Relationship between anticoagulant activity of heparin and susceptibility to periodate oxidation

Fransson, Lars‐Âke; Lewis, Walter

doi:10.1016/0014-5793(79)80065-4

Cited by 18 publications

(5 citation statements)

References 17 publications

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“…While limited characterization of NACH using GPC and NMR had been previously reported, − recent advances by our laboratory and others now make more detailed structural EIC of disaccharides analyses including, disaccharide compositional analysis, bottom-up analysis, and top-down analysis of heparin products possible. USP heparin, prepared from porcine intestinal heparin, D-NACH, and NACH were each exhaustively treated with an equiunit mixture of heparin lyase I, II, and III and then subjected to disaccharide analysis using HPLC–MS .…”

Section: Resultsmentioning

confidence: 99%

“…Most NACHs are prepared through the selective chemical treatment of a heparin to remove its anticoagulant activity. The method most often applied is the periodate oxidation of heparin to selectively oxidize the vicinal hydroxyl groups present in heparin’s nonsulfated UA residues, such as the GlcA residues present in heparin’s AT-pentasaccharide binding site. − The current study uses sophisticated top-down and bottom-up high performance liquid chromatography–mass spectrometry (HPLC–MS) to examine the structure of NACH prepared from either porcine intestinal heparin or the low molecular weight heparin, dalteparin, and the ability of these two NACH preparations to selectively bind to heparin-binding proteins.…”

Section: Introductionmentioning

confidence: 99%

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Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications

Ouyang

Zhang

et al. 2019

J. Med. Chem.

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Heparin is a polypharmacological agent with anticoagulant activity. Periodate oxidation of the nonsulfated glucuronic acid residue results in non-anticoagulant heparin derivative (NACH) of reduced molecular weight. Similar treatment of a low molecular weight heparin, dalteparin, also removes its anticoagulant activity, affording a second heparin derivative (D-NACH). A full structural characterization of these two derivatives reveals their structural differences. SPR studies display their ability to bind to several important heparin-binding proteins, suggesting potential new therapeutic applications.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications

Ouyang

Zhang

et al. 2019

J. Med. Chem.

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“…Only about one-third of the molecules in heparin preparations bind with high affinity to antithrombin and this fraction (in the following deroted "high-affinity heparin") accounts for most of the anticoagulant activity of the unfractionated material (3)(4)(5). Characterization of fragments obtained on digesting a heparin-antithrombin complex with bacterial heparinase indicated that the antithrombin-binding site in heparin molecules involves a sequence of about [12][13][14][15][16] monosaccharide units (6). Recently, Rosenberg et al (7) claimed that a tetrasaccharide sequence with a N-sulfated glucosamine residue at its reducing end, a N-acetylated internal glucosamine unit, and one residue each of D-glucuronic and L-iduronic acid would represent a critical structural element required for anticoagulant activity.…”

mentioning

confidence: 99%

Structure of the antithrombin-binding site in heparin.

Lindahl¹,

Bäckström²,

Höök³

et al. 1979

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

318

165

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Heparin preparations from pig intestinal mucosa and from bovine lung were separated by chromatography on antithrombin-Sepharose into a high-affinity fraction (with high anticoagulant activity) and a low-affinity fraction (with low anticoagulant activity). Antithrombin-binding heparin fragments (12-16 monosaccharide units) were prepared, either by digesting a high-affinity heparin-antithrombin complex with bacterial heparinase or by partial deaminative cleavage of the unfractionated polysaccharide with nitrous acid followed by affinity chromatography on (7) claimed that a tetrasaccharide sequence with a N-sulfated glucosamine residue at its reducing end, a N-acetylated internal glucosamine unit, and one residue each of D-glucuronic and L-iduronic acid would represent a critical structural element required for anticoagulant activity.The present study involves the structural characterization of antithrombin-binding regions from two different types'of heparin, isolated from pig intestinal mucosa and from bovine lung, respectively.

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“…Nonanticoagulant heparin (glycol-split heparin, gsHep) was provided by Dilafor (Stockholm, Sweden), chemically generated by periodate oxidation of pig intestinal mucosa heparin, followed by alkaline β-oxidation of the product as previously described [20]. The average molecular weight of gsHep was approximately 6 kDa as determined by high performance gel permeation chromatography according to manufacturer's data.…”

Section: Methodsmentioning

confidence: 99%

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Wat

Hawrylyshyn

Baczyk

et al. 2018

Biology of Reproduction

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Low molecular weight heparin (LMWH) is being investigated as a potential preventative therapy against preeclampsia. There is evidence suggesting that LMWH may prevent preeclampsia through anticoagulation-independent mechanisms. In this study, we compared the in vitro placental, endothelial, and anti-inflammatory effects of a LMWH (dalteparin) with a non-anticoagulant, glycol-split heparin derivative (gsHep). In contrast with dalteparin, gsHep did not interact with antithrombin III, possess significant anti-Factor Xa activity, or significantly prolong in vitro plasma clotting time. However, dalteparin and gsHep were otherwise mechanistically similar, both interacting with soluble fms-like tyrosine kinase-1 (sFlt1) and promoting secretion of the pro-angiogenic protein placental growth factor, but not the anti-angiogenic sFlt1, from healthy placental villous explants. Placental explant media pre-treated with dalteparin or gsHep significantly stimulated endothelial cell tube formation compared to untreated explants. Lastly, dalteparin and gsHep both significantly suppressed inflammation by inhibiting complement activation and leukocyte adhesion to endothelial cells that were activated using serum from preeclamptic women. Our data suggest that non-anticoagulant heparin derivatives may be utilized as a tool to distinguish the anticoagulationindependent mechanisms of LMWH, and provide insight into the role of anticoagulation in the prevention of preeclampsia.

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Relationship between anticoagulant activity of heparin and susceptibility to periodate oxidation

Cited by 18 publications

References 17 publications

Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications

Non-Anticoagulant Low Molecular Weight Heparins for Pharmaceutical Applications

Structure of the antithrombin-binding site in heparin.

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

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