title: Synthesis of mannoheptose derivatives and their evaluation as inhibitors of the lectin LecB from the opportunistic pathogen Pseudomonas aeruginosa.
abstract: Biofilm formation and chronic infections with Pseudomonas aeruginosa depend on lectins produced by the bacterium. The bacterial C-type lectin LecB binds to the two monosaccharides l-fucose and d-mannose and conjugates thereof. Previously, d-mannose derivatives with amide and sulfonamide substituents at C6 were reported as potent inhibitors of the bacterial lectin LecB and LecB-mediated bacterial surface adhesion. Because d-mannose establishes a hydrogen bond via its 6-OH group with Ser23 of LecB in the crystal structure and may be beneficial for binding affinity, we extended d-mannose and synthesized mannoheptoses bearing the free 6-OH group as well as amido and sulfonamido-substituents at C7. Two series of diastereomeric mannoheptoses were synthesized and the stereochemistry was determined by X-ray crystallography. The potency of the mannoheptoses as LecB inhibitors was assessed in a competitive binding assay. The data reveal a diastereoselectivity of LecB for (6S)-mannoheptose derivatives with increased activity over methyl α-d-mannoside.
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany; Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), D-66123 Saarbrücken, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany.
authors.forename: Roman
authors.initials: R
authors.lastname: Sommer
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany; Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), D-66123 Saarbrücken, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hauck
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stifel
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany.
authors.forename: Inigo
authors.initials: I
authors.lastname: Göttker-Schnetmann
authors.affiliation: Department of Chemistry and Graduate School Chemical Biology, University of Konstanz, D-78457 Konstanz, Germany; Chemical Biology of Carbohydrates, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), D-66123 Saarbrücken, Germany; Deutsches Zentrum für Infektionsforschung (DZIF), Standort Hannover-Braunschweig, Germany. Electronic address: alexander.titz@helmholtz-hzi.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Titz
mesh_terms: D000588:Amines / Q000737:chemistry; D018360:Crystallography, X-Ray; D006539:Heptoses / Q000138:chemical synthesis* / Q000737:chemistry; D037102:Lectins / Q000037:antagonists & inhibitors*; D008024:Ligands; D008766:Methylmannosides / Q000138:chemical synthesis / Q000737:chemistry; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000737:chemistry* / Q000472:pathogenicity
chemical_list: D000588:Amines; D006539:Heptoses; C534600:LecB protein, Pseudomonas aeruginosa; D037102:Lectins; D008024:Ligands; D008766:Methylmannosides; D009570:Nitriles; C430593:cyanohydrin; C413547:mannoheptose; C008466:methylmannoside
keywords: Inhibitor; Lectin; Pseudomonas aeruginosa