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.

该项目描述了开发共价化学探针“工具包”的策略，以抑制与治疗性相关的蛋白质 - 蛋白质相互作用（PPI），这对于多种疾病至关重要。该项目将开发经过精心设计的分子，以采用特定的形状，以便它们可以模仿另一个蛋白质表面的识别，并结合蛋白质，然后对所讨论的蛋白质进行修饰，以在特定位点添加一组新的原子。模拟分子将是可构型的，可根据需要选择性地识别不同的蛋白质表面。该修饰将由一个反应性基团在包含硼“受体”的模拟分子上进行，并且它们将被靶向用于修改所讨论蛋白质上特定氨基酸的侧链 - 通常一种含有氧或氮原子“供体”。这种化学探针的“工具包”（模拟物）代表了一种靶向非酶蛋白的新方法。代理将通过动态或不可逆的共价机制进行调谐以结合。它们作为介导与治疗相关的蛋白质 - 蛋白质相互作用（PPI）的一般方法将使用特定蛋白质系统（HIF1Alpha/p300）进行评估，该方法在低氧反应和许多固体群癌中都很重要。除了用作PPI的破坏者外，该方法对：（i）介导蛋白质错误折叠，（ii）特定位点特异性蛋白质标记，（iii）生物成像，（iv）肿瘤靶向，（v）治疗性耗竭和（vi）蛋白质映射。

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