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.
Highlights
Chemokine receptor 4 (CCR4) is highly expressed on Th2 cells
Like the CCR4 antibody, the special antibodies against CCL17 and CCL22 can reduce airway eosinophilia and hyperresponsiveness in asthmatic mice elicited by ovalbumin (OVA)[10,11]
Compared with compound 22 and compound 6b25, compound 8a exhibited a similar significant inhibition of chemotaxis of CCR4 transfected HEK293 to both CCL22 and CCL17, but showed a more positive efficiency in inhibiting of chemotaxis to C27 (Fig. 2d,e and f)
Summary
CCR4 is highly expressed on Th2 cells. CCR4 ligands include CCL22 and CCL17. For studying the specificity of compounds, we chose chemotaxis inhibition assays with different receptors and ligands. For determining the potency of compounds in blocking the interaction of CCR4 in vivo, we used the ovalbumin induced allergic asthma model in mice. Chemokine receptor 4 (CCR4) is highly expressed on Th2 cells and plays a key role in Th2 T cell recruitment into the asthmatic airways[2,3,4,5]. Further studies show that CKLF1 C-terminal peptides C19 can inhibit cell chemotaxis induced by CKLF1, CCL17 and CCL11 in vitro and reduce airway eosinophilia, lung inflammation, and airway hyperresponsiveness in the asthmatic mouse model[15,16]. Antagonists targeting the interaction of CCR4 and their ligands could be attractive medicines against allergic asthma by inhibiting Th2 cell migration to inflammatory sites
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