Development of synthetic glycan affinity reagents to study the capsular structure of fungal pathogens

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Among fungal pathogens, the opportunistic species 'Cryptococcus neoformans' is unique in having a large, complex capsule that is responsible for its ability to cause severe infections in humans. Cryptococcus is an emerging global health threat, responsible for more than 200,000 annual deaths worldwide. The capsule of Cryptococcus plays a key role in modulating the intricate interactions between the fungus and the host. Lectins and anti-glycan antibodies are currently the main tools to recognise and study polysaccharides contained within the capsule, regarding their chemical composition, organization, and architecture. However, they either lack specificity or are limited on the saccharide chains that they can recognise. It is the goal of this interdisciplinary research project to develop such saccharide recognition tools and provide unprecedented and comprehensive insights into the composition, organization, and architecture of the Cryptococcus capsule. The first steps will consist of a modular synthetic approach, which involves concepts of molecular recognition, molecular assembly, multivalency and dynamic combinatorial chemistry, to generate peptide based-affinity reagents with exquisite specificity and high affinity for distinct saccharide chains. Next fluorescent tags will be chemically conjugated to the peptide based-affinity reagents for facilitating imaging studies. Finally, the novel glycan affinity reagents will be subsequently employed to create a high-resolution chemical mapping of the Cryptococcus capsule.