title: Orthogonal ring-closing alkyne and olefin metathesis for the synthesis of small GTPase-targeting bicyclic peptides.
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.
authors.affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.|Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
authors.forename: Philipp M
authors.initials: PM
authors.lastname: Cromm
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.|Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim/Ruhr, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schaubach
authors.affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.|Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
authors.forename: Jochen
authors.identifier: http://orcid.org/0000-0001-7641-1066
authors.initials: J
authors.lastname: Spiegel
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.|Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mülheim/Ruhr, Germany.
authors.forename: Alois
authors.initials: A
authors.lastname: Fürstner
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.|Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Strasse 15, D-44227 Dortmund, Germany.|Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Tom N
authors.initials: TN
authors.lastname: Grossmann
authors.affiliation: Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Strasse 11, D-44227 Dortmund, Germany.|Technische Universität Dortmund, Fakultät für Chemie and Chemische Biologie, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
mesh_terms: D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D015394:Molecular Structure; D020559:Monomeric GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020691:rab GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D000475:Alkenes; D010456:Peptides, Cyclic; C082377:RAB8A protein, human; D020559:Monomeric GTP-Binding Proteins; D020691:rab GTP-Binding Proteins