Application of Combinatorial Libraries and Protein Engineering to the Discovery of Novel Anti-Thrombotic Drugs
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Combinatorial libraries and protein engineering represent two new powerful tools in drug discovery and development. The application of a combinatorial ssDNA library to thrombin led to the discovery of a sequence-specific nucleotide-based thrombin inhibitor (thrombin aptamer). The thrombin aptamer has a novel tertiary structure revealed by NMR and shows potent rapid anticoagulation with a short half-life in vivo. It has been used successfully to replace heparin in a canine cardiopulmonary bypass model. Functional mapping of the surface residues of thrombin led to the generation of a modified thrombin with markedly diminished procoagulant properties while retaining its ability to activate protein C. This engineered thrombin functions as a protein C activator and demonstrates potent anticoagulation in vivo without prolongation of the bleeding time.
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