Medicinal chemistry / Small Molecules

Migration of cells and invasion into healthy tissue are hallmarks of cancer. Such metastasis formation exerts a huge impact on mortality. Remodeling of the extracellular matrix is key for release of cells from the primary tumor and migration to sites of metastasis formation. Meprin α is a metalloproteinase that is involved in these processes and an influence of meprin activity on migration and invasiveness of tumor cells was already shown.

Within the project "MeGrate - Validation of the proteinase meprin α as an antimigratory target in cancer", a research team from Fraunhofer IZI, led by Dr. Daniel Ramsbeck, Head of the Astacin Proteinase Unit, together with researchers from the Institute for Molecular Medicine and Cell Research at the University of Freiburg, is investigating Meprin α as a drug target for various types of cancer. Focus is on breast-, colon- and hepatocellular cancer.

Furthermore, the scientists aim to analyse the molecular structure of meprin α in complex with potent inhibitors. After successful target validation, the researchers hope that this will enable the subsequent optimization of meprin inhibitors in follow-up drug discovery projects.

The project is funded by the German Federal Ministry of Education and Research (BMBF) for the period from May 1, 2020 to April 30, 2022.

Increasing resistance of pathogenic microorganisms is a major challenge for the treatment of infectious diseases. There are predictions that in the next few years the effectiveness of existing antibiotics will decline sharply, resulting in a significant increase in the mortality of bacterial infections.

So-called pathoblockers or antivirulence agents represent a new strategy for the treatment of infectious diseases. The aim is to develop active substances that do not kill bacteria but target properties that determine their pathogenic effect, the so-called virulence factors. Communication, nutrition and other relevant metabolic processes of pathogens that enable infection are thus to be impaired. An important group of these virulence factors are proteases, which are secreted by the bacteria and perform a wide variety of tasks. One such protease as a potential antivirulent drug target is aureolysin from Staphylococcus aureus, a metalloprotease that is considered among other enzymes to be an important virulence factor of resistant S. aureus strains. So far, however, hardly any inhibitors of aureolysin are known. Within the scope of the project, therefore, the first inhibitors are to be identified by means of focused screening. In the longer term, these first inhibitors should serve as lead structures to develop therapeutically applicable active substances.

The project "Screening to identify aureolysin inhibitors as novel pathoblockers for Staphylococcus aureus therapy (AureoScreen)" is supported by the state of Saxony-Anhalt with funding from the European Regional Development Fund (ERDF).

In the context of drug development, despite enormous progress in computer-aided prediction of various parameters of drug candidates, one still has to rely on investigating as wide a variety of chemically diverse molecules as possible. This usually involves adding different substituents to a constant basic structure in order to investigate their influence on the activity of the compounds, but also their toxicity or pharmacokinetics. This requires a relatively large number of different derivatives, since even small chemical differences can have a major impact on the properties mentioned. Such compound libraries typically contain several dozen compounds, but can also grow to several hundred derivatives on an industrial scale. In order to enable a broad chemical variability, the so-called flow-chemistry is to be established within the scope of the project. This will make it possible to produce a large number of compounds simply and quickly in flow-through microreactors. This state-of-the-art technology will be established in a joint project with PerioTrap Pharmaceuticals GmbH. Basic scaffolds developed there will be further derivatized at the Fraunhofer IZI Department of Drug Design and Target Validation in order to advance the development of drug candidates.

The project, which started on December 7, 2020, will run until July 31, 2022, and is funded by the German Federal State of Saxony-Anhalt with money from the European Regional Development Fund (ERDF).

Project coordination: Kathrin Tan.