Universität Düsseldorf: Arbeitsgebiete

Our research is focused on the development of molecules modulating disease-relevant carbohydrate–protein interactions in infection, inflammatory diseases, and cancer. Many biological processes in this context are mediated by a group of carbohydrate-binding proteins called C-type lectin receptors (CLRs). These proteins are expressed on innate immune cells, such as macrophages and dendritic cells, which assume important roles in innate and adaptive immunity.

By designing small molecule glycomimetic ligands that selectively bind certain members of the CLR family, we aim to harness the functions of CLRs for therapeutic applications. These compounds can serve as e.g., inhibitors of viral entry, immunomodulatory agents (vaccine adjuvants), or for targeted delivery purposes. By grafting these ligands to multivalent supports, we synthesize functional nanomaterials for therapeutic applications. By understanding the specific details that drive carbohydrate–protein interactions on a molecular level, we aim to improve our ability to design efficient and selective glycomimetics. For this, we study protein–ligand binding thermodynamics and kinetics of mono- and multivalent compounds by various biophysical techniques.

Figure 1. Potential applications of CLR-targeted therapeutics. Reproduced from Ref. 1 with permission from the Royal Society of Chemistry.

Structure-based drug design

Lectin binding sites are often polar, shallow, and solvent-exposed. This poses a particular challenge for drug design, because putative ligands are in constant competition with solvent molecules. Thus, binding affinities of natural carbohydrates are often low, due to the thermodynamic costs of desolvation. By employing structural information from X-ray crystallographic experiments or molecular modeling, we aim to design carbohydrate-derived CLR-ligands that can overcome the intrinsic drawbacks associated with polar carbohydrate scaffolds. Commonly employed strategies include the reduction of desolvation penalties and the extension into secondary binding pockets. The thusly generated glycomimetic molecules provide the added benefit of high selectivity compared with their natural carbohydrate precursors, which commonly bind to many different lectin receptors.

Figure 2. A) Typical structure of a CLR carbohydrate recognition domain. B) Structure and domain organization in different classes of myeloid CLRs. Reproduced from Ref. 1 with permission from the Royal Society of Chemistry.

Multivalent Glycoconjugates

Natural glycans presented on cell surfaces usually comprise repeated units of complex oligosaccharides. Thus, CLRs have evolved to recognize these multivalent displays, not monomeric carbohydrates, with high affinity. As a consequence, the presentation of monovalent glycomimetics on an oligo- or multivalent support can drastically improve the binding affinity of CLR ligands. Our group focuses on the development of glycopolymers based on a biocompatible poly-l-lysine backbone. In addition, we are investigating other oligovalent scaffolds tailored to the oligomeric assembly of the specific receptor target. A particular challenge in the design of those molecules is the choice of appropriate linker moieties. By studying the binding thermodynamics of oligovalent lectin ligands, we aim to improve our understanding of the various energetic contributions associated with different linker moieties and provide the means for a more rational ligand design process.

Figure 3. A) Schematic representations of oligo- and multivalent glycomimetics. B) Whitesides model adapted from Ref. 2 accounting for various thermodynamic contributions of oligovalent interactions.

References

Cramer J., Medicinal Chemistry of the Myeloid C-Type Lectin Receptors Mincle, Langerin, and DC-SIGN, RSC Medicinal Chemistry, 2021, 12, 1985–2000.
Krishnamurthy, Estroff, Whitesides, Multivalency in Ligand Design. In Fragment‐based Approaches in Drug Discovery; Jahnke, W., Erlanson, D., Eds.; 2006; 11–53.