AG Fuchs

The group of Prof. Fuchs is investigating the following topics:

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The focus of the group is the application of particular secondary plant metabolites in targeted tumor therapies, in gene therapy, and in inflammation.

Targeted tumor therapies comprise a variety of active and passive immunotherapies, metabolic targeting, and targeted toxins. In our group, we are focusing on plant toxins as pharmaceutically active component and their combination with targeting moieties that endow the therapeutic agent with specificity in order to improve the therapeutic window. In particular, we prepare either fusion proteins or chemical conjugates of antibodies and natural ligands with plant ribosome-inactivating proteins, especially dianthin.[1] One of the major challenges of such an approach is the release of the protein toxin into the cytosol after binding to the target receptor and subsequent internalization. Regrettably, most of the payload is degraded in endolysosomes or recycled back to the surface. However, to be active the toxin needs to enter the cytosol to reach the ribosomes. To solve this problem, we use particular secondary plant metabolites of the group of saponins that we call endosomal escape enhancers. They mediate the release of the toxin from intracellular vesicles, which results in an increase of efficacy by several orders of magnitude shown in cell culture models and in syngeneic and xenograft mouse models.[2-3]


The success in targeted tumor therapies prompted us to expand the application of EEEs to gene therapy approaches . The non-viral uptake of genes harbors even more challenges than that of proteins, as the strongly negatively charged DNA must be complexed for stabilization and protection against degradation. Similar to the toxins, the DNA needs to be released to the cytosol in order to reach the nucleus, which presents the major obstacle in current gene therapy approaches. Despite the present challenges in the field, gene therapy offers immense potential to improve current therapies and opens up possibilities for untreated diseases. Therefore, we founded a European consortium of 12 partners to solve all the comprehensive problems associated with non-viral gene transfer and are jointly working on this topic in the European ENDOSCAPE project. The aim of the project is the design and generation of a protective scaffold that bears all required compounds including the gene, the EEEs and the targeting ligand. You are invited to follow us at LinkedIn: https://www.linkedin.com/company/endoscapeproject/.


While certain saponins are suitable as endosomal escape enhancers other particular saponins exhibit anti-inflammatory effects . Although a number of plant sources with anti-inflammatory saponins are well known, neither the molecular mechanism of their cellular action nor the structural features of the saponins required for the interactions are finally known yet. Therefore, we aim to solve the structure-function relationships of anti-inflammatory saponins and want to contribute to describe a pharmacophore for anti-inflammatory drugs in general. During the work, we also expect to identify new so far unknown saponins.


References:
[1] H. Fuchs, Toxins 2019, 11, 592.
[2] H. Fuchs, A. Weng, R. Gilabert-Oriol, Toxins 2016, 8, 200.
[3] H. Fuchs, N. Niesler, A. Trautner, S. Sama, G. Jerz, H. Panjideh, A. Weng, Biomedicines 2017, 5, 14.

 

 

AG Fuchs Gruppe