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Within chemical biology, covalent chemical probes play an important role \u2013 they can be used to label proteins according to a certain trait, which include post-translational modifications (PTMs), an enzymatic activity or the affinity towards a drug. Synthetic chemistry allows the synthesis of broad-spectrum probes or probes with very specific reactivity. A variety of read-outs are possible through the use of different chemical handles (biotin, fluorophores, bioorthogonal functional groups). Identification of targets is possible by proteomics methods.<\/p>\n
Our laboratory develops and applies small molecule tools for peptidases (often referred to as proteases), with a focus on serine and cysteine proteases, and intramembrane proteases.<\/p>\n
Proteases and ABPs<\/strong> Proteases are generally translated as inactive zymogens and need proteolytic processing to become active. Once active, a variety of regulatory mechanisms exist to keep protease activity in check \u2013 for example, PTMs, the presence of endogenous inhibitors, and the degradation of proteases (Figure 1A). However, only the active protease species is able to convert a substate to a product, which leads to a downstream effect.<\/p>\n To specifically label the active form of proteases, we develop and use activity-based probes (ABPs \u2013 Figure 1B). These are often derived from electrophilic inhibitors that react in a mechanism-based manner with the active site machinery. This reaction leads to covalent attachment of a detection tag, which can be used for visualisation, analysis or enrichment of the active protease species. For their synthesis we make use of different solution and solid phase chemistries. The latter is preferred, since they can be easily carried out and facilitate optimisation for different protease targets.<\/p>\n
\nProteases are enzymes responsible for the cleavage of peptide bonds. They are not only involved in digestive processes and protein turnover, but also play a crucial role in regulatory processes, such as apoptosis, blood coagulation and antigen presentation. Therefore, it is not surprising that misregulation of proteases can lead to a wide variety of diseases.<\/p>\n