Enabling first-in-class site-selective protein modification strategies beyond cysteine

本项目的核心目标是为蛋白质上各种氨基酸(AAs)的位置选择性修饰提供一种通用的方法。尽管在半胱氨酸的位置选择性修饰方面已经取得了很大的进展，但化学生物学家的工具箱中还缺乏对其他氨基酸(如酪氨酸、赖氨酸、组氨酸)进行位置选择性修饰的可靠和容易获得的策略。这导致了研究中的瓶颈，因为使用半胱氨酸或非选择性的其他氨基酸修饰并不总是合适和/或适合于目的。通过利用半胱氨酸作为栖息地“鱼”的其他(近端)残基的功能化，我们的目标是解锁一个通用的，一流的，各种氨基酸的战略。除了研究这些连接背后的基本化学，我们还将把它们应用于临床相关的蛋白质，如抗体。抗体-药物结合物(ADC)代表了一类领先的靶向抗癌治疗药物，在过去3年中有7种药物获得批准。新的选址建造方法被认为对下一代ADC至关重要，因此人们热衷于寻找新的方法--例如这里提出的那些方法。因此，这个项目在EPSRC化学生物学和生物化学研究领域内，介于物理科学和医疗技术的研究主题之间。该项目将包括对学生进行有机合成、化学生物学和生物偶联技术的广泛研究和培训。它将涉及试剂设计、合成计划、多步骤合成和蛋白质结合实验以及相关的广泛的生物结合分析。在调查了试剂范围并优化了反应方案后，将构建最终的抗体结合物，以展示在最先进水平上可能的改进和机会。

The core aim of this project is to unlock a general method for the site-selective modification of various amino acids (AAs) on proteins. Whilst great progress has been made on site-selective cysteine modification, reliable and readily accessible strategies for the site-selective modification of other AAs (e.g. tyrosine, lysine, histidine) are missing from the chemical biologist's toolbox. This has resulted in bottlenecks in research as the use of cysteine, or unselective other amino acid modification, is not always appropriate and/or fit-for-purpose. Through exploiting cysteine instead as a perch to "fish" for the functionalisation of other (proximal) residues we aim to unlock a general, first-in-class, strategy for various AAs. In addition to investigating the fundamental chemistry behind these ligations, we will be applying them to clinically relevant proteins such as antibodies. Antibody-drug conjugates (ADCs) represent a leading class of targeted anti-cancer therapeutics, with 7 approved in the last 3 years. New site-selective methods for their construction are considered vital for the next generation of ADCs, so new methods - such as those proposed here - are keenly sought. As such this project is within the EPSRC Research Area of Chemical Biology and Biological Chemistry, and sits between the Research Themes of Physical Sciences and Healthcare Technologies. The project will involve extensive research and training for the student in Organic Synthesis, Chemical Biology and bioconjugation techniques. It will involve reagent design, synthetic planning, multi-step synthesis and protein conjugation experiments with associated extensive bioconjugate analysis. After investigating the reagent scope and optimising the reaction protocols, final antibody conjugates will be constructed to demonstrate the improvements and opportunities possible over the state-of-the art.