Synthesis of Phosphonodisaccharide Analogue from Neisseria Meningitidis A Capsular Polysaccharide

PS2 Poster session 2 Even numbers
Location (hall): 
Start/end time: 
Tuesday, July 2, 2019 - 15:45 to 17:15
Cristina Manuela

Cristina Manuela Santi1, Ludovic Auberger1, Luigi Lay1

1Università Degli Studi Di Milano, Milano, Italy

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[1][2]; 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 [3].

Considering that the 3-O-acetylation was revealed to be crucial for immunogenicity [4], 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. 

Scheme 1: Retrosynthetic strategy

  1. Laforce FM, Djingarey M, Viviani S. Successful African introduction of a new Group A meningococcal conjugate vaccine : Future challenges and next steps. Hum Vaccin Immunother. 2018, 14,1098–1102. 
  2. Hollingshead S, Tang CM. An Overview of Neisseria meningitidis. In: Neisseria meningitidis. 2019, 1–16. 
  3. Torres-Sanchez MI, Zaccaria C, Buzzi B, Miglio G, Lombardi G, Polito L, Russo G, Lay L. Synthesis and biological evaluation of phosphono analogues of capsular polysaccharide fragments from Neisseria meningitidis A. Chem - A Eur J. 2007, 13, 6623–6635. 
  4. Berry DS, Lynn F, Lee C-H, Frasch CE, Bash MC. Effect of O acetylation of Neisseria meningitidis serogroup A capsular polysaccharide on development of functional immune responses. Infect Immun, 2002, 70, 3707-3713.