Dynamic Chemical Probes with New Modes of Action to Deconvolute Therapeutic Protein-Protein Interaction Networks

该项目将制定一项战略，以开发和评估共价化学探针的“工具包”，以抑制在多种疾病中至关重要的治疗相关蛋白质-蛋白质相互作用(PPI)。这些试剂将由构象预先组织的阿尔法螺旋多肽模拟支架组成，这些支架配备了亲电弹头。支架可被功能化以提供给定蛋白质表面的互补接触，并在目标蛋白质表面上显示的模拟和亲核氨基酸侧链(N-和O-中心)之间形成共价键。这些试剂将被设计为通过动态或不可逆机制结合，具有高亲和力相互作用的潜力。它们作为调节PPI的一般方法的效用将通过与罗布·尤因和保罗·斯基普博士合作的蛋白质组工作流程，对照治疗上重要的靶点进行评估。

This project will develop a strategy for the development and evaluation of a 'toolkit' of covalent chemical probes for the inhibition of therapeutically-relevant protein-protein interactions (PPIs) that are critical in myriad diseases. These agents will consist of conformationally-preorganised alpha helical peptidomimetic scaffolds armed with electrophilic warheads. The scaffolds may be functionalised to provide complementary contacts for a given protein surface and to form a covalent bond between the mimetic and a nucleophilic amino acid side-chains (N- and O-centred) displayed on the surface of the target protein. The agents will be designed to bind via either a dynamic or irreversible mechanism with the potential for a high-affinity interaction. Their utility as a general method for mediating PPIs will be evaluated against therapeutically important targets using proteomic workflows in collaboration with Drs Rob Ewing and Paul Skipp.