Membrane Spanners Based on a Dimeric α,γ-Cyclic Peptide Core

Abstract

In this article, we describe the design, synthesis and transmembrane ion transport properties of a small library of molecular membrane-spanning ionophores based on dimer-forming cyclic peptide scaffolds decorated with flexible pendants. Thanks to the modular synthetic approach, it is possible to obtain a variety of α,γ-cyclic peptides with different internal diameters as well as a number of pendant groups that are perpendicularly projected from the peptide backbone. These groups are incorporated by a copper-catalysed cycloaddition between azide-modified oligo-ethylene glycol-based tentacles of different lengths and properties and cyclic peptides bearing a different number of propargyl groups attached at the amide skeleton. This methodology allowed the preparation of different ‘spanners’ and the identification of new artificial transporters that can rectify transmembranal pH gradients with EC50 values in the medium μM range.