Glycoprotein-inspired materials promote the proteolytic release of cell surface L-selectin.
The proteolytic release, or shedding, of a cell surface protein can serve a regulatory role; the process liberates a soluble form of the protein into circulation while downregulating its cell surface concentration. The characteristics that render a protein susceptible to proteolytic cleavage are not known. We hypothesized that the clustering of a protein at the cell surface might target it for proteolysis. To test this hypothesis, we synthesized molecules that display multiple copies of sulfated galactose residues, termed neoglycopolymers, that are designed to mimic natural ligands for the cell adhesion protein L-selectin. We found that treatment of human neutrophils with the neoglycopolymers resulted in a dose-dependent loss of L-selectin from the cell surface, while monovalent compounds and unsulfated neoglycopolymers had no effect. Because L-selectin is an important mediator in the inflammatory response, such compounds could lead to novel antiinflammatory drugs. Moreover, molecules that control receptor shedding can be used to alter cellular responsiveness to specific ligands or to promote responses at distal sites; consequently, these results have broad implications for regulating the location and presentation of important biomolecules.
Department of Chemistry, University of Wisconsin-Madison 53706, USA.
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EJ
Gordon
L E
LE
Strong
L L
LL
Kiessling
D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006023:Glycoproteins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D019041:L-Selectin / Q000378:metabolism*; D007962:Leukocytes / Q000187:drug effects* / Q000378:metabolism; D016256:Lewis X Antigen / Q000737:chemistry; D008024:Ligands; D009844:Oligosaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology; D000080506:Sialyl Lewis X Antigen
D006023:Glycoproteins; D016256:Lewis X Antigen; D008024:Ligands; D009844:Oligosaccharides; D011108:Polymers; D000080506:Sialyl Lewis X Antigen; D019041:L-Selectin