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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

Lutan Zhou
1   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
3   University of Chinese Academy of Sciences, Beijing, China
,
Na Gao   *
4   School of Pharmaceutical Sciences, South Central University for Nationalities, Wuhan, China
,
Huifang Sun
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
3   University of Chinese Academy of Sciences, Beijing, China
,
Chuang Xiao
5   School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, China
,
Lian Yang
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
,
Lisha Lin
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
3   University of Chinese Academy of Sciences, Beijing, China
,
Ronghua Yin
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
,
Zi Li
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
,
Hongbin Zhang
1   Key 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
1   Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education and Yunnan Province, School of Chemical Science and Technology, Yunnan University, Kunming, China
6   Suzhou Banbutang Biological Technology Co., LTD, Suzhou, China
,
Jinhua Zhao
2   State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China
4   School of Pharmaceutical Sciences, South Central University for Nationalities, Wuhan, China
› Author Affiliations Funding This work was funded in part by the National Natural Science Foundation of China (81773737, 81872774, 81703374, 81673330 and 31900926), and Yunnan Provincial Science and Technology Department in China (2018HC012 and 2019ZF011–2). Also, it was supported by the grants from the Dongwu Leading Talent Plan of Scientific-and-Technological Innovation and Entrepreneurship.
Further Information

Publication History

02 September 2019

23 January 2020

Publication Date:
14 April 2020 (online)

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Abstract

A native fucosylated glycosaminoglycan from sea cucumber Holothuria fuscopunctata (nHG), mainly branched with Fuc3S4S, 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

* These authors contributed equally to this work.


Supplementary Material

 

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