title: Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants.
abstract: Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the only clinically approved antidote to heparin, has shown adverse effects and ineffectiveness against low-molecular weight heparins and fondaparinux, a heparin-related medication. Alternative approaches based on cationic molecules and recombinant proteins have several drawbacks including limited efficacy, toxicity, immunogenicity, and high cost. Thus, there is an unmet clinical need for safer, rapid, predictable, and cost-effective anticoagulant-reversal agents for all clinically used heparins. We report a design strategy for a fully synthetic dendritic polymer-based universal heparin reversal agent (UHRA) that makes use of multivalent presentation of branched cationic heparin binding groups (HBGs). Optimization of the UHRA design was aided by isothermal titration calorimetry studies, biocompatibility evaluation, and heparin neutralization analysis. By controlling the scaffold's molecular weight, the nature of the protective shell, and the presentation of HBGs on the polymer scaffold, we arrived at lead UHRA molecules that completely neutralized the activity of all clinically used heparins. The optimized UHRA molecules demonstrated superior efficacy and safety profiles and mitigated heparin-induced bleeding in animal models. This new polymer therapeutic may benefit patients undergoing high-risk surgical procedures and has potential for the treatment of anticoagulant-related bleeding problems.
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Rajesh A
authors.initials: RA
authors.lastname: Shenoi
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Manu Thomas
authors.initials: MT
authors.lastname: Kalathottukaren
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Travers
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Benjamin F L
authors.initials: BF
authors.lastname: Lai
authors.affiliation: Michael Smith Laboratories, Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: A Louise
authors.initials: AL
authors.lastname: Creagh
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Dirk
authors.initials: D
authors.lastname: Lange
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Kai
authors.initials: K
authors.lastname: Yu
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Marie
authors.initials: M
authors.lastname: Weinhart
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Ben H
authors.initials: BH
authors.lastname: Chew
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia V5Z 1M9, Canada.
authors.forename: Caigan
authors.initials: C
authors.lastname: Du
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Brooks
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada.
authors.forename: Cedric J
authors.initials: CJ
authors.lastname: Carter
authors.affiliation: Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Morrissey
authors.affiliation: Michael Smith Laboratories, Department of Chemical and Biological Engineering, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Haynes
authors.affiliation: Centre for Blood Research and Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. Department of Chemistry, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada. jay@pathology.ubc.ca.
authors.forename: Jayachandran N
authors.initials: JN
authors.lastname: Kizhakkedathu
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology; D002151:Calorimetry; D006493:Heparin / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D006493:Heparin