希望的药剂，用于通过抑制LAT 4 H和阻断LTB 4生物合成来潜在治疗ALI和IPF患者。
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.