Polymers carrying sLex‐mimetics are superior inhibitors of E‐selectin‐dependent leukocyte rolling in vivo
Open Access
- 3 November 2003
- journal article
- fj express-summarie
- Published by Wiley in The FASEB Journal
- Vol. 18 (1), 152-154
- https://doi.org/10.1096/fj.03-0346fje
Abstract
Selectins mediate leukocyte rolling and may represent good anti-inflammatory drug targets. Detailed knowledge regarding the structure of selectin ligands has permitted development of selectin antagonists with varying specificities and activity. Efficacy of monovalent selectin antagonists may be increased by presenting them on a polymer backbone. We have synthesized a range of multivalent selectin antagonists and characterized their activity by using intravital microscopy of the mouse cremaster muscle. The monovalent inhibitor CGP77175A inhibited E-selectin-dependent leukocyte rolling at a dose of 3 mg/kg. Multivalent presentation of CGP77175A on a modified polylysine backbone (degree of polymerization = 1200; 50% of the polylysines carry the inhibitor) greatly enhanced in vivo activity giving an inhibitor that produced an equivalent effect at 0.1 mg/kg. The polylysine conjugate was also longer acting than the monovalent antagonist. In spite of greatly enhanced activity against E-selectin compared with monovalent inhibitor, the multivalent inhibitor had no measurable effect on P- or L-selectin-dependent leukocyte rolling.Keywords
Funding Information
- British Heart Foundation (FS/98051)
This publication has 38 references indexed in Scilit:
- Glycosulfopeptides modeled on P‐selectin glycoprotein ligand‐1 inhibit P‐selectin‐dependent leukocyte rolling in vivoThe FASEB Journal, 2002
- Control of leukocyte rolling velocity in TNF-α–induced inflammation by LFA-1 and Mac-1Blood, 2002
- Pharmacology of Selectin Inhibitors in Ischemia/Reperfusion StatesAnnual Review of Pharmacology and Toxicology, 2000
- Interactions of the Cytoplasmic Domain of P-Selectin with Clathrin-coated Pits Enhance Leukocyte Adhesion under FlowThe Journal of cell biology, 1998
- The α(1,3)Fucosyltransferase Fuc-TVII Controls Leukocyte Trafficking through an Essential Role in L-, E-, and P-selectin Ligand BiosynthesisCell, 1996
- The alpha 4-integrin supports leukocyte rolling and adhesion in chronically inflamed postcapillary venules in vivo.The Journal of Experimental Medicine, 1996
- P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin.The Journal of cell biology, 1995
- Multivalent sialyl-LeX: potent inhibitors of E-selectin-mediated cell adhesion; reagent for staining activated endothelial cellsGlycobiology, 1994
- Leukocyte-endothelial cell recognition: Three (or more) steps to specificity and diversityCell, 1991
- The neutrophil selectin LECAM-1 presents carbohydrate ligands to the vascular selectins ELAM-1 and GMP-140Cell, 1991