Research

Molecular Drug Targeting

The Rademacher lab is concerned with basic and applied research into Molecular Drug Targeting.

In particular, the skin represents an attractive organ for the application of novel vaccines since it harbours a large reservoir of resident immune cells capable of eliciting a systemic response against antigens. Here, Langerhans cells (LCs) are located in the epidermis, the upper layer of the skin. Insights generated over the past decades have highlighted the ability of LCs to promote a systemic cytotoxic T cell as well as protective B cell responses. These responses were primarily investigated using antibody-based delivery of antigens to LCs and were especially effective when Langerin was used as a targeted receptor. Langerin is a LC-restricted C-type lectin receptor. We have developed a small molecule ligand specific for Langerin that we explore as the basis for antigen delivery via nanoparticle formulations. These nanoparticulate formulations can encapsulate small molecules and protein antigens and release their cargo intracellularly. We were able to show specific uptake of these liposomes into Langerin-expressing model cells as well as primary human LCs. Furthermore, we study their endosomal fate and intracellular processing. Overall, these highly specific nanoparticles potentially build the basis for innovative delivery of vaccines via the skin.

For the identification of such target ligands we have made use of rational structure-based design as well as fragment based lead discovery approaches. In our search for small molecule modulators of C-type lectin receptor function, we make use of the structural plasticity of these lectins. Previously, we have highlighted the discrepancy between the static picture of these proteins as inferred from X-ray crystallography and the experimental description of susceptibility of these proteins for drug-like molecule binding. In particular, we found that besides the shallow and featureless carbohydrate recognition site, several secondary sites exist that are partially druggable and offer possibilities for inhibitor design against C-type lectins. These insights are complemented by our studies into the receptor flexibility using protein NMR in combination with molecular dynamics simulations, revealing an allosteric network of communicating amino acid side chains. This network regulates the Ca2+affinity and partially its pH sensitivity in human Langerin. Based on these insights on existence of druggable secondary sites and the presence of allostery, we were able to develop a series of allosteric inhibitors of C-type lectins in the low micromolar affinity regime.

Publications:

• ORCID: 0000-0001-7082-7239
• PubMed-NCBI
• u:cris