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

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...

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Veröffentlicht in:Angewandte Chemie International Edition 2020-07, Vol.59 (28), p.11273-11277
Hauptverfasser: White, Andrew M., Veer, Simon J., Wu, Guojie, Harvey, Peta J., Yap, Kuok, King, Gordon J., Swedberg, Joakim E., Wang, Conan K., Law, Ruby H. P., Durek, Thomas, Craik, David J.
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Sprache:eng
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Zusammenfassung: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
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202003435