Receptor recognition of carbohydrates is an important principle of many aspects of life, such as cellular communication and pathogen recognition. For instance, mammalian lectins are mediators of cell migration, pathogen uptake and processing, and signal integration leading to a defined cellular immune response. Small molecules as modulators for the receptor/glycan interaction by blocking the recognition site of these lectins would be very beneficial for basic research in glycobiology as well as for therapeutic intervention. Unfortunately, X-ray crystallographic analyses of a number of mammalian lectins involved in immune cell regulation have revealed that the carbohydrate recognition sites are rather shallow and featureless. This renders lectin receptors rather unattractive for rational design of small molecule inhibitors. Moreover, previous reports on high-throughput screening campaigns against glycan binding proteins have solidified this opinion, stating that glycan-binding protein are undruggable. These data suggest that the identification of hits and advancing them into lead structures is challenging, if not impossible. Nevertheless, no systematic study has been reported to assess the druggability of a mammalian lectin family. To this end we chose C-type lectins, representing a large mammalian lectin family to re-evaluate the druggability of these receptors. A set of family members was selected and recombinantly expressed. Biophysical techniques such as NMR and SPR, as well as computational algorithms were applied. We will discuss these results in the light of potential glycomimetic drugs against C-type lectin receptors.

Druggability of mammalian C-type lectin receptors

248th National Meeting (2014)

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