Allosteric inhibition of a mammalian lectin


  • J. Aretz
  • U.R. Anumala
  • F.F. Fuchsberger
  • N. Molavi
  • N. Ziebart
  • H. Zhang
  • M. Nazaré
  • C. Rademacher


  • Journal of the American Chemical Society


  • J Am Chem Soc 140 (44): 14915-14925


  • 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.