选择性抑制内源性凝血途径的FuCS寡糖构效关系与机制研究

出血风险限制了抗凝药物的临床应用。内源性凝血途径与病理性血栓形成密切相关而非止血功能所必需，其选择性抑制剂已成为低出血倾向抗凝药物研究新方向。源于海参的岩藻糖基化硫酸软骨素（FuCS）寡糖可选择性抑制内源性途径末端复合物Xase，但限于结构复杂性及获得性困难，其抗凝药物化学研究尚难深入。课题前期基于“半合成”策略首次完成了FuCS抗凝活性最小九糖片段的合成，为解决此类寡糖的获得性问题开辟了方向。课题拟进一步拓展“半合成”策略，围绕FuCS九糖进行结构改造，构建衍生物库，总结抑制内源性途径的构效关系，发现高活性候选寡糖分子，评估体内抗栓及口服有效性，阐明其抗凝作用机制及对止血功能影响，验证Xase作为抗凝药物研发新靶点的可行性。完善“半合成”策略构建FuCS寡糖库，开展基于抗凝新靶点的药物化学及化学生物学研究，对于丰富糖胺聚糖合成化学、明晰内源性凝血调控机制、发展低风险抗凝药物具有重要意义。

Current anticoagulant drugs are associated with significant bleeding tendency. The intrinsic coagulation pathway is closely related to pathological thrombosis rather than hemostasis, thus selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants. Fucosylated chondroitin sulfate (FuCS), a structurally distinct glycosaminoglycan isolated from sea cucumber, is a lead compound as an intrinsic factor Xase complex inhibitor. However, further pharmacological studies have been hindered by the scarcity of homogeneous oligosaccharides owing to the low yields of extraction and purification from natural sources. Based on the semi-synthetic strategy devised by our group, this project aims to perform derivatization of the minimal active nonasaccharide fragment and summarize structure–activity relationships in order to promote the discovery of candidate oilgosaccharides. Further anticoagulant studies will evaluate their in vivo inhibition of venous thrombus, oral effency, and risk of bleeding, which helps verify the feasibility of novel anticoagulants targeting the intrinsic factor Xase. Improving the "semi-synthesis" strategy to construct FuCS oligosaccharide library and carrying out medicinal chemistry and chemical biology research based on the Xase target are of great significance to enrich the glycosaminoglycan synthesis, clarify endogenous coagulation regulation, and develop low-risk anticoagulants.