Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability† †Electronic supplementary information (ESI) available: Crystallographic data; spectroscopic data with 1H NMR spectra, HPLC profiles and MS spectra. CCDC 1063793 and 1063796–1063799. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5sc01699a

Diastereomeric norbornapeptides represent globular scaffolds with geometries determined by the chirality of amino acid residues and sharing structural features of β-turns and α-helices.
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.