Supramolecular Designs on Dynamic Covalent Protein Recognition

动态共价蛋白识别的超分子设计

• 批准号: EP/S028722/1
• 负责人: Sam Thompson
• 金额: $ 31.2万
• 依托单位: University of Southampton
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FS028722%2F1
• 关键词: Supramolecular; Designs; Dynamic; Covalent; Protein

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.

该项目描述了一种共价化学探针“工具包”的开发策略，用于抑制治疗相关蛋白质-蛋白质相互作用（PPIs），这在无数疾病中至关重要。该项目将开发经过精心设计的分子，采用一种特定的形状，这样它们就可以模仿另一种蛋白质表面的识别，与蛋白质结合，然后对蛋白质进行修饰，在特定位置添加一组新的原子。模拟分子将是可配置的，以选择性地识别不同的蛋白质表面所需。修饰将由含有硼“受体”的模拟分子上的反应基团进行，它们将被靶向修饰所讨论的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“工具箱”（模拟物）代表了一种针对非酶蛋白的全新方法。这些试剂可以通过动态或不可逆的共价机制进行调节。它们作为介导治疗相关蛋白-蛋白相互作用（PPIs）的一般方法的效用将使用特定的蛋白质系统（Hif1alpha/p300）进行评估，该系统在缺氧反应和许多实体肿瘤癌症中很重要。除了用作PPIs的干扰物之外，该方法在以下方面具有很大的前景：(i)介导蛋白质错误折叠，（ii）位点特异性蛋白质标记，（iii）生物成像，（iv）肿瘤靶向，(v)治疗耗散，以及（vi）蛋白质定位。

项目成果

Single-molecule nanopore dielectrophoretic trapping of a-synuclein with lipid membranes

脂膜单分子纳米孔介电泳捕获α-突触核蛋白

• DOI: 10.1016/j.xcrp.2022.101243
• 发表时间: 2023
• 期刊: Cell Reports Physical Science
• 影响因子: 8.9
• 作者: Wu J