Construction and characterisation of a heparan sulphate heptasaccharide microarray

Yang, Jianhong; Hsieh, Po Hung; Liu, Xinyue; Zhou, Wen; Zhang, Xing; Zhao, Jing; Xu, Yongmei; Zhang, Fuming; Linhardt, Robert J.; Liu, Jian

doi:10.1039/c6cc08204a

Cited by 45 publications

(42 citation statements)

References 32 publications

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“…Subsequently, these compounds were subjected to purity and structural analysis as described in the text. The synthesis of Compound 7* to 11* was reported in previous publications 17, 45 . Panel B shows the schemes for the syntheses of compound 1 to 6 .…”

Section: Figmentioning

confidence: 99%

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Wang

Hsieh

et al. 2017

J. Am. Chem. Soc.

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The sulfation at the 3-OH position of glucosamine is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis of 3-O-sulfated heparan sulfate. As a rare modification present in heparan sulfate, the availability of 3-O-sulfated oligosaccharides is very limited. Here, we report the use of a chemoenzymatic synthetic approach to synthesize six 3-O-sulfated oligosaccharides, including three hexasaccharides and three octasaccharides. The synthesis was achieved by rearranging the enzymatic modification sequence to accommodate the substrate specificity of 3-O-sulfotransferase 3. We studied the impact of 3-O-sulfation on the conformation of the pyranose ring of 2-O-sulfated iduronic acid using NMR, and on the correlation between ring conformation and anticoagulant activity. We identified a novel octasaccharide that interacts with antithrombin and displays anti factor Xa activity. Interestingly, the octasaccharide displays a faster clearance rate than fondaparinux, an FDA approved pentasaccharide drug, in a rat model, making this octasaccharide a potential short acting anticoagulant drug candidate that could reduce bleeding risk. Having access to a set of critically important 3-O-sulfated oligosaccharides offers the potential to develop new heparan sulfate-based therapeutics.

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Section: Figmentioning

confidence: 99%

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Wang

Hsieh

et al. 2017

J. Am. Chem. Soc.

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“…9 The development of HS oligosaccharide arrays has, however, been stymied by the difficulties of preparing large collections of these compounds 10 and previously reported HS arrays contained relatively small numbers of compounds that can not provide detailed structure–activity relationships. 11 To address this deficiency, we describe here a synthetic methodology that can provide large numbers of differently sulfated HS oligosaccharides by selective sulfation of hydroxyls and amines of a limited number of tetrasaccharides prepared by a modular approach. It readily provided an unprecedented library of 47 HS-oligosaccharides, which were used for the development of a microarray.…”

Section: Introductionmentioning

confidence: 99%

Heparan Sulfate Microarray Reveals That Heparan Sulfate–Protein Binding Exhibits Different Ligand Requirements

Zong¹,

Venot²,

Li³

et al. 2017

J. Am. Chem. Soc.

121

106

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Heparan sulfates (HS) are linear sulfated polysaccharides that modulate a wide range of physiological and disease-processes. Variations in HS epimerization and sulfation provide enormous structural diversity, which is believed to underpin protein binding and regulatory properties. The ligand requirements of HS-binding proteins have, however, been defined in only a few cases. We describe here a synthetic methodology that can rapidly provide a library of well-defined HS oligosaccharides. It is based on the use of modular disaccharides to assemble several selectively protected tetrasaccharides that were subjected to selective chemical modifications such as regioselective O- and N-sulfation and selective desulfation. A number of the resulting compounds were subjected to enzymatic modifications by 3-O-sulfotransferases-1 (3-OST1) to provide 3-O-sulfated derivatives. The various approaches for diversification allowed one tetrasaccharide to be converted into 12 differently sulfated derivatives. By employing tetrasaccharides with different backbone compositions, a library of 47 HS-oligosaccharides was prepared and the resulting compounds were used to construct a HS microarray. The ligand requirements of a number of HS-binding proteins including fibroblast growth factor 2 (FGF-2), and the chemokines CCL2, CCL5, CCL7, CCL13, CXCL8, and CXCL10 were examined using the array. Although all proteins recognized multiple compounds, they exhibited clear differences in structure–binding characteristics. The HS microarray data guided the selection of compounds that could interfere in biological processes such as cell proliferation. Although the library does not cover the entire chemical space of HS-tetrasaccharides, the binding data support a notion that changes in cell surface HS composition can modulate protein function.

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“…In addition, the introduction of pNP-group allows the oligosaccharides to bind to the C 18 resin for product purification. Furthermore, the pNP –group can be further derivatized to an azido or an amine group to affix the oligosaccharides on the chips for glycan microarray analysis [19] . The pNP-glucuronic acid residues can be selectively cleaved when treatment with periodate oxidation followed by Smith degradation or alkaline elimination.…”

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confidence: 99%

Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides

Liu

2017

Angew Chem Int Ed

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Chondroitin sulfate (CS) is a sulfated polysaccharide that plays essential physiological roles. Here, we report to utilize an enzyme-based method to synthesize a library of CS oligosaccharides consisting of 15 different CS oligosaccharides. The library covers 4-O-sulfated and 6-O-sulfated oligosaccharides with the size ranging from trisaccharide to nonasaccharide. We also demonstrate the synthesis of unnatural 6-O-sulfated CS pentasaccharides containing either a 6-O-sulfo 2-azido galactosamine or a 6-O-sulfo galactosamine residue. The availability of structurally defined CS oligosaccharides offers a novel approach to investigate the biological functions of CS.

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Construction and characterisation of a heparan sulphate heptasaccharide microarray

Cited by 45 publications

References 32 publications

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Synthesis of 3-O-Sulfated Oligosaccharides to Understand the Relationship between Structures and Functions of Heparan Sulfate

Heparan Sulfate Microarray Reveals That Heparan Sulfate–Protein Binding Exhibits Different Ligand Requirements

Enzymatic Synthesis of Homogeneous Chondroitin Sulfate Oligosaccharides

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