Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice.
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.
Arakawa
Masayuki
M
Department of Life Sciences, The University of Tokyo, 3-8-1 Komaba, Tokyo 153-8902.
Shiozuka
Masataka
M
Nakayama
Yuki
Y
Hara
Takahiko
T
Hamada
Masa
M
Kondo
Shin'ichi
S
Ikeda
Daishiro
D
Takahashi
Yoshikazu
Y
Sawa
Ryuichi
R
Nonomura
Yoshiaki
Y
Sheykholeslami
Kianoush
K
Kondo
Kenji
K
Kaga
Kimitaka
K
Kitamura
Toshio
T
Suzuki-Miyagoe
Yuko
Y
Takeda
Shin'ichi
S
Matsuda
Ryoichi
R
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
D000599:Amino Acids, Diamino; D016189:Dystrophin; D005839:Gentamicins; D012335:RNA, Ribosomal; C100200:negamycin