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

Bartoloni, Marco; Jin, Xian; Marcaida, Maria José; Banha, João; Di Bonaventura, Ivan; Bongoni, Swathi; Bartho, Kathrin; Gräbner, Olivia; Sefkow, Michael; Darbre, Tamis; Reymond, Jean-Louis (2015). Bridged bicyclic peptides as potential drug scaffolds: synthesis, structure, protein binding and stability. Chemical Science, 6(10), pp. 5473-5490. The Royal Society of Chemistry 10.1039/C5SC01699A

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Bartoloni, Marco; Jin, Xian; Di Bonaventura, Ivan; Darbre, Tamis and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

2041-6520

Publisher:

The Royal Society of Chemistry

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

22 Jan 2016 14:58

Last Modified:

22 Jan 2016 14:58

Publisher DOI:

10.1039/C5SC01699A

BORIS DOI:

10.7892/boris.74721

URI:

https://boris.unibe.ch/id/eprint/74721

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