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The synthesis and application of novel activity-based probes for the visualization of cysteine proteases.
Book - Dissertation
Proteases are enzymes that cut proteins by catalyzing the hydrolysis of the peptide bond. They can be found in almost every organism, where they play a part in many biological pathways and are involved in various human diseases. For example, cathepsins, a class of cysteine proteases, are upregulated in various cancers, making them an interesting biomarker and suitable targets for tumor labeling. An excellent method for the detection of proteases is the use of activity-based probes (ABP). These probes allow visualization in biological settings as well as detailed biochemical analysis after imaging. The problem with the existing ABPs is that they are commonly synthesized as optical probes, making them less attractive for application in in vivo models. In my PhD, I will propose a novel method for visualizing active cysteine proteases using F-MRI. I will design and synthesize ABPs targeting cathepsins that will be visualized by F-NMR upon reaction with their target. Next, I will test their efficiency in a novel multi-cellular 3D system using F-NMR. After successful in vitro experiments, I will move on to an in vivo tumor model. To prove the multi-applicability of this approach, I will also design probes that target caspase. Many current cancer treatments rely on the induction of apoptosis. Since activation of caspases is a downstream process in apoptosis, it can be used to visualize the efficacy of these treatments. These probes will be used to test the efficacy of cancer treatments in cell lines and, if successful, in a mouse model.