This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Na+ binding is required for the procoagulant, but not the anticoagulant activity of thrombin. This discovery has enabled us to engineer novel thrombin analogs selectively compromised in their procoagulant properties. We started testing in our primate model designer enzymes with high selectivity toward the natural anticoagulant, protein C, to assess their effects on thrombosis and hemostasis. Consistent with the predictions, several molecules have shown anticoagulant and antithrombotic effects. We have been comparing the effects of some of these mutants with the direct administration of activated protein C and other antithrombotic agents. The latest completed series of studies revealed the pharmacological potential of the protein C activator enzyme, W215A/E217A, which is a 36kD thrombin analog. W215A/E217A proved to be two to three orders of magnitude more potent and significantly safer in our primate model than an accepted anticoagulant, enoxaparin, in the prevention of thrombus formation. In fact, W215A/E217A is the most potent antithrombotic molecule known to date.
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