Langerin Receptor-Targeting Chimaeras (LangTACs) for Langerhans Cell-specific Degradation of Extracellular Proteins

• Applicant: Dr. Benedikt Schwarze
• Subject Area: Biochemistry ; Biophysics ; Pharmacy ; Cell Biology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532926150

To expand the druggable space of the proteome, the therapeutic approach called targeted protein degradation (TPD) has been conceptualised to tackle disease-associated proteins, which are traditionally difficult to address in a specific manner. Also, the degradation of proteins has been shown in many cases to be more efficient in eliminating pathogenic proteins in a disease situation compared to inhibition by small molecules or antibodies. To this end, protein degradation platforms, like the proteolysis-targeting chimaeras (PROTACs), have revolutionised drug discovery. These chimeric molecules exploit the cytosolic ubiquitin-proteasome system (UPS). However, this approach is largely limited to intracellular proteins while the secreted proteome stays out of reach. Very recently, the concept of TPD has been expanded to the extracellular site by developing lysosome-targeting chimaeras (LYTACs) which bind and direct cell membrane-associated or secreted proteins outside the cell via suitable endocytosis-mediating receptors to the second major mammalian degradation system, the autophagic-lysosomal pathway (ALP). Thus, the LYTACs platform represents another revolution in drug discovery. The first few examples of this kind not only showed impressively the potential of this approach but also revealed that selectivity and target scope of the different degradation pathways urge for co-opting more receptors for lysosomal degradation leading to more tissue selectivity or degradation efficacy. This is where the proposed project starts: The goal is to establish the endocytosis-mediating C-type lectin receptor (CLR) langerin as a target receptor for extracellular protein degradation. Langerin is cell-specifically expressed on Langerhans cells (LCs), a subset of dendritic cells of the immune system mainly populating the epidermis of the skin. A recently developed selective glycomimetic small molecule ligand provides the basis for this to become a novel LYTAC platform. This new strategy would allow for expanding the possibilities of the LYTAC platform to immune cells of the skin. In this way, high cell-type specificity could be achieved which was previously only conceivable for liver cells with their liver-specific asialoglycoprotein receptor. Additionally, the fact that the skin is easily accessible via topical applications circumvents many pharmacokinetic issues emerging from the systemic administration of drugs. To fulfil the proposed objectives, several aspects of the system will be studied in a stepwise manner to deliver proof-of-concept for this approach: i) synthesis of heterobifunctional chimaeras selective for langerin, ii) determination of cellular uptake efficacy of the new chimaeras and simple protein test systems, iii) degradation of therapeutically relevant proteins from the extracellular site.

• DFG Programme: WBP Fellowship
• International Connection: Austria
• Host: Professor Dr. Christoph Rademacher