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


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 ?-turns and ?-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.

SUBMITTER: Bartoloni M 

PROVIDER: S-EPMC5949603 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Bartoloni Marco M   Jin Xian X   Marcaida Maria José MJ   Banha João J   Dibonaventura Ivan I   Bongoni Swathi S   Bartho Kathrin K   Gräbner Olivia O   Sefkow Michael M   Darbre Tamis T   Reymond Jean-Louis JL  

Chemical science 20150713 10


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 <sup>1</sup>H-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 r  ...[more]

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