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.

Synthesis of stabilized analogues of fragments of Neisseria meningitidis type A capsular polysaccharide / M.I. Torres Sanchez, C. Zaccaria, L. Poletti, G. Lombardi, G. Russo, L. Lay. ((Intervento presentato al 6.. convegno Italian-Spanish Symposium on Organic Chemistry tenutosi a Taormina (Messina) nel 2006.

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

C. Zaccaria
Secondo
;
L. Poletti;G. Russo
Penultimo
;
L. Lay
Ultimo
2007

Abstract

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.
19-giu-2007
Settore CHIM/06 - Chimica Organica
Università di Messina
Synthesis of stabilized analogues of fragments of Neisseria meningitidis type A capsular polysaccharide / M.I. Torres Sanchez, C. Zaccaria, L. Poletti, G. Lombardi, G. Russo, L. Lay. ((Intervento presentato al 6.. convegno Italian-Spanish Symposium on Organic Chemistry tenutosi a Taormina (Messina) nel 2006.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/30969
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