Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing.

A growing number of approaches to "staple" α-helical peptides into a bioactive conformation using cysteine cross-linking are emerging. Here, the replacement of l-cysteine with "cysteine analogues" in combinations of different stereochemistry, side chain length and beta-carbon substitution, is explored to examine the influence that the thiol-containing residue(s) has on target protein binding affinity in a well-explored model system, p53-MDM2/MDMX, which is constituted by the interaction of the tumour suppressor protein p53 and proteins MDM2 and MDMX, which regulate p53 activity. In some cases, replacement of one or more l-cysteine residues afforded significant changes in the measured binding affinity and target selectivity of the peptide.