Deutsch
 
Benutzerhandbuch Datenschutzhinweis Impressum Kontakt
  DetailsucheBrowse

Datensatz

DATENSATZ AKTIONENEXPORT

Freigegeben

Zeitschriftenartikel

Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides

MPG-Autoren
/persons/resource/persons194827

Schaubach,  Sebastian
Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie;
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

/persons/resource/persons58380

Fürstner,  Alois
Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie;
Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society;

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

Externe Ressourcen
Es sind keine Externen Ressourcen verfügbar
Volltexte (frei zugänglich)
Es sind keine frei zugänglichen Volltexte verfügbar
Ergänzendes Material (frei zugänglich)

[349]SI.pdf
(Ergänzendes Material), 3MB

Zitation

Cromm, P. M., Schaubach, S., Spiegel, J., Fürstner, A., Grossmann, T. N., & Waldmann, H. (2016). Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides. Nature Communications, 7: 11300. doi:10.1038/ncomms11300.


Zitierlink: http://hdl.handle.net/11858/00-001M-0000-002A-60E2-6
Zusammenfassung
Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries. We also demonstrate that the formed alkyne macrocycle can be functionalized subsequently. The orthogonal RCM/RCAM system was successfully used to evolve a monocyclic peptide inhibitor of the small GTPase Rab8 into a bicyclic ligand. This modified peptide shows the highest affinity for an activated Rab GTPase that has been reported so far. The RCM/RCAM-based formation of bicyclic peptides provides novel opportunities for the design of bioactive scaffolds suitable for the modulation of challenging protein targets.