Tetra-(Polyfluoroaryl)-Porphyrin Templated Multicyclic Peptides: Novel, Functional and Responsive Scaffolds for Miniaturised Biosensors

四（多氟芳基）-卟啉模板多环肽：用于小型生物传感器的新型功能性响应支架

• 批准号: EP/R020299/1
• 负责人: Christopher Coxon
• 金额: $ 12.82万
• 依托单位: Liverpool John Moores University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FR020299%2F1
• 关键词: Tetra; Polyfluoroaryl; Porphyrin; Templated; Multicyclic

This First Grant will help to establish a new multidisciplinary 'chemical biology' team within the School of Pharmacy and Biomolecular Sciences at Liverpool John Moores University, UK, focused on using peptide and fluorine chemistry to interrogate biological problems e.g. enzyme mechanisms and disease diagnosis. Individuals are increasingly interested in knowing more about their health and ways to improve it through changes in diet or exercise, with tests available to determine the risk of developing a disease. Early detection of abnormalities in a sample (e.g. blood), can help diagnose diseases; however, patients are often not aware they are ill or at risk, which results in late diagnosis and treatment. Developing new technologies to allow early diagnosis and screen people for the invisible tell-tale signs of disease is, therefore, important as this will impact on a) health-screening services which are becoming a rapidly growing business worldwide, and b) for the NHS to reduce the cost of treatment and to help people live longer, healthier lives in the UK.Our immune system produces specific antibodies during disease, which can also be used to diagnose disease in lab tests. However, antibodies outside the body do not survive long, especially in warm environments. This makes testing unstable, expensive and requires chemicals to visualise the disease-causing molecule or organism. This creates transport and storage problems for testing kits, especially in the developing world, where testing for Ebola and Zika viruses (amongst others) and drug-resistance bacteria are a concern.New chemistry approaches have started to be developed, which make 'miniature antibodies' that will fluoresce a different colour when they find the disease-causing agent. Miniaturised antibodies, called multicyclic peptides are a significant advance over existing technologies, since they are: a) more stable to temperature and bodily fluids (last longer), b) 100-times smaller than antibodies (can get places that antibodies can't reach), c) cheaper to manufacture, d) conceptually designable to target any cause of disease, e) will not require additional chemicals to visualise the cause; f) the same shape as antibodies and made from the same building blocks, and so, look the same to e.g. bacteria.The project will:a) First make a group of peptides, which will share some of the same important features of an antibody for recognising disease-causing agents. Advantageously, these can be purposely designed and made rapidly compared with producing antibodies. However, at this stage, they are not the correct shape to recognise a 'target'.b) Optimise methods to attach these to a fluorescent 'template' (polyfluoroaryl-porphyrin) to hold it in the correct shape to appear to be the same as a much larger and more complex antibody. c) Finally, we will measure properties of the 'miniature antibodies', including how bright it fluoresces under UV light, how long it survives e.g. in blood or at higher temperature, and use techniques to see what shape it is i.e. how similar it is to an antibody. Through partnering with a UK biotechnology company, we will conduct some preliminary work to understand how these can be used to detect, for example, antibiotic-resistant 'superbugs' or the Clostridium difficile toxin - a major cause of hospital-acquired illness.In future, we envisage that these new miniature antibodies will be used in testing kits that can be used for health screening at home, in the developing world, hospitals and in research labs around the world.

第一笔拨款将帮助英国利物浦约翰摩尔大学药学与生物分子科学学院建立一个新的多学科“化学生物学”团队，重点关注使用肽和氟化学来探究生物学问题，例如酶机制和疾病诊断。人们越来越有兴趣了解更多关于他们的健康和如何通过改变饮食或锻炼来改善健康，并通过测试来确定患疾病的风险。早期检测样本（例如血液）中的异常可以帮助诊断疾病;然而，患者通常不知道他们生病或处于危险之中，这导致诊断和治疗延迟。因此，开发新技术以允许早期诊断和筛查人们看不见的疾病迹象是重要的，因为这将影响a）健康筛查服务，该服务正在成为全球快速增长的业务，以及B）NHS降低治疗成本并帮助人们在英国活得更长，更健康。我们的免疫系统在疾病期间产生特异性抗体，它也可以在实验室测试中用于诊断疾病。然而，体外的抗体不能存活很长时间，特别是在温暖的环境中。这使得测试不稳定，昂贵，并需要化学物质来可视化致病分子或有机体。这给检测试剂盒带来了运输和储存问题，尤其是在发展中国家，埃博拉病毒和寨卡病毒（以及其他病毒）以及耐药性细菌的检测是一个问题。新的化学方法已经开始开发，这种方法可以制造“微型抗体”，当它们发现致病因子时，会发出不同颜色的荧光。被称为多环肽的微型化抗体是现有技术的重大进步，因为它们：a）对温度和体液更稳定（持续时间更长），B）比抗体小100倍（可以到达抗体无法到达的地方），c）制造成本更低，d）概念上可设计为针对任何疾病原因，e）不需要额外的化学物质来可视化原因; f）与抗体形状相同，并且由相同的构建模块制成，因此，对例如细菌来说看起来相同。该项目将：a）首先制造一组肽，这些肽将具有与抗体相同的一些重要特征，用于识别致病因子。有利的是，与产生抗体相比，这些可以被有目的地设计和快速制备。然而，在这个阶段，它们不是正确的形状来识别“目标”。B）优化方法以将它们连接到荧光“模板”（多氟芳基-卟啉）上，以使其保持正确的形状，从而看起来与更大和更复杂的抗体相同。c）最后，我们将测量“微型抗体”的特性，包括它在紫外光下发出的荧光有多亮，它在血液或更高温度下存活多久，并使用技术来观察它的形状，即它与抗体的相似程度。通过与一家英国生物技术公司合作，我们将开展一些初步工作，以了解如何将这些抗体用于检测耐药性“超级细菌”或艰难梭菌毒素--这是医院获得性疾病的主要原因。未来，我们设想这些新型微型抗体将用于检测试剂盒，可用于家庭、发展中国家、在世界各地的医院和研究实验室里。

项目成果

Peptide-Tetrapyrrole Supramolecular Self-Assemblies: State of the Art.

• DOI: 10.3390/molecules26030693
• 发表时间: 2021-01-28
• 期刊: Molecules (Basel, Switzerland)
• 作者: Dognini P;Coxon CR;Alves WA;Giuntini F
• 通讯作者: Giuntini F

Perfluoroaryl and Perfluoroheteroaryl Reagents as Emerging New Tools for Peptide Synthesis, Modification and Bioconjugation.

• DOI: 10.1002/chem.202103305
• 发表时间: 2022-02-01
• 期刊: CHEMISTRY-A EUROPEAN JOURNAL
• 影响因子: 4.3
• 作者: Brittain, William D. G.;Coxon, Christopher R.
• 通讯作者: Coxon, Christopher R.

Frontispiece: Perfluoroaryl and Perfluoroheteroaryl Reagents as Emerging New Tools for Peptide Synthesis, Modification and Bioconjugation

卷首文章：全氟芳基和全氟杂芳基试剂作为肽合成、修饰和生物共轭的新兴工具

• DOI: 10.1002/chem.202280762
• 发表时间: 2022
• 期刊: Chemistry - A European Journal
• 作者: Brittain W

Probing Peptidylprolyl Bond cis/trans Status Using Distal 19 F NMR Reporters.

使用远端 19 F NMR 报告仪探测肽基脯氨酰键顺式/反式状态。

• DOI: 10.1002/chem.202203017
• 发表时间: 2023
• 期刊: Chemistry (Weinheim an der Bergstrasse, Germany)
• 作者: Killoran PM

Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing.

• DOI: 10.1002/chem.201804163
• 发表时间: 2018-11
• 期刊: Chemistry
• 作者: S. Verhoork;Claire E. Jennings;Neshat Rozatian;J. Reeks;Jieman Meng;Emily K. Corlett;Fazila Bunglawala;M. Noble;Andrew G. Leach;Christopher R. Coxon