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

Session: 
S5.1 Glycomimetics
Code: 
FL5.1.1
Location (hall): 
Glucose
Start/end time: 
Tuesday, July 2, 2019 - 15:15 to 15:20
Ludovic
Auberger

Ludovic Auberger1, Jacopo Enotarpi1,2, Marta Tontini3, Maria Rosaria Romano3, Jeroen Codée2, Roberto Adamo3, Luigi Lay1

1University of Milan, Department of Chemistry, Milan, Italy, 2University of Leiden, Leiden Institute of Chemistry, Leiden, The Netherlands, 3R&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.

  1. 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.
  2. Frasch, C. E. Production and control of Neisseria meningitidis vaccines. Adv. Biotechnol. Processes 1990, 13, 123−145.
  3. 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.
  4. 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.
  5. This project has received funding from the H2020-MSCA-ITN-2015 “Glycovax” under grant agreement No 675671.

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