Short peptides often lose their secondary structure and functional binding ability when excised from the native protein environment. In order to retain the native conformation of the peptides, chemists have rationally developed a myriad of cyclisation strategies. Stabilisation of alpha-helical peptides by means of hydrocarbon stapling has remained a popular strategy for probing protein-protein interactions. When stapled, the peptides are intramolecularly constrained via an alkenyl linker and depending on the macrocycle ring size, mixtures of cis and trans stapled peptide isomers may be attained.
Using the p53-MDM2 complex as a model system, we have demonstrated that stapled peptide configurational isomers can have different biophysical and biological properties. This presentation will focus on chemical strategies for a targeted synthesis of the more active peptide isomer and the re-purposing of the metathesis catalyst to enable formation of saturated stapled peptides. The hydrogenation reaction can be carried out under one-pot conditions, without the use of sealed tubes or specialised pressure equipment. In certain cases, enhancement of p53 activation was observed, highlighting the importance of identifying the impact of cis/trans isomer and saturated analogues of all-hydrocarbon stapled peptides.