Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy

Thu Phuong Tran; Christian Ørnbøl Larsen; Tobias Røndbjerg; Martina de Foresta; Micha Ben Achim Kunze; Ales Marek; Jacob Hartvig Løper; Lotte-Emilie Boyhus; Astrid Knuhtsen; Kresten Lindorff-Larsen; Daniel Sejer Pedersen

doi:10.1002/chem.201700128

Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy

Thu Phuong Tran, Christian Ørnbøl Larsen, Tobias Røndbjerg, Martina de Foresta, Micha Ben Achim Kunze, Ales Marek, Jacob Hartvig Løper, Lotte-Emilie Boyhus, Astrid Knuhtsen, Kresten Lindorff-Larsen, Daniel Sejer Pedersen

Biomolecular Sciences

17 Citations (Scopus)

Abstract

The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide–alkyne cycloaddition (CuAAC) has emerged as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i+7)- and (i, i+9)-stapled peptides with a single free alkyne positioned on the staple, which can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access to radiolabelled stapled peptides by catalytic tritiation of the alkyne positioned on the staple.

Original language	English
Journal	Chemistry: A European Journal
Volume	23
Issue number	14
Pages (from-to)	3490-3495
Number of pages	6
ISSN	0947-6539
DOIs	https://doi.org/10.1002/chem.201700128
Publication status	Published - 8 Mar 2017

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10.1002/chem.201700128

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Tran, T. P., Larsen, C. Ø., Røndbjerg, T., de Foresta, M., Kunze, M. B. A., Marek, A., Hartvig Løper, J., Boyhus, L.-E., Knuhtsen, A., Lindorff-Larsen, K., & Pedersen, D. S. (2017). Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy. Chemistry: A European Journal, 23(14), 3490-3495. https://doi.org/10.1002/chem.201700128

Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy. / Tran, Thu Phuong; Larsen, Christian Ørnbøl; Røndbjerg, Tobias et al.
In: Chemistry: A European Journal, Vol. 23, No. 14, 08.03.2017, p. 3490-3495.

Research output: Contribution to journal › Journal article › Research › peer-review

Tran, TP, Larsen, CØ, Røndbjerg, T, de Foresta, M, Kunze, MBA, Marek, A, Hartvig Løper, J, Boyhus, L-E, Knuhtsen, A, Lindorff-Larsen, K & Pedersen, DS 2017, 'Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy', Chemistry: A European Journal, vol. 23, no. 14, pp. 3490-3495. https://doi.org/10.1002/chem.201700128

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title = "Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy",

abstract = "The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide–alkyne cycloaddition (CuAAC) has emerged as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i+7)- and (i, i+9)-stapled peptides with a single free alkyne positioned on the staple, which can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access to radiolabelled stapled peptides by catalytic tritiation of the alkyne positioned on the staple.",

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AU - Røndbjerg, Tobias

AU - de Foresta, Martina

AU - Kunze, Micha Ben Achim

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AU - Hartvig Løper, Jacob

AU - Boyhus, Lotte-Emilie

AU - Knuhtsen, Astrid

AU - Lindorff-Larsen, Kresten

AU - Pedersen, Daniel Sejer

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AB - The introduction of macrocyclic constraints in peptides (peptide stapling) is an important tool within peptide medicinal chemistry for stabilising and pre-organising peptides in a desired conformation. In recent years, the copper-catalysed azide–alkyne cycloaddition (CuAAC) has emerged as a powerful method for peptide stapling. However, to date CuAAC stapling has not provided a simple method for obtaining peptides that are easily diversified further. In the present study, we report a new diversity-oriented peptide stapling (DOPS) methodology based on CuAAC chemistry. Stapling of peptides incorporating two azide-modified amino acids with 1,3,5-triethynylbenzene efficiently provides (i, i+7)- and (i, i+9)-stapled peptides with a single free alkyne positioned on the staple, which can be further conjugated or dimerised. A unique feature of the present method is that it provides easy access to radiolabelled stapled peptides by catalytic tritiation of the alkyne positioned on the staple.

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JO - Chemistry: A European Journal

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Diversity-oriented peptide stapling: a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy

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