Thrombotic and vascular disorders are among the leading cause of deaths in the US annually. Unfractionated heparin and low-molecular-weight heparins have become major anticoagulant drugs for use in these hematological disorders with combined annual sales of more than $ 3 billion. Unfortunately heparin and low molecular weight-based anticoagulation therapy is beset with several problems including bleeding complications. Heparin anticoagulation therapy is primarily based on the ability to accelerate the inhibition of factor Xa and thrombin by antithrombin, a plasma serine proteinase inhibitor. At the molecular level, heparin binding induces a conformational change in antithrombin ('activation') to greatly enhance its ability to inhibit factor Xa. However, the polyanionic nature of heparin also results in non-specific interactions leading to the numerous undesirable side effects. Alternative approaches based on rationally designed small non-sugar heparin-mimics that eliminate these side effects and possibly possess advantages, such as oral activity, are therefore highly desirable. Our central hypothesis is that efficient activation of antithrombin leading to specific inhibition of factor Xa can be achieved with small non-sugar molecules. We propose to synthesize and study rationally designed small organic molecules as conformational activators of antithrombin. Towards this end we will I) synthesize and characterize rationally designed bicyclic-unicyclic, bicyclic-linker-unicyclic and bicyclic-bicyclic activators of antithrombin, II) investigate the molecular interaction of antithrombin with designed, small heparin mimetics using biochemical and biophysical techniques, and III) design rational advanced organic, non-sugar activators based on initial promising leads. Detailed investigation of the rationally designed molecules will provide the knowledge to deduce quantitative structure-function relationship critical for the design of an effective non-sugar heparin-mimic.
These aims will be investigated utilizing computerized molecular modeling; fluorescence spectroscopic study of interactions; rapid kinetic determination mechanism of interaction; enzyme kinetics; and synthetic organic chemistry. This fundamental research will establish the principles of effective conformational activation of antithrombin by small nonheparin molecules for accelerated inhibition of factor Xa. Successful completion of this research will contribute fundamental knowledge for the design of an effective anticoagulant I) with reduced non-specific adverse effects normally associated with heparin therapy and II) with better oral activity.
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