GLYCOPROTEIN-INSPIRED MATERIALS PROMOTE THE PROTEOLYTIC RELEASE OF CELL-SURFACE L-SELECTIN

The proteolytic release, or shedding, of a cell surface protein can se rve a regulatory role; the process liberates a soluble form of the pro tein into circulation while downregulating its cell surface concentrat ion. The characteristics that render a protein susceptible to proteoly tic cleavage are not known. We hypothesized that the clustering of a p rotein at the cell surface might target it for proteolysis. To test th is hypothesis, we synthesized molecules that display multiple copies o f sulfated galactose residues, termed neoglycopolymers, that are desig ned to mimic natural ligands for the cell adhesion protein L-selectin. We found that treatment of human neutrophils with the neoglycopolymer s resulted in a dose-dependent loss of L-selectin from the cell surfac e, while monovalent compounds and unsulfated neoglycopolymers had no e ffect. 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 alte r cellular responsiveness to specific ligands or to promote responses at distal sites; consequently, these results have broad implications f or regulating the location and presentation of important biomolecules. (C) 1998 Elsevier Science Ltd. All rights reserved.