Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation

Smith, Frances R.; Meehan, Declan; Griffiths, Rhys C.; Knowles, Harriet J.; Zhang, Peiyu; Williams, Huw E.L.; Wilson, Andrew J.; Mitchell, Nicholas J.

Abstract

Synthetic methods that enable the macrocyclisation of peptides facilitate the development of 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.

Citation

Smith, F. R., Meehan, D., Griffiths, R. C., Knowles, H. J., Zhang, P., Williams, H. E., Wilson, A. J., & Mitchell, N. J. (2024). Peptide macrocyclisation via intramolecular interception of visible-light-mediated desulfurisation. Chemical Science, 15(25), 9612-9619. https://doi.org/10.1039/d3sc05865d

• Journal Article Type: Article
• Acceptance Date: Apr 30, 2024
• Online Publication Date: May 14, 2024
• Publication Date: Jul 7, 2024
• Deposit Date: May 24, 2024
• Publicly Available Date: May 24, 2024
• Journal: Chemical Science
• Print ISSN: 2041-6520
• Electronic ISSN: 2041-6539
• Publisher: Royal Society of Chemistry
• Peer Reviewed: Peer Reviewed
• Volume: 15
• Issue: 25
• Pages: 9612-9619
• DOI: https://doi.org/10.1039/d3sc05865d
• Public URL: https://nottingham-repository.worktribe.com/output/35159161
• Publisher URL: https://pubs.rsc.org/en/content/articlelanding/2024/sc/d3sc05865d