Development of new ligation systems for the preparation of peptide-drug conjugates

开发用于制备肽-药物缀合物的新型连接系统

• 批准号: 2480995
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2480995
• 关键词: Development; new; ligation; systems; preparation

the research questions the project is trying to address/the objectives of the projectAntibody-drug or peptide-drug conjugates (ADCs) are three-component therapeutics frequently used in oncology medicine which consist of a protein recognition motif, a linker, and a payload - typically a cytotoxic drug. Optimisation of each component to achieve biological activity is a major research question and requires design and analysis of targeting, uptake, release and pharmacological activities. This research project aims to target active compounds to a subset of immune cells known as monocytes. These conjugates have high activity/specificity and are active in cancer models, but the current preparation methods rely on use of synthetic proteins that are not sufficiently scalable for us to develop them further. The Butterworth group (University of Manchester) have developed peptide-drug conjugates that utilise a specific cytokine-receptor interaction to specifically target active compounds, and the Greaney group (University of Manchester) have developed metal-free ligation chemistry on simple small molecule systems that demonstrate exciting chemoselectivity and compatibility with aqueous conditions. This PhD project sets out an ambitious plan to unite the two approaches and define a new toolset for the construction of potent, selective ADCs on scale, and is supported by the biotechnology company LifeArc. ADCs are at the forefront of pharmaceutical industry research and are a key focus of many pharmaceutical companies in the UK.the approach that will be taken to answer these questions (what the student will actually be doing)We will develop two approaches to realise the synthesis of novel peptide-drug conjugates:1) Apply medicinal chemistry principles to the optimisation of amine donors for transglutaminase (an enzyme that facilitates conjugation), thus reducing the equivalents of this component required to achieve selective conjugation. Chemoenzymatic conjugation methods can proceed with high efficiency under biocompatible conditions, but typically require laborious syntheses of appropriately tagged linker-warhead combinations, limiting optimisation of the linker-payload component. 2) Examine novel ligation chemistries to broaden scope beyond alkyne/azide chemistry. The Smiles arylation chemistry developed in the Greaney lab works in water, and is efficient and reliable. Further, the components of the reaction are very bio-compatible, with sulfonamides being mainstays of medicinal chemistry prized for their metabolic stability, and alkynes being the archetypal click component having proven application in numerous chemical biology studies. The chemistry has the powerful feature of generating a fluorescent linkage, creating a functional readout for successful ligation and tracking of cellular uptake and distribution.the novel engineering and/or physical sciences content of the research (the science that places it within EPSRC's remit).The studentship will create an ambitious, cross-disciplinary research environment which sits within both the EPSRC remits of physical sciences and healthcare technologies, addressing the following areas: Catalysis, Chemical biology and biological chemistry, and synthetic chemistry.

抗体-药物或肽-药物偶联物（ADC）是肿瘤医学中常用的三组分治疗剂，其由蛋白质识别基序、接头和有效载荷（通常为细胞毒性药物）组成。优化每种组分以实现生物活性是一个主要的研究问题，需要设计和分析靶向、摄取、释放和药理活性。该研究项目旨在将活性化合物靶向称为单核细胞的免疫细胞亚群。这些缀合物具有高活性/特异性，并且在癌症模型中具有活性，但目前的制备方法依赖于使用合成蛋白质，这些合成蛋白质的规模不足以使我们进一步开发它们。巴特沃思小组（曼彻斯特大学）已经开发了肽-药物缀合物，其利用特异性的精氨酸-受体相互作用来特异性靶向活性化合物，并且Greaney小组（曼彻斯特大学）已经开发了在简单的小分子系统上的无金属连接化学，其表现出令人兴奋的化学选择性和与水性条件的相容性。这个博士项目提出了一个雄心勃勃的计划，将这两种方法结合起来，并定义了一个新的工具集，用于大规模构建有效的选择性ADC，并得到了生物技术公司LifeArc的支持。ADC处于制药行业研究的前沿，是英国许多制药公司的重点关注点。（学生实际要做的事情）我们将开发两种方法来实现新型肽-药物缀合物的合成：1）应用药物化学原理优化转氨酶的胺供体（一种促进缀合的酶），从而减少实现选择性缀合所需的该组分的当量。化学酶促缀合方法可以在生物相容性条件下高效进行，但通常需要费力地合成适当标记的接头-弹头组合，限制了接头-有效载荷组分的优化。2)研究新的连接化学，以扩大范围超出炔/叠氮化物化学。Greaney实验室开发的Smiles芳基化化学在水中工作，并且高效可靠。此外，反应的组分是非常生物相容的，磺胺类药物是药物化学的支柱，因其代谢稳定性而受到重视，炔类是原型点击组分，已在许多化学生物学研究中得到证实。该化学具有产生荧光连接的强大功能，为成功连接和跟踪细胞摄取和分布创建功能读数。该研究的新工程和/或物理科学内容（将其置于EPSRC职权范围内的科学）。该奖学金将创造一个雄心勃勃的，跨学科研究环境，它位于物理科学和医疗技术的EPSRC范围内，涉及以下领域：催化、化学生物学与生物化学、合成化学。