Metal-Assisted Folding of Prolinomycin Allows Facile Design of Functional Peptides

Abstract

Cyclic peptides have been proposed as privileged scaffolds that might mimic the folding and function of natural proteins. However, simple cyclic peptides typically cannot fold into well-defined structures. Herein, we describe a foldable cyclic peptide scaffold on which functional side chains can be displayed for targeted recognition of biomolecules. The foldable scaffold is based on prolinomycin, a proline-rich analogue of valinomycin. We report synthetic mutants of prolinomycin that retain the metal-assisted folding behavior under physiological conditions. The predictable structure formation of prolinomycin makes it a powerful platform to enable the development of synthetic receptors for biomolecules of interest. We demonstrate the potential of this scaffold by creating prolinomycin mutants that selectively bind anionic vesicles and bacterial cells.

Keywords: K+ binding; cyclic peptide; peptide design; prolinomycin.