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Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing
Authors:Sanne J M Verhoork  Dr Claire E Jennings  Neshat Rozatian  Dr Judith Reeks  Jieman Meng  Emily K Corlett  Fazila Bunglawala  Prof Martin E M Noble  Dr Andrew G Leach  Dr Christopher R Coxon
Institution:1. School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, James Parsons Building, Byrom St, Liverpool, L3 3AF UK;2. Northern Institute for Cancer Research, Newcastle University, Paul O'Gorman Building, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH UK;3. Department of Chemistry, Durham University, South Road, Durham, DH1 3LE UK
Abstract: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.
Keywords:cancer  computational modelling  cysteine  hexafluorobenzene  peptides
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