title: Diversity-oriented synthesis of inner core oligosaccharides of the lipopolysaccharide of pathogenic Gram-negative bacteria.
abstract: Lipopolysaccharide (LPS) is a potent virulence factor of pathogenic Gram-negative bacteria. To better understand the role of LPS in host-pathogen interactions and to elucidate the antigenic and immunogenic properties of LPS inner core region, a collection of well-defined L-glycero-D-manno-heptose (Hep) and 3-deoxy-α-D-manno-oct-2-ulosonic acid (Kdo)-containing inner core oligosaccharides is required. To address this need, we developed a diversity-oriented approach based on a common orthogonal protected disaccharide Hep-Kdo. Utilizing this new approach, we synthesized a range of LPS inner core oligosaccharides from a variety of pathogenic bacteria including Y. pestis, H. influenzae, and Proteus that cause plague, meningitis, and severe wound infections, respectively. Rapid access to these highly branched core oligosaccharides relied on elaboration of the disaccharide Hep-Kdo core as basis for the elongation with various flexible modules including unique Hep and 4-amino-4-deoxy-β-L-arabinose (Ara4N) monosaccharides and branched Hep-Hep disaccharides. A regio- and stereoselective glycosylation of Kdo 7,8-diol was key to selective installation of the Ara4N moiety at the 8-hydroxyl group of Kdo moiety of the Hep-Kdo disaccharide. The structure of the LPS inner core oligosaccharides was confirmed by comparison of (1)H NMR spectra of synthetic antigens and isolated fragments. These synthetic LPS core oligosaccharides can be covalently bound to carrier proteins via the reducing end pentyl amine linker, to explore their antigenic and immunogenic properties as well as potential applications such as diagnostic tools and vaccines.
authors.affiliation: Department of Biomolecular Systems, Max Planck Institute of Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany.
authors.forename: You
authors.initials: Y
authors.lastname: Yang
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Oishi
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Martin
authors.forename: Peter H
authors.initials: PH
authors.lastname: Seeberger
mesh_terms: D000942:Antigens, Bacterial / Q000737:chemistry; D002352:Carrier Proteins / Q000737:chemistry; D002855:Chromatography, Thin Layer; D018604:Epitope Mapping; D006090:Gram-Negative Bacteria / Q000737:chemistry*; D006193:Haemophilus influenzae / Q000737:chemistry; D008070:Lipopolysaccharides / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D009844:Oligosaccharides / Q000138:chemical synthesis*; D011511:Proteus / Q000737:chemistry; D021241:Spectrometry, Mass, Electrospray Ionization; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013056:Spectrophotometry, Ultraviolet; D037521:Virulence Factors / Q000737:chemistry*; D015010:Yersinia pestis / Q000737:chemistry
chemical_list: D000942:Antigens, Bacterial; D002352:Carrier Proteins; D008070:Lipopolysaccharides; D009844:Oligosaccharides; D037521:Virulence Factors