Biology subjects

Rademacher, C.

Publications and source records attributed to Rademacher, C..

3 recordsLinked to original sources

bioRxiv2018

A specific, glycomimetic Langerin ligand for human Langerhans cell targeting

Langerhans cells are a subset of dendritic cells residing in the epidermis of the human skin. As such, they are key mediators of immune regulation and have emerged as prime targets for novel transcutaneous cancer vaccines. Importantly, the induction of protective T cell immunity by these vaccines requires the efficient and specific delivery of both tumor-associated antigens and adjuvants. Langerhans cells uniquely express Langerin (CD207), an endocytic C-type lectin receptor. Here, we report the discovery of a specific, glycomimetic Langerin ligand employing a heparin-inspired design strategy that integrated NMR spectroscopy and molecular docking. The conjugation of these glycomimetics to liposomes enabled the specific and efficient targeting of Langerhans cells in the human skin. This delivery platform provides superior versatility and scalability over antibody-based approaches and thus addresses current limitations of dendritic cell-based immunotherapies.

immunology↗

bioRxiv2017

Wall teichoic acid is a pathogen-associated molecular pattern of Staphylococcus aureus that is recognized by langerin (CD207) on skin Langerhans cells

Staphylococcus aureus is a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD). Epicutaneous exposure to S. aureus induces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The underlying molecular mechanisms of the association between S. aureus and skin inflammation are poorly understood. Here, we demonstrate that human LCs directly interact with S. aureus through the pattern-recognition receptor langerin (CD207). Human, but not mouse, langerin interacts with S. aureus through the conserved {beta}-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminating S. aureus from other staphylococcal species. Importantly, the specific S. aureus WTA glycoprofile strongly influences the level of Th1-and Th17-polarizing cytokines that are produced by in vitro generated LCs. Finally, in a murine epicutaneous infection model, S. aureus induced a more pronounced influx of inflammatory cells and pro-inflammatory cytokine transcripts in skin of human langerin transgenic mice compared to wild-type mice. Our findings provide molecular insight into the unique pro-inflammatory capacities of S. aureus in relation to inflammatory skin disease.

microbiology↗

bioRxiv2017

Discovery of BAZ2A Bromodomain Ligands

The bromodomain adjacent to zinc finger domain protein 2A (BAZ2A) is implicated in aggressive prostate cancer. The BAZ2A bromodomain is a challenging target because of the shallow pocket of its natural ligand, the acetylated side chain of lysine. Here, we report the successful screening of a library of nearly 1500 small molecules by high-throughput docking and force field-based binding-energy evaluation. For seven of the 20 molecules selected in silico, evidence of binding to the BAZ2A bromodomain is provided by ligand-observed NMR spectroscopy. Two of these compounds show a favorable ligand efficiency of 0.42 kcal/mol per non-hydrogen atom in a competition-binding assay. The crystal structures of the BAZ2A bromodomain in complex with four fragment hits validate the predicted binding modes. The binding modes of compounds 1 and 3 are compatible with ligand growing for optimization of affinity for BAZ2A and selectivity against the close homologue BAZ2B.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC=\"FIGDIR/small/122317_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (36K):\norg.highwire.dtl.DTLVardef@aba498org.highwire.dtl.DTLVardef@c32ddeorg.highwire.dtl.DTLVardef@1f85fc0org.highwire.dtl.DTLVardef@15671bb_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗