title: Rational design, synthesis, and biological evaluation of lactam-bridged gramicidin A analogues: discovery of a low-hemolytic antibacterial peptide.
abstract: A linear peptide, gramicidin A (GA), folds into a β(6.3) -helix, functions as an ion channel in the cell membrane, and exerts antibacterial activity. Herein we describe the rational design, synthesis, and biological evaluation of lactam-bridged GA analogues. The GA analogue with a 27-membered macrolactam was found to adopt a stable β(6.3) -helical conformation and exhibits higher ion-exchange activity than GA. Furthermore, this GA analogue retains the potent antibiotic activity of GA, but its hemolytic activity and toxicity toward mammalian cells are significantly lower than those of GA. This study thus dissociates the antibacterial and hemolytic/cytotoxic activities of GA, and charts a rational path forward for the development of new ion-channel-based antibiotics.
authors.affiliation: Graduate School of Phramaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
authors.forename: Ji
authors.initials: J
authors.lastname: Mao
authors.forename: Takefumi
authors.initials: T
authors.lastname: Kuranaga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamamoto
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Sekimizu
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D001424:Bacterial Infections / Q000188:drug therapy; D002460:Cell Line; D055808:Drug Discovery; D006096:Gramicidin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology*; D017433:Protein Structure, Secondary
chemical_list: D000900:Anti-Bacterial Agents; D010455:Peptides; D006096:Gramicidin
keywords: antibiotics; ion channels; natural products; peptides; structure-activity relationships