Synthetic studies toward pseudopentasaccharide repeating unit of Streptococcus pneumoniae zwitterionic polysaccharide

Abstract

Streptococcus pneumoniae is one of the most common gram positive pathogens that colonizes the upper respiratory tract and causes and severe infections like otitis media, sinusitis, and more life threatening diseases like pneumonia, bacteremia and meningitis. S. pneumoniae has a thick polysaccharide capsule that covers the peptidoglycan cell wall. There are around 94 distinct capsular serotypes and all the 94 serotypes differ in virulence, prevalence and extent of drug resistance. All pneumococci possess two common polysaccharide antigens: C-polysaccharide and F-antigen. The C-polysaccharide is a cell-wall teichoic acid composed of tetrasaccharides attached together through ribitol phospho-diesters, and therefore it is classified as a ribitol teichoic acid. C-polysaccharide also contains phosphocholine substituents. The F-antigen is a lipoteichoic acid with a polysaccharide identical to C-polysaccharide and this part is linked to a diacylated glycerol residue via a glucose residue. The above mentioned oligosaccharides fall under the category of unique polysaccharides called as zwitteroinic polysaccharides (ZPSs). In the last decade, several studies have shown convincing evidence that ZPSs are immunomodulatory polysaccharides and they specifically activate T cells. Research has also showed that zwitterionic charges and molecular weight around 8 kDa are essential for the biological activity of the ZPSs that were isolated from the gram-negative anaerobic Bacteroides fragilis. Recently, it was confirmed that a minimum chain length of 2 to 3 repeating units are required for cytokine induction from pneumococcal lipoteichoic acids isolated from two different strains (Fp 23 and R6) of Streptococcus pneumonia. Because of the unique ability of zwitterionic polysaccharides to elicit T-cell immune response, few research groups have reported the syntheses of complex zwitterionic oligosaccharides. Here we report a convergent approach for the attempted synthesis of the monomer (pentasaccharide) of C-polysaccharide isolated from a noncapsulated pneumococcal strain CSR SCS2. We employed three orthogonal protecting groups (NAP, Allyl and TBS) that can be selectively removed to install phosphocholine and to oligomerize the repeating unit respectively. Access to this important ZPSs with 2 to 4 repeating units will provide an opportunity to investigate the immunological activity of these oligosaccharides, and to demonstrate the advantages of chemical synthesis for obtaining small quantities of pure complex oligosaccharides.