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Issue 10, 2015
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Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability

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Abstract

Double cyclization of short linear peptides obtained by solid phase peptide synthesis was used to prepare bridged bicyclic peptides (BBPs) corresponding to the topology of bridged bicyclic alkanes such as norbornane. Diastereomeric norbornapeptides were investigated by 1H-NMR, X-ray crystallography and CD spectroscopy and found to represent rigid globular scaffolds stabilized by intramolecular backbone hydrogen bonds with scaffold geometries determined by the chirality of amino acid residues and sharing structural features of β-turns and α-helices. Proteome profiling by capture compound mass spectrometry (CCMS) led to the discovery of the norbornapeptide 27c binding selectively to calmodulin as an example of a BBP protein binder. This and other BBPs showed high stability towards proteolytic degradation in serum.

Graphical abstract: Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability

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Publication details

The article was received on 09 May 2015, accepted on 12 Jul 2015 and first published on 13 Jul 2015


Article type: Edge Article
DOI: 10.1039/C5SC01699A
Citation: Chem. Sci., 2015,6, 5473-5490
  • Open access: Creative Commons BY license
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    Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability

    M. Bartoloni, X. Jin, M. J. Marcaida, J. Banha, I. Dibonaventura, S. Bongoni, K. Bartho, O. Gräbner, M. Sefkow, T. Darbre and J. Reymond, Chem. Sci., 2015, 6, 5473
    DOI: 10.1039/C5SC01699A

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