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Allosteric inhibition of a mammalian lectin

Item Type:Article
Title:Allosteric inhibition of a mammalian lectin
Creators Name:Aretz, J. and Anumala, U.R. and Fuchsberger, F.F. and Molavi, N. and Ziebart, N. and Zhang, H. and 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 (U.S.A)
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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