Carboxylate polyanions accelerate inhibition of thrombin by heparin cofactor II

Church, Frank C.; Treanor, Rita E.; Sherrill, G.Bradley; Whinna, Herbert C.

doi:10.1016/0006-291x(87)91119-3

Cited by 29 publications

(12 citation statements)

References 34 publications

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“…'ZSI-labeled tbrombin (with approx. 3 x 10" dpm/mol proteinase) was prepared as detailed previously [16]. DEGRthrombin [lo] and lysine-modified HCII [17] were prepared essentially as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…PAGE was performed in the Laemmli buffer system with 7.5% polyacrylamide gels [18]. Plasma incubation with 12sI-labeled thrombin was performed essentially as described previously [12,16]. Extrinsic fluorescence measurements of DEGR-thrombin in the absence and presence of various polyanions were performed as described [lo].…”

Section: Other Determinations and Methodsmentioning

confidence: 99%

“…Inhibition rate constants were calculated as detailed [16]. The anticoagulant activity of the phosphate-containing polyanions was measured using an aPTT clotting assay following the manufacturer's procedure.…”

Section: Assaysmentioning

confidence: 99%

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Antithrombin action of phosvitin and other phosphate‐containing polyanions is mediated by heparin cofactor II

et al. 1988

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We have examined the antithrombin effects of various phosphate-containing polyanions (including linear polyphosphates, polynucleotides and the phosphoserine glycoprotein, phosvitin) on the glycosaminoglycan-binding plasma proteinase inhibitors, antithrombin III (ATIII) and heparin cofactor II (HCII). These phosphate-containing polyanions accelerate the HCII-thrombin reaction, as much as 1600-fold in the case of phosvitin. The HCII-thrombin reaction with both phosvitin and polynucleotides appears to follow the ternary complex mechanism. The HCII-thrombin complex is rapidly formed in the presence of these phosphate polyanions (each at 10 fig/ml) when 'ZSI-labeled thrombin is incubated with human plasma (ex vivo). None of these phosphate polyanions accelerate the ATIII-thrombin reaction. Our results suggest that the antithrombotic effect of these phosphate-containing polyanions is mediated by HCII activation and not by ATIII.

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Section: Methodsmentioning

confidence: 99%

Section: Other Determinations and Methodsmentioning

confidence: 99%

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Antithrombin action of phosvitin and other phosphate‐containing polyanions is mediated by heparin cofactor II

et al. 1988

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“…46 Modeling reveals that polyaspartate polymer has a charge density of -0.31 charges per Å, approximately 33% lower than PAA. Thus, our results with PAAs are extremely interesting because they demonstrate some structural requirements, specifically the need for appropriate charge density.…”

Section: Discussionmentioning

confidence: 99%

Antithrombin Activation by Nonsulfated, Non-Polysaccharide Organic Polymer

Monien

Desai

2005

J. Med. Chem.

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Accelerated antithrombin inhibition of procoagulant enzymes has been exclusively achieved with polysulfated polysaccharides. We reasoned that antithrombin activation should be possible with nonsulfated activators based only on carboxylic acid groups. As a proof of the principle, linear poly(acrylic acid)s were found to bind to antithrombin and accelerate inhibition of factor Xa and thrombin. Our work demonstrates that molecules completely devoid of sulfate groups can activate antithrombin effectively and, more importantly, suggests that it may be possible to develop orally bioavailable, carboxylate-based antithrombin activators.

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“…Peptide nanofiber assemblies with charged surface are a class of attractive scaffolds for interaction with the external surfaces of protein drugs. [19][20][21][22][23] And the size and flexibility of peptide nanofibers make them afford a sufficient surface area contact with the target drugs and recognize the external surfaces of drugs, 19 resulting in a significant increase in loading efficiency.…”

Section: Introductionmentioning

confidence: 99%