Synthesis and evaluation of α-helix mimetics based on a trans-fused polycyclic ether: sequence-selective binding to aspartate pairs in α-helical peptides

Abstract

Inspired by the topological similarity between ladder-like cyclic ether skeletons and α-helical peptides, a trans-fused 6/6/6/6 tetracyclic ether containing two hydroxyl groups separated by a distance of 4.8 Å was designed as a scaffold for a nonpeptidic α-helix mimetic. Two alkyl guanidinium groups were attached to the hydroxyl groups to develop a synthetic receptor for the specific recognition of i + 4 spaced aspartate pairs on the surface of an α-helical peptide. A circular dichroism (CD) titration showed that this mode of molecular recognition stabilizes α-helical structures of peptides containing i + 4 spaced aspartate pairs.