Shigella sonnei is a major causative organism of shigellosis worldwide, that appears the most prevalent of Shigellae in developed countries. We are designing synthetic oligosaccharide-based immunogens as possible vaccine candidates against this organism using an approach similar to the synthetic vaccine project targeting a conjugate vaccine against S. dysenteriae type 1. The O-SP of S. sonnei consists of a disaccharide repeating unit containing the unique sugars 2-acetamido-2-deoxy-l-altruronic acid and 2-acetamido-4-amino- 2,4,6-trideoxy-d-galactose in a- and b-linked form, respectively. As the first stage towards the synthesis of higher-membered saccharide fragments of the O-SP, we have developed synthetic routes to the frame-shifted disaccharide repeating units of the O-SP starting from monosaccharide precursors. In these endeavours numerous methodical problems were encountered due to the presence of two acetamido, one amino and one carboxyl group in the targeed molecules. While solutions have been worked out for many of the difficulties, much work remains to be done to synthesize higher-membered oligosaccharides of this system. The synthetic mono- and di- saccharides were recognized by a hyperimmune polyclonal rabbit serum raised against S. sonnei as assayed by the passive hemolysis inhibition test. The IC50 values were in the mM range and were about 3-6-fold lower for the disaccharides than for the monosaccharides. These data lend further support for the published structure of the native polysaccharide and show that higher-membered oligosaccharides will be necessary to achieve stronger antibody-binding. We are currently exploring synthetic strategies to higher-membered oligosaccharides that are suitable for covalent attachment to proteins.
