抑制RORγt活性及Th17分化的新型化合物研究

Discovery of a novel compounds as potent RORγt inverse agonists and suppressing Th17 cell differentiation

目的我们在实验中偶然发现了一种能抑制RORγt活性的新型化合物,拟通过鉴定该化合物对Th17体外分化及其细胞因子分泌的影响对其进行生物学评价,以确定该化合物是否可作为一种新型的自身免疫病候选药物。方法构建能在Jurkat细胞中稳定表达Gal4-RORγt的荧光素酶报告系统,通过该体系发现了一种对RORγt有显著抑制活性的新型化合物,并在小鼠Th17细胞分化实验中对该化合物的作用效果进行体外验证。在此基础上,对该化合物进行生物功能分析,包括EC50、CC50的测定以及T细胞特异性分析。结果通过体外验证实验,我们确定该化合物(编号为compound 2)能显著的抑制Th17分化及其细胞因子IL-17A、IL-17F的表达和分泌。在后续的生物学评价中,我们还发现该化合物对RORγt有较高的抑制效率,较低的细胞毒性和较强的T细胞特异性。结论本研究中得到的化合物compound 2可作为一种潜在的新型前导化合物应用于治疗自身免疫性疾病和一些炎症性疾病。

To develop a therapeutic agent against Th17-mediated autoimmune diseases, we have identified a promising compound that potently inhibited RORγt activity. Furthermore, we have confirmed the effects of the candidate on Th17 development in vitro to verify its biological activity. The compound was successfully applied in a Gal4-RORγt reporter system in stable Jurkat cells to suppress the activity of RORγt. The identified compound was then carried on the experiment of mouse Th17 differentiation in vitro and confirmed to suppress Th17 differentiation and IL-17 expression and production. Moreover, we had determined the values of EC50, CC50 and T cell specificity of the candidate. Taken together, we identified compound 2（the compound was numbered in our lab） potently inhibited RORγt activity, suppressed Th17 differentiation and IL-17 production. Furthermore, the candidate displayed a high T cell specificity and highly therapeutic efficiency with low cytotoxicity. Our data indicate that the novel compound as promising candidate that has potential as a therapeutic for autoimmune diseases involving Th17 cells.