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 both express P-selectin, which binds PSGL-1 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 non-occlusive 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.
Elliot L Chaikof, Daniel James Wong, Diane D Park, Simon S Park, Carolyn Haller, Jiaxuan Chen, Erbin Dai, Liying Liu, Appi Reddy Mandhapati, Pradheep Eradi, Bibek Dhakal, Walter Wever, Melinda Hanes, Lijun Sun, Richard D Cummings