Reversible stapling of unprotected peptides via chemoselective methionine bis-alkylation/dealkylation

Abstract

A general peptide reversible macrocyclization strategy is developed based on a facile and chemoselective methionine bis-alkylation/dealkylation process.

A sulfonium tethered peptide ligand rapidly and selectively modifies protein cysteine in vicinity

“…Based on Deming's pioneering work of selective methionine alkylation, we recently developed a bisalkylation modication of Met to generate cyclic peptides with better cellular uptake and stability. 40,41 Taking the current protein labelling demands into consideration, we envisioned that this method could be further developed into a novel and facile methodology to full the multiple purposes mentioned above. As shown in Scheme 1, the bis-alkylation between Cys and Met could generate a cyclic peptide with a tuneable tether and an on-tether sulfonium center, which could help in improving the peptide's stability and cellular uptake.…”

Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles

“…One such method relies on the use of distance-matching tethers that covalently link two amino acid side chains ( e.g. Cys,1–9 Lys,10–15 Trp,16–18 and Met19). Alternative stabilisation strategies such as alkene,20–25 oxime,26,27 1,2,3-trizole,28–30 hydrazide,31 alkyne,32 spiropyran,33 as well as mixed cross-linkages have also been published 34,35.…”

Recognition of ASF1 by Using Hydrocarbon‐Constrained Peptides

“…In the context of α‐helix‐mediated PPIs, considerable effort has been exerted on developing methods for constraining (or “stapling”) peptides in an α‐helical conformation. This approach has been used to confer enhanced proteolytic stability, enhanced cell‐uptake and, in some cases, enhanced target affinity on constrained peptide sequences . We recently introduced a series of reagents and approaches for constraining peptides in a helical conformation .…”