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

Verhoork, SJM, Jennings, CE, Rozatian, N, Reeks, J, Meng, J, Corlett, EK, Bunglawala, F, Noble, MEM, Leach, AG and Coxon, CR (2018) Tuning the binding affinity and selectivity of perfluoroaryl-stapled peptides by cysteine-editing. Chemistry - A European Journal. ISSN 0947-6539 (Accepted)

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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 we explore the replacement of L-cysteine with 'cysteine analogues' in combinations of different stereochemistry, side chain length and beta-carbon substitution, 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. 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-cysteines favourably alter the positions of key functional amino acid side chains, which is likely to cause changes in binding affinity, in agreement with measured SPR data.

Item Type: Article
Uncontrolled Keywords: 03 Chemical Sciences
Subjects: Q Science > QD Chemistry
Divisions: Pharmacy & Biomolecular Sciences
Publisher: Wiley
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Date Deposited: 08 Oct 2018 09:16
Last Modified: 08 Oct 2018 09:24
DOI or Identification number: 10.1002/chem.201804163
URI: http://researchonline.ljmu.ac.uk/id/eprint/9426

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