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Modify-catch-release-repeat: Reversible bioconjugations for controlled release of small molecules from antibodies and their fragments

修改-捕获-释放-重复：可逆生物缀合，用于从抗体及其片段中控制释放小分子

基本信息

批准号：
EP/S013741/1
负责人：
Martin Fascione
金额：
$ 52.86万
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：
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%2FS013741%2F1
关键词：
Modify catch release repeat Reversible

项目摘要

Protein based drugs are revolutionising the precision treatment of cancer and other complex disease, and often consist of large macromolecules like antibody proteins, that can act when they are attached to a small molecule drug. An example of this new type of "biologic" medicine are antibody-drug conjugates (ADCs) which are leading the way in personalised chemotherapy treatments for cancer, with >100 such drugs in clinical trials or pharmaceutical pipeline all over the world. However, the bottleneck in progressing this field further is not the antibodies, or the drugs available, but the chemistry required to stitch these two components together, and developments in this area of chemistry lag decades behind other branches of small molecule organic chemistry. A major challenge in the construction of these medicines is the difficulty in building linkages between small molecules and proteins that are stable enough to survive in the body during circulation, but then also labile enough to break-down inside the targeted cancer cells, which is required for full activity. An ideal solution to this problem would be the development of a reversible linkage which is stable until exposed to an external small molecule trigger which would then catalyse break-down of the linkage. A reversible method such as this would also have a wide ranging cost-effective application in the in vitro purification of therapeutic proteins, including 'fishing' antibodies and other proteins out of complex mixtures before preparing them for clinical applications- akin to a 'catch-and-release' strategy. Nature makes abundant use of similar reversible modifications including glycosylation, phosphorylation, acetylation and lipidation, which all act as dynamic switches, as yet however our ability as chemists to emulate these enzymatic modifications pales in comparison. In this project we will take inspiration from Nature and address this limitation by developing a new chemical method which will allow the reversible attachment of small molecules to protein scaffolds. We ultimately aim to deploy this method, both in vitro and in vivo, for the tandem purification and modification of antibody fragments, and the subsequent controlled release of a drug inside bladder cancer cells- a disease which results in 15 deaths every day in the UK. To achieve this goal we will assemble a team with multidisciplinary expertise at the University of York, working at the interface of small molecule and protein chemistry, glycoscience, bladder cancer cell biology, and antibody production. We will also establish a collaborative relationship with a UK biotech specialising in the development of antibody-drug conjugates (ADCs). This unique combination will facilitate the development of a novel reversible protein bioconjugation platform method, which will be used to overcome the challenges presented in the production of these 21st century therapeutics.

基于蛋白质的药物正在彻底改变癌症和其他复杂疾病的精确治疗，它们通常由像抗体蛋白这样的大分子组成，当它们附着在小分子药物上时就可以起作用。这种新型“生物”药物的一个例子是抗体-药物偶联物（adc），它在癌症的个性化化疗治疗中处于领先地位，全世界有100多种此类药物正在临床试验或制药管道中。然而，这一领域进一步发展的瓶颈不是抗体，也不是可用的药物，而是将这两种成分结合在一起所需的化学物质，而且这一化学领域的发展落后于小分子有机化学的其他分支几十年。构建这些药物的一个主要挑战是很难在小分子和蛋白质之间建立联系，这些联系足够稳定，可以在体内循环过程中存活，但同时也足够不稳定，可以在目标癌细胞内分解，这是充分发挥活性所必需的。这个问题的理想解决方案是开发一种可逆的链接，这种链接在暴露于外部小分子触发之前是稳定的，然后催化链接的破坏。像这样的可逆方法在治疗性蛋白质的体外纯化方面也具有广泛的成本效益应用，包括在准备用于临床应用之前从复杂的混合物中“捞出”抗体和其他蛋白质——类似于“捕获和释放”策略。自然界大量使用类似的可逆修饰，包括糖基化、磷酸化、乙酰化和脂化，它们都充当动态开关，然而，作为化学家，我们模拟这些酶修饰的能力相比之下相形见绌。在这个项目中，我们将从大自然中获得灵感，并通过开发一种新的化学方法来解决这一限制，这种方法将允许小分子可逆地附着在蛋白质支架上。我们的最终目标是在体外和体内使用这种方法，用于抗体片段的串联纯化和修饰，以及随后在膀胱癌细胞内控制药物的释放——这种疾病在英国每天导致15人死亡。为了实现这一目标，我们将在约克大学组建一支具有多学科专业知识的团队，在小分子和蛋白质化学、糖科学、膀胱癌细胞生物学和抗体生产的界面上工作。我们还将与一家专门从事抗体-药物偶联物（adc）开发的英国生物技术公司建立合作关系。这种独特的组合将促进一种新的可逆蛋白质生物偶联平台方法的发展，该方法将用于克服这些21世纪治疗药物生产中提出的挑战。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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

Bump-and-hole engineering of human polypeptide N-acetylgalactosamine transferases to dissect their protein substrates and glycosylation sites in cells.

DOI：
10.1016/j.xpro.2022.101974
发表时间：
2023-03-17
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Calle, Beatriz;Gonzalez-Rodriguez, Edgar;Mahoney, Keira E.;Cioce, Anna;Bineva-Todd, Ganka;Tastan, Omur Y.;Roustan, Chloe;Flynn, Helen;Malaker, Stacy A.;Schumann, Benjamin
通讯作者：
Schumann, Benjamin

Correction: Rapid sodium periodate cleavage of an unnatural amino acid enables unmasking of a highly reactive a-oxo aldehyde for protein bioconjugation

更正：高碘酸钠快速裂解非天然氨基酸，能够揭示用于蛋白质生物共轭的高活性 a-oxo 醛