A PSGL-1 glycomimetic reduces thrombus burden without affecting hemostasis
| Autor: | Liying Liu, Pradheep Eradi, Diane D. Park, Carolyn A. Haller, Walter Wever, Lijun Sun, Erbin Dai, Simon S. Park, Elliot L. Chaikof, Bibek Dhakal, Jiaxuan Chen, Daniel J. Wong, Appi Reddy Mandhapati, Richard D. Cummings, Melinda S. Hanes |
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| Rok vydání: | 2020 |
| Předmět: |
Endothelium
Platelet Aggregation Immunology Pharmacology Biochemistry Thrombosis and Hemostasis Polyethylene Glycols Mice Glycomimetic medicine Animals Humans Platelet Amino Acid Sequence Platelet activation Thrombus Hemostasis Membrane Glycoproteins business.industry Microcirculation Thrombosis Cell Biology Hematology medicine.disease Mice Inbred C57BL Venous thrombosis P-Selectin medicine.anatomical_structure business Half-Life |
| Zdroj: | Blood |
| ISSN: | 1528-0020 |
| Popis: | Events mediated by the P-selectin/PSGL-1 pathway play a critical role in the initiation and propagation of venous thrombosis by facilitating the accumulation of leukocytes and platelets within the growing thrombus. Activated platelets and endothelium express P-selectin, which binds P-selectin glycoprotein ligand-1 (PSGL-1) that is expressed on the surface of all leukocytes. We developed a pegylated glycomimetic of the N terminus of PSGL-1, PEG40-GSnP-6 (P-G6), which proved to be a highly potent P-selectin inhibitor with a favorable pharmacokinetic profile for clinical translation. P-G6 inhibits human and mouse platelet-monocyte and platelet-neutrophil aggregation in vitro and blocks microcirculatory platelet-leukocyte interactions in vivo. Administration of P-G6 reduces thrombus formation in a nonocclusive model of deep vein thrombosis with a commensurate reduction in leukocyte accumulation, but without disruption of hemostasis. P-G6 potently inhibits the P-selectin/PSGL-1 pathway and represents a promising drug candidate for the prevention of venous thrombosis without increased bleeding risk. |
| Databáze: | OpenAIRE |
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