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Pure Appl. Chem., 2013, Vol. 85, No. 9, pp. 1879-1891

Published online 2013-04-28

Linear and cyclic oligo-β-(1→6)-D-glucosamines: Synthesis, conformations, and applications for design of a vaccine and oligodentate glycoconjugates

Marina L. Gening1, Yury E. Tsvetkov1, Denis V. Titov1, Alexey G. Gerbst1, Olga N. Yudina1, Alexey A. Grachev1, Alexander S. Shashkov2, Sébastien Vidal3, Anne Imberty4, Tanmoy Saha5, Dnyaneshwar Kand5, Pinaki Talukdar5, Gerald B. Pier6 and Nikolay E. Nifantiev1*

1 Laboratory of Glycoconjugate Chemistry, N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow, Russia
2 Laboratory of Nuclear Magnetic Resonance, N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow, Russia
3 Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, Laboratoire de Chimie Organique 2 – Glycochimie UMR 5246, CNRS, Université Claude Bernard Lyon 1, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
4 Centre de Recherche sur les Macromolécules Végétales, UPR5301-CNRS, affiliated with Université Joseph Fourier and ICMG, BP 53, 38041 Grenoble, France
5 Indian Institute of Science Education and Research (IISER), Pune, Maharashtra 411021, India
6 Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA 021145, USA

Abstract: Poly-β-(1→6)-N-acetyl-D-glucosamine is an exopolysaccharide secreted by numerous pathogenic bacteria, including Staphylococcus aureus, Escherichia coli, Yersinia pestis, Bordetella pertussis, Acinetobacter baumannii, Burkholderia spp., and others. A convergent approach was developed for the synthesis of oligosaccharide fragments consisting of 5, 7, 9, and 11 glucosamine or N-acetylglucosamine units and for the preparation of five nona-β-(1→6)-D-glucosamines with various N-acetylation patterns. Penta- and nona-β‑(1→6)-D-glucosamines conjugated to protein carriers through a specially developed sulfhydryl linker proved to be highly immunogenic in mice and rabbits and elicited antibodies that mediated opsonic killing of multiple strains of S. aureus (including methicillin-resistant S. aureus, MRSA) and E. coli, and protected against S. aureus skin abscesses and lethal E. coli and B. cenocepacia peritonitis. These findings provide a basis for the construction of a unique semisynthetic vaccine against multiple bacterial targets. Conformational studies by means of special NMR experiments and computer modeling revealed that the oligo-β-(1→6)-D-glucosamine chain exists mostly in a helix-like conformation, where the terminal monosaccharides are arranged close to each other. Owing to this feature, oligoglucosamines consisting of 2 to 7 residues easily form products of cycloglycosylation. Cyclooligo-β-(1→6)-D-glucosamines represent a new family of functionalized cyclic oligosaccharides. Owing to their molecular architectonics, these compounds are convenient scaffolds for the design of conjugates with defined valency, symmetry, flexibility, and function.