Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation

Griffiths, Rhys C.; Smith, Frances R.; Long, Jed E.; Williams, Huw E. L.; Layfield, Robert; Mitchell, Nicholas J.

Abstract

© 2020 The Authors. Published by Wiley-VCH GmbH The development of site-selective chemistry targeting the canonical amino acids enables the controlled installation of desired functionalities into native peptides and proteins. Such techniques facilitate the development of polypeptide conjugates to advance therapeutics, diagnostics, and fundamental science. We report a versatile and selective method to functionalize peptides and proteins through free-radical-mediated dechalcogenation. By exploiting phosphine-induced homolysis of the C−Se and C−S bonds of selenocysteine and cysteine, respectively, we demonstrate the site-selective installation of groups appended to a persistent radical trap. The reaction is rapid, operationally simple, and chemoselective. The resulting aminooxy linker is stable under a variety of conditions and selectively cleavable in the presence of a low-oxidation-state transition metal. We have explored the full scope of this reaction using complex peptide systems and a recombinantly expressed protein.

Citation

Griffiths, R. C., Smith, F. R., Long, J. E., Williams, H. E. L., Layfield, R., & Mitchell, N. J. (2020). Site-Selective Modification of Peptides and Proteins via Interception of Free-Radical-Mediated Dechalcogenation. Angewandte Chemie International Edition, 59(52), 23659-23667. https://doi.org/10.1002/anie.202006260

• Journal Article Type: Article
• Acceptance Date: Aug 28, 2020
• Online Publication Date: Sep 6, 2020
• Publication Date: Dec 21, 2020
• Deposit Date: Sep 8, 2020
• Publicly Available Date: Sep 7, 2021
• Journal: Angewandte Chemie - International Edition
• Print ISSN: 1433-7851
• Electronic ISSN: 1521-3773
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 59
• Issue: 52
• Pages: 23659-23667
• DOI: https://doi.org/10.1002/anie.202006260
• Keywords: General Chemistry; Catalysis
• Public URL: https://nottingham-repository.worktribe.com/output/4888769
• Publisher URL: https://onlinelibrary.wiley.com/doi/abs/10.1002/anie.202006260
• Additional Information: This is the peer reviewed version of the following article: Griffiths, R., Smith, F..R., Long, J..E., Williams, H., Layfield, R. and Mitchell, N. (2020), Site‐Selective Modification of Peptides and Proteins via Interception of Free Radical‐Mediated Dechalcogenation. Angew. Chem. Int. Ed.. Accepted Author Manuscript, which has been published in final form at https://doi.org/10.1002/anie.202006260. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.