Unveiling the Disaccharide-Branched Glycosaminoglycan and Anticoagulant Potential of Its Derivatives,Biomacromolecules

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Unveiling the Disaccharide-Branched Glycosaminoglycan and Anticoagulant Potential of Its Derivatives
Biomacromolecules ( IF 5.5 ) Pub Date : 2021-02-22 , DOI: 10.1021/acs.biomac.0c01739
Ronghua Yin _{1,

2} , Lutan Zhou ₂ , Na Gao ₁ , Lisha Lin _{2,

3} , Huifang Sun _{2,

3} , Dingyuan Chen _{2,

3} , Ying Cai ₂ , Zhili Zuo ₂ , Kaifeng Hu ₂ , Shengxiong Huang ₂ , Jikai Liu ₁ , Jinhua Zhao _{1,

2}

Affiliation

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_4S(6S)-α1,2-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.

中文翻译：

揭示二糖支链的糖胺聚糖及其衍生物的抗凝潜力

糖胺聚糖（GAGs）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起着至关重要的作用。但是，除了海参中的岩藻糖分支的糖以外，很少发现有糖分支的GAG。自30年前以来就存在关于二糖支链GAG的猜测，尽管尚未得到证实。在这里，我们报告了一个GAG，其中含有Thelenota ananas的半乳糖-岩藻糖分支。这种独特的分支被确认为d -Gal _4S（6S） -α1,2-升-fUC _3S通过从制备的寡糖的结构解析T.凤梨插科打诨。生物测定法表明，具有较大聚合度的低聚物可通过靶向内在肌腱酶表现出有效的抗凝作用。事实证明，七糖是保留抗凝潜力的最小片段，在sc体内显示对静脉血栓形成的抑制率为92.6％。剂量为8 mg / kg，无明显出血风险。这些结果不仅解决了长期存在的关于假单胞菌中双糖支化GAG的问题，而且为开发更安全的抗凝剂开辟了新的机会。

更新日期：2021-03-08

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