Journal
ACS CHEMICAL BIOLOGY
Volume 11, Issue 9, Pages 2407-2413Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.6b00561
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Funding
- German Research Foundation [RA1944/2-1]
- Max Planck Society
- Beilstein Institute for the Advancement of the Chemical Sciences
- Max Planck-RIKEN Joint center for Systems Chemical Biology
- Collaborative Research Center [765]
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C-type lectin receptors (CLRs) play a pivotal role in pathogen defense and immune homeostasis. Langerin, a CLR predominantly expressed on Langerhans cells, represents a potential target receptor for the development of anti-infectives or immunomodulatory therapies. As mammalian carbohydrate binding sites typically display high solvent exposure and hydrophilicity, the recognition of natural monosaccharide ligands is, characterized by low affinities. Consequently, glycomimetic ligand design poses challenges that extend to the development of suitable assays. Here, we report the first application of F-19 R-2-filtered NMR to address these challenges for a CLR, i.e., Langerin. The homogeneous, monovalent assay was essential to evaluating the in silico design of 2-deoxy-2-carboxamido-alpha-mannoside analogs and enabled the implementation of a fragment screening against the carbohydrate binding site. With the identification of both potent monosaccharide analogs and fragment hits, this study represents an important advancement toward the design of glycomimetic Langerin ligands and highlights the importance of assay development for other CLRs.
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