MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China.
Bio-Cell Co. Ltd, Beijing, 100000, China.
Carbohydr Polym. 2020 Dec 1;249:116824. doi: 10.1016/j.carbpol.2020.116824. Epub 2020 Jul 30.
Non-anticoagulant biological functions of heparin-based drugs have drawn increasing attention. However, the exploration into the non-anticoagulant activities of various low molecular weight heparins was associated with bleeding risks in clinical practice and often led to controversial conclusions due to the structural differences. In this study, we aimed to establish a process to produce a library of heparin derivatives with structural diversity and reduced/abolished anticoagulant activity through the combination of chemical modifications and enzymatic cleavage of heparins. The depolymerization characteristics of various selectively modified heparin derivatives by three heparinases were comprehensively analyzed. The order of periodate treatment and heparinase-I depolymerization was proved to significantly change the structural characteristics of the oligosaccharide products. Finally, among several heparin derivatives that screened in the bleomycin-induced cell apoptosis model, the low molecular weight partially 6-O-/N-desulfated heparins showed the strongest anti-apoptotic activities. This study provided a useful approach for future development of novel heparin-derivative medications.
肝素类药物的非抗凝生物功能引起了越来越多的关注。然而，在临床实践中，对各种低分子量肝素的非抗凝活性的探索与出血风险相关，并且由于结构差异，往往导致有争议的结论。在这项研究中，我们旨在建立一种通过化学修饰和肝素酶切割相结合的方法来制备具有结构多样性和降低/消除抗凝活性的肝素衍生物文库的过程。全面分析了三种肝素酶对各种选择性修饰的肝素衍生物的解聚特性。证明高碘酸盐处理和肝素酶-I 解聚的顺序会显著改变寡糖产物的结构特征。最后，在博来霉素诱导的细胞凋亡模型中筛选的几种肝素衍生物中，低分子量部分 6-O-/N-脱硫酸肝素表现出最强的抗凋亡活性。这项研究为新型肝素衍生物药物的未来发展提供了一种有用的方法。
