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

Philipp M. Cromm, Sebastian Schaubach, Jochen Spiegel, Alois Fürstner (), Tom N. Grossmann () and Herbert Waldmann ()
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Philipp M. Cromm: Max-Planck-Institute of Molecular Physiology
Sebastian Schaubach: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie
Jochen Spiegel: Max-Planck-Institute of Molecular Physiology
Alois Fürstner: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie
Tom N. Grossmann: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie
Herbert Waldmann: Max-Planck-Institute of Molecular Physiology

Nature Communications, 2016, vol. 7, issue 1, 1-7

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11300

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