Enzymatic Late‐Stage Halogenation of Peptides

Schnepel, Christian; Moritzer, Ann‐Christin; Gäfe, Simon; Montua, Nicolai; Minges, Hannah; Nieß, Anke; Niemann, Hartmut H.; Sewald, Norbert

Abstract

The late-stage site-selective derivatisation of peptides has many potential applications in structure-activity relationship studies and postsynthetic modification or conjugation of bioactive compounds. The development of orthogonal methods for C−H functionalisation is crucial for such peptide derivatisation. Among them, biocatalytic methods are increasingly attracting attention. Tryptophan halogenases emerged as valuable catalysts to functionalise tryptophan (Trp), while direct enzyme-catalysed halogenation of synthetic peptides is yet unprecedented. Here, it is reported that the Trp 6-halogenase Thal accepts a wide range of amides and peptides containing a Trp moiety. Increasing the sequence length and reaction optimisation made bromination of pentapeptides feasible with good turnovers and a broad sequence scope, while regioselectivity turned out to be sequence dependent. Comparison of X-ray single crystal structures of Thal in complex with d-Trp and a dipeptide revealed a significantly altered binding mode for the peptide. The viability of this bioorthogonal approach was exemplified by halogenation of a cyclic RGD peptide.

Citation

Schnepel, C., Moritzer, A., Gäfe, S., Montua, N., Minges, H., Nieß, A., Niemann, H. H., & Sewald, N. (2023). Enzymatic Late‐Stage Halogenation of Peptides. ChemBioChem, 24(1), Article e202200569. https://doi.org/10.1002/cbic.202200569

• Journal Article Type: Article
• Acceptance Date: Oct 19, 2022
• Online Publication Date: Nov 23, 2022
• Publication Date: Jan 3, 2023
• Deposit Date: Jan 1, 2025
• Journal: ChemBioChem
• Print ISSN: 1439-4227
• Electronic ISSN: 1439-7633
• Publisher: Wiley-VCH Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 1
• Article Number: e202200569
• DOI: https://doi.org/10.1002/cbic.202200569
• Public URL: https://durham-repository.worktribe.com/output/3263505