Vortrag im Rahmen des Institutsseminars Biologische Chemie

Prof. Dr. Christoph Rademacher, Department für Pharmazeutische Wissenschaften, Universität Wien

Small molecule Modulators of C-type Lectin Receptor Function: From Fragment-based Design to Topical  Vaccines

In a multicellular organism, mammalian receptors recognizing carbohydrate structures mediate many important aspects of life such as self/non-self-differentiation, cell adhesion and migration. In particular, carbohydrate binding proteins expressed by cells of the innate immune system have gained increased interest for their restricted expression pattern and for offering the opportunity to modulate cellular functions. However, chemical probes that specifically address these receptors are sparse and carbohydrates as their natural ligands only offer limited affinity and specificity. Hence, the development of small molecules capable of binding to carbohydrate receptors and consequently modulating their biological function is an important task.

Unfortunately, carbohydrate recognition sites are rather flat and featureless, often solvent exposed and highly hydrophilic, thus being less accessible for drug-like molecules. We used fragments (MW 150 – 250 Da) of such drug-like molecules to probe the surface of several carbohydrate binding proteins for the availability of binding sites suitable for modulating of lectin function. Fragment screening was performed using several orthogonal methods such as NMR, SPR, and flow cytometry and hits were evolved into micromolar binders for targets from the C-type lectin family (Langerin, DC-SIGN). Lessons learned about lectin structure and dynamics, as well as the development of chemical probes and their immune cell modulation will be covered in this presentation [1-3].

References
 
[1] J. Aretz, H. Baukmann, E. Shanina, J. Hanske, R. W. Wawrzinek, V. A. Zapol'skii, P. H. Seeberger, D. E. Kaufmann, C. Rademacher, Angew. Chem. Int. Ed. 2017, 56, 1-6
 
[2] J. Hanske, S. Aleksić, M. Ballaschk, M. Jurk, E. Shanina, M. Beerbaum, P. Schmieder, B. G. Keller, C. Rademacher, J Am Chem Soc, 2016, 138, 12176-86.
 
[3] E. C. Wamhoff, J. Hanske, L. Schnirch, J. Aretz, M. Grube, D. Varon Silva, C. Rademacher, ACS Chem Biol, 2016, 11, 2407-13

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