Synthesis of stabilized analogues of fragments of Neisseria meningitidis type A capsular polysaccharide

The resistance to Neisseria meningitidis (N. m.), a gram-negative bacterium causing meningitis, is mediated by the presence of antibodies directed against its capsular polysaccharides (CPS), which are associated with different serogroups. One of the most virulent is serotype A (Men A), whose CPS is constituted of (6)-N-acetylmannosamine -1-O-Phosphate as a repeating unit. The already existing vaccines against N.m. give a T-cell independent immune response, therefore inefficient in infants. The response can be improved by conjugation of the saccharidic portion to a protein carrier, which invokes T-cell involvement. In addition, anomeric phosphodiester bridges are chemically labile and therefore not appropriate for a vaccine. To overcome these problems, phosphonate 4 and its oligomers 5 and 7 have been synthesised as stable analogues of the repeating unit of Men A CPS. Key steps of the synthetic strategy are: a) Synthesis of building blocks 3 and 4, the latter bearing a spacer at the reducing end suitable for conjugation to a proper protein carrier; b) Coupling of 3 with 4 via Mitsunobu reaction providing 5, followed by 6'-O-deacetylation and a second Mitsunobu coupling to give trimer 7. After removal of the protecting groups, the synthesized compounds have been evaluated through a competitive ELISA assay (IC50 values) by use of Men A antiserum. Moreover, preliminary approaches towards the carba-analogue 8 of N-acetylmannosamine 1-O-phosphate, a key building block for the synthesis of a new type of Men A analogues, will be also discussed.