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

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 Jaraquemada-Peláez, Nicole Rhoads, Manu Thomas Kalathottukaren, Peter K. Henke, Suzana K. Straus, Caigan Du, Edward M. Conway, Michael Holinstat, Charles A. Haynes, James H. Morrissey () and Jayachandran N. Kizhakkedathu ()
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Chanel C. La: University of British Columbia
Stephanie A. Smith: University of Michigan Medical School
Sreeparna Vappala: University of British Columbia
Reheman Adili: University of Michigan Medical School
Catherine E. Luke: University of Michigan Medical School
Srinivas Abbina: University of British Columbia
Haiming D. Luo: University of British Columbia
Irina Chafeeva: University of British Columbia
Matthew Drayton: University of British Columbia
Louise A. Creagh: University of British Columbia
Maria Guadalupe Jaraquemada-Peláez: University of British Columbia
Nicole Rhoads: Bloodworks Research Institute
Manu Thomas Kalathottukaren: 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
Michael Holinstat: University of Michigan Medical School
Charles A. Haynes: University of British Columbia
James H. Morrissey: University of Michigan Medical School
Jayachandran N. Kizhakkedathu: University of British Columbia

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37709-0

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