Application and Structural Analysis of Triazole-Bridged Disulfide Mimetics in Cyclic Peptides

Andrew M. White, Simon J. de Veer, Guojie Wu, Peta J. Harvey, Kuok Yap, Gordon J. King, Joakim E. Swedberg, Conan K. Wang, Ruby H. P. Law, Thomas Durek, David J. Craik

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2 Citations (Scopus)

Abstract

Ruthenium-catalysed azide–alkyne cycloaddition (RuAAC) provides access to 1,5-disubstituted 1,2,3-triazole motifs in peptide engineering applications. However, investigation of this motif as a disulfide mimetic in cyclic peptides has been limited, and the structural consequences remain to be studied. We report synthetic strategies to install various triazole linkages into cyclic peptides through backbone cyclisation and RuAAC cross-linking reactions. These linkages were evaluated in four serine protease inhibitors based on sunflower trypsin inhibitor-1. NMR and X-ray crystallography revealed exceptional consensus of bridging distance and backbone conformations (RMSD<0.5 Å) of the triazole linkages compared to the parent disulfide molecules. The triazole-bridged peptides also displayed superior half-lives in liver S9 stability assays compared to disulfide-bridged peptides. This work establishes a foundation for the application of 1,5-disubstituted 1,2,3-triazoles as disulfide mimetics.

Original languageEnglish
Pages (from-to)11273-11277
Number of pages5
JournalAngewandte Chemie - International Edition
Volume59
Issue number28
DOIs
Publication statusPublished - 6 Jul 2020

Keywords

  • disulfide mimetics
  • inhibitors
  • peptides
  • peptidomimetics
  • triazole bridges

Cite this

White, A. M., de Veer, S. J., Wu, G., Harvey, P. J., Yap, K., King, G. J., Swedberg, J. E., Wang, C. K., Law, R. H. P., Durek, T., & Craik, D. J. (2020). Application and Structural Analysis of Triazole-Bridged Disulfide Mimetics in Cyclic Peptides. Angewandte Chemie - International Edition, 59(28), 11273-11277. https://doi.org/10.1002/anie.202003435