Rhomboid proteases occur in almost all organisms and are involved in various biological processes and diseases. They are therefore of interest as a starting point for new drugs that inhibit their activity. The Chemical Proteomics group is developing research methods with which they can observe the activity of rhomboid proteases. That way, the group has already identified new inhibitors for these enzymes and is currently working to optimise them. In addition, the inhibitors are further developed into activity-based probes, which can help to elucidate functional roles and biochemical mechanisms of these fascinating enzymes.
Another important aspect of the work in this project is the identification of the target proteins of low molecular weight drugs, so-called “small molecules”. Many of these small molecules bind specifically to certain enzymes and inhibit or activate them. In order to detect the enzymes that interact with the active substances, the Chemical Proteomics group also develops molecular tools: small molecule probes that are bound to a carrier such as resin and contain or imitate the active substance molecule. Thus, target proteins can be enriched from a sample. However, nonspecific bindings of other proteins to the carrier often falsify the result. The group therefore develops linkers that are attached between the carrier and the molecular probe and can be split by a chemical reaction so that the target proteins, which are bound to the probes, can be separated from unspecifically bound proteins. This step decreases “background noise” in mass spectrometric analyses by reducing the nonspecific signals. This can make the evaluation more difficult and distort the results.
For all these tasks, the group needs techniques for the production of new chemical components, such as protease inhibitors and activity-based probes. In order to make the manufacturing processes as simple as possible, the group uses methods that are based on solid phase synthesis. The advantage of these methods is that the manufacturing process can take place automatically or manually and allows a fast synthesis and optimisation of the molecular tools.