Structured cyclic peptide mimics by chemical ligation

We report the development of a beta-turn mimic that allows the direct formation of cyclic peptides through a spontaneous cyclisation under standard solid phase peptide synthesis (SPPS) cleavage conditions. The mimic is formed via an acylhydrazone, which is either reduced in situ by triisopropylsilane-trifluoroacetic acid, or which can be isolated and reduced in a separate step. This method uses commercially available reagents and is compatible with manual and automated SPPS methods. The cyclisation is tolerant of polar residues at the C-terminal position, with the exception of asparagine, for which a subsequent structural rearrangement similar to aspartimide formation was observed. The cyclisation method has been shown to tolerate ring sizes equivalent to 5-10 amino acid residues. We have used this method to design and synthesise potential selective integrin binding sequences with controlled conformations.