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

在真菌病原体中，机会性物种“新型隐球菌”的独特之处在于它有一个大而复杂的荚膜，这是它能够引起人类严重感染的原因。隐球菌是一种新兴的全球健康威胁，每年在全世界造成20多万人死亡。隐球菌囊在调节真菌与宿主之间复杂的相互作用中起着关键作用。凝集素和抗聚糖抗体是目前识别和研究胶囊内多糖的主要工具，涉及它们的化学成分、组织和结构。然而，它们要么缺乏特异性，要么仅限于它们能识别的糖链。该跨学科研究项目的目标是开发这种糖类识别工具，并对隐球菌胶囊的组成、组织和结构提供前所未有的全面见解。第一步将包括模块化合成方法，包括分子识别，分子组装，多价和动态组合化学的概念，以产生基于肽的亲和试剂，对不同的糖链具有精致的特异性和高亲和力。接下来，荧光标签将被化学偶联到基于肽的亲和试剂上，以促进成像研究。最后，新的聚糖亲和试剂将随后用于创建隐球菌胶囊的高分辨率化学图谱。

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.