title: Multivalent sialyl Lewis x ligands of definite structures as inhibitors of E-selectin mediated cell adhesion.
abstract: We report on the efficiencies of structurally different but well defined multivalent sLex-ligands (di- and trivalent sLex-peptides and sLexbearing liposomes) to block receptor mediated HepG2-cell binding. Using three types of binding assays with distinct receptor accommodations (soluble anti-sLexmonoclonal antibody CSLEX1, immobilized E-selectin, activated HUVECs), we quantified considerable differences of the inhibition efficiencies for the same multivalent sLex-ligands. Compared to the monovalent sLexthe inhibition powers of both (sLex)2-peptides and (sLex)3-peptides were enhanced up to 50-fold for cell binding to the soluble antibody, and that of sLex-liposomes by 7 orders of magnitude. Directed to immobilized E-selectin the inhibition activity was enhanced only 3-fold for (sLex)2-peptides, 10-fold for (sLex)3-peptides but 5 orders of magnitude for sLex-liposomes, respectively. Further decrease of the inhibition efficiencies of glycoligands prepared was observed for cell binding to activated HUVECs. Compared to monovalent sLexwe measured relative efficiencies of 1 for (sLex)2-peptides, of 2 for (sLex)3-peptides but about 20,000 for sLex-liposomes. We concluded that the multivalency of the sLex-ligands prepared is an essential but not sufficient precondition for a high inhibition potency. Additionally, structural properties of the inhibitors determine their binding behavior, which must be considered for the design of potential therapeutic probes.
authors.affiliation: Max-Delbrck-Centre for Molecular Medicine and BioTez GmbH, Robert Röble Strasse 10, D-13122 Berlin, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Stahn
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
authors.forename: F
authors.initials: F
authors.lastname: Kernchen
authors.forename: J
authors.initials: J
authors.lastname: Schreiber
mesh_terms: D000911:Antibodies, Monoclonal; D001665:Binding Sites; D001667:Binding, Competitive; D002240:Carbohydrate Sequence; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D002478:Cells, Cultured; D019040:E-Selectin / Q000737:chemistry / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D016256:Lewis X Antigen / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008081:Liposomes; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009844:Oligosaccharides / Q000737:chemistry* / Q000378:metabolism*; D000080506:Sialyl Lewis X Antigen
chemical_list: D000911:Antibodies, Monoclonal; D019040:E-Selectin; D016256:Lewis X Antigen; D008024:Ligands; D008081:Liposomes; D009844:Oligosaccharides; D000080506:Sialyl Lewis X Antigen