title: Modular synthesis of heparan sulfate oligosaccharides for structure-activity relationship studies.
abstract: Although hundreds of heparan sulfate binding proteins have been identified and implicated in a myriad of physiological and pathological processes, very little information is known about the ligand requirements for binding and mediating biological activities by these proteins. This difficulty results from a lack of technology for establishing structure-activity relationships, which in turn is due to the structural complexity of natural heparan sulfate (HS) and difficulties of preparing well-defined HS oligosaccharides. To address this deficiency, we developed a modular approach for the parallel combinatorial synthesis of HS oligosaccharides that utilizes a relatively small number of selectively protected disaccharide building blocks, which can easily be converted into glycosyl donors and acceptors. The utility of the modular building blocks has been demonstrated by the preparation of a library of 12 oligosaccharides, which has been employed to probe the structural features of HS for inhibiting the protease, BACE-1. The complex variations in activity with structural changes support the view that important functional information is embedded in HS sequences. Furthermore, the most active derivative provides an attractive lead compound for the preparation of more potent compounds, which may find use as a therapeutic agent for Alzheimer's disease.
authors.affiliation: Complex Carbohydrate Research Center, University of Georgia, 315 Riverbend Road, Athens, Georgia 30602, USA.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Arungundram
authors.forename: Kanar
authors.initials: K
authors.lastname: Al-Mafraji
authors.forename: Jinkeng
authors.initials: J
authors.lastname: Asong
authors.forename: Franklin E
authors.initials: FE
authors.lastname: Leach
authors.forename: I Jonathan
authors.initials: IJ
authors.lastname: Amster
authors.forename: Andre
authors.initials: A
authors.lastname: Venot
authors.forename: Jeremy E
authors.initials: JE
authors.lastname: Turnbull
authors.forename: Geert-Jan
authors.initials: GJ
authors.lastname: Boons
mesh_terms: D002240:Carbohydrate Sequence; D006497:Heparan Sulfate / Q000138:chemical synthesis* / Q000737:chemistry; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship
chemical_list: D006497:Heparan Sulfate