Supramolecular Designs on Dynamic Covalent Protein Recognition

该项目描述了一种战略，用于开发一种共价化学探针的“工具包”，用于抑制在无数疾病中至关重要的治疗相关的蛋白质-蛋白质相互作用(PPI)。该项目将开发经过精心设计的分子，采用特定的形状，使它们可以模仿一个蛋白质表面对另一个蛋白质表面的识别，结合到蛋白质上，然后对有问题的蛋白质进行修饰，在特定的位置添加一组新的原子。模拟分子将被配置为根据需要选择性地识别不同的蛋白质表面。这种修饰将由含有硼“受体”的模拟分子上的反应基团进行，它们的目标是修饰相关蛋白质上特定氨基酸的侧链--通常是含有氧或氮原子“供体”的氨基酸。这种化学探针(模拟物)的“工具包”代表了一种以非酶蛋白为靶标的全新方式。这些试剂将可以通过动态或不可逆的共价机制进行结合。它们作为调节与治疗相关的蛋白质-蛋白质相互作用(PPI)的一般方法的有效性将使用特定的蛋白质系统(Hif1pha/p300)进行评估，该蛋白质系统在缺氧反应和许多实体肿瘤癌症中非常重要。除了将它们用作PPI的干扰物外，该方法还有望：(I)介导蛋白质错误折叠，(Ii)位置特异性蛋白质标记，(Iii)生物成像，(Iv)肿瘤靶向，(V)治疗性消耗，和(Vi)蛋白质图谱。

This project describes a strategy for the development of a 'toolkit' of covalent chemical probes for the inhibition of therapeutically-relevant protein-protein interactions (PPIs) that are critical in myriad diseases. The project will develop molecules that have been carefully designed to adopt a particular shape such that they can mimic the recognition of one protein surface by another, bind to the protein, and then carry out a modification on the protein in question to add a new group of atoms to a particular site. The mimic molecules will be configurable to selectively recognise different protein surfaces as desired. The modification will be carried out by a reactive group on the mimic molecules containing a boron "acceptor" and they will be targeted to modify the side-chain of a specific amino acid on the protein in question - usually one containing an oxygen or nitrogen atom "donor". This 'toolkit' of chemical probes (the mimics) represents a fundamentally new way of targeting non-enzymatic proteins. The agents will be tuneable to bind via either a dynamic or irreversible covalent mechanism. Their utility as a general method for mediating therapeutically-relevant protein-protein interactions (PPIs) will be evaluated using a particular protein system (Hif1alpha/p300) that is important in the hypoxic response and in many solid-tumour cancers. Beyond their use as disruptors of PPIs the approach holds great promise for: (i) mediating protein misfolding, (ii) site-specific protein labelling, (iii) bio imaging, (iv) tumour targeting, (v) therapeutic depletion, and (vi) protein mapping.