Mao Ji, Kuranaga Takefumi, Hamamoto Hiroshi, Sekimizu Kazuhisa, Inoue Masayuki
Graduate School of Phramaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan).
ChemMedChem. 2015 Mar;10(3):540-5. doi: 10.1002/cmdc.201402473. Epub 2014 Dec 15.
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.
线性肽短杆菌肽A（GA）折叠成β(6.3) -螺旋，在细胞膜中作为离子通道发挥作用，并具有抗菌活性。在此，我们描述了内酰胺桥连GA类似物的合理设计、合成及生物学评价。发现具有27元大环内酰胺的GA类似物能采用稳定的β(6.3) -螺旋构象，且表现出比GA更高的离子交换活性。此外，该GA类似物保留了GA的强效抗生素活性，但其溶血活性和对哺乳动物细胞的毒性显著低于GA。因此，本研究将GA的抗菌活性与溶血/细胞毒性活性分离，为开发新型基于离子通道的抗生素指明了合理方向。
