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 Citationer (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.

Originalsprog	Engelsk
Tidsskrift	Chemistry: A European Journal
Vol/bind	23
Udgave nummer	14
Sider (fra-til)	3490-3495
Antal sider	6
ISSN	0947-6539
DOI	https://doi.org/10.1002/chem.201700128
Status	Udgivet - 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.
I: Chemistry: A European Journal, Bind 23, Nr. 14, 08.03.2017, s. 3490-3495.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › 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, bind 23, nr. 14, s. 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 - Tran, Thu Phuong

AU - Larsen, Christian Ørnbøl

AU - Røndbjerg, Tobias

AU - de Foresta, Martina

AU - Kunze, Micha Ben Achim

AU - Marek, Ales

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

Abstract

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