花生衣原花青素类化合物JAK2激活构效关系及作用机制研究

血小板是由骨髓巨核细胞分化而形成，主要参与凝血和止血。化疗诱导血小板减少症（CIT）是肿瘤化疗的严重毒副作用之一。花生衣为豆科植物落花生（Arachis hypogaea）的种皮，具有“凉血止血”之功效，临床适用于治疗血小板减少症，疗效确切。本项目前期研究发现花生衣中分离得到原花青素A1（Proanthocyanidin A1，PS-1）及其立体异构体具有促进血小板生成活性，PS-1通过激活JAK2促进巨核细胞增殖分化，改善CIT，是首次发现的天然药物来源的JAK2激活剂。本项目拟定进一步对花生衣中原花青素类化合物进行高效分离、结构鉴定及结构优化研究，评价原花青素类化合物及其衍生物JAK2激活及促进血小板生成药效活性及作用机制，探索该类化合物JAK2激活构效关系、与JAK2结合模式及结合位点，为新型基于JAK2激活的抗CIT药物发现提供科学依据。

Blood platelet is formed by the differentiation of megakaryocytes of bone marrow, which is mainly involved in coagulation and hemostasis. Chemotherapy-induced thrombocytopenia (CIT) is one of the serious toxic side effects of tumor chemotherapy. Peanut skin, the seed coat of Arachis hypogaea, possesses the effect of cooling blood and hemostasis, which can be used for the treatment of thrombocytopenia in clinic. Our previous study found that proanthocyanidin A1 (PS-1) and its stereoisomer were the main active components of peanut skin in promoting the prodcution of platelet. In addition, PS-1 promotes the proliferation and differentiation of megakaryocytes by activating JAK2 and is also the first naturally occurring JAK2 activator to be discovered. In the following study, the separation, the structural identification and modification of proanthocyanidins in peanut skin will be conducted. Furthermore, the action mechanisms of proanthocyanidins, the structure-activity relationship, and the binding mode and site of proanthocyanidins to JAK2 will also be explored. Taken together, this work will provide scientific evidence for proanthocyanidins as JAK2 activators for the treatment of CIT.