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

该项目的核心目标是为蛋白质上各种氨基酸（AAs）的位点选择性修饰提供一种通用方法。虽然在半胱氨酸位点选择性修饰方面已经取得了很大的进展，但在化学生物学家的工具箱中，对其他氨基酸（如酪氨酸、赖氨酸、组氨酸）进行位点选择性修饰的可靠和容易获得的策略仍然缺失。这导致了研究中的瓶颈，因为使用半胱氨酸或其他非选择性氨基酸修饰并不总是合适和/或适合目的。通过利用半胱氨酸作为其他（近端）残基功能化的“钓竿”，我们的目标是为各种aa解锁一种通用的、一流的策略。除了研究这些连接背后的基础化学外，我们还将把它们应用于临床相关的蛋白质，如抗体。抗体-药物偶联物（adc）是一类领先的靶向抗癌治疗药物，在过去3年中有7个获批。新的位置选择方法被认为对下一代adc至关重要，因此迫切需要新的方法-例如这里提出的方法。因此，该项目属于EPSRC化学生物学和生物化学研究领域，位于物理科学和医疗保健技术研究主题之间。该项目将涉及有机合成、化学生物学和生物偶联技术方面的广泛研究和培训。它将包括试剂设计、合成计划、多步骤合成和蛋白质偶联实验，以及相关的广泛的生物偶联分析。在研究试剂范围和优化反应方案后，将构建最终的抗体偶联物，以证明在最先进的技术上可能存在的改进和机会。

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.