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Journal Article

Constraining an Irregular Peptide Secondary Structure through Ring-Closing Alkyne Metathesis

MPS-Authors

Glas,  Adrian
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie;
Chemical Genomics Centre of the Max Planck Society;

Bier,  David
Chemical Genomics Centre of the Max Planck Society;
University of Eindhoven, Department of Biomedical Engineering, Institute of Complex Molecular Systems;
Department of Chemistry, University of Duisburg–Essen;

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Fürstner,  Alois
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

Grossmann,  Tom N.
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie;
VU University Amsterdam, Department of Chemistry and Pharmaceutical Sciences;
Chemical Genomics Centre of the Max Planck Society;

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Citation

Cromm, P. M., Wallraven, K., Glas, A., Bier, D., Fürstner, A., Ottmann, C., et al. (2016). Constraining an Irregular Peptide Secondary Structure through Ring-Closing Alkyne Metathesis. ChemBioChem: A European Journal of Chemical Biology, 17(20), 1915-1919. doi:10.1002/cbic.201600362.


Cite as: http://hdl.handle.net/11858/00-001M-0000-002B-A449-2
Abstract
Macrocyclization can be used to constrain peptides in their bioactive conformations, thereby supporting target affinity and bioactivity. In particular, for the targeting of challenging protein–protein interactions, macrocyclic peptides have proven to be very useful. Available approaches focus on the stabilization of α-helices, which limits their general applicability. Here we report for the first time on the use of ring-closing alkyne metathesis for the stabilization of an irregular peptide secondary structure. A small library of alkyne-crosslinked peptides provided a number of derivatives with improved target affinity relative to the linear parent peptide. In addition, we report the crystal structure of the highest-affinity derivative in a complex with its protein target 14-3-3ζ. It can be expected that the alkyne-based macrocyclization of irregular binding epitopes should give rise to new scaffolds suitable for targeting of currently intractable proteins.