A PSGL-1 glycomimetic reduces thrombus burden without affecting hemostasis
Daniel J. Wong, Dayoung Park, Simon Park, Carolyn A. Haller, Jiaxuan Chen, Erbin Dai, Liying Liu, Appi Reddy Mandhapati, Pradheep Eradi, Bibek Dhakal, Walter J. Wever, Melinda S. Hanes, Lijun Sun, Richard D. Cummings, Elliot L. Chaikof
Abstract
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.