A new antagonist for CCR4 attenuates allergic lung inflammation in a mouse model of asthma

被引:34
作者
Zhang, Yang [1 ,5 ]
Wu, Yinfang [3 ]
Qi, Hui [1 ,6 ]
Gong, Hongwei [2 ,4 ]
Zhang, Yan [1 ]
Xu, Enquan [1 ]
Li, Song [2 ]
Ma, Dalong [1 ]
Xiao, Junhai [2 ]
Wang, Ying [1 ]
Li, Wen [3 ]
Shen, Huahao [3 ]
机构
[1] Peking Univ, Sch Basic Med Sci, Dept Immunol, Minist Hlth,Key Lab Immunol,Hlth Sci Ctr, Beijing 100191, Peoples R China
[2] Beijing Inst Pharmacol & Toxicol, Lab Comp Aided Drug Design & Discovery, State Key Lab Toxicol & Med Countermeasures, Beijing 100850, Peoples R China
[3] Zhejiang Univ, Affiliated Hosp 2, Dept Resp Med, Sch Med,Inst Resp Dis, Hangzhou 310009, Zhejiang, Peoples R China
[4] Jilin Univ, Sch Pharmaceut Sci, Changchun 130021, Jilin, Peoples R China
[5] Peking Univ, Hosp 1, Dept Hematol, Beijing 100034, Peoples R China
[6] Capital Med Univ, Beijing Childrens Hosp, Beijing 100045, Peoples R China
基金
中国国家自然科学基金;
关键词
CHEMOKINE-LIKE FACTOR-1; T-CELLS; AIRWAY INFLAMMATION; FUNCTIONAL LIGAND; OPTIMIZATION; POTENT; HYPERRESPONSIVENESS; RECRUITMENT; DERIVATIVES; CYTOKINE;
D O I
10.1038/s41598-017-11868-9
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
CCR4 is highly expressed on Th2 cells. CCR4 ligands include CCL22 and CCL17. Chemokine-like factor 1 can also mediate chemotaxis via CCR4. We designed and synthetized novel CCR4 antagonists, which were piperazinyl pyridine derivatives, for disrupting the interaction between three ligands and CCR4. We also determined whether these novel CCR4 antagonists could alleviate allergic asthma in a mouse. For identifying the potent compounds in vitro, we used chemotaxis inhibition and competition binding assays induced by CCL22, CCL17 and one of CKLF1' s C-terminal peptides, C27. We found compound 8a which showed excellent potency in blocking the interaction of CCR4 and its three ligands. For studying the specificity of compounds, we chose chemotaxis inhibition assays with different receptors and ligands. We found compound 8a had excellent receptor specificity and exerted few influence on the interaction of other receptors and their ligands. In the 3-(4,5-dimethylthiazol-2yl)- 2,5-diphenyltetrazolium bromide assay, compound 8a had no obvious cytotoxicity till the higher concentration (16 mu M). For determining the potency of compounds in blocking the interaction of CCR4 in vivo, we used the ovalbumin induced allergic asthma model in mice. Our study demonstrated that CCR4 blockaded by compound 8a effectively attenuated airway hyperresponsiveness, airway eosinophilia and Th2 cytokines.
引用
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页数:10
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