Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants

• DOI: 10.1126/scitranslmed.3009427
• Publication Date: 2014-10-29T18:21:03Z
• Authors: Rajesh A. Shenoi; Manu Thomas Kalat...; Richard J. Travers; Benjamin F. L. Lai; A. Louise Creagh; Dirk Lange; Kai Yu; Marie Weinhart; Ben H. Chew; Caigan Du; Donald E. Brooks; Cedric J. Carter; James H. Morrissey; Charles A. Haynes; Jayachandran N. K...
• Keywords: 0301 basic medicine; 03 medical and health sciences; Heparin; Anticoagulants; Calorimetry; 3. Good health

Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and treatment thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring neutralization suitable antidotes. Protamine, only clinically approved antidote to heparin, has shown adverse effects ineffectiveness against low-molecular weight heparins fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules recombinant proteins several drawbacks including limited efficacy, toxicity, immunogenicity, high cost. Thus, there is an unmet clinical need safer, rapid, predictable, cost-effective anticoagulant-reversal agents all heparins. We report design strategy fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use multivalent presentation branched binding groups (HBGs). Optimization UHRA was aided by isothermal titration calorimetry studies, biocompatibility evaluation, analysis. By controlling scaffold's molecular weight, nature protective shell, HBGs polymer scaffold, we arrived at lead completely neutralized activity The optimized demonstrated superior efficacy safety profiles mitigated heparin-induced in animal models. This new therapeutic may benefit patients undergoing high-risk potential anticoagulant-related problems.