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.
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Phuong Thu
authors.initials: PT
authors.lastname: Tran
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Christian Ørnbøl
authors.initials: CØ
authors.lastname: Larsen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Tobias
authors.initials: T
authors.lastname: Røndbjerg
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Martina
authors.initials: M
authors.lastname: De Foresta
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200, Copenhagen, Denmark.
authors.forename: Micha B A
authors.initials: MB
authors.lastname: Kunze
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, 16610, Prague 6, Czech Republic.
authors.forename: Ales
authors.initials: A
authors.lastname: Marek
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Jacob Hartvig
authors.initials: JH
authors.lastname: Løper
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Lotte-Emilie
authors.initials: LE
authors.lastname: Boyhus
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Astrid
authors.initials: A
authors.lastname: Knuhtsen
authors.affiliation: Structural Biology and NMR Laboratory, Department of Biology, University of Copenhagen, Ole Maaloes Vej 5, 2200, Copenhagen, Denmark.
authors.forename: Kresten
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.affiliation: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100, Copenhagen, Denmark.
authors.forename: Daniel Sejer
authors.identifier: http://orcid.org/0000-0003-3926-7047
authors.initials: DS
authors.lastname: Pedersen
keywords: CuAAC; bioconjugate chemistry; peptide chemistry; peptidomimetics; radiolabelling