Abstract
Mammalian C-type lectin receptors (CTLRS) are involved in many aspects of immune cell regulation such as pathogen recognition, clearance of apoptotic bodies, and lymphocyte homing. Despite a great interest in modulating CTLR recognition of carbohydrates, the number of specific molecular probes is limited. To this end, we predicted the druggability of a panel of 22 CTLRs using DoGSiteScorer. The computed druggability scores of most structures were low, characterizing this family as either challenging or even undruggable. To further explore these findings, we employed a fluorine-based nuclear magnetic resonance screening of fragment mixtures against DC-SIGN, a receptor of pharmacological interest. To our surprise, we found many fragment hits associated with the carbohydrate recognition site (hit rate = 13.5%). A surface plasmon resonance-based follow-up assay confirmed 18 of these fragments (47%) and equilibrium dissociation constants were determined. Encouraged by these findings we expanded our experimental druggability prediction to Langerin and MCL and found medium to high hit rates as well, being 15.7 and 10.0%, respectively. Our results highlight limitations of current in silico approaches to druggability assessment, in particular, with regard to carbohydrate-binding proteins. In sum, our data indicate that small molecule ligands for a larger panel of CTLRs can be developed.
Highlights
Glycans are present in a large diversity on cell surfaces and are essential in many aspects of life such as embryonic development, cell–cell communication, and regulation of the immune system [1]
STRUCTURE-BASED SEQUENCE ALIGNMENT IDENTIFIES CANONICAL CARBOHYDRATE-BINDING SITES A comparative framework between the C-type lectin receptors (CTLRs) served as the starting point of our druggability prediction
We explored the ability of a set of CTLRs to accommodate inhibitors to modulate the receptor–carbohydrate interaction
Summary
Glycans are present in a large diversity on cell surfaces and are essential in many aspects of life such as embryonic development, cell–cell communication, and regulation of the immune system [1]. CTLRs are present in a variety of tissues and the glycan specificity of receptors present on cells of the innate immune system has been studied extensively They function as homing receptors on leukocytes as well as pattern recognition receptors [2, 3, 7]. A well-studied pattern recognition receptor is the dendritic cell-specific intercellular adhesion molecules-3-grabbing non-integrin (DC-SIGN) [8, 9] This CTLR is expressed on dendritic cells and macrophages and is involved in the recognition of a large array of pathogens such as Mycobacterium tuberculosis, Leishmania, HCV, Ebola, and HIV [3, 10,11,12,13,14,15]. It was demonstrated that DC-SIGN promotes HIV trans-infection of T cells and has since drawn attention as a therapeutic target in anti-viral therapy [10, 16, 17]
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