Converting One-Face α-Helix Mimetics into Amphiphilic α-Helix Mimetics as Potent Inhibitors of Protein-Protein Interactions

Abstract

Many biologically active alpha-helical peptides adopt amphiphilic helical structures that contain hydrophobic residues on one side and hydrophilic residues on the other side. Therefore, alpha-helix mimetics capable of mimicking such amphiphilic helical peptides should possess higher binding affinity and specificity to target proteins. Here we describe an efficient method for generating amphiphilic alpha-helix mimetics. One-face alpha-helix mimetics having hydrophobic side chains on one side was readily converted into amphiphilic alpha-helix mimetics by introducing appropriate charged residues on the opposite side. We also demonstrate that such two-face amphiphilic alpha-helix mimetics indeed show remarkably improved binding affinity to a target protein, compared to one-face hydrophobic alpha-helix mimetics. We believe that generating a large combinatorial library of these amphiphilic alpha-helix mimetics can be valuable for rapid discovery of highly potent and specific modulators of protein-protein interactions.