Enteric diseases remain a major burden worldwide.1 Shigellosis, or bacillary dysentery, caused by the non-capsulated Gram negative bacteria Shigella, is one of the “big five” diarrhoeal diseases. Shigella flexneri, which prevails in developing countries, is the major cause of the endemic form of the disease. Due to serotype diversity and variable geographical distribution of Shigella species, there is a strong unmet need for a broadly available multivalent vaccine for Shigellosis.2
Based on the observation that protection against re-infection is mainly achieved by antibodies specific for the O-antigen (O-Ag) moiety of the cell-surface lipopolysaccharide (LPS), immunogens consisting of synthetic fragments of the putative O-Ag conjugated to carrier proteins have been considered as a possible alternative to detoxified ShigShigella LPS-protein conjugates. Along this line, the development of a multivalent synthetic carbohydrate-based Shigella vaccine is a major objective in our laboratory.
Herein, we first highlight the concept of synthetic carbohydrate-based vaccines against bacterial diseases. In doing so, we will focus on SF2a-TT15, a vaccine candidate against S. flexneri 2a.3 We then present the concise and convergent syntheses of oligosaccharide fragments of the O-Ags of S. flexneri 3a and S. flexneri 6,4 respectively, two other prevalent serotypes. Our schemes provide an access to fragments containing one or more O-Ag repeats through iteration with tri- and disaccharide building blocks, in the former case. In contrast, a protected tetrasaccharide corresponding to one O-Ag repeat was identified as a suitable building block in the latter case.
1. Kosek M. et al, Bull. WHO 2003, 81, 197.,
2. Levine M. M. et alNat. Rev. Microbiol. 2007, 5, 540.
3. Phalipon, A. et al, J. Immunol. 2009, 182, 2241.
4. Perepelov A. V. et al, FEMS Immunol. Med. Microbiol. 2012, 66, 201.