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| Item Type: | Article |
|---|---|
| Title: | Allosteric inhibition of a mammalian lectin |
| Creators Name: | Aretz, J., Anumala, U.R., Fuchsberger, F.F., Molavi, N., Ziebart, N., Zhang, H., Nazaré, M. and Rademacher, C. |
| Abstract: | Glycan-binding proteins are key components of central physiological and cellular processes such as self/nonself recognition, cellular tissue homing, and protein homeostasis. Herein, C-type lectins are a diverse protein family that play important roles in the immune system, rendering them attractive drug targets. To evaluate C-type lectin receptors as target proteins for small molecule effectors, chemical probes are required which are, however, still lacking. To overcome the supposedly poor druggability of C-type lectin receptors and to identify starting points for chemical probe development, we screened murine Langerin using 1H and 19F NMR against a library of 871 drug-like fragments. Subsequently, hits were validated by surface plasmon resonance and enzyme-linked lectin assay. Using structure-activity relationship studies and chemical synthesis, we identified thiazolopyrimidine derivatives with double-digit micromolar activity that displayed Langerin selectivity. Based on 1H-15N HSQC NMR and competitive binding and inhibition experiments, we demonstrate that thiazolopyrimidines allosterically inhibit Langerin. To the best of our knowledge, this is the first report of drug-like allosteric inhibitors of a mammalian lectin. |
| Keywords: | Allosteric Site, C-Type Lectins, Mannose-Binding Lectins, Molecular Structure, Pyrimidines, Structure-Activity Relationship, Surface Antigens, Surface Plasmon Resonance, Animals, Mice |
| Source: | Journal of the American Chemical Society |
| ISSN: | 0002-7863 |
| Publisher: | American Chemical Society |
| Volume: | 140 |
| Number: | 44 |
| Page Range: | 14915-14925 |
| Date: | 7 November 2018 |
| Official Publication: | https://doi.org/10.1021/jacs.8b08644 |
| PubMed: | View item in PubMed |
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