Premium
Diversity‐Oriented Peptide Stapling: A Third Generation Copper‐Catalysed Azide–Alkyne Cycloaddition Stapling and Functionalisation Strategy
Author(s) -
Tran Phuong Thu,
Larsen Christian Ørnbøl,
Røndbjerg Tobias,
De Foresta Martina,
Kunze Micha B. A.,
Marek Ales,
Løper Jacob Hartvig,
Boyhus LotteEmilie,
Knuhtsen Astrid,
LindorffLarsen Kresten,
Pedersen Daniel Sejer
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201700128
Subject(s) - cycloaddition , azide , peptide , alkyne , combinatorial chemistry , chemistry , click chemistry , peptidomimetic , catalysis , stereochemistry , organic chemistry , biochemistry
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.