The diverse array of chemical functionality displayed by the 20 canonical amino acids presents both challenges and opportunities for the site-selective modification of peptides and proteins. To be effective, bioconjugation techniques must be rapid, operationally simple, high-yielding under mild conditions, and chemoselective. Owing to the superior nucleophilicity of the thiol group of cysteine (Cys), and its relatively low abundance across eukaryotic proteomes (ca. 2%), many reported techniques target this residue to selectively install groups of interest. To contribute to the bioconjugate chemistry tool kit, we are exploring the site-selective modification of peptides and proteins via interception of free-radical-mediated desulfurisation.
By exploiting the homolytic lability of the C-S bond of Cys, we have developed a visible-light-mediated desulfurative C(sp3)–C(sp3) bond-forming reaction that permits the site-selective installation of modified sidechains into peptides and proteins.[1] Rapid, operationally simple and tolerant to ambient atmosphere, our chemistry enables the incorporation of a range of lysine (Lys) post-translational modifications (PTMs), and PTM mimics[2] into model peptides and proteins, and facilitates effective peptide cyclisation. Furthermore, by employing persistent radical traps, we have developed a broadly applicable protein bioconjugation technique to install groups of interest via formation of an amino-oxy linkage.[3] In addition to Cys-selective chemistry, we are also investigating the photocatalytic C2-alkylation of tryptophan (Trp) using bromodifluoroacetate/acetamide radical precursors.[4]