Constraining an Irregular Peptide Secondary Structure through Ring-Closing Alkyne Metathesis.
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.
Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, 44227, Dortmund, Germany.|Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.
Philipp M
PM
Cromm
VU University Amsterdam, Department of Chemistry and Pharmaceutical Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
Kerstin
K
Wallraven
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.|Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.
Adrian
A
Glas
Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany.|University of Eindhoven, Department of Biomedical Engineering, Institute of Complex Molecular Systems, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.|Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany.
David
D
Bier
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany.|Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470, Mülheim/Ruhr, Germany.
Alois
A
Fürstner
University of Eindhoven, Department of Biomedical Engineering, Institute of Complex Molecular Systems, Den Dolech 2, 5612 AZ, Eindhoven, The Netherlands.|Department of Chemistry, University of Duisburg-Essen, Universitätsstrasse 7, 45141, Essen, Germany.
Christian
C
Ottmann
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227, Dortmund, Germany. t.n.grossmann@vu.nl.|VU University Amsterdam, Department of Chemistry and Pharmaceutical Sciences, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. t.n.grossmann@vu.nl.|Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, 44227, Dortmund, Germany. t.n.grossmann@vu.nl.
Tom N
0000-0003-0179-4116
TN
Grossmann
D048948:14-3-3 Proteins / Q000737:chemistry; D000480:Alkynes / Q000737:chemistry*; D003500:Cyclization; D008958:Models, Molecular; D015394:Molecular Structure; D010455:Peptides / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry
D048948:14-3-3 Proteins; D000480:Alkynes; D010455:Peptides; D054852:Small Molecule Libraries
macrocyclization; peptide secondary structures; peptidomimetics; protein-protein interactions; ring-closing alkyne metathesis