Development of heparin antagonists with focused biological activity

Heparin, a complex glycosaminoglycan, has long been used to temporarily render the blood incoagulable during extracorporeal circulation, cardiovascular surgery, and other arterial interventions. But bleeding complications are especially common when the arterial tree is violated, occurring in as many as 10-15% of cases. For cardiovascular surgery and many related interventions, protamine has long been the standard antagonist when acute and complete neutralization of heparin s anticoagulant effect is necessary. Protamine s efficacy is related in part to its total net cationic charge, but unfortunately so is its toxicity. For these reasons, there is renewed interest in developing heparin antagonists which will replace the use of protamine. At Commonwealth Biotechnologies, Inc., we have used a rationale design approach for the preparation of a family of low molecular weight helix peptides which bind heparin with high affinity. For each of the new compounds, we have assessed their ability to bind heparin using isothermal titration calorimetry and circular dichroism spectrometry and have examined potential complexes formed with the anticoagulant pentasaccharide unit of heparin using molecular modeling techniques. The biological potencies of these compounds were assessed in ex vivo experiments where their ability to compete with antithrombin for binding heparin was determined. The best of the compounds, designated HepArrestTM, is highly effective in reversing heparin-mediated and HepArrest is a safer drug than protamine because of reduced adverse hemodynamic side effects compared with those associated with protamine. HepArrest binds low molecular weight heparins and causes reversal of anticoagulation by low molecular weight heparins, as determined by activated partial thromboplastin time, thrombin time, or factor Xa neutralization assays. These highly promising preclinical results indicate that HepArrest is a novel heparin neutralizing agent that may well fill a substantial unmet need for vascular surgeons and cardiac anesthesiologists who perform coronary artery bypass grafts and several other major vascular surgeries, as well as for cardiologists and interventional radiologists.