Synthesis and Antigenic Evaluation of Oligosaccharide Mimics of Vi Antigen from Salmonella typhi

Abstract

Salmonella typhi is responsible for typhoid fever, which is a serious health threat in developing countries. As a virulent factor of Salmonella typhi, the purified Vi polysaccharide (Vi PS) has become an effective vaccine to combat typhoid fever. The chemical synthesis can provide homogeneous and well-defined molecules for the development of Vi-based vaccines. However, the synthesis of Vi oligosaccharides in high yields and with exclusive α-stereoselectivities remains very challenging. In this paper, a series of Vi pseudooligosaccharides, including pseudo tetra-, hexa-, and octa-saccharides were efficiently synthesized. These oligosaccharide analogues were conjugated by carbon chain tether through olefin cross metathesis or by the 1,2,3-triazole moiety through copper (I)-catalyzed alkyne-azide cycloaddition reaction (CuAAC). The binding affinities of these oligosaccharide mimics to anti-Vi antibodies were investigated. These results will be beneficial to the further development of Vi-based oligosaccharide vaccines.

A stabilized glycomimetic conjugate vaccine inducing protective antibodies against Neisseria meningitidis serogroup A

“…Differently from these approaches, we envisaged the use of synthetic chemistry to generate stabilized MenA glycomimetics 27,28 . Mimics, in which structural changes are implemented to improve specific features of the natural polysaccharide have so far not been incorporated in conjugate vaccines inducing protective immune responses 29 . Given the exquisite recognition of antigens by antibodies it is a grand challenge to develop mimetics that sufficiently mimic their natural counterpart so that they can raise antibodies against the parent bacterium.…”

Recent Advances in the Synthesis of Glycoconjugates for Vaccine Development

“…The authors speculated that improved affinities could be ascribed to the presence of an acetyl group at C-4 of the upstream residue in place of the methyl ether present in Sinaÿ’s structures. More recently, Ye et al [ 142 ] synthesized a series of Vi pseudo-oligosaccharides 179 – 183 ( Figure 20 ) conjugated by carbon chain spacers through olefin cross metathesis or by the 1,2,3-triazole moiety through Huisgen cycloaddition reaction. The binding affinities to anti-Vi antibodies of proposed mimics 179 – 183 were investigated, showing that the affinity of divalent compounds was generally comparable to the monovalents of the same length.…”

Synthetic Glycans and Glycomimetics: A Promising Alternative to Natural Polysaccharides

“…Chemical synthesis of Vi oligosaccharides remains very challenging in view of the structural features of the exclusive α‐linkage and the low reactivity of the hydroxyl at C‐4 position. Recently, our group efficiently synthesized a series of tetramethylene‐ or 1,2,3‐triazole‐linked oligosaccharide mimetics of Vi antigen in virtue of olefin cross metathesis or copper‐ catalyzed azide‐alkyne cycloaddition reaction (CuAAC) (Figure ) . These glycomimetics were prepared to mimic the natural Vi oligosaccharide fragments with the hope that these oligosaccharide derivatives could compete with natural Vi polysaccharides to bind with anti‐Vi antibodies.…”

“…Recently,o ur group efficiently synthesized as eries of tetramethylene-or 1,2,3-triazole-linked oligosaccharide mimetics of Vi antigen in virtue of olefin cross metathesis or coppercatalyzed azide-alkyne cycloaddition reaction (CuAAC) ( Figure 14). [51] These glycomimetics were prepared to mimic the natural Vi oligosaccharide fragments with the hope that these oligosaccharide derivatives could compete with natural Vi polysaccharides to bind with anti-Vi antibodies. The competitive ELISA assay showedt hat the antigenic activity of pseudooctasaccharides linked by either the tetramethylene or the triazole was similart ot he natural tetrasaccharide.…”