Tuning the Binding Affinity and Selectivity of Perfluoroaryl‐Stapled Peptides by Cysteine‐Editing. Issue 1 (27th November 2018)

• Record Type: Journal Article
• Authors: Verhoork, Sanne J. M.; Jennings, Claire E.; Rozatian, Neshat; Reeks, Judith; Meng, Jieman; Corlett, Emily K.; Bunglawala, Fazila; Noble, Martin E. M.; Leach, Andrew G.; Coxon, Christopher R.
• Is Part Of: Chemistry. Volume 25:Issue 1(2019)
• Page Start: 177
• Page End: 182
• Publication Date: 2018-11-27
• Subjects: cancer -- computational modelling -- cysteine -- hexafluorobenzene -- peptides; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.201804163
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: A growing number of approaches to "staple" α‐helical peptides into a bioactive conformation using cysteine cross‐linking are emerging. Here, the replacement ofl ‐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 morel ‐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 twod ‐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. Abstract : Cysteine‐editing : Stapled peptides can be prepared by cysteine cross‐linking with hexafluorobenzene. Replacement of one or morel ‐cysteine residues with "cysteine analogues" changes both the peptide target affinity and selectivity for proteins MDM2/MDMX as demonstrated by surface plasmon resonance measurements.