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- Title
Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design.
- Authors
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, Maria; Rhoads, Nicole; Kalathottukaren, Manu Thomas; Henke, Peter K.; Straus, Suzana K.; Du, Caigan; Conway, Edward M.; Holinstat, Michael; Haynes, Charles A.; Morrissey, James H.
- 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.
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37709-0