Electrochemical Modification of Polypeptides at Selenocysteine

Mild strategies for the selective modification of peptides and proteins are in demand for applications in therapeutic peptide and protein discovery, and in the study of fundamental biomolecular processes. Herein, we describe the development of an electrochemical selenoetherification (e-SE) platform for the efficient site-selective functionalization of polypeptides. This methodology utilizes the unique reactivity of the 21st amino acid, selenocysteine, to effect formation of valuable bioconjugates through stable selenoether linkages under mild electrochemical conditions. The power of e-SE is highlighted through late-stage C-terminal modification of the FDA-approved cancer drug leuprolide and assembly of a library of anti-HER2 affibody conjugates bearing complex cargoes. Following assembly by e-SE, the utility of functionalized affibodies for in vitro imaging and targeting of HER2 positive breast and lung cancer cell lines is also demonstrated. An electrochemical selenoetherification (e-SE) methodology that enables efficient and selective functionalization of polypeptides is described. e-SE employs mild reaction conditions to facilitate the formation of stable selenoether-linked conjugates through contraction of diselenide bonds. Compatibility with diverse functionalities and complex cargoes is demonstrated through assembly of valuable bioactive polypeptide conjugates.image

Automated summary

This study describes the development of an electrochemical selenoetherification (e-SE) platform for the selective and efficient functionalization of polypeptides under mild conditions. The unique reactivity of selenocysteine allows the formation of stable selenoether-linked conjugates through electrochemical reactions. The utility of this platform is demonstrated through the modification of a FDA-approved cancer drug and the assembly of complex anti-HER2 affibody conjugates. The functionalized affibodies show potential applications in in vitro imaging and targeting of HER2-positive tumor cells.