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

Marina L. Gening, Yury E. Tsvetkov, Denis V. Titov, Alexey G. Gerbst, Olga N. Yudina, Alexey A. Grachev, Alexander S. Shashkov, Sébastien Vidal, Anne Imberty, Tanmoy Saha, Dnyaneshwar Kand, Pinaki Talukdar (+2 others)
2013 Pure and Applied Chemistry  
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
more » ... tylation 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.
doi:10.1351/pac-con-12-09-06 fatcat:ogwxehxjnzd2dbyl3uzp4qqny4