Glycan-binding proteins are key components of central physiological and cellular processes such as self-/non-self-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 Ctype lectin receptors and to identify starting points for chemical probe development, we screened murine langerin using 1 H and 19 F 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 1 H− 15 N 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.
Dendritic cells (DC)
are antigen-presenting cells coordinating
the interplay of the innate and the adaptive immune response. The
endocytic C-type lectin receptors DC-SIGN and Langerin display expression
profiles restricted to distinct DC subtypes and have emerged as prime
targets for next-generation immunotherapies and anti-infectives. Using
heteromultivalent liposomes copresenting mannosides bearing aromatic
aglycones with natural glycan ligands, we serendipitously discovered
striking cooperativity effects for DC-SIGN+ but not for
Langerin+ cell lines. Mechanistic investigations combining
NMR spectroscopy with molecular docking and molecular dynamics simulations
led to the identification of a secondary binding pocket for the glycomimetics.
This pocket, located remotely of DC-SIGN’s carbohydrate bindings
site, can be leveraged by heteromultivalent avidity enhancement. We
further present preliminary evidence that the aglycone allosterically
activates glycan recognition and thereby contributes to DC-SIGN-specific
cell targeting. Our findings have important implications for both
translational and basic glycoscience, showcasing heteromultivalent
targeting of DCs to improve specificity and supporting potential allosteric
regulation of DC-SIGN and CLRs in general.
Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portal If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.