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Intravascular Targeting of a New Anticoagulant Heparin Compound

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Since most thrombotic reactions occur on the vessel wall, interaction of anticoagulants with vascular components is critical. Heparin (H) is the primary drug for treatment and prevention of thrombosis. To improve H's efficacy and bioavailability, a covalent complex of H and its biological target, antithrombin (AT), was developed. While H has a short, variable intravenous half-life leading to unpredictable anticoagulation, clearance of covalent ATH complex is slower. H's variable anticoagulant effect arises from interactions with plasma and vessel wall proteins. ATH has increased bioavailability due to lower plasma protein and endothelial binding relative to H. Pharmacodynamic studies demonstrate that the AT moiety can regulate ATH binding to target tissues. For example, blood vessel binding is enhanced using ATH containing recombinant AT with oligomannose structures that can interact with endothelial mannose receptor lectins. Furthermore, recent work has shown that inhibition of factor VIIa/tissue factor complex by ATH is significantly faster than AT + H. Similarly, thrombin bound to endothelial thrombomodulin is inhibited more efficiently by ATH than by AT + H, which might improve regulation of thrombin generation. Overall, linking H to AT may prevent unwanted protein interactions and allow vessel wall sites to be targeted. This review examines ATH biodistribution.

Keywords: Anticoagulants; antithrombin; endothelium; heparin; plasma proteins

Document Type: Research Article

Publication date: June 1, 2009

More about this publication?
  • Cardiovascular & Hematological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in cardiovascular and hematological disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in cardiovascular and hematological disorders. As the discovery, identification, characterization and validation of novel human drug targets for cardiovascular and hematological drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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