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Tandem organocatalysis for the bi-functional modification of proteins

蛋白质双功能修饰的串联有机催化

基本信息

批准号：
EP/P030653/1
负责人：
Martin Fascione
金额：
$ 12.82万
依托单位：
University of York
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FP030653%2F1
关键词：
Tandem organocatalysis bi functional modification

项目摘要

This first grant will help to establish a new multidisciplinary 'chemical biology' team within the Department of Chemistry at University of York, UK, focused on performing synthetic chemistry on proteins. The ability to selectively modify and subsequently harness and even tune the biological properties of macromolecules like proteins and enzymes using synthetic chemistry has heralded a revolution in the worldwide pharmaceutical industry, and the associated field of chemical biology. For example; seven out of the top ten selling drugs worldwide are now 'biologics' (i.e. complex proteins, macromolecule combinations, often decorated with small organic moieties), which are constructed using rapidly developing "bioconjugation" methods, as opposed to only a decade ago when this list was made up solely of small molecule drugs. Increasingly proteins are also modified by chemical ligation with small molecule tags with function enhancing properties for use in both industry and academia. Examples include conjugation of compounds such as polyethyleneglycol (PEG) to improve the half-life of probes and therapeutics; attachment of fluorescent and spectroscopic probes for in vivo imaging and tracking of macromolecules; and construction of proteins bearing 'mimics' of native in vivo modifications, which have played a role in the development of lead compounds for treatment of tropical parasitic diseases. Despite the obvious utility of these constructs however, there are limiting technical challenges facing chemists focusing on the 'bioconjugation' of macro/small molecule fusions, most notably the strive to achieve chemoselectivity- that is the ability to modify only one specific site on a protein backbone selectively in the presence of many others. This struggle is compounded by the fact that these new age synthetic challenges cannot be approached in the same way as the synthetic organic community has approached the synthesis of small molecules and natural products in the past- primarily using chemistry pioneered in organic solvents in a fumehood, often at elevated temperatures, at high concentration and in the absence of detrimental contaminants. Instead, bioconjugations using proteins must often take place in water, at neutral pH, at dilute concentration, and in the presence of a smorgasbord of chemical functionality present within the amino acid backbone of the protein itself. It is a necessity therefore, that new methods for the chemical modification of proteins which take place under these biologically compatible conditions continue to be developed in order to meet the ever-increasing demand for proteins with modulated function and utility. In this project we aim to contribute to this innovation drive for new protein bioconjugation methods, while also establishing a new paradigm for bioconjugation by redefining the chemistry of an unfashionable and oft forsaken protein motif and subsequently developing a new tandem strategy for the chemical modification of proteins using chemistry enabled and under the control of small molecule catalysts. We will then showcase the utility of this method in a collaborative chemical biology study of direct therapeutic relevance.

这笔第一笔赠款将有助于在英国约克大学化学系内建立一个新的多学科“化学生物学”团队，专注于对蛋白质进行合成化学。使用合成化学选择性地修饰并随后利用甚至调整蛋白质和酶等大分子的生物学特性的能力，预示着全球制药行业以及相关化学生物学领域的一场革命。例如，全球最畅销的十种药物中，有七种现在是生物制剂(即复杂的蛋白质、大分子组合，通常装饰着小的有机部分)，它们是使用快速发展的“生物偶联”方法构建的，而十年前，这份清单仅由小分子药物组成。越来越多的蛋白质也通过与小分子标签的化学连接来修饰，这些小分子标签具有增强功能的特性，用于工业和学术界。例如，聚乙二醇类化合物的偶联以改善探针和治疗药物的半衰期；连接荧光和光谱探针用于体内成像和跟踪大分子；以及构建带有天然体内修饰的蛋白质，这在开发用于治疗热带寄生虫病的先导化合物方面发挥了作用。然而，尽管这些结构有明显的效用，但化学家们面临着有限的技术挑战，他们专注于大分子/小分子融合的“生物结合”，最突出的是努力实现化学选择性--即在有许多其他位点存在的情况下，只选择性地修饰蛋白质骨架上的一个特定位点。这一斗争因以下事实而变得更加复杂：这些新时代的合成挑战不能像过去合成有机社区处理小分子和天然产品的合成那样--主要使用在通风、通常在高温、高浓度和没有有害污染物的情况下在有机溶剂中开创的化学。相反，使用蛋白质的生物结合必须经常在水中、在中性pH、稀释浓度下进行，并在蛋白质本身的氨基酸骨架中存在一系列化学功能的情况下进行。因此，有必要继续开发在这些生物相容条件下对蛋白质进行化学修饰的新方法，以满足日益增长的对具有调节功能和用途的蛋白质的需求。在这个项目中，我们的目标是为新的蛋白质生物结合方法的创新驱动做出贡献，同时通过重新定义一个不流行的和经常被遗弃的蛋白质基序的化学，并随后开发一种新的串联策略，使用化学启用并在小分子催化剂的控制下对蛋白质进行化学修饰，从而建立一个新的生物结合的范例。然后，我们将在直接治疗相关的协作化学生物学研究中展示这种方法的实用性。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Aldehyde-Mediated Protein-to-Surface Tethering via Controlled Diazonium Electrode Functionalization Using Protected Hydroxylamines.

使用受保护的羟胺通过受控重氮电极功能化实现醛介导的蛋白质与表面束缚。

DOI：
10.1021/acs.langmuir.9b01254
发表时间：
2020
期刊：
the ACS journal of surfaces and colloids
影响因子：
0
作者：
Yates ND
通讯作者：
Yates ND

Biocatalytic Transfer of Pseudaminic Acid (Pse5Ac7Ac) Using Promiscuous Sialyltransferases in a Chemoenzymatic Approach to Pse5Ac7Ac-Containing Glycosides

DOI：
10.1021/acscatal.0c02189
发表时间：
2020-09-04
期刊：
ACS CATALYSIS
影响因子：
12.9
作者：
Flack, Emily K. P.;Chidwick, Harriet S.;Fascione, Martin A.
通讯作者：
Fascione, Martin A.

The characterisation of a galactokinase from Streptomyces coelicolor.

DOI：
10.1016/j.carres.2018.12.005
发表时间：
2019-01
期刊：
Carbohydrate research
影响因子：
3.1
作者：
T. Keenan;Rhys Mills;E. Pocock;Darshita Budhadev;F. Parmeggiani;S. Flitsch;M. Fascione
通讯作者：
T. Keenan;Rhys Mills;E. Pocock;Darshita Budhadev;F. Parmeggiani;S. Flitsch;M. Fascione

Site-selective C-C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations.

DOI：
10.1039/c8sc01617h
发表时间：
2018-07-07
期刊：
Chemical science
影响因子：
8.4
作者：
Spears RJ;Brabham RL;Budhadev D;Keenan T;McKenna S;Walton J;Brannigan JA;Brzozowski AM;Wilkinson AJ;Plevin M;Fascione MA
通讯作者：
Fascione MA

Reconstitution and optimisation of the biosynthesis of bacterial sugar pseudaminic acid (Pse5Ac7Ac) enables preparative enzymatic synthesis of CMP-Pse5Ac7Ac.