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Publication 131  

  1. Covalent inhibitors: an opportunity for rational target selectivity
    R. Lagoutte, R. Patouret, N. Winssinger
    Curr. Opin. Chem. Biol. 2017, 39, 54-63

There is a resurging interest in compounds that engage their target through covalent interactions. Cysteine’s thiol is endowed with enhanced reactivity, making it the nucleophile of choice for covalent engagement with a ligand aligning an electrophilic trap with a cysteine residue in a target of interest. The paucity of cysteine in the proteome coupled to the fact that closely related proteins do not necessarily share a given cysteine residue enable a level of unprecedented rational target selectivity. The recent demonstration that a lysine’s amine can also be engaged covalently with a mild electrophile extends the potential of covalent inhibitors. The growing database of protein structures facilitates the discovery of covalent inhibitors while the advent of proteomic technologies enables a finer resolution in the selectivity of covalently engaged proteins. Here, we discuss recent examples of discovery and design of covalent inhibitors.

DOI: 10.1016/j.cbpa.2017.05.008 

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