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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.
Treatments to prevent thrombosis are suboptimal. Here, the authors identify a lead an antithrombotic drug targeting polyphosphate based on switchable protonation states for the anion-binding groups, demonstrating antithrombotic activity in multiple mouse models, not causing bleeding, and well tolerated.
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1 University of British Columbia, Centre for Blood Research, Life Sciences Institute, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Chemistry, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
2 University of Michigan Medical School, Department of Biological Chemistry, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370)
3 University of British Columbia, Centre for Blood Research, Life Sciences Institute, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
4 University of Michigan Medical School, Department of Pharmacology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370); Bloodworks Research Institute, Seattle, USA (GRID:grid.280646.e) (ISNI:0000 0004 6016 0057)
5 University of Michigan Medical School, Department of Surgery, Section of Vascular Surgery, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370)
6 University of British Columbia, Department of Chemical and Biological Engineering, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Michael Smith Laboratories, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
7 University of British Columbia, Department of Chemistry, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
8 Bloodworks Research Institute, Seattle, USA (GRID:grid.280646.e) (ISNI:0000 0004 6016 0057)
9 University of British Columbia, Department of Urological Sciences, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
10 University of British Columbia, Centre for Blood Research, Life Sciences Institute, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, The School of Biomedical Engineering, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)
11 University of Michigan Medical School, Department of Pharmacology, Ann Arbor, USA (GRID:grid.214458.e) (ISNI:0000000086837370)
12 University of British Columbia, Centre for Blood Research, Life Sciences Institute, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Chemistry, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, Department of Pathology and Laboratory Medicine, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830); University of British Columbia, The School of Biomedical Engineering, Vancouver, Canada (GRID:grid.17091.3e) (ISNI:0000 0001 2288 9830)