Complex glycan structures have evolved as versatile regulators of many aspects of health and disease such as in immune cell recognition, development, hormone activity, tissue organization, and metastasis. Many functions of carbohydrates are tightly coupled to their recognition by glycan binding proteins (GBPs). Only the side-by-side analysis of the recognition process at atomic resolution and functional studies in a relevant biological environment provide means to fully elucidate a carbohydrate structure-function relationship. Therefore, we apply biophysical techniques, such as nuclear magnetic resonance (NMR) and combine the results with computational methods. We develop small molecule modulators to expand these investigations into the biochemical and cell biological roles of glycan/protein interactions.
Many naturally occurring glycans are recognized by more than one lectin. The reverse also holds true, so that the majority of lectins are not highly specific for one single complex carbohydrate structure. The origin of this ambiguity can be described by the so-called “Red Queen Effect”, a concept in evolution that explains the pressure of co-evolving components of a biological system and its consequences (Varki A., Cell, 2006, 126(5), 841-5). Building on the existing carbohydrate scaffold by chemical modification is a route towards the development of highly specific and defined tools to study glycobiology, towards glycomimetic drugs (Wamhoff et al. 2016).
To do so, we apply nuclear magnetic resonance (NMR), which is an extremely versatile biophysical technique providing structural insight into weak glycan/protein interactions. In the Structural Glycobiology group, we use a broad palette of techniques to develop probes for glycobiology on the basis of a detailed description of the recognition process. Saturation transfer difference NMR and transferred nuclear Overhauser effects are only two examples allowing us to deduce important structural feature of these weak interactions. Moreover, NMR and SPR screening techniques are employed to expand the structural information and develop carbohydrates into specific glycan analogs. Both methods complement each other very well in the identification of actives from screening mixtures.
In particular, we follow a fragment-based drug design approach to develop novel glycan binding protein ligands. Here, small heterocyclic fragments of drug-like molecules are screening using NMR and SPR-based protocols as well as chemical fragment arrays on solid supports (Aretz et al. 2016a). Actives are identified and evolved to higher affinity ligands (Aretz et al. 2016b). These studies go alongside with virtual screening and molecular modeling techniques to complement our insights and yield a more comprehensive picture of the interaction (Aretz et al. 2014).
We would like to thank the following agencies for their support: