title: 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.
abstract: 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 1 and 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 well-known clinical safety for potential treatment in patients with ALI and IPF via pharmacologically inhibiting LAT4H and blocking LTB4 biosynthesis.
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.|Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China.
authors.forename: Weiqiang
authors.initials: W
authors.lastname: Lu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Yao
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Ouyang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Ningning
authors.initials: N
authors.lastname: Dong
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Dang
authors.initials: D
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China.
authors.forename: Xingwu
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Zengrui
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Yun
authors.identifier: 0000-0003-2340-1109
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University , Shanghai 200011, China.
authors.forename: Shien
authors.initials: S
authors.lastname: Zou
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences and School of Life Sciences, East China Normal University , Shanghai 200241, China.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jian
authors.identifier: 0000-0002-7521-8798
authors.initials: J
authors.lastname: Li
authors.affiliation: Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education), School of Chemistry & Chemical Engineering, Guangxi Normal University , Guilin 541004, China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Zeng
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, Sichuan, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Lin
authors.affiliation: State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy , Chengdu 610041, Sichuan, China.|Center for Complex Networks Research, Northeastern University , Boston, Massachusetts 02115, United States.|Center for Cancer Systems Biology and Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School , Boston, Massachusetts 02215, United States.
authors.forename: Feixiong
authors.identifier: 0000-0002-1736-2847
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology , Shanghai 200237, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Huang
mesh_terms: D055371:Acute Lung Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors*; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology / Q000517:prevention & control*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects*
chemical_list: D056572:Histone Deacetylase Inhibitors; D007975:Leukotriene B4; D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase