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

Access to Document

10.1002/chem.201700128

Cite this

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

@article{36ccf9aa4a2c44bc9eb4386feba4f833,

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.",

author = "Tran, {Thu Phuong} and Larsen, {Christian {\O}rnb{\o}l} and Tobias R{\o}ndbjerg and {de Foresta}, Martina and Kunze, {Micha Ben Achim} and Ales Marek and {Hartvig L{\o}per}, Jacob and Lotte-Emilie Boyhus and Astrid Knuhtsen and Kresten Lindorff-Larsen and Pedersen, {Daniel Sejer}",

note = "{\textcopyright} 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2017",

month = mar,

day = "8",

doi = "10.1002/chem.201700128",

language = "English",

volume = "23",

pages = "3490--3495",

journal = "Chemistry: A European Journal",

issn = "0947-6539",

publisher = "Wiley - V C H Verlag GmbH & Co. KGaA",

number = "14",

}

TY - JOUR

T1 - Diversity-oriented peptide stapling

T2 - a third generation copper-catalysed azide–alkyne cycloaddition stapling and functionalisation strategy

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

PY - 2017/3/8

Y1 - 2017/3/8

N2 - 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.

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.

U2 - 10.1002/chem.201700128

DO - 10.1002/chem.201700128

M3 - Journal article

C2 - 28106305

SN - 0947-6539

VL - 23

SP - 3490

EP - 3495

JO - Chemistry: A European Journal

JF - Chemistry: A European Journal

IS - 14

ER -

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

Abstract

Access to Document

Fingerprint

Cite this