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

25 April 2024, Version 3
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

Synthetic methods that enable the macrocyclisation of peptides facilitate the development of more effective therapeutic and diagnostic tools. Herein we report a peptide cyclisation strategy based on intramolecular interception of visible-light-mediated cysteine desulfurisation. This method allows cyclisation 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/therapeutic relevance. The method is applied to replace the native disulfide of the peptide hormone, oxytocin, with a proteolytically/redox-stable hydrocarbon, and internal macrocyclisation of an MCL-1-binding peptide.

Keywords

Macrocyclization
Peptide
Photochemistry
Radical chemistry

Supplementary materials

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