One-pot iterative native chemical ligation–desulfurisation chemistry leveraging a coumarin-based photolabile protecting group for cysteine

Lucas Kambanis; Timothy S. Chisholm; Peter H. G. Egelund; Sameer S. Kulkarni; Richard J. Payne

doi:10.1071/CH25124

RESEARCH ARTICLE (Open Access)

One-pot iterative native chemical ligation–desulfurisation chemistry leveraging a coumarin-based photolabile protecting group for cysteine

Lucas Kambanis ^A ^B , Timothy S. Chisholm ^A , Peter H. G. Egelund ^A ^B , Sameer S. Kulkarni ^A ^B and Richard J. Payne

^A ^B ^*

+ Author Affiliations

- Author Affiliations

^A School of Chemistry, The University of Sydney, Sydney, NSW 2006, Australia.

^B Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW 2006, Australia.

^* Correspondence to: richard.payne@sydney.edu.au

Handling Editor: Ed Nice

Australian Journal of Chemistry 78, CH25124 https://doi.org/10.1071/CH25124

Submitted: 31 July 2025 Accepted: 27 August 2025 Published online: 23 September 2025

© 2025 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

An iterative one-pot peptide native chemical ligation (NCL)–desulfurisation strategy, featuring 7-diethylamino-3-methyl coumarin (DEAMC) as an orthogonal protecting group for cysteine, is described. We show that selective desulfurisation of unprotected cysteine residues can be achieved in the presence of DEAMC-protected cysteine residues, allowing subsequent DEAMC photodeprotection and native chemical ligation to be performed without purification. The efficiency of this approach was exemplified through the one-pot synthesis of a 60-residue mucin-1 peptide.

Keywords: coumarin, cysteine, desulfurisation, native chemical ligation, one-pot synthesis, photolabile, solid-phase peptide synthesis.

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