基于FG结构片段的P-选择素抑制剂发现及其抗血栓活性研究

现有临床抗血栓药均存在共性的出血危险，低出血倾向的新靶点抗血栓药已现曙光，而抑制凝血机制被激活之前的病理过程还可以进一步避免出血倾向。P-选择素(P-sel)因在血栓性疾病的炎症相关的病理过程具有重要作用而受高度关注。目前，国际在研的P-sel小分子抑制剂都存在与寡糖合成困难相关的活性相对较弱的“瓶颈”。前期研究发现，岩藻糖化糖胺聚糖(FG)寡糖片段可以高亲和力结合P-sel并强效抑制其结合PSGL-1(P-sel配基)或其活性SLeX寡糖位点，而其细胞及体内的活性强度仍需提高。鉴于PSGL-1另含特征性硫酸酪氨酸(TyrS)和簇聚SLeX结构，本项目拟利用结构多样性的FG寡糖，半合成含有类似TyrS结构和/或簇聚寡糖衍生物，突破寡糖全合成技术限制，探索获得具有强效抗炎抗血栓活性的P-sel抑制剂，辨析其药理药效学活性特点，并探讨其潜在临床价值。

The antithrombotic drugs that are currently available in clinic share the same defects of increasing bleeding risk. Although some antithrombotic drugs with new targets have showed low bleeding risk, and are being developed, inhibition of the early pathological phase of thrombosis before the coagulation or platelet activation might further avoid bleeding side effect. The important roles of P-selectin in pathological process of thrombotic disease have attracted increasing attention. However, to date the reported small molecular inhibitors of P-selectin have relatively weak activity, and the synthesis of effective oligosaccharides has been challenging. Previous studies showed that oligosaccharides from fucosylated glycosaminoglycan (FG) could bind to P-selectin with high affinity, thus potently inhibiting its binding to PSGL-1 (P-selectin glycoprotein ligand-1) or SLeX (sialyl Lewis X, active oligosaccharide site of PSGL-1), while their activity in cell and in vivo levels were not so strong as expected. Given that PSGL-1 contains the characteristic structures of SLeX cluster and tyrosine sulfate (TyrS), this project intends to screen lead compounds from FG oligosaccharides with diverse structures and to semi-synthesize their derivatives with TyrS- and/or SLeX cluster-like structure. By this strategy, the limitations of oligosaccharides synthesis can be circumvented. Then after obtaining potent P-selectin inhibitors, their anti-inflammatory and antithrombotic activity will be evaluated both in vitro and in vivo. Finally, the pharmacodynamics and pharmacological mechanisms of these P-selectin inhibitors will be studied to analyze their potential clinical value as a novel antithrombotic drug.