Antithrombin Activation by Nonsulfated, Non-Polysaccharide Organic Polymer

Monien, Bernhard H.; Desai, Umesh R.

doi:10.1021/jm0492960

Cited by 29 publications

(42 citation statements)

References 47 publications

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“…In contrast, the antithrombin affinities of non-saccharide ligands, e.g. small aromatic sulfates such as ECS and CS (19,32) and larger polymers such as polyacrylic acids (33,34), have been measured using 6-p-toluidinylnaphthalene-2-sulfonate, an external probe. In this study, we found that the interaction of our synthetic DHPs with antithrombin resulted in a decrease in intrinsic tryptophan fluorescence (Fig.…”

Section: A Specific Sulfated Dhp Sdso3 Preferentially Inhibits Factmentioning

confidence: 99%

Interaction of Antithrombin with Sulfated, Low Molecular Weight Lignins

Henry¹,

Connell²,

Liang

et al. 2009

Journal of Biological Chemistry

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Antithrombin (AT), 3 a plasma glycoprotein and a member of the serpin superfamily of proteins, is a major regulator of the coagulation cascade. Its primary targets are thrombin, factor Xa (fXa), and factor IXa (fIXa) (1). It has also been suggested to inhibit several other coagulation enzymes (2-6), albeit with much weaker inhibitory efficiency. Antithrombin alone is a rather poor inhibitor of factors IIa, Xa, and IXa and requires the presence of heparin to exhibit its full anticoagulant potential.Heparin is a highly sulfated polysaccharide that greatly enhances the rate of AT inhibition of these enzymes under physiological conditions (1). This acceleration forms the basis for heparin's use as an anticoagulant for the past several decades. Yet heparin is associated with bleeding complications and suffers from a number of other limitations. In addition, the animal origin of the drug is also a cause for concern as suggested by recent incidences of oversulfated chondroitin sulfate contaminating unfractionated heparin (UFH) preparations and resulting in numerous deaths (7-9). Although low molecular weight heparins (LMWHs) are superior to UFH with respect to therapeutic complications, the iatrogenic bleeding risk is not completely eliminated. Likewise, fondaparinux, or the minimal antithrombin binding pentasaccharide sequence (H5), is also associated with bleeding (10, 11) and lacks an effective antidote to reverse excessive anticoagulation.The major reason for the limitations of UFH and LMWH therapies is the presence of numerous negative charges on each polymeric chain. UFH and LMWH are linear co-polymers of glucosamine and uronic acid residues that are decorated with numerous sulfate groups generating a massive polyanion (12,13). This polyanion is capable of interacting with a large number of plasma proteins and proteins present on cells lining the vasculature, which likely induce many of the UFH and LMWH complications (14,15). Fondaparinux displays a much better pharmacological profile primarily because of its limited number of sulfate and carboxylate groups.To design better anticoagulants that are less polyanionic and more hydrophobic than UFHs and LMWHs, we recently pre-* This work was supported, in whole or in part, by National Institutes of Health Grants HL069975 and HL090586. This work was also supported by Grant EIA 0640053N from the American Heart Association National Center, Grant 6-46064 from the A. D. Williams Foundation, and a grant from the Mizutani Foundation for Glycoscience, Japan.

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Section: A Specific Sulfated Dhp Sdso3 Preferentially Inhibits Factmentioning

confidence: 99%

Interaction of Antithrombin with Sulfated, Low Molecular Weight Lignins

Henry¹,

Connell²,

Liang

et al. 2009

Journal of Biological Chemistry

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“…Using the K LAH value determined independently, the equilibrium dissociation constant of the PAA3450-antithrombin interaction (K PAA3450 ) was calculated to be 1.2 µM, which compares favorably with the value determined in direct titration (1.3 µM). 13 PAA-Accelerated Inhibition of Thrombin in the Presence of EFGH''. To test whether PAA interacts with PBS, we determined the influence of the tetrasaccharide EFGH′′ on the PAA-promoted antithrombin inhibition of thrombin.…”

Section: Acceleration Of Thrombin Inhibition By Paa2280mentioning

confidence: 99%

“…13 The PAA molecules, having no resemblance to a heparinlike polysaccharide scaffold but possessing a charge density comparable to heparin, increased the secondorder rate constant of factor Xa and thrombin inhibition several hundred-fold ( Figure 1). This was in striking contrast to other carboxylate polymers, poly(Asp) and poly(Glu), that have been known to display poor antithrombin activation properties.…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Poly(acrylic acid) Acceleration of Antithrombin Inhibition of Thrombin: Implications for the Design of Novel Heparin Mimics

2005

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The bridging mechanism of antithrombin inhibition of thrombin is a dominant mechanism contributing a massive ∼2500-fold acceleration in the reaction rate and is also a key reason for the clinical usage of heparin. Our recent study of the antithrombin-activating properties of a carboxylic acid-based polymer, poly(acrylic acid) (PAA), demonstrated a surprisingly high acceleration in thrombin inhibition (Monien, B. H.; Desai, U. R. J. Med. Chem. 2005, 48, 1269. To better understand this interesting phenomenon, we have studied the mechanism of PAAdependent acceleration in antithrombin inhibition of thrombin. Competitive binding studies with low-affinity heparin and a heparin tetrasaccharide suggest that PAA binds antithrombin in both the pentasaccharide-and the extended heparin-binding sites, and these results are corroborated by molecular modeling. The salt-dependence of the K D of the PAA-antithrombin interaction shows the formation of five ionic interactions. In contrast, the contribution of nonionic forces is miniscule, resulting in an interaction that is significantly weaker than that observed for heparins. A bell-shaped profile of the observed rate constant for antithrombin inhibition of thrombin as a function of PAA concentration was observed, suggesting that inhibition proceeds through the "bridging" mechanism. The knowledge gained in this mechanistic study highlights important rules for the rational design of orally available heparin mimics.

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“…In addition a number of investigators have shown that polymers exposing carboxylic groups at the surface have relatively good blood-contacting features. These materials may even exhibit "heparin mimic" properties [17][18][19] and thus enhance the antithrombogenicity of the biomaterial.…”

Section: Introductionmentioning

confidence: 99%

Poly(ether imide) membranes: studies on the effect of surface modification and protein pre-adsorption on endothelial cell adhesion, growth and function

Tzoneva

Seifert

Albrecht

et al. 2008

Journal of Biomaterials Science, Polymer Edition

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Surface modifications of poly(ether imide) (PEI) membranes with carboxylic groups were tested in comparison to pure PEI and poly(ethylene terephtalate) (PET) for their ability to support attachment, growth and function of human umbilical vein endothelial cells (HUVEC) in respect to endothelization of the above materials. Flat sheet PEI membranes were modified by covalent binding of iminodiacetic acid (IDA) for different periods of time (1 to 30 min) to obtain surfaces with various content of carboxylic groups. In addition, fibronectin (FN) and fibrinogen (FNG) preadsorption on the various membranes were studied on their effect on HUVEC behaviour. Results show a decreased protein adsorption and HUVEC adhesion, growth and function in terms of prostacyclin production with an increase carboxylic groups.Preadsorption of the membranes with FN or FNG promoted activity of HUVEC, which became superior to cells on PET. FN-coated membranes were found to be better substrate for HUVEC adhesion and prostacyclin production, while on FNG-coated membranes cells grew better. Overall it can be concluded that PEI is a promising materials for endothelial cells immobilization as it is needed for improving the hemocompatibility of cardiovascular devices.

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Antithrombin Activation by Nonsulfated, Non-Polysaccharide Organic Polymer

Cited by 29 publications

References 47 publications

Interaction of Antithrombin with Sulfated, Low Molecular Weight Lignins

Interaction of Antithrombin with Sulfated, Low Molecular Weight Lignins

Mechanism of Poly(acrylic acid) Acceleration of Antithrombin Inhibition of Thrombin: Implications for the Design of Novel Heparin Mimics

Poly(ether imide) membranes: studies on the effect of surface modification and protein pre-adsorption on endothelial cell adhesion, growth and function

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