Site-Selective Installation of Nϵ-Modified Sidechains into Peptide and Protein Scaffolds via Visible-Light-Mediated Desulfurative C–C Bond Formation

Abstract

Post-translational modifications (PTMs) enhance the repertoire of protein function and mediate or influence the activity of many cellular processes. The preparation of site-specifically and homogeneously modified proteins, to apply as tools to understand the biological role of PTMs, is a challenging task. Herein, we describe a visible-light-mediated desulfurative C(sp3)–C(sp3) bond forming reaction that enables the site-selective installation of Nϵ-modified sidechains into peptides and proteins of interest. Rapid, operationally simple, and tolerant to ambient atmosphere, we demonstrate the installation of a range of lysine (Lys) PTMs into model peptide systems and showcase the potential of this technology by site-selectively installing an NϵAc sidechain into recombinantly expressed ubiquitin (Ub).