Issue 10, 2015

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 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

Supplementary files

Article information

Article type
Edge Article
Submitted
09 5 2015
Accepted
12 7 2015
First published
13 7 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2015,6, 5473-5490

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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