Diversity‐Oriented Peptide Stapling: A Third Generation Copper‐Catalysed Azide–Alkyne Cycloaddition Stapling and Functionalisation Strategy. Issue 14 (16th February 2017)

• Record Type: Journal Article
• Authors: Tran, Phuong Thu; Larsen, Christian Ørnbøl; Røndbjerg, Tobias; De Foresta, Martina; Kunze, Micha B. A.; Marek, Ales; Løper, Jacob Hartvig; Boyhus, Lotte‐Emilie; Knuhtsen, Astrid; Lindorff‐Larsen, Kresten; Pedersen, Daniel Sejer
• Is Part Of: Chemistry. Volume 23:Issue 14(2017)
• Page Start: 3490
• Page End: 3495
• Publication Date: 2017-02-16
• Subjects: bioconjugate chemistry -- CuAAC -- peptide chemistry -- peptidomimetics -- radiolabelling; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201700128
• Languages: English
• ISSNs: 0947-6539

Abstract

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. Abstract : CuAAC‐tastic ! A diversity‐oriented peptide stapling (DOPS) and functionalisation strategy based on sequential copper‐catalysed azide–alkyne cycloaddition (CuAAC) reactions has been developed. Bis‐azido‐containing peptides are efficiently ( i, i +7) and ( i, i +9) stapled in a double CuAAC using 1, 3, 5‐triethynylbenzene. Further CuAAC functionalisations with a variety of azides is uncomplicated. Importantly, the alkyne on the staple is easily reduced, which provides a simple method for the radiolabelling of peptides with tritium.