Synthetic Multivalent Ligands Designed to Induce LSelectin Shedding

The release of a cell surface protein, often termed shedding, can serve to regulate its density on the cell surface and also affects the concentration of the soluble form in circulation [234]. L-selectin shedding is believed to occur during the inflammatory response, and this process may be involved in regulating cell rolling rates [187]. We hypothesized that multivalent ligand binding may cluster L-selectin and thereby trigger shedding. To test this idea, the ability of the 3',6'-disulfo-Lewis x polymer 62 to cause L-selectin release from the cell surface was evaluated [41]. The amount of L-selectin on the cell surface of neutrophils after treatment with ligand was assessed by flow cytometry using the anti-L-selectin antibody, DREG56. Although the monovalent compound 64 had no effect on L-selectin levels, exposure of neutrophils to polymeric compound 62 led to a reduction in the amount of cell surface L-selectin. The ability of multivalent ligand 62 to induce L-selectin shedding suggests that natural ligands might function similarly. The demonstration that synthetic ligands can be designed to promote the shedding of a cell surface receptor has implications for understanding the mechanisms cells use to control protein display and for manipulating the concentration of cell surface receptors. The ability to trigger this response by exposure to a synthetic multivalent ligand also suggests a new therapeutic strategy for targeting the inflammatory response.

61 R6 = H, R6' = S03~ 63 R6 = H, R6' = S03~ 3',6'-disulfo Lex(Glc)

62 R6 = S03~, R6' = H 64 R6 = S03~, R6' = H 3',6-disulfo Lex(Glc)

Figure 31 Kiessling's disulfated Lex constructs 63 and 64 elicited different physiological effects when appended on ^ multivalent displays to afford 61 and 62. n n a

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