Synthesis of group b streptococcal oligosaccharide libraries for structure-based optimization of vaccine candidates

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Synthesis of group b streptococcal oligosaccharide libraries for structure-based optimization of vaccine candidates

Linda Del Bino 1 , Davide Oldrini 1 , Maria Michelina Raso 2 , Filippo Carboni 1 , Riccardo De Ricco 1 , Rossella Cuffaro 1 , Maria Rosaria Romano 1 , Immaculada Margarit y Ros 1 , Francesco Berti 1 , Roberto Adamo 1

1 GSK, Siena, Italy, 2 GSK Vaccines Institute for Global Health, Siena, Italy

Despite substantial progresses in the prevention of group B Streptococcus (GBS) diseases with the introduction of intrapartum antibiotic prophylaxis, this pathogen remains a leading cause of neonatal infections. On the basis of variation in the sugar composition of the capsular polysaccharide (CPS), which is a major virulence factor, ten serotypes of GBS have been identified and in the last few years CPS conjugate vaccines representing the most frequent serotypes have been tested in phase I/II clinical studies, showing promise for further development.[1]

The elucidation of polysaccharide epitopes (commonly defined as glycotopes) presented on the bacterial capsule is relevant for understanding the mechanism of action of glycoconjugates and designing synthetic carbohydrate-based vaccines. Recently, an X-ray/NMR based approach was applied to determine a functional epitope of GBS PSIII, which appeared composed of six residues included within two repeating units, paving the way towards the use of synthetic structures for vaccine development.[2]

The repeating units of GBS serotypes Ia, Ib and III share similarities in their sugar composition, such as the NeuNAcβ(1–›3)Gal branch and the GlcNAcβ(1–›3)Gal motif. A flexible and convergent synthetic route could offer access to GBS CPS Ia, Ib and III defined fragments. In particular, we envisaged the regioselective glycosylation of galactose 3-OH to form the disaccharide motif GlcNAcβ(1–›3)Gal as a key step for the synthesis of fragments of the three serotypes. For this reason we designed an alternative synthetic approach taking advantage of the well-recognized major reactivity of Gal 3-OH compared to the 4-OH: a number of glucosamine donors and galactose acceptors with a different pattern of protective groups were screened in order to optimize the regioselective glycosylation and a faster access to the target disaccharide.

The applied innovative synthetic design led to the first synthesis of the pentasaccharide repeating unit of GBS CPS serotype Ib. Furthermore, oligosaccharide libraries from the CPS serotypes Ia and III were prepared. A combined screening approach, including competitive ELISA, competitive SPR and STD-NMR, on the synthetic fragment collections could help to gain new molecular insights into interactions of oligosaccharides with mAbs and to identify optimal or sub-optimal glycotopes for conjugation to carrier proteins and immunological evaluation.

Figure 1. Regioselective approach to disaccharide 3

A. Nuccitelli, C.D. Rinaudo, D. Maione, Ther Adv Vaccines 2015, Vol. 3(3), 76–90

F. Carboni, R. Adamo, F. Berti et al. PNAS 2017, 114 (19,) 5017-5022

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