基于Th17/Treg平衡调节作用的木香烃内酯抗溃疡性结肠炎药构效关系研究

Th17/Treg失衡导致的肠道免疫应答异常与溃疡性结肠炎（UC）的发生发展密切相关。通过抑制Th17细胞分化和/或促进Treg细胞分化，恢复Th17/Treg平衡是治疗UC的重要策略之一。前期研究发现木香烃内酯在DSS诱导的小鼠结肠炎模型上具有显著的抗UC作用，其作用机制是通过阻断JAK2/STAT3信号通路，抑制Th17细胞分化，恢复Th17/Treg平衡，最终发挥抗UC作用。但是在前期成药性评价中，发现木香烃内酯存在水溶性低、酸稳定性差、口服生物利用度低等成药性问题，限制了其临床应用。因此，本项目将通过鉴定木香烃内酯的代谢产物和酸降解产物，揭示造成口服生物利用度低的结构因素；采用化学转化法和全合成法构建结构多样性的衍生物库，通过细胞水平筛选，总结构效关系，明确木香烃内酯结构中的关键药效团；经多轮次的结构优化，期望发现活性和成药性都得到显著改善的抗UC药物候选物。

The abnormal intestinal immune response caused by Th17/Treg imbalance is closely related to the occurrence and development of ulcerative colitis (UC). Restoring Th17/Treg balance by inhibiting Th17 cell differentiation and/or promoting Treg cell differentiation is one of the important strategies for the treatment of UC. Previous studies have found that costunolide has a significant anti-UC effect on DSS-induced mouse colitis model, and its mechanism of action is found to inhibit Th17 cell differentiation by blocking JAK2/STAT3 signaling pathway, restore Th17/Treg balance, and finally play the role of anti-UC. However, the poor druggability such as low water solubility, poor acid stability and low oral bioavailability which were found in the early evaluation of druggability limit the clinical application of costunolide. Therefore, in this project, we will identify the metabolites and acid degradation products of costunolide to reveal the structural factors that cause low oral bioavailability. Structurally diverse derivative library was constructed by chemical transformation and total synthesis to identify the key pharmacophore of costunolide through the structure-activity relationship study based on cell level screening. It is expected to find the anti-uc drug candidates with significantly improved potency and druggability after multiple rounds of structural optimization.