Tuning the Binding Affinity and Selectivity of Perfluoroaryl-Stapled Peptides by Cysteine-Editing |
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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 |
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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 |
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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. |
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Keywords: | cancer computational modelling cysteine hexafluorobenzene peptides |
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