Unveiling the Disaccharide-Branched Glycosaminoglycan and Anticoagulant Potential of Its Derivatives
Unveiling the Disaccharide-Branched Glycosaminoglycan and Anticoagulant Potential of Its Derivatives
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揭示二糖支链糖胺聚糖及其衍生物的抗凝潜力
DOI：
10.1021/acs.biomac.0c01739
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发表时间：
2021-02-22
影响因子：
6.2
通讯作者：
Zhao, Jinhua
中科院分区：
文献类型：
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作者：
Yin, Ronghua;Zhou, Lutan;Zhao, Jinhua
糖胺多糖(GAG)是由线性重复二糖组成的保守多糖，在动物界的多种生物学过程中发挥着重要作用。然而，除了海参中的岩藻糖基之外，糖基基团很少出现。自30年前以来，人们一直在猜测双糖分支的GAG的存在，尽管还没有得到证实。在这里，我们报告了一个含有半乳糖-岩藻糖枝的GAG。经结构鉴定，确定该支链为D-半乳糖(4)-S(6S)-α1，2-L-Fuc(3S)。生物测定表明，聚合度较大的低聚物通过靶向固有的张力酶而显示出强大的抗凝血作用。七糖是保留抗凝作用的最小片段，sc时对体内静脉血栓的抑制率为92.6%。8 mg/kg，无明显出血危险。这些结果不仅解决了海参总科中存在二糖支链GAG的长期问题，而且为开发更安全的抗凝血剂开辟了新的机会。
Glycosaminoglycans (GAGs) are conserved polysaccharides composed of linear repeating disaccharides and play crucial roles in multiple biological processes in animal kingdom. However, saccharide-branched GAGs are rarely found, except the fucose-branched one from sea cucumbers. There was conjecture about the presence of disaccharide-branched GAG since 30 years ago, though not yet confirmed. Here, we report a GAG containing galactose-fucose branches from Thelenota ananas. This unique branch was confirmed as D-Gal(4)S(6S)-alpha 1,2-L-Fuc(3S) by structural elucidation of oligosaccharides prepared from T. ananas GAG. Bioassays indicated that oligomers with a larger degree of polymerization exhibited a potent anticoagulation by targeting the intrinsic tenase. Heptasaccharide was proven as the minimum fragment retaining the anticoagulant potential and showed 92.6% inhibition of venous thrombosis in vivo at sc. of 8 mg/kg with no obvious bleeding risks. These results not only solve a long-standing question about the presence of disaccharide-branched GAG in Holothuroidea, but open up new opportunities to develop safer anticoagulants.