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Issue 11, 2017
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A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway

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Abstract

The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry. We incorporate the new amino acids into a β-catenin-binding domain of Axin (469–482) and develop a new category of stapled peptides with the retention of the native side chains. These stapled peptides exhibit high α-helicity, strong proteolytic stability and good cell permeability. Biochemical experiments demonstrate that these stapled peptides can activate β-catenin more efficiently than canonical stapled peptides due to the presence of extra side chains. We expect that the new side-chain-retention stapling method would expand the scope of the all-hydrocarbon stapled peptide strategy by retaining some important peripheral residues for protein–protein interactions or preserving key hydrophilic side chains to improve solubility.

Graphical abstract: A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway

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Publication details

The article was received on 30 May 2017, accepted on 29 Aug 2017 and first published on 29 Aug 2017


Article type: Edge Article
DOI: 10.1039/C7SC02420G
Citation: Chem. Sci., 2017,8, 7368-7373
  • Open access: Creative Commons BY license
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    A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway

    Y. Wu, Y. Li, X. Li, Y. Zou, H. Liao, L. Liu, Y. Chen, D. Bierer and H. Hu, Chem. Sci., 2017, 8, 7368
    DOI: 10.1039/C7SC02420G

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