A heparin derivatives library constructed by chemical modification and enzymatic depolymerization for exploitation of non-anticoagulant functions

Yang Ji; Yi Wang; Wen Zeng; Xiang Mei; Shanshan Du; Yishu Yan; Jie Hao; Zhenqing Zhang; Yuan Lu; Chong Zhang; Jun Ge; Xin-Hui Xing

doi:10.1016/j.carbpol.2020.116824

A heparin derivatives library constructed by chemical modification and enzymatic depolymerization for exploitation of non-anticoagulant functions

Carbohydr Polym. 2020 Dec 1:249:116824. doi: 10.1016/j.carbpol.2020.116824. Epub 2020 Jul 30.

Authors

Yang Ji¹, Yi Wang¹, Wen Zeng¹, Xiang Mei², Shanshan Du³, Yishu Yan¹, Jie Hao⁴, Zhenqing Zhang⁴, Yuan Lu¹, Chong Zhang⁵, Jun Ge⁶, Xin-Hui Xing⁷

Affiliations

¹ MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China.
² Bio-Cell Co. Ltd, Beijing, 100000, China.
³ MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China; State Key Laboratory Base for Eco-Chemical Engineering in College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, China.
⁴ Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, 215021, China.
⁵ MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China; Centre for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China.
⁶ MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, China.
⁷ MOE Key Laboratory of Industrial Biocatalysis, Institute of Biochemical Engineering, Department of Chemical Engineering, Tsinghua University, Beijing, 100084, China; Centre for Synthetic and Systems Biology, Tsinghua University, Beijing, 100084, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Shenzhen, 518055, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, China. Electronic address: xhxing@tsinghua.edu.cn.

PMID: 32933671
DOI: 10.1016/j.carbpol.2020.116824

Abstract

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.

Keywords: Glycoengineering; Heparin derivatives; Heparinase; Low molecular weight heparin; Non-anticoagulant activity.

MeSH terms

Antibiotics, Antineoplastic / adverse effects
Anticoagulants / pharmacology*
Apoptosis / drug effects*
Bleomycin / adverse effects*
Cells, Cultured
Epithelial Cells / drug effects*
Epithelial Cells / pathology
Hemolysis / drug effects
Heparin / pharmacology*
Heparin Lyase / metabolism*
Humans
Lung / drug effects*
Lung / pathology

Substances

Antibiotics, Antineoplastic
Anticoagulants
Bleomycin
Heparin
Heparin Lyase