Polymerized liposome assemblies: Bifunctional macromolecular selectin inhibitors mimicking physiological selectin ligands

Richard E. Bruehl, Falguni Dasgupta, Tamiko R. Katsumoto, Jennifer H. Tan, Carolyn R. Bertozzi, Wayne Spevak, Dong June Ahn, Steven D. Rosen, Jon O. Nagy

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Monomeric sialyl Lewisx (sLex) and sLex-like oligosaccharides are minimal structures capable of supporting selectin binding in vitro. However, their weak binding interactions do not correlate with the high-affinity binding interactions witnessed in vivo. The polyvalent display of carbohydrate groups found on cell surface glycoprotein structures may contribute to the enhanced binding strength of selectin-mediated adhesion. Detailed biochemical analyses of physiological selectin ligands have revealed a complicated composition of molecules that bind to the selectins in vivo and suggest that there are other requirements for tight binding beyond simple carbohydrate multimerization. In an effort to mimic the high-affinity binding, polyvalent scaffolds that contain multicomponent displays of selectin-binding ligands have been synthesized. Here, we demonstrate that the presentation of additional anionic functional groups in the form of sulfate esters, on a polymerized liposome surface containing a multimeric array of sLex-like oligosaccharides, generates a highly potent, bifunctional macromolecular assembly. This assembly inhibits L-, E-, and P-selectin binding to GlyCAM-1, a physiological ligand better than sLex-like liposomes without additional anionic charge. These multivalent arrays are 4 orders of magnitude better than the monovalent carbohydrate. Liposomes displaying 3′-sulfo LewisX-like oligosaccharides, on the other hand, show slight loss of binding with introduction of additional anionic functional groups for E- and P-selectin and negligible change for L-selectin. The ability to rapidly and systematically vary the composition of these assemblies is a distinguishing feature of this methodology and may be applied to the study of other systems where composite binding determinants are important for high-affinity binding.

Original languageEnglish
Pages (from-to)5964-5974
Number of pages11
JournalBiochemistry
Volume40
Issue number20
DOIs
Publication statusPublished - 2001 May 22

ASJC Scopus subject areas

  • Biochemistry

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    Bruehl, R. E., Dasgupta, F., Katsumoto, T. R., Tan, J. H., Bertozzi, C. R., Spevak, W., Ahn, D. J., Rosen, S. D., & Nagy, J. O. (2001). Polymerized liposome assemblies: Bifunctional macromolecular selectin inhibitors mimicking physiological selectin ligands. Biochemistry, 40(20), 5964-5974. https://doi.org/10.1021/bi002921s