Tuning the binding affinity and selectivity of perfluoroaryl-stapled peptides by cysteine-editing

Sanne JM Verhoork, Claire Jennings, Neshat Rozatian, Judith Reeks, Jieman Meng, Emily K Corlett, Fazila Bunglawala, Martin E. M. Noble, Andrew G Leach, Christopher R Coxon

Research output: Contribution to journalArticlepeer-review


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. Computationally constructed homology models indicate that some modifications, such as incorporating two d-cysteine residues, favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured surface plasmon resonance data.
Original languageEnglish
Pages (from-to)177-182
JournalChemistry - A European Journal
Issue number1
Publication statusPublished - 26 Sept 2018


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