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Sci Rep. 2017 Nov 8;7(1):15038. doi: 10.1038/s41598-017-11868-9.

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

Author information

1
Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Immunology, Ministry of Health, Peking University Health Science Center, Beijing, 100191, China.
2
Department of Hematology, Peking University First Hospital, Beijing, 100034, China.
3
Department of Respiratory Medicine, the Second Affiliated Hospital School of Medicine of Zhejiang University, Zhejiang University institute of Respiratory Diseases, Hangzhou, 310009, China.
4
Beijing Children's Hospital, Capital Medical University, Beijing, 100045, China.
5
Laboratory of Computer-Aided Drug Design & Discovery, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
6
School of Pharmaceutical Sciences, Jilin University, Changchun, 130021, China.
7
Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Immunology, Ministry of Health, Peking University Health Science Center, Beijing, 100191, China. yw@bjmu.edu.cn.
8
Department of Respiratory Medicine, the Second Affiliated Hospital School of Medicine of Zhejiang University, Zhejiang University institute of Respiratory Diseases, Hangzhou, 310009, China. liwenzjhz0408@163.com.
9
Department of Respiratory Medicine, the Second Affiliated Hospital School of Medicine of Zhejiang University, Zhejiang University institute of Respiratory Diseases, Hangzhou, 310009, China. hshen@mail.hz.zj.cn.

Abstract

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-2-yl)-2,5-diphenyltetrazolium bromide assay, compound 8a had no obvious cytotoxicity till the higher concentration (16 μM). 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.

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