Identification of the minimal glycotope of streptococcus pneumoniae 7F capsular polysaccharide using synthetic oligosaccharides

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Identification of the minimal glycotope of streptococcus pneumoniae 7F capsular polysaccharide using synthetic oligosaccharides

Mauro Sella 1,2 , Petra Ménová 3 , Peter Seeberger 1,2

1 Max Planck Institute of Colloids and Interfaces, Potsdam, Germany, 2 Freie Universität Berlin, Berlin, Germany, 3 University of Chemistry and Technology, Prague, Czech Republic

Streptococcus pneumoniae 7F (ST7F), one of the more than 90 described serotypes, was one of the most prevalent serotypes causing infections before the introduction of a 13-valent conjugate vaccine (PCV13/Prevnar13®). Pneumococcal conjugate vaccines based on naturally-derived capsular polysaccharides (CPSs) have been successfully developed [1] and have shown remarkable efficacy. However, novel semi or fully synthetic vaccines represent an alternative offering potential advantages such as higher structural homogeneity and purity of the antigens, simpler conjugation strategies and a highly reproducible and potentially less expensive manufacturing process. Moreover, for many serotypes little is known about the true structures of immunogenic and protective epitopes. In a medicinal chemistry approach aimed at creating new potent semisynthetic glycoconjugate vaccines, the identification of such antigenic determinants is essential. In this regard short synthetic oligosaccharides represent useful tools [2].

In this work a library containing various oligosaccharides, ranging from tri- to hexasaccharides representing fragments of the ST7F CPS repeating unit [3], has been prepared by solution phase techniques. Starting from seven orthogonally protected monosaccharides, a set of disaccharide building blocks has been created. Afterward, a series of [n+2] glycosylations followed by global deprotections furnished all target oligosaccharides. A combination of “state of the art” glycosylation protocols together with recently developed protecting group manipulations allowed the formation of challenging 1,2-cis linkages displayed within the native structure.

Synthesized structures carried a reducing-end linker that enabled covalent immobilization on microarray glass slides [4]. Glycan arrays were probed with a polyvalent human antipneumococcal serum and bindings were visualized and quantified with fluorescence-tagged secondary antibodies. Results of inhibition assays revealed two specific portions of the repeating unit playing a critical role in antibody binding. An additional inhibition assay also showed cross-reactivity of antibodies towards the structurally related CPS from serotype 7A, confirming the presence of shared epitopes between the serotypes.

These results represent a starting point for the rational design of a synthetic antigen which, upon conjugation to an immunogenic carrier protein, could translate into an anti-serotype 7F semisynthetic vaccine candidate.

Costantino, P.; Rappuoli, R.; Berti, F., The design of semi-synthetic and synthetic glycoconjugate vaccines. Expert. Opin. Drug Discov. 2011, 6 (10), 1045-1066.

Anish, C.; Schumann, B.; Pereira, Claney L.; Seeberger, Peter H., Chemical Biology Approaches to Designing Defined Carbohydrate Vaccines. Chemistry & Biology 2014, 21 (1), 38-50.

Moreau, M.; Richards, J. C.; Perry, M. B.; Kniskern, P. J., Application of high-resolution n.m.r. spectroscopy to the elucidation of the structure of the specific capsular polysaccharide of streptococcus pneumoniae type 7F. Carbohydrate Research 1988, 182 (1), 79-99.

Park, S.; Gildersleeve, J. C.; Blixt, O.; Shin, I., Carbohydrate microarrays. Chem. Soc. Rev. 2013, 42 (10), 4310-4326.

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