Neisseria meningitidis is one of the major causes of bacterial meningitis. In particular, N. Meningitidis serogroup A (MenA) caused significant severe epidemics of meningococcal meningitis in the sub-Saharan Africa. Thanks to the introduction of the MenAfriVac vaccine, the serogroup A disease has almost vanished in 2017; however, it is important to persist with a strict control with a dedicated vaccination program.
MenAfriVac, compared to the previous vaccines, can be stored at temperatures up to 40°C for a maximum of four days. A further advancement could be the production of a more thermally stable vaccine, using MenA capsular polysaccharide synthetic analogues as antigens.
MenA capsular polysaccharide consists of (1->6)-linked-2-acetamido-2-deoxy-α-D-mannopyranosyl phosphate residues acetylated at C-3 to an extent of 70-90%. Since its stability issues are mostly due to the intrinsic lability of the anomeric phosphodiester linkages, our group synthesized isosteric, not acetylated phosphono analogues, where the anomeric oxygen of the phosphodiester is replaced by a methylene group. Their high stability to hydrolysis and ability to be recognised by anti-MenA serum were proved .
Considering that the 3-O-acetylation was revealed to be crucial for immunogenicity , we undertook the synthesis of 3-O-acetylated phosphono analogues of MenA polysaccharide.
In this communication we describe the strategies we explored for an efficient synthesis of phosphonodisaccharide 1 (Scheme 1). The target compound could be achieved by Mitsunobu coupling of phosphonate 2 with mannoside 3, which bears an amino-ending spacer suitable for protein conjugation.
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