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Tuning peptide structure and function through fluorobenzene stapling.

Cyclic peptides are promising next-generation therapeutics with improved biological stability and activity. A catalyst-free stapling method for cysteine-containing peptides was developed. This enables fine-tuning of the macrocycle by using the appropriate regioisomers of fluorobenzene linkers. Stapling was performed on the unprotected linear peptide or, more conveniently, directly on-resin after peptide synthesis. NMR spectroscopy and circular dichroism studies demonstrate that the type of stapling can tune the secondary structures of the peptides. The method was applied to a set of potential agonists for melanocortin receptors, generating a library of macrocyclic potent ligands with ortho , meta or para relationships between the thioethers. Their small but significant difference in potency and efficacy demonstrates how the method allows facile fine-tuning of macrocyclic peptides towards biological targets from the same linear precursor.