Ligand-based targeted delivery for murine Langerin

Invading pathogens are recognized by cells of the immune system by the carbohydrate structures present on their surface. This recognition process is enabled by receptors, which in turn are found on the immune cells. The Langerhans cells of the skin are such immune cells and reside mainly in the epidermis, the uppermost layer of the skin. The receptor Langerin is produced by these cells and is involved in the recognition of various viruses, fungi and bacteria and subsequently initiates a cascade of processing steps that results in the activation of further immune cells. In this project, compounds are identified that can mimic the binding to the receptor. This can be done via the natural recognition site of the receptor or via so-called allosteric sites. The aim is to investigate how the choice of the site but also the binding affinity between ligand and receptor affects the uptake process. The answer to this question helps to understand how pathogens are recognized and processed in the body, but will also enable the development of new therapeutic approaches, e.g. in vaccine research.

How do drugs reach their site of action? Answering this fundamental question can help reduce side effects or even make certain therapies possible in the first place. This is especially true for modern therapies that involve gene editing, where the targeted delivery of drugs in the body is crucial. In the past, sugar-like molecules have been very successfully used to deliver drugs to the liver. A specific receptor in the liver recognizes these sugar structures and takes up the entire cargo, including the drug. In our work, we are looking for similar sugar-like building blocks that bind to receptors on immune cells in the skin. The idea is to use this easily accessible organ as an entry point to bring medicines into the body. In this project, we focused on a very specific question: does the interaction between sugar-like molecules and their receptors always have to occur at the well-known sugar-binding site? Or can novel binding modes be created and how would these affect the way drugs are processed inside the cell? Our investigations provided many exciting insights into our skin model system that can now be applied to other receptors as well. For example, we discovered alternative binding sites that do not recognize sugars, but still allow drugs to enter the cell. We also found that these receptors can be blocked through a novel mechanism that relies on a previously unknown binding site. This could be highly relevant for other members of the same receptor family that are involved in inflammatory processes.