Effects of Native Fucosylated Glycosaminoglycan, Its Depolymerized Derivatives on Intrinsic Factor Xase, Coagulation, Thrombosis, and Hemorrhagic Risk

Lutan Zhou; Na Gao; Huifang Sun; Chuang Xiao; Lian Yang; Lisha Lin; Ronghua Yin; Zi Li; Hongbin Zhang; Xu Ji; Jinhua Zhao

doi:10.1055/s-0040-1708480

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2020; 120(04): 607-619
DOI: 10.1055/s-0040-1708480

Coagulation and Fibrinolysis

Georg Thieme Verlag KG Stuttgart · New York

Effects of Native Fucosylated Glycosaminoglycan, Its Depolymerized Derivatives on Intrinsic Factor Xase, Coagulation, Thrombosis, and Hemorrhagic Risk

Authors

Lutan Zhou

¹Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

³University of Chinese Academy of Sciences, Beijing, China
Na Gao^*

⁴School of Pharmaceutical Sciences, South Central University for Nationalities, Wuhan, China
Huifang Sun

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

³University of Chinese Academy of Sciences, Beijing, China
Chuang Xiao

⁵School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China
Lian Yang

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
Lisha Lin

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

³University of Chinese Academy of Sciences, Beijing, China
Ronghua Yin

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
Zi Li

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
Hongbin Zhang

¹Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China
Xu Ji

¹Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China

⁶Suzhou Banbutang Biological Technology Co., LTD, Suzhou, China
Jinhua Zhao

²State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China

⁴School of Pharmaceutical Sciences, South Central University for Nationalities, Wuhan, China

Abstract

A native fucosylated glycosaminoglycan from sea cucumber Holothuria fuscopunctata (nHG), mainly branched with Fuc_3S4S, exhibited potent anticoagulant activity by intrinsic tenase iXase (FIXa-FVIIIa complex) and antithrombin-dependent factor IIa (FIIa) inhibition, but also had the effects of FXII activation and platelet aggregation. For screening a selective iXase inhibitor, depolymerized nHG (dHG-1 ∼ –6) and a pure octasaccharide (oHG-8) were prepared. Like nHG, dHG-1 ∼ –6 and oHG-8 could potently inhibit iXase, and competitive binding assay indicated that dHG-5 and oHG-8 could bind to FIXa. Nevertheless, dHG-5 and oHG-8 had no effects on FXII and platelet activation. nHG, dHG-5, and oHG-8 could significantly prolong the activated partial thromboplastin time of human, rat, and rabbit plasma. In the rat deep venous thrombosis model, dHG-5 and oHG-8 showed potent antithrombotic effects in a dose-dependent manner, while the thrombus inhibition rate of nHG at high dose was markedly reduced. Additionally, dHG-5 and oHG-8 did not increase bleeding at the doses up to 10-fold of the effectively antithrombotic doses compared with nHG and low molecular weight heparin in the mice tail-cut model. Considering that dHG-5 possesses strong anti-iXase and antithrombotic activities, and its preparation process is simpler and its yield is higher compared with oHG-8, it might be a promising antithrombotic candidate.

Keywords

dHG-5 - iXase - anticoagulant - antithrombotic - hemorrhagic risk

Full Text

References

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