A conotoxin peptidomimetic was developed as a potential muscle relaxant that is highly potent and blood plasma stable.

Low molecular weight gelators that are not easily degraded by enzymes have a range of potential applications. Here, we report new Fmoc-protected dipeptides in which the amide carbonyl group has been replaced by an oxetane ring. Remarkably one of these peptidomimetics, but not the corresponding dipeptide, is an effective gelator, forming hydrogels at a concentration of 3 mg mL. On assembly, there is a lack of beta-sheet structure, implying that there is no requirement for this motif in such a gel. Furthermore, the modified dipeptide is also stable to proteolysis compared to the parent dipeptide.

Stapled peptides are an important class of conformationally constrained, bioactive α‐helical peptides. They have been used extensively as chemical probes for the regulation of protein–protein interactions (PPIs), with one currently progressing through late‐stage clinical trials as a peptide drug candidate. Their ability to interact with shallow protein–protein interfaces, which have previously proven to be challenging to target with small molecules, has led to their rapid uptake by the chemical biology and drug discovery communities. Stapled peptides overcome some of the undesirable physicochemical properties that limit the use of peptides as therapeutics. They generally exhibit good binding affinity and specificity as they aim to accurately reproduce the α‐helix recognition motif from a PPI interface. They are protease resistant and in some instances have shown good cell permeability. The development of stapled peptides has thus resulted in a transformative shift by validating difficult PPIs as therapeutic targets and providing promising drug candidates. Key Concepts Stapled peptides are conformationally constrained α‐helical peptides. Stapling reduces the entropic penalty of folding to produce the bioactive conformation, thus giving an increase in binding affinity over an unfolded peptide. Through mimicking the interface these compounds have good binding affinity and specificity. Proteolytic stability is enhanced through the induction of secondary structure and the effective shielding of the peptide backbone from recognition by protease enzymes. Cell permeability can be enhanced by peptide stapling as the distribution of lipophilicity compared to the native peptide is altered. Key PPIs implicated in cancer, including p53‐MDM2/MDMX, Aurora‐A/TPX2 and the Bcl family, have been probed using stapled peptides.

Stapled peptides are a unique class of cyclic α‐helical peptides that are conformationally constrained via their amino acid side‐chains. They have been transformative to the field of chemical biology and peptide drug discovery through addressing many of the physicochemical limitations of linear peptides. However, there are several issues with current chemical strategies to produce stapled peptides. For example, two distinct unnatural amino acids are required to synthesize i, i+7 alkene stapled peptides, leading to high production costs. Furthermore, low purified yields are obtained due to cis/trans isomers produced during ring‐closing metathesis macrocyclisation. Here we report the development of a new i, i+7 diyne‐girder stapling strategy that addresses these issues. The asymmetric synthesis of nine unnatural Fmoc‐protected alkyne‐amino acids facilitated a systematic study to determine the optimal (S,S)‐stereochemistry and 14‐carbon diyne‐girder bridge length. Diyne‐girder stapled T‐STAR peptide 29 was demonstrated to have excellent helicity, cell permeability and stability to protease degradation. Finally, we demonstrate that the diyne‐girder constraint is a Raman chromophore with potential use in Raman cell microscopy. Development of this highly effective, bifunctional diyne‐girder stapling strategy leads us to believe that it can be used to produce other stapled peptide probes and therapeutics.