title: Converting One-Face α-Helix Mimetics into Amphiphilic α-Helix Mimetics as Potent Inhibitors of Protein-Protein Interactions.
abstract: 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. Here we describe an 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 that such two-face amphiphilic α-helix mimetics indeed show remarkably improved binding affinity to a target protein, compared to 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 protein-protein interactions.
authors.affiliation: New Drug Development Center, Daegu Gyeongbuk Medical Innovation Foundation , Daegu 701-310, South Korea.
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology (POSTECH) , Pohang 790-784, South Korea.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology (POSTECH) , Pohang 790-784, South Korea.
authors.forename: Hyun Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Molecular Biosciences and Centre for Computational Biology, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Huisun
authors.initials: H
authors.lastname: Lee
authors.affiliation: Department of Molecular Biosciences and Centre for Computational Biology, The University of Kansas , Lawrence, Kansas 66047, United States.
authors.forename: Wonpil
authors.initials: W
authors.lastname: Im
authors.affiliation: Department of Chemistry, Pohang University of Science and Technology (POSTECH) , Pohang 790-784, South Korea.|Department of Biochemistry and Molecular Biology, Indiana University School of Medicine , Indianapolis, Indiana 46202, United States.
authors.forename: Hyun-Suk
authors.initials: HS
authors.lastname: Lim
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D060066:Protein Interaction Maps / Q000187:drug effects*; D017433:Protein Structure, Secondary; D060327:Solid-Phase Synthesis Techniques / Q000379:methods
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D057786:Peptidomimetics
keywords: amphiphilic α-helix mimetics; combinatorial library; protein−protein interaction inhibitor; solid-phase synthesis