Peptide-carbohydrate mimicry: synthesis and immunological evaluation of experimental bacterial vaccines

One of the most pressing global issues in human health today includes the need to develop new, safer, and more effective vaccines against the ever increasing range of emerging, re-emerging, and antibiotic-resistant infectious diseases. The discovery that peptides could mimic the structure of microbial polysaccharides in carbohydrate-specific immunological reactions, and hence have potential as surrogate vaccines, is emerging as a new paradigm in vaccine research and development to replace traditional carbohydrate vaccines against microbial infections. While the basis and origin of mimicry at the molecular level between these two chemically unrelated molecules (carbohydrate and peptide), but functionally equivalent molecular structures have been determined, the requirements for immunogenicity of these carbohydrate-mimetic peptides in raising a long-lasting, cross-reactive protective immune response against the original microbial polysaccharides are currently unknown. This knowledge is fundamental for the development of effective surrogate vaccines to target microbial surface carbohydrates. This thesis deals with the examination of the immunogenicity in mice of two carbohydrate-mimetic peptides, DRPVPY and MDWNMHAA, both identified from phage-displayed libraries, as mimics of the cell-surface polysaccharides of two pathogenic bacteria Streptococcus Group A and Shigella flexneri Y. As a crucial part of the studies, an efficient strategy has been developed to synthesize experimental vaccines comprising these two mimetic peptides, as well as a polysaccharide (ten repeating units) of Shigella flexneri Y. The results obtained from the immunogenicity studies provide insight into the requirements for immunologically cross-reactive mimics of carbohydrates, as well as demonstrate whether these two mimetic peptides could be used as surrogates in the development of vaccines against the two respective bacterial pathogens. Rational drug design, which is emerging as a powerful technique to improve upon initial discoveries, has been used in this thesis work to design a second generation of ligands for anti-carbohydrate antibodies, hopefully with much higher affinity. Two glycopeptides comprising features of both the original polysaccharide and the mimetic peptide have been designed by molecular modeling using information based on X-ray crystal structures of the two bound original ligands. Synthetic strategies have successfully been developed in this thesis work to synthesize the designed chimeric glycopeptides.