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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Bartoloni Marco, Jin Xian, Marcaida Marie José, Banha João, Dibonaventura Ivan, Bongoni Swathi, Bartho Kathrin, Gräbner Olivia, Sefkow Michael, Darbre Tamis, Reymond Jean-Louis,
Project A Chemical Space Approach to Bioactive Peptides
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Original article (peer-reviewed)

Journal Chemical Science
Volume (Issue) 6
Page(s) 5473 - 5490
Title of proceedings Chemical Science
DOI 10.1039/c5sc01699a

Open Access

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.
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