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Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design

Author

Listed:
  • Chanel C. La

    (University of British Columbia
    University of British Columbia)

  • Stephanie A. Smith

    (University of Michigan Medical School)

  • Sreeparna Vappala

    (University of British Columbia
    University of British Columbia)

  • Reheman Adili

    (University of Michigan Medical School
    Bloodworks Research Institute)

  • Catherine E. Luke

    (University of Michigan Medical School)

  • Srinivas Abbina

    (University of British Columbia
    University of British Columbia)

  • Haiming D. Luo

    (University of British Columbia
    University of British Columbia)

  • Irina Chafeeva

    (University of British Columbia
    University of British Columbia)

  • Matthew Drayton

    (University of British Columbia
    University of British Columbia)

  • Louise A. Creagh

    (University of British Columbia
    University of British Columbia)

  • Maria Guadalupe Jaraquemada-Peláez

    (University of British Columbia)

  • Nicole Rhoads

    (Bloodworks Research Institute)

  • Manu Thomas Kalathottukaren

    (University of British Columbia
    University of British Columbia)

  • Peter K. Henke

    (University of Michigan Medical School)

  • Suzana K. Straus

    (University of British Columbia)

  • Caigan Du

    (University of British Columbia)

  • Edward M. Conway

    (University of British Columbia
    University of British Columbia
    University of British Columbia
    University of British Columbia)

  • Michael Holinstat

    (University of Michigan Medical School)

  • Charles A. Haynes

    (University of British Columbia
    University of British Columbia)

  • James H. Morrissey

    (University of Michigan Medical School)

  • Jayachandran N. Kizhakkedathu

    (University of British Columbia
    University of British Columbia
    University of British Columbia
    University of British Columbia)

Abstract

Current treatments to prevent thrombosis, namely anticoagulants and platelets antagonists, remain complicated by the persistent risk of bleeding. Improved therapeutic strategies that diminish this risk would have a huge clinical impact. Antithrombotic agents that neutralize and inhibit polyphosphate (polyP) can be a powerful approach towards such a goal. Here, we report a design concept towards polyP inhibition, termed macromolecular polyanion inhibitors (MPI), with high binding affinity and specificity. Lead antithrombotic candidates are identified through a library screening of molecules which possess low charge density at physiological pH but which increase their charge upon binding to polyP, providing a smart way to enhance their activity and selectivity. The lead MPI candidates demonstrates antithrombotic activity in mouse models of thrombosis, does not give rise to bleeding, and is well tolerated in mice even at very high doses. The developed inhibitor is anticipated to open avenues in thrombosis prevention without bleeding risk, a challenge not addressed by current therapies.

Suggested Citation

  • Chanel C. La & Stephanie A. Smith & Sreeparna Vappala & Reheman Adili & Catherine E. Luke & Srinivas Abbina & Haiming D. Luo & Irina Chafeeva & Matthew Drayton & Louise A. Creagh & Maria Guadalupe Jar, 2023. "Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37709-0
    DOI: 10.1038/s41467-023-37709-0
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    References listed on IDEAS

    as
    1. Nigel Mackman, 2008. "Triggers, targets and treatments for thrombosis," Nature, Nature, vol. 451(7181), pages 914-918, February.
    2. Linda Labberton & Ellinor Kenne & Andy T. Long & Katrin F. Nickel & Antonio Di Gennaro & Rachel A. Rigg & James S. Hernandez & Lynn Butler & Coen Maas & Evi X. Stavrou & Thomas Renné, 2016. "Neutralizing blood-borne polyphosphate in vivo provides safe thromboprotection," Nature Communications, Nature, vol. 7(1), pages 1-14, November.
    Full references (including those not matched with items on IDEAS)

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