Mammalian carbohydrate receptors are involved in cell migration, pathogen recognition, uptake and processing, and determine many aspects of cellular communication. In particular, a large number of carbohydrate receptors are found on cells of the innate immune system. Strikingly, many of these receptors are uniquely expressed on defined immune cell subsets allowing to specifically address these cells in their complex biological environment. Hence, these cells, initiators and regulators of an effective immune response, are attractive targets for the therapeutic modulation of the immune reaction.<br/>Consequently, small molecule inhibitors of these carbohydrate-protein interactions would be beneficial for basic research as well as for therapeutic intervention. Unfortunately, carbohydrate-binding sites are often rather featureless and flat and are therefore considered either challenging or undruggable, hampering the development of small molecule inhibitors. Additionally, only a limited number of high throughput screening attempts have been successful against this class of biomolecules. Here, we summarize our work on the development of glycan receptor-specific ligands primarily resulting from fragment-based screening approaches using biophysical assay such as <sup>19</sup>F NMR, STD NMR, HSQC NMR, and SPR. These assays are complemented by in silico approaches as well as screening on chemical fragment microarrays and also by a recently developed cell-based assay that allowed screening our 900-member fragment library. Based on these chemical probes resulting from fragment-based design, we explore basic immunological questions as well as applied aspects such as small molecule targeted delivery of stimulants to specific immune cell subsets.

Fragment-based ligand design of carbohydrate receptor ligands

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.