title: Tunable heparan sulfate mimetics for modulating chemokine activity.
abstract: Heparan sulfate (HS) glycosaminoglycans participate in critical biological processes by modulating the activity of a diverse set of protein binding partners. Such proteins include all known members of the chemokine superfamily, which are thought to guide the migration of immune cells through their interactions with HS. Here, we describe an expedient, divergent synthesis to prepare defined HS glycomimetics that recapitulate the overall structure and activity of HS glycosaminoglycans. Our approach uses a core disaccharide precursor to produce a variety of differentially sulfated glycopolymers. We demonstrate that a specific trisulfated mimetic antagonizes the chemotactic activity of the proinflammatory chemokine RANTES with potency similar to that of heparin, without inhibiting serine proteases in the blood coagulation cascade. Our work provides a general strategy for modulating chemokine activity and dissecting the pleiotropic functions of HS/heparin through the presentation of defined sulfation motifs within polymeric scaffolds.
authors.affiliation: Division of Chemistry and Chemical Engineering, California Institute of Technology and Howard Hughes Medical Institute, 1200 East California Boulevard, Pasadena, California 91125, USA.
authors.forename: Gloria J
authors.initials: GJ
authors.lastname: Sheng
authors.forename: Young In
authors.initials: YI
authors.lastname: Oh
authors.forename: Shuh-Kuen
authors.initials: SK
authors.lastname: Chang
authors.forename: Linda C
authors.initials: LC
authors.lastname: Hsieh-Wilson
mesh_terms: D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D018946:Chemokine CCL5 / Q000378:metabolism*; D006497:Heparan Sulfate / Q000737:chemistry*; D051379:Mice
chemical_list: D018946:Chemokine CCL5; D006497:Heparan Sulfate