基于JAK-STAT信号通路抑制的海南雪花属植物中抗RA活性成分的发现及其作用机制研究

选择性JAK(Janus激酶)抑制剂类抗类风湿性关节炎(RA)药物因其选择性强，毒副作用小已成为当前抗RA药物研发的热点方向。目前已上市或处于临床研究阶段的JAK抑制剂类抗RA药物均为小分子合成药物，尚未见天然JAK抑制剂类抗RA药物的上市。我们在前期研究中发现海南特有植物海南雪花的总生物碱提取物不仅具有显著的抗RA活性而且具有选择性JAK抑制活性，进而，在活性评价结果的指导下对该提取物中的化学成分进行了初步研究，发现了系列结构新颖、JAK抑制活性显著的生物碱，基于以上这些，本项目拟采用植物化学-生物学相结合的方法对三种海南雪花属植物中化学成分进行系统研究，进而对分离得到的化合物的抗RA活性和JAK抑制活性进行评价，寻找并发现具有显著活性的化合物，总结构效关系，开展活性化合物基于JAK-STAT信号通路抑制的作用机制研究，为选择性强、毒副作用小的JAK抑制剂类抗RA新药的开发奠定理论基础。

Selective JAK (Janus kinase) inhibitors for the treatment of rheumatoid arthritis (RA) have currently become the hotspot of the development of anti-RA drugs because of their significant selectivity and less toxic side effects. The JAK inhibitors used as anti-RA drugs currently on the market or in clinical research are all small molecule synthetic drugs, and no natural JAK inhibitor developed as anti-RA drug has been listed. In our preliminary study, we found that the anti-RA activity and the inhibitory activities on JAK of the total alkaloid extract of Argostemma hainanicum, a Chinese endemic plant only distributed in Hainan island, were very significant in vitro. Under the guidance based on the results of activity evaluation experiments, a chemical investigation on A. hainanicum was carried out and had led to the isolation of a series of novel alkaloids with significant selective inhibitory activities on JAK. Based on the above those findings, adopting a combination of phytochemical-biological methods, this project intends to systematically study on chemical constituents from three species of the genus Argostemma distributed in Hainan Island. Furthermore, the studies on the anti-RA activities, the inhibitory activities on JAK, the tructure-activity relationships and the mechanisms of action based on the inhibitory activities on JAK-STAT signaling pathway of these isolated compounds from three species of the genus Argostemma distributed in Hainan Island could lay a theoretical foundation for the development of new JAK inhibitors used as anti-RA drugs with significant selectivity and less toxic side effects.