Peptide Macrocyclization via Intramolecular Interception of Visible-Light-Mediated Desulfurization

Synthetic methods that enable the macrocyclization of peptides facilitate the development of more effective therapeutic and diagnostic tools. Herein we report a novel peptide cyclization strategy based on intramolecular interception of visible-light-mediated cysteine desulfurization. This method allows cyclization of unprotected peptides in an aqueous solution via the installation of a hydrocarbon linkage. We explore the limits of this chemistry using a range of model peptides of increasing length and complexity, including peptides of biological relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin with a proteolytically/redox-stable hydrocarbon, and internal macrocyclization of an MCL-1-binding peptide.