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Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design La, Chanel C.; Smith, Stephanie A.; Vappala, Sreeparna; Adili, Reheman; Luke, Catherine E.; Abbina, Srinivas; Luo, Haiming D.; Chafeeva, Irina; Drayton, Matthew; Creagh, Louise A.; de Guadalupe Jaraquemada-Peláez, María; Rhoads, Nicole; Kalathottukaren, Manu Thomas; Henke, Peter K.; Straus, Suzana; Du, Caigan; Conway, Edward M.; Holinstat, Michael; Haynes, C. A.; Morrissey, James H.; Kizhakkedathu, Jayachandran N.

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.

Item Metadata

Title
Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design
Creator
La, Chanel C.; Smith, Stephanie A.; Vappala, Sreeparna; Adili, Reheman; Luke, Catherine E.; Abbina, Srinivas; Luo, Haiming D.; Chafeeva, Irina; Drayton, Matthew; Creagh, Louise A.; de Guadalupe Jaraquemada-Peláez, María; Rhoads, Nicole; Kalathottukaren, Manu Thomas; Henke, Peter K.; Straus, Suzana; Du, Caigan; Conway, Edward M.; Holinstat, Michael; Haynes, C. A.; Morrissey, James H.; Kizhakkedathu, Jayachandran N.
Date Issued
2023-04-26
Description
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.
Genre
Article
Type
Text
Language
eng
Date Available
2024-11-20
Provider
Vancouver : University of British Columbia Library
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
DOI
10.14288/1.0447305
URI
http://hdl.handle.net/2429/89687
Affiliation
Applied Science, Faculty of; Medicine, Faculty of; Science, Faculty of; Non UBC; Biomedical Engineering, School of; Chemical and Biological Engineering, Department of; Chemistry, Department of; Pathology and Laboratory Medicine, Department of; Urologic Sciences, Department of
Citation
La, C.C., Smith, S.A., Vappala, S. et al. Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design. Nature Communications 14, 2177 (2023).
Publisher DOI
10.1038/s41467-023-37709-0
Peer Review Status
Reviewed
Scholarly Level
Faculty; Researcher; Postdoctoral; Graduate
Rights URI
http://creativecommons.org/licenses/by-nc-nd/4.0/
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Attribution-NonCommercial-NoDerivatives 4.0 International