A Nanosensor for Ultrasensitive Detection of Oversulfated Chondroitin Sulfate Contaminant in Heparin

Kalita, Mausam; Balivada, Sivasai; Swarup, Vimal P.; Mencio, Caitlin; Raman, Karthik; Desai, Umesh R.; Troyer, Deryl L.; Kuberan, Balagurunathan

doi:10.1021/ja409170z

Cited by 48 publications

(44 citation statements)

References 28 publications

(38 reference statements)

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“…As described above, 1 exhibited some FXII activation; oversulfated chondroitin sulfates (OSCSs) exhibit this effect, and such a side effect may cause acute hypersensitivity reactions and endanger the lives of patients (28)(29)(30). Compared with 1, low concentrations of 2 exhibited significantly reduced FXII activation, whereas high concentrations (>16 μg/mL) of 2 and 8 still activated FXII.…”

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

confidence: 94%

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

Zhao

Xiao

et al. 2015

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

111

148

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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: Compounds 5-8 Exhibit Strong Anticoagulant Activities By Selmentioning

confidence: 94%

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

Zhao

Xiao

et al. 2015

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

111

148

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“…This construct proved to be a good substrate for heparinase, and the resulting release of the dye from the nanoparticle allowed recovery of fluorescence (otherwise quenched in the nanoparticle), which was exploited for analytical purposes. The presence of OSCS in the heparin samples resulted in diminished fluorescence recovery because heparinase activity is inhibited by such contaminants …”

Section: Heparin and Heparan Sulfatementioning

confidence: 99%

Chemical Derivatization of Sulfated Glycosaminoglycans

2016

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Sulfated glycosaminoglycans (GAGs) are a family of complex polysaccharides ubiquitously distributed in extracellular matrices and at cell surfaces and playing key roles in a myriad of biological processes. Their structures are based on disaccharide building blocks, usually containing an amino sugar and an uronic acid, decorated with one or more sulfate groups. Many efforts to gain access to a large number of sulfated GAG polysaccharides with potential tailored biomedical applications, usually based on suitable chemical (and chemo-enzymatic) derivatization procedures that modified the native polysaccharide structures, have been reported in the last two decades. In this review we survey such reactions on the basis of (i) the sulfated GAG substrate [(fucosylated) chondroitin sulfate, dermatan sulfate, heparin, and heparan sulfate], and (ii) the sort of structural modification (sulfation pattern modification, oxidation, carboxy group derivatization, N- and O-acylation, reducing-end functionalization)

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“…Since the 1990s, porcine mucosa has been the sole source of heparin in western countries because of potential prion contamination and the risk of infection with bovine spongiform encephalopathy. In late 2007 and early 2008, contamination of porcine heparin from China with an ''unnatural'' fully O-sulfated chondroitin sulfate [19][20] resulted in adverse events, including fatalities. As a consequence, US authorities are considering the reintroduction of bovine heparin, which continues to be produced and used clinically in South American countries, in order to diversify the sourcing of heparin.…”

Section: Discussionmentioning

confidence: 99%

Characterization of PF4-Heparin Complexes by Photon Correlation Spectroscopy and Zeta Potential

Bertini

Fareed

Madaschi

et al. 2017

Clin Appl Thromb Hemost

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Heparin-induced thrombocytopenia (HIT) is associated with antibodies to complexes between heparin and platelet factor 4 (PF4), a basic protein usually found in platelet alpha granules. Heparin-induced thrombocytopenia antibodies preferentially recognize macromolecular complexes formed between positively charged PF4 and polyanionic heparins over a narrow range of molar ratios. The aim of this work was to study the complexes that human PF4 forms with heparins from various species, such as porcine, bovine, and ovine; heparins from various organs, such as mucosa and lung; and different low-molecular-weight heparins (LMWHs) at several stoichiometric ratios to evaluate their sizes and charges by photo correlation spectroscopy and zeta potential measurements. The resulting data of the PF4 complexes with unfractionated heparins (UFHs), LMWHs and their fractions, and oligosaccharide components suggest that the size of aggregates is not only a simple function of average molecular weight but also of the molecular weight distribution of the sample. Moreover, it was found that lower concentrations of the tested ovine-derived mucosal heparin are required to form the large PF4/heparin complexes as compared to mucosal porcine and bovine heparin.

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A Nanosensor for Ultrasensitive Detection of Oversulfated Chondroitin Sulfate Contaminant in Heparin

Cited by 48 publications

References 28 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

Chemical Derivatization of Sulfated Glycosaminoglycans

Characterization of PF4-Heparin Complexes by Photon Correlation Spectroscopy and Zeta Potential

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