Desulfurative modification of cysteine residues in peptides and proteins via the installation and photoexcitation of thieno[2,3-c]-pyrroles

Abstract

Late-stage modification of peptides and post-translational modifications of proteins are of significant value in research, drug discovery and therapeutic development. We report the discovery of novel photoactivity in the thieno[2,3-c]-pyrrole chromophore, which enables the desulfurization of Cys residues to generate L-alanyl radicals. This approach allowed for the efficient incorporation of Trp, Tyr and Phe bioisosteres into peptides at the Cys position. Furthermore, we developed a new reagent to install the photoreactive thieno[2,3-c]-pyrrole on the Cys residues in a biocompatible manner, enabling photodesulfurization in both cell lysates and live cells. The new thieno[2,3-c]-pyrrole photochemical strategy provides a powerful platform for biochemical investigations and the development of small-molecule and protein-based drugs.