Over the years, a wide variety of methods have been established for the modification of various amino acids on peptides/proteins, e.g., Cysteine, Lysine. However, the absence of a reliable strategy for modification of the C-terminus has persisted. To the best of our knowledge, the only general method for C-terminal modification is that pioneered by Macmillian et al. (Nature Chem., 2017, 10, 205-211). However, this strategy is decarboxylative, uses an Ir photocatalyst, requires pH 3.5 for good yields and introduces a highly unnatural group onto the protein. Prima facie, the lack of methods for C-terminus modification seems logical as it is conceptually difficult to activate/react only one carboxylic acid in the presence of all others. In this project, the Chudasama and Baker research groups are proposing to develop an organic-chemistry-led first-in-class method for the site-selective modification of C-terminal cysteines. This will enable site-selective conjugation of native antibodies as the vast majority of clinically relevant antibodies bear a C-terminal cysteine (thus leading to the various applications of antibody conjugates, e.g., use in cancer imaging, therapy, diagnostics, immunotherapy, etc. whilst also providing a fundamental addition to the chemical biologist’s toolbox in a broader context). Our core concept is to utilise sulfur selective chemistries to deliver coupling reagents to the carboxylate on the C-terminus, which will then enable site-specific amide bond formation. Encouragingly, we have published two key preliminary results in the area (Chem. Commun., 2022, 58, 5359-5362; Chem. Sci., 2024, 15, 8557-8568), which sets the groundwork for application on various antibody scaffolds.
Please note that if the applicant successfully secures this studentship, they will receive a stipend enhancement of £2,500 in addition to the standard stipend for each of the four years of the programme.
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