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Bio-organic chemistry and Chemical biology

After the elucidation of the genomes of several organisms the field of proteomics now faces the task to identify and characterize the functions of the genome products (i.e. the expressed proteins in a cell, tissue or organism). Most proteomic experiments deal with global monitoring of protein abundance, which is not necessarily related to function and activity. Proteases are perhaps the best example of this discrepancy between activity and abundance. Virtually all proteases are synthesized as inactive zymogens and need to undergo an activation step. Once active, their function is tightly regulated by post-translational processes. To uncover the functions of proteases it is therefore desirable to specifically monitor the dynamic levels of their activities.
   Chemical or activity-based proteomics uses small molecule probes to specifically modify small subsets of active enzymes. This allows to focus on the active subpartition of proteins that are responsible for biochemical transformations.
   The small molecules used in chemical proteomics are termed activity-based probes (ABPs) and consist of three basic elements (see Figure 1): a reactive warhead that is able to covelently modify an enzyme’s active site, a tag that facilitates enrichment and/or visualization of the enzyme activity, and a spacer that both separates the two previous elements and influences the selectivity of the reactive warhead.

ABP
Figure 1: the anatomy of an activity-based probe.

One of the major research areas of our laboratory is the development of new activity-based probes. We make use of both solution and solid-phase chemistries to create straightforward syntheses that can easily be carried out and facilitate optimization for different protease targets. With these probes we aim to uncover regulation mechanisms of protease activity and uncover proteases as diagnostic markers and targets for therapeutic intervention.

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The latest paper from our lab, a review on Activity-based probes for the study of proteases in ChemMedChem >>

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The laboratory website at the Technical University Munich.

www.stevenverhelst.nl


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