Functional proteomics covalent inhibitors

Activity-based protein profiling (ABPP) is a chemical proteomic strategy in which active-site-directed covalent probes are used to profile the functional states of enzymes in complex proteomes. Activity-based probes (ABPs) can distinguish active enzymes from their inactive zymogens or inhibitor-bound forms. They contain a reactive group intended to modify enzyme active sites covalently and a reporter group (typically rhodamine or biotin) that assists in detection and identification of protein targets. 

Of the approaches listed above the last two (chemical proteomics and ABPP) are currently receiving the most interest and have complementary fields of applications. The affinity-based approach is perfectly suitable for reversible inhibitors, but is limited to quite strong binders. The focus of this chapter will be on the other of these two approaches, namely the activity-based approach to natural product identification. An essential requirement for this approach is that the natural product of investigation contains a reactive functional group that reacts with the protein target, forming a covalent bond. Fortunately, a considerable number of natural products contain such reactive groups [19]. Mostly, electrophilic moieties such as epoxides, Michael acceptors, disulfides, lactones, (3-lactams, quinones, etc. can be found. 

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