Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase

Wu, Mingyi; Wen, Dandan; Gao, Na; Xiao, Chuang; Yang, Lian; Xu, Li; Wu, Lian; Peng, Wenlie; Jiang, Jianmin; Zhao, Jinhua

doi:10.1016/j.ejmech.2014.12.054

Cited by 115 publications

(119 citation statements)

References 52 publications

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“…The native FG (HPLC purity 99.9%; average molecular mass 70 kDa) (1; Fig. 2A) was isolated and purified from the sea cucumber S. variegatus as previously described (24,31). Depolymerized 1 (i.e., 2) with an anTal-ol terminal was prepared via the partial deacetylation-deaminative cleavage of 1 as previously described (17).…”

Section: Methodsmentioning

confidence: 99%

“…The APTT, PT, and TT of 1-8, LMWH, and dermatan sulfate (DS) were determined using assay kits on a coagulometer (TECO; MC-4000) as described previously (44). The inhibition of the intrinsic tenase was determined using the previously described method (31,45) with modifications and the reagents in the BIOPHEN FVIII:C Kit (HYPHEN BioMed).…”

Section: Methodsmentioning

confidence: 99%

“…The activation of human FXII in the presence of samples of 1-8 was assessed using a previously described method (31,46). Turbidimetric measurements of platelet aggregation by 1-8 were performed using a Chrono-log 700 aggregometer according to Born's method (31,47). Venous blood from a young healthy volunteer (a 26-y-old male, ∼65 kg) was anticoagulated with 3.8% (wt/wt) sodium citrate.…”

Section: Methodsmentioning

confidence: 99%

“…Additionally, medicinal properties in vivo of other promising compounds such as 6 and 7 may also be distinct and worthy of further elucidation in the future. Discussion FG, a novel glycosaminoglycan derivate from sea cucumber, is markedly different from typical mammalian glycosaminoglycans, such as dermatan sulfate and chondroitin sulfate, because of its unique sulfated fucose side chains, although it possesses a chondroitin sulfate-like backbone (31). In recent years, FG has attracted increasing attention from researchers because of its high yields (∼1%) from the dried body wall of sea cucumber and because of its biological activities, including anticoagulant, antithrombotic, anticancer, and anti-HIV activities (14,(31)(32)(33).…”

Section: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 99%

“…Discussion FG, a novel glycosaminoglycan derivate from sea cucumber, is markedly different from typical mammalian glycosaminoglycans, such as dermatan sulfate and chondroitin sulfate, because of its unique sulfated fucose side chains, although it possesses a chondroitin sulfate-like backbone (31). In recent years, FG has attracted increasing attention from researchers because of its high yields (∼1%) from the dried body wall of sea cucumber and because of its biological activities, including anticoagulant, antithrombotic, anticancer, and anti-HIV activities (14,(31)(32)(33). Over the past 30 y, the basic structure of FG has been studied using chemical methods such as desulfation, defucosylation, and methylation together with NMR analyses and analyses of the products formed by digesting the partially defucosylated chondroitin sulfate with chondroitinase AC or ABC (20)(21)(22).…”

Section: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 99%

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Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylationdeaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.T hrombotic disease is seriously harmful to human health and is one of the major causes of death in modern society (1). Despite their long-term and widespread use as anticoagulants, heparin, low-molecular-weight heparin (LMWH), and coumarins still have a major unresolved issue: the risk of serious bleeding during therapy (1-3). It is generally recognized that the risk of bleeding associated with these agents is related to the nonselectivity of their anticoagulant activity. Therefore, selective inhibitors of human factor Xa (FXa) and thrombin (FIIa), such as dabigatran, rivaroxaban, and apixaban, which have predictable pharmacokinetics, have recently been developed; however, these agents have not effectively reduced the risk of bleeding in clinical applications (4-7).Components of the intrinsic coagulation pathway are promising targets for antithrombotic therapy because they are important for thrombosis but are not required for hemostasis (1,8). The development of new anticoagulant agents that inhibit components of the intrinsic pathway and that have a lower risk of causing bleeding has thus become a research focus (9-11). Factor IXa (FIXa), a serine protease, and factor VIIIa (FVIIIa), a protein cofactor, form a Ca 2+ -and phospholipid surface-dependent complex referred to as the intrinsic tenase complex, which efficiently converts zymogen factor X (FX) to FXa (1,12,13). Because the intrinsic tenase is the final and rate-limiting enzyme complex in the intrinsic pathway, the development of inhibitors of this enzyme complex is important for meeting clinical demands (1). However, limited progress has been achieved due to the unavailability of selective inhibitors with welldefined structures.Fucosylated glycosaminoglycan (FG; 1 in Fig. 1), which is a complex acidic polysaccharide isolated from sea cucumber, has recently attracted considerable attention because of its various bioactivities (14). Notably, FG has potent anticoagula...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 99%

Section: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Zhao

Xiao

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

116

152

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Synthesis of Fucosylated Chondroitin Sulfate Nonasaccharide as a Novel Anticoagulant Targeting Intrinsic Factor Xase Complex

et al. 2018

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Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan, and its oligosaccharides exhibit excellent anticoagulant activity with lower risks of adverse effects and bleeding. Herein we report a facile approach to the synthesis of FuCS hexa‐ and nonasaccharides on the basis of the enzymatic degradation of chondroitin over 12 linear steps. As compared with a clinical low‐molecular‐weight heparin drug (enoxaparin), the nonasaccharide synthesized in this study displayed similar APTT activity and selective intrinsic factor Xase complex inhibitory activity ((12.9±0.83) nm) by binding to factor IXa with high affinity, thus offering promise for the development of new anticoagulant agents targeting the intrinsic coagulation pathway.

show abstract

Synthesis of Fucosylated Chondroitin Sulfate Nonasaccharide as a Novel Anticoagulant Targeting Intrinsic Factor Xase Complex

et al. 2018

Self Cite

View full text Add to dashboard Cite

Fucosylated chondroitin sulfate (FuCS) is a structurally distinct glycosaminoglycan, and its oligosaccharides exhibit excellent anticoagulant activity with lower risks of adverse effects and bleeding. Herein we report a facile approach to the synthesis of FuCS hexa- and nonasaccharides on the basis of the enzymatic degradation of chondroitin over 12 linear steps. As compared with a clinical low-molecular-weight heparin drug (enoxaparin), the nonasaccharide synthesized in this study displayed similar APTT activity and selective intrinsic factor Xase complex inhibitory activity ((12.9±0.83) nm) by binding to factor IXa with high affinity, thus offering promise for the development of new anticoagulant agents targeting the intrinsic coagulation pathway.

show abstract

Anticoagulant and antithrombotic evaluation of native fucosylated chondroitin sulfates and their derivatives as selective inhibitors of intrinsic factor Xase

Cited by 115 publications

References 52 publications

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan

Synthesis of Fucosylated Chondroitin Sulfate Nonasaccharide as a Novel Anticoagulant Targeting Intrinsic Factor Xase Complex

Synthesis of Fucosylated Chondroitin Sulfate Nonasaccharide as a Novel Anticoagulant Targeting Intrinsic Factor Xase Complex

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