Final Report Summary - SUZUKI PEPTIDES (Peptide ligands with restricted mobility through a Suzuki reaction: Design, synthesis and evaluation)
Natural cyclic peptides containing an aryl-aryl bond are abundant, diverse and constitute a heterogeneous group, including compounds which show antimicrobial or cytotoxic activities. A common feature of all of them is the rigidity imposed by the presence of the biaryl bridge. The biaryl system also provides a site for aromatic-aromatic or p-cation interactions with the residues present on protein surfaces. This last structural feature has so far not been exploited in the design of peptide ligands for protein surface recognition. With this in mind, the scope of our project was to prepare cyclic peptide ligands which were further constrained by means of a biaryl bond. We envision this type of biaryl-containing bicyclic peptides as constrained scaffolds, which can be customised according to the corresponding target. With this in mind, we have developed a synthetic methodology for the preparation of model biaryl bicyclic peptides, which is based on an intramolecular Suzuki-Miyaura reaction. Different synthetic approaches have been explored, regarding solution versus on-resin peptide modification, protection schemes and solid-supports. Our optimised procedure consists in the on-resin modification of the linear peptide solid-phase peptide synthesis, on resin borylation and Suzuki-Miyaura reaction, combined with head-to-tail cyclisation in solution. This way, several bicyclic biaryl peptides have been prepared, applying this synthetic procedure to other model sequences, incorporating side-chain functionalities. To the best of our knowledge, this is the first example of biaryl bicyclic peptides obtained through an on-resin intramolecular Suzuki-Miyaura reaction. Furthermore, the developed synthetic methodology can be applied for the preparation of tailored sequences for the interaction with selected targets.