Lagoutte Roman, Patouret Remi, Winssinger Nicolas
Faculty of Science, Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest Ansermet, CH-1205 Geneva, Switzerland.
Faculty of Science, Department of Organic Chemistry, NCCR Chemical Biology, University of Geneva, 30 quai Ernest Ansermet, CH-1205 Geneva, Switzerland.
Curr Opin Chem Biol. 2017 Aug;39:54-63. doi: 10.1016/j.cbpa.2017.05.008. Epub 2017 Jun 10.
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.
人们对通过共价相互作用作用于靶点的化合物的兴趣正在复苏。半胱氨酸的硫醇具有增强的反应活性，使其成为与配体进行共价结合的亲核试剂的首选，该配体将亲电陷阱与感兴趣靶点中的半胱氨酸残基对齐。蛋白质组中半胱氨酸的稀缺，再加上密切相关的蛋白质不一定共享特定的半胱氨酸残基，使得能够实现前所未有的合理靶点选择性水平。最近的研究表明，赖氨酸的胺也可以与温和的亲电试剂发生共价结合，这扩展了共价抑制剂的潜力。不断增长的蛋白质结构数据库促进了共价抑制剂的发现，而蛋白质组学技术的出现使得共价结合蛋白质的选择性能够得到更精细的解析。在此，我们讨论共价抑制剂发现和设计的近期实例。
