Invited Speaker

Rational Design of Non-Saccharide Mimetics of Heparin
Umesh R. Desai
United States

Deep vein thrombosis and pulmonary embolism, two major thrombotic disorders, are reported in millions of patients around the world. Heparin, a polyanionic polysaccharide introduced some eight decades ago, and low-molecular-weight heparins (LMWHs), introduced in the mid-1990s, have become major anticoagulant drugs for use in the thrombotic disorders. Despite its success, heparin therapy suffers from a number of side effects, primarily bleeding complications and patient-to-patient response variability. The highly anionic character of heparin (and LMWH) introduces non-specific binding to plasma proteins, platelets, and endothelial cells resulting in the majority of adverse effects. New anticoagulants that reduce these adverse effects and possibly add advantages, such as oral activity and/or inhibition of clot-bound enzymes, are highly desirable. To devise such molecules, we initiated a program on the rational design of organic molecules that mimic the function of heparin. The central hypothesis of our work is that conformational activation of antithrombin can be achieved with synthetic, non-saccharide, organic, molecules that are radically different from heparin (or heparin pentasaccharide). A rational design strategy involving molecular modeling, organic synthesis, and biophysical and biochemical studies has been developed, which has led to the design of bicyclic-unicyclic isoquinoline-based potent antithrombin activators. The talk will describe the novel approach, its potential, and the results achieved so far.