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

• Published in: Nature communications 2016-04, Vol.7 (1), p.11300-11300, Article 11300
• Main Authors: Cromm, Philipp M., Schaubach, Sebastian, Spiegel, Jochen, Fürstner, Alois, Grossmann, Tom N., Waldmann, Herbert
• Format: Article
• Language: English
• Subjects: 639/638/309; 639/638/403; 639/638/92/60; Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - metabolism; Humanities and Social Sciences; Models, Chemical; Molecular Sequence Data; Molecular Structure; Monomeric GTP-Binding Proteins - chemistry; Monomeric GTP-Binding Proteins - metabolism; multidisciplinary; Peptides, Cyclic - chemical synthesis; Peptides, Cyclic - chemistry; Peptides, Cyclic - metabolism; Protein Binding; rab GTP-Binding Proteins - chemistry; rab GTP-Binding Proteins - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11300

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. Bicyclic peptides can inhibit biological targets hard to address with small molecules. Here, the authors combine two orthogonal ring-closing reactions to produce bicyclic peptides with improved bioactivity thereby providing a strategy that can greatly improve the structural diversity of such peptides.