Design of ligand-based targeted delivery vehicles for the murine C-type lectin receptor Langerin

• Applicants: Professor Dr. Marc Nazare; Professor Dr. Christoph Rademacher
• Subject Area: Pharmacy
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 441778902

C-type lectin receptors (CLRs) represent the largest and most diverse family of mammalian carbohydrate-binding proteins. In particular, CLRs that are expressed as immune cell receptors on professional antigen presenting cells fulfill important functions in health and disease rendering them attractive drug targets. Such small molecule modulators of CLRs function as potential immune stimulants (i.e. adjuvants) or can be utilized as targeting moieties attached to nanoparticles for the active delivery of immunomodulatory cargo in e.g. cancer immunotherapy. However, CLR druggability is considered rather low, suggesting an increased risk of failure of future drug discovery campaigns. Overall, this presumption leads to a shortage of drug-like CLR effectors, which could on the one hand be used to explore important fundamentals in CLR immunobiology as well as having a high potential of being translated into clinical applications. To this end, we have identified several series of small molecule ligands for the murine receptor Langerin. This CLR is expressed in mice on specific dendritic cells of the skin, so-called Langerhans cells, as well as on dendritic cells of the blood. Both dendritic cell subsets are attractive targets for small molecule-based immunomodulation. The Langerin ligands previously discovered will be subject to fragment growing approaches to increase affinity and specificity to finally serve as targeting ligands attached to nanoparticles. Fundamental insight will be generated how ligand-based targeted delivery of immunomodulators is influenced by the biochemical properties of the targeting ligand such as location of the receptor binding site, their affinity and kinetics, which we hypothesize to result in an altered uptake as well as routing, release, and processing of the cargo. A close inspection of the structure activity landscape of these targeting ligands based on biophysical, biochemical and cell-biological characterization is the prime goal of this proposal and will not only open the field of CLRs to the development of immunomodulatory approaches, but at the same time provide fundamental insights into ligand-based targeted delivery.

• DFG Programme: Research Grants
• International Connection: Austria
• Cooperation Partner: Privatdozentin Dr. Patrizia Stoitzner