α-Helices are the most commonly found form of protein secondary structures and often involved in protein-protein interactions (PPIs) as recognition motifs. Many biologically active α-helical peptides adopt amphiphilic helical structures that contain hydrophobic residues on one side and hydrophilic residues on the other side. Therefore, α-helix mimetics capable of mimicking such amphiphilic helical peptides should possess higher binding affinity and specificity to target proteins. In this study, we demonstrated efficient method for generating amphiphilic α-helix mimetics. One-face α-helix mimetics having hydrophobic side chains on one side was readily converted into amphiphilic α-helix mimetics by introducing appropriate charged residues on the opposite side. We also demonstrate such two-face amphiphilic α-helix mimetics indeed show remarkably improved binding affinity to a target protein, compared to typical one-face hydrophobic α-helix mimetics. We believe that generating a large combinatorial library of these amphiphilic α-helix mimetics can be valuable for rapid discovery of highly potent and specific modulators of PPIs.

Converting one-face α-helix mimetics into amphiphilic α-helix mimetics as potent inhibitors of protein-protein interactions

251st National Meeting (2016)

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