title: Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice.
abstract: The ability of aminoglycoside antibiotics to promote read-through of nonsense mutations has attracted interest in these drugs as potential therapeutic agents in genetic diseases. However, the toxicity of aminoglycoside antibiotics may result in severe side effects during long-term treatment. In this paper, we report that negamycin, a dipeptide antibiotic, also restores dystrophin expression in skeletal and cardiac muscles of the mdx mouse, an animal model of Duchenne muscular dystrophy (DMD) with a nonsense mutation in the dystrophin gene, and in cultured mdx myotubes. Dystrophin expression was confirmed by immunohistochemistry and immunoblotting. We also compared the toxicity of negamycin and gentamicin, and found negamycin to be less toxic. Furthermore, we demonstrate that negamycin binds to a partial sequence of the eukaryotic rRNA-decoding A-site. We conclude that negamycin is a promising new therapeutic candidate for DMD and other genetic diseases caused by nonsense mutations.
authors.affiliation: Department of Life Sciences, The University of Tokyo, 3-8-1 Komaba, Tokyo 153-8902.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Arakawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Shiozuka
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nakayama
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hara
authors.forename: Masa
authors.initials: M
authors.lastname: Hamada
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Kondo
authors.forename: Daishiro
authors.initials: D
authors.lastname: Ikeda
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Sawa
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Nonomura
authors.forename: Kianoush
authors.initials: K
authors.lastname: Sheykholeslami
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Kaga
authors.forename: Toshio
authors.initials: T
authors.lastname: Kitamura
authors.forename: Yuko
authors.initials: Y
authors.lastname: Suzuki-Miyagoe
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Matsuda
mesh_terms: D000599:Amino Acids, Diamino / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001933:Brain Stem / Q000187:drug effects / Q000502:physiology; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D005839:Gentamicins / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D012335:RNA, Ribosomal / Q000378:metabolism
chemical_list: D000599:Amino Acids, Diamino; D016189:Dystrophin; D005839:Gentamicins; D012335:RNA, Ribosomal; C100200:negamycin