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.

Gsprotein peptidomimetics as allosteric modulators of the β2-adrenergic receptor

“…[18][19][20] Among the many available methods for peptide stapling we favour CuAAC-stapling between amino acids with azido-and alkynyl-modied side chains. 21,22 This methodology was originally developed by Tornoe et al 23 and later optimised by According to our analysis the red residues represent the best (i, i + 4)stapling positions by appropriate substitution with amino acids 1-4 (staples A-C). Staple position D was included to validate the design (a negative control).…”

Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

“…Peptide "stapling" has been developed as av ersatile method for targeting a-helix mediated PPIs as well as those mediated by irregular binding interfaces. [12][13][14][15] Constraining ap eptide in an a-helical conformation has been shown to increasep eptide proteolytic stability, [24,25] improvec ellular uptake, [26][27][28] and enhance target binding affinity through pre-organization of the bioactive conformation, [29,30] The toolbox for constraining peptides into ab ioactive (helical) conformation includes:h ydrocarbon "staples", [31,32] lactamb ridges, [33][34][35] Cu I -catalysed azidealkynec ycloaddition, [36][37][38][39][40] hydrogen-bond surrogates, [41,42] and other chemistries. [43,44] Addingt ot his toolbox, the use of, simple disulfideb ridges, crosslinking of (homo)cysteine residues and other modifications of thiols have been described.…”

Tritiodefluorination of alkyl C–F groups

“…Tritium is the most versatile radioisotope used for identifying organic compounds in biochemical research . Most frequently, tritiations are carried out using carrier‐free tritium gas in the presence of a noble metal catalyst in order to reduce double or triple bonds, tritiodehalogenation of appropriate synthetic precursors or to carry out 1 H/ 3 H exchanges on the desired molecule . Catalytic dehalogenations of organic halides, using tritium gas, provide a state‐of‐the‐art approach of site‐selective labeling, while yielding high specific activity (SA) of the labeled material (Figure ) .…”