title: Design, synthesis, and immunochemical characterization of a chimeric glycopeptide corresponding to the Shigella flexneri Y O-polysaccharide and its peptide mimic MDWNMHAA.
abstract: Two glycopeptide chimeras corresponding to the Shigella flexneri Y O-polysaccharide and its peptide mimic were designed in an attempt to improve the binding affinity by increasing the entropy of binding relative to the original octapeptide mimic of the O-polysaccharide. The design was based on the X-ray crystal structures of a monoclonal antibody SYA/J6 in complex with its cognate ligands, a pentasaccharide corresponding to the S. flexneri Y O-polysaccharide and the octapeptide mimic, MDWNMHAA. Both chimeric molecules consist of a rhamnose trisaccharide linked through an alpha- or beta-thioglycosidic linkage to a MDW moiety in which the W unit has been modified. We predicted that omission of the NMHAA moiety would obviate the bound water molecules that provided complementarity with the antibody-combining site, and the conformational restriction resulting from imposition of an alpha-turn at the C-terminus of the peptide. The glycopeptides were then docked into the active site of SYA/J6 using the program autodock 3.0, and the structures were optimized. The best models obtained in each case showed that the chimeric molecules, with either an alpha- or beta-thioglycosidic linkage, might be reasonable surrogate ligands for the antibody. We report here the synthesis of the alpha-glycopeptide employing solution and solid-phase strategies. Immunochemical characterization indicated that the alpha-glycopeptide unfortunately did not inhibit binding of SYA/J6 to the S. flexneri Y lipopolysaccharide.
authors.affiliation: Department of Chemistry, Simon Fraser University, Burnaby, BC, Canada V5A 1S6.
authors.forename: B Rehana
authors.initials: BR
authors.lastname: Hossany
authors.forename: Blair D
authors.initials: BD
authors.lastname: Johnston
authors.forename: Xin
authors.initials: X
authors.lastname: Wen
authors.forename: Silvia
authors.initials: S
authors.lastname: Borrelli
authors.forename: Yue
authors.initials: Y
authors.lastname: Yuan
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Johnson
authors.forename: B Mario
authors.initials: BM
authors.lastname: Pinto
mesh_terms: D002240:Carbohydrate Sequence; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004797:Enzyme-Linked Immunosorbent Assay; D006020:Glycopeptides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000276:immunology; D007150:Immunohistochemistry / Q000379:methods*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011135:Polysaccharides, Bacterial / Q000737:chemistry* / Q000276:immunology*; D012763:Shigella flexneri / Q000378:metabolism*
chemical_list: D006020:Glycopeptides; D011135:Polysaccharides, Bacterial