Small Molecule Modulators of C-type Lectin Receptors

An allosteric inhibitor of murine Langerin was identified from fragment-based screening (Aretz et al., 2018)

In our search for small molecule modulators of C-type lectin receptor function, we make use of the structural plasticity of these lectins. Previously, we have highlighted the discrepancy between the static picture of these proteins as inferred from X-ray crystallography and the experimental description of susceptibility of these proteins for drug-like molecule binding. In particular, we found that besides the shallow and featureless carbohydrate recognition site, several secondary sites exist that are partially druggable and offer possibilities for inhibitor design against C-type lectins. These insights are complemented by our studies into the receptor flexibility using protein NMR in combination with molecular dynamics simulations, revealing an allosteric network of communicating amino acid sidechains. This network regulates the Ca2+ affinity and partially its pH sensitivity in human Langerin. Based on these insights on existence of druggable secondary sites and the presence of allostery, we were able to develop a series of allosteric inhibitors of murine Langerin in the low micromolar affinity regime.

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Further reading

Wawrzinek, R.; Wamhoff, E.-C.; Lefebre, J.; Rentzsch, M.; Bachem, G.; Domeniconi, G.; Schulze, J.; Fuchsberger, F. F.; Zhang, H.; Modenutti, C.; Schnirch, L.; Marti, M. A.; Schwardt, O.; Bräutigam, M.; Guberman, M.; Hauck, D.; Seeberger, P. H.; Seitz, O.; Titz, A.; Ernst, B.; Rademacher, C.
A Remote Secondary Binding Pocket Promotes Heteromultivalent Targeting of DC-SIGN.
J Am Chem Soc 2021, 143 (45), 18977–18988.

Aretz, J.; Anumala, U. R.; Fuchsberger, F. F.; Molavi, N.; Ziebart, N.; Zhang, H.; Nazaré, M.; Rademacher, C.
Allosteric Inhibition of a Mammalian Lectin.
J Am Chem Soc 2018, 140 (44), 14915–14925.

Schulze, J.; Baukmann, H.; Wawrzinek, R.; Fuchsberger, F. F.; Specker, E.; Aretz, J.; Nazaré, M.; Rademacher, C.
 CellFy: A Cell-Based Fragment Screen against C-Type Lectins.
Acs Chem Biol 2018, 13 (12), 3229–3235. 

Aretz, J.; Baukmann, H.; Shanina, E.; Hanske, J.; Wawrzinek, R.; Zapol’skii, V. A.; Seeberger, P. H.; Kaufmann, D. E.; Rademacher, C.
Identification of Multiple Druggable Secondary Sites by Fragment Screening against DC-SIGN.
Angewandte Chemie Int Ed 2017, 56 (25), 7292–7296. 

Wamhoff, E.-C.; Hanske, J.; Schnirch, L.; Aretz, J.; Grube, M.; Silva, D. V.; Rademacher, C.
19 F NMR-Guided Design of Glycomimetic Langerin Ligands.
Acs Chem Biol 2016, 11 (9), 2407–2413. 

Aretz, J.; Wamhoff, E.-C.; Hanske, J.; Heymann, D.; Rademacher, C.
Computational and Experimental Prediction of Human C-Type Lectin Receptor Druggability. 
Front Immunol 2014, 5 (JUL), 323.