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

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.