Synthesis of Neisseria Meningitidis A Carba Analogues as Hydrolytically Stable Antigens for Antimeningococcal Glycoconjugate Vaccines

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Synthesis of Neisseria Meningitidis A Carba Analogues as Hydrolytically Stable Antigens for Antimeningococcal Glycoconjugate Vaccines

Ludovic Auberger 1 , Jacopo Enotarpi 1,2 , Marta Tontini 3 , Maria Rosaria Romano 3 , Jeroen Codée 2 , Roberto Adamo3, Luigi Lay 1

1 University of Milan, Department of Chemistry, Milan, Italy, 2 University of Leiden, Leiden Institute of Chemistry, Leiden, The Netherlands, 3 R&D Centre, GlaxoSmithKline GSK, Siena, Italy

The Gram-negative encapsulated bacterium Neisseria meningitidis type A (MenA) is a major cause of meningitis in developing countries, especially in the sub-Saharan region of Africa [1]. The development and manufacture of an efficient glycoconjugate vaccine against MenA is largely hampered by the poor stability in water of the natural capsular polysaccharide (CPS)[2], composed of (1→6)-linked 2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate repeating units, with acetyl substituents. As a consequence, most of MenA glycoconjugates currently available have been licensed as lyophilisates. The availability of MenA polysaccharide mimics resistant to hydrolysis, however, is highly attractive for the development of a more stable glycoconjugate vaccine in liquid formulation. To this end, we envisaged that the replacement of the endocyclic ring oxygen with a methylene group to get a carbocyclic analogue will lead to the loss of the acetalic character of the phosphodiester and consequently to the enhancement of its chemical stability [3], [4].

We describe herein our synthetic approach to non-acetylated phosphodiester-linked carba oligomers of MenA CPS containing up to 7 repeating units. The increased stability of the synthetic carba oligomers was first confirmed by an accelerated stability study, then selected fragments were conjugated to CRM197 (a diphtheria toxin mutant) as a protein carrier. The immunological profile of the resulting neo-glycoconjugates was carefully investigated, with the purpose to highlight the effect of the carbohydrate chain length on the immunoactivity [5].

Figure 1. Structures of MenA CPS repeating unit and target carba-oligomers.

Tan L. K. K.; Carlone G. M.; Borrow R. Advances in the development of vaccines against Neisseria meningitidis. N. Engl. J. Med. 2010, 362, 1511-1520.

Frasch, C. E. Production and control of Neisseria meningitidis vaccines. Adv. Biotechnol. Processes 1990, 13, 123−145.

Gao, Q.; Zaccaria, C.; Tontini, M.; Poletti, L.; Costantino, P.; Lay, L. Synthesis and preliminary biological evaluation of carba analogues from Neisseria meningitidis A capsular polysaccharide. Org. Biomol. Chem. 2012, 10, 6673-6681.

Gao Q.; Tontini M.; Brogioni G.; Nilo A.; Filippini S.; Harfouche C.; Polito L.; Romano M. R.; Costantino P.; Berti F.; Adamo R.; Lay L. ACS Chem. Biol. 2013, 8, 2561.

This project has received funding from the H2020-MSCA-ITN-2015 “Glycovax” under grant agreement No 675671.

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