蛋白酪氨酸磷酸酶1B（PTP1B）天然抑制剂是胰岛素抵抗（IR）治疗药物研究的重要源头。潺槁木为海南典型药用植物，资源丰富且被用于治疗IR。课题组首次发现其改善IR的有效部位富含阿朴菲生物碱类成分（APA），且APA发挥功效与抑制PTP1B密切相关。本项目拟在前期研究基础上，综合运用天然药物化学、药理学、分子生物学等方法，系统获得有效部位中的APA；体外评价APA改善IR作用、与PTP1B的结合能力和抑制PTP1B酶的活性，剖析构效关系；遴选结构新颖、活性显著的APA，足量制备；考察其对ob/ob小鼠生理病理指标的影响，评估其改善IR的功效；通过检测遴选APA对细胞和组织中PTP1B及其下游蛋白表达、磷酸化、基因表达水平的影响，结合选择性拮抗剂和RNA干扰验证其功效与抑制PTP1B的相关性，阐明其分子机制。最终，发现新型先导化合物，为潺槁木的研究提供科学依据，为IR治疗药物的研究奠定基础。

Natural inhibitors of Protein tyrosine phosphatase 1B (PTP1B) were important sources for developing agents in curing insulin resistance (IR). Litsea glutinosa, a natural medicinal plant with abundant resources in Hainan province, has been used in treating IR. Previously, our research group firstly found that the extract of Litsea glutinosa showed significant activities in ameliorating IR. Further pharmacological investigations have been successfully carried out by which the active fraction was determined. Tentatively chemical investigation displayed that the active fraction was rich in aporphine alkaloids (APA), and these chemical constituents exhibited significant activities in curing IR. Furthermore, the potential mechanisms were found to be closely related to inhibiting PTP1B. On the basis of those previous works, this project is aimed to systemically investigate the medicinal plant by integrating modern methods including natural product chemistry, and pharmacology, etc. By applying these approaches, the APA in the effective part will be fully isolated and structurally characterized. Next, the binding abilities between APA and PTP1B in silico, their activities in improving IR, and inhibiting the enzyme of PTP1B will be evaluated completely. By analyzing the results obtained from the above three aspects, the structure-activity relationship will be investigated. Compounds with interesting structures and significant biological activities will be selected and then prepared in large amount. Following, the target compounds will be orally taken by ob/ob mice. After checking the biochemical indexes and tissue pathology, their activities in improving IR will be deeply evaluated. Finally, by detecting protein and RNA expression levels of PTP1B and its down proteins and genes, applying antagonist and RNA interference, the potential mechanisms will be determined. In this way, our findings will establish solid scientific foundation, facilitating not only in finding new lead compounds, but also providing scientific data for investigating both Litsea glutinosa and new agents in curing IR.