Abstract：
Thromboembolic diseases pose a serious risk to human health worldwide. Fucosylated chondroitin sulfate (FCS) is reported to have good anticoagulant activity with a low bleeding risk. Molecular weight plays a significant role in the anticoagulant activity of FCS, and FCS smaller than octasaccharide in size has no anticoagulant activity. Therefore, identifying the best candidate for developing novel anticoagulant FCS drugs is crucial. Herein, native FCS was isolated from sea cucumber Cucumaria frondosa (FCScf) and depolymerized into a series of lower molecular weights (FCScfs). A comprehensive assessment of the in vitro anticoagulant activity and in vivo bleeding risk of FCScfs with different molecule weights demonstrated that 10 kDa FCScf (FCScf-10 K) had a greater intrinsic anticoagulant activity than low molecular weight heparin (LMWH) without any bleeding risk. Using molecular modeling combined with experimental validation, we revealed that FCScf-10 K can specifically inhibit the formation of the Xase complex by binding the negatively charged sulfate group of FCScf-10 K to the positively charged side chain of arginine residues on the specific surface of factor IXa. Thus, these data demonstrate that the intermediate molecular weight FCScf-10 K is a promising candidate for the development of novel anticoagulant drugs.
摘要：
血栓栓塞性疾病对全球人类健康构成严重威胁。据报道，岩藻糖基化硫酸软骨素（FCS）具有良好的抗凝血活性，出血风险低。分子量在FCS的抗凝血活性中起着重要作用，小于八糖的FCS没有抗凝血活性。因此,确定开发新型抗凝FCS药物的最佳候选药物至关重要.在这里，从海参黄瓜（FCScf）中分离出天然FCS，并解聚成一系列较低分子量（FCScfs）。对不同分子量的FCScfs的体外抗凝血活性和体内出血风险的综合评估表明，10kDaFCScf（FCScf-10K）比低分子量肝素（LMWH）具有更大的内在抗凝血活性，没有任何出血风险。使用分子建模结合实验验证，我们揭示了FCScf-10K可以通过将FCScf-10K的带负电荷的硫酸基团与因子IXa特定表面上精氨酸残基的带正电荷的侧链结合来特异性抑制Xase复合物的形成。因此，这些数据表明，中等分子量的FCScf-10K是开发新型抗凝药物的有希望的候选者。
