Site-selective functionalisation of peptides and proteins via free-radical-induced dechalcogenation

通过自由基诱导的脱硫作用对肽和蛋白质进行位点选择性功能化

• 批准号: EP/S028323/1
• 负责人: Nicholas Mitchell
• 金额: $ 54.58万
• 依托单位: University of Nottingham
• 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%2FS028323%2F1
• 关键词: Site; selective; functionalisation; peptides; proteins

The development of chemistry that enables researchers to decorate proteins at defined positions with a range of functional molecular 'tags' has the potential to generate significant scientific impact. The application of such techniques to the modification of protein-based 'biologic' drugs, a class that currently dominates the pharmaceutical market, facilitates the development of more effective treatments for disease. Within the context of fundamental science, the preparation of proteins that carry naturally occurring modifications provides tools to interrogate biological pathways and enable a greater understanding of cellular biochemistry. As a result, bioconjugate techniques are used routinely in academic and industrial labs across the world. This proposal describes the development of a novel and versatile approach to protein functionalisation that presents advances over current methods.Due to the characteristic chemical properties of proteins, synthetic methods that facilitate modification of these biological molecules must operate under a specific set of conditions. Successful bioconjugation reactions proceed in water at ambient temperature, afford high yield at low concentrations and demonstrate selectivity for one of the 21 naturally occurring (canonical) amino acid residues. Reactions that follow this template enable modification of a target protein without degradation of the amino acid sequence or the formation of undesired by-products. With these aspects in mind, we have developed a novel, efficient and selective reaction that can be tuned to target two natural amino acids; cysteine and selenocysteine. The method is rapid, quantitative and sustainable, proceeding under conditions ideal for protein chemistry. The protocol requires no precious metal catalyst or costly/unstable reagents and is operationally simple, allowing application across scientific disciplines to maximise impact within the chemical and biological sciences. This New Investigator Award will enable us to establish a multidisciplinary team focused on the development and application of our new synthetic platform. It is envisaged that a broad range of functionality could be installed into a protein of interest using this approach; the inclusion of contrast agents for medical imaging, drug-conjugates for therapy and reactive tags or natural protein modifications to facilitate the investigation of complex biological processes will be evaluated. Proteins modified with chemical groups that will enable further investigation of protein degradation and tools to target, image and treat highly invasive forms of cancer will also be delivered within the remit of this project. Furthermore, this collaboration will enable us to establish a base of expertise, technology, and training in protein bioconjugation within the School of Chemistry, University of Nottingham.The development of new, versatile chemistry that can be applied to install a range of functional groups into a protein, to suit many specific applications, would be a powerful addition to the methodology currently available to researchers.

化学的发展，使研究人员能够装饰蛋白质在定义的位置与一系列功能分子的“标签”有可能产生重大的科学影响。将这些技术应用于基于蛋白质的“生物”药物的修饰，这是目前主导制药市场的一类药物，有助于开发更有效的疾病治疗方法。在基础科学的背景下，携带天然修饰的蛋白质的制备提供了询问生物途径的工具，并使人们能够更好地理解细胞生物化学。因此，生物缀合物技术在世界各地的学术和工业实验室中被常规使用。该提案描述了一种新的和多功能的蛋白质功能化方法的发展，该方法比现有方法具有进步性。由于蛋白质的特征化学性质，促进这些生物分子修饰的合成方法必须在特定条件下操作。成功的生物缀合反应在环境温度下在水中进行，在低浓度下提供高产率，并证明对21个天然存在的（典型的）氨基酸残基之一的选择性。遵循该模板的反应能够修饰靶蛋白而不降解氨基酸序列或形成不期望的副产物。考虑到这些方面，我们已经开发出一种新型的，高效的和选择性的反应，可以调整到目标两种天然氨基酸;半胱氨酸和硒代半胱氨酸。该方法是快速，定量和可持续的，在蛋白质化学的理想条件下进行。该协议不需要贵金属催化剂或昂贵/不稳定的试剂，操作简单，允许跨学科应用，以最大限度地提高化学和生物科学的影响。这个新的研究者奖将使我们能够建立一个多学科的团队，专注于我们新的合成平台的开发和应用。设想使用这种方法可以将广泛的功能安装到感兴趣的蛋白质中;将评估用于医学成像的造影剂、用于治疗的药物缀合物和反应性标签或天然蛋白质修饰以促进复杂生物过程的研究。用化学基团修饰的蛋白质，将使进一步研究蛋白质降解和工具的目标，成像和治疗高度侵入性形式的癌症也将在该项目的职权范围内提供。此外，此次合作将使我们能够在诺丁汉大学化学学院建立蛋白质生物缀合的专业知识、技术和培训基础。开发新的、多功能的化学方法，可以应用于将一系列官能团安装到蛋白质中，以适应许多特定的应用，将是对研究人员目前可用方法的有力补充。

项目成果

The Chemical Synthesis of Site-Specifically Modified Proteins Via Diselenide-Selenoester Ligation.

通过二硒化物-硒酯连接化学合成位点特异性修饰的蛋白质。

• DOI: 10.1007/978-1-0716-1617-8_18
• 发表时间: 2021
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Griffiths RC

Chemoselective Late-Stage Functionalization of Peptides via Photocatalytic C2-Alkylation of Tryptophan.

• DOI: 10.1021/acs.orglett.3c01795
• 发表时间: 2023-07-28
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Lee, Joanna C.;Cuthbertson, James D.;Mitchell, Nicholas J.
• 通讯作者: Mitchell, Nicholas J.

Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation.

• DOI: 10.1002/anie.202006260
• 发表时间: 2020-12-21
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Griffiths RC;Smith FR;Long JE;Williams HEL;Layfield R;Mitchell NJ
• 通讯作者: Mitchell NJ