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

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Autorschaft

  • Rajesh A. Shenoi
  • Manu Thomas Kalathottukaren
  • Richard J. Travers
  • Benjamin F. L. Lai
  • Marie Weinhart

Externe Organisationen

  • University of Illinois Urbana-Champaign (UIUC)
  • University of British Columbia

Details

OriginalspracheEnglisch
Aufsatznummer260ra150
FachzeitschriftScience Translational Medicine
Jahrgang6
Ausgabenummer260
PublikationsstatusVeröffentlicht - 29 Okt. 2014
Extern publiziertJa

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 anticoagulantrelated bleeding problems.

ASJC Scopus Sachgebiete

Zitieren

Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. / Shenoi, Rajesh A.; Kalathottukaren, Manu Thomas; Travers, Richard J. et al.
in: Science Translational Medicine, Jahrgang 6, Nr. 260, 260ra150, 29.10.2014.

Publikation: Beitrag in FachzeitschriftArtikelForschungPeer-Review

Shenoi, RA, Kalathottukaren, MT, Travers, RJ, Lai, BFL, Creagh, AL, Lange, D, Yu, K, Weinhart, M, Chew, BH, Du, C, Brooks, DE, Carter, CJ, Morrissey, JH, Haynes, CA & Kizhakkedathu, JN 2014, 'Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants', Science Translational Medicine, Jg. 6, Nr. 260, 260ra150. https://doi.org/10.1126/scitranslmed.3009427
Shenoi, R. A., Kalathottukaren, M. T., Travers, R. J., Lai, B. F. L., Creagh, A. L., Lange, D., Yu, K., Weinhart, M., Chew, B. H., Du, C., Brooks, D. E., Carter, C. J., Morrissey, J. H., Haynes, C. A., & Kizhakkedathu, J. N. (2014). Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Science Translational Medicine, 6(260), Artikel 260ra150. https://doi.org/10.1126/scitranslmed.3009427
Shenoi RA, Kalathottukaren MT, Travers RJ, Lai BFL, Creagh AL, Lange D et al. Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Science Translational Medicine. 2014 Okt 29;6(260):260ra150. doi: 10.1126/scitranslmed.3009427
Shenoi, Rajesh A. ; Kalathottukaren, Manu Thomas ; Travers, Richard J. et al. / Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. in: Science Translational Medicine. 2014 ; Jahrgang 6, Nr. 260.
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T1 - Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants

AU - Shenoi, Rajesh A.

AU - Kalathottukaren, Manu Thomas

AU - Travers, Richard J.

AU - Lai, Benjamin F. L.

AU - Creagh, A. Louise

AU - Lange, Dirk

AU - Yu, Kai

AU - Weinhart, Marie

AU - Chew, Ben H.

AU - Du, Caigan

AU - Brooks, Donald E.

AU - Carter, Cedric J.

AU - Morrissey, James H.

AU - Haynes, Charles A.

AU - Kizhakkedathu, Jayachandran N.

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N2 - 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 anticoagulantrelated bleeding problems.

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