Negamycin analogue with readthrough-promoting activity as a potential drug candidate for duchenne muscular dystrophy.

Abstract

A series of (+)-negamycin 1 analogues were synthesized, and their readthrough-promoting activity was evaluated for nonsense mutations in Duchenne muscular dystrophy (DMD). A structure-activity relationship study indicated that 11b was the most potent drug candidate. Immunohistochemical analyses suggested that treatment with 11b restored dystrophin expression in mdx mice, a DMD mouse model. Furthermore, 11b decreased serum creatine kinase (CK) levels, an indicator of muscle fiber destruction. Most importantly, 11b demonstrated lower toxicity than 1, and thus, it could be a useful candidate for long-term treatment of DMD.

• Authors: Akihiro Taguchi, Shigenobu Nishiguchi, Masataka Shiozuka, Takao Nomoto, Mayuko Ina, Shouta Nojima, Ryoichi Matsuda, Yoshiaki Nonomura, Yoshiaki Kiso, Yuri Yamazaki, Fumika Yakushiji, Yoshio Hayashi
• Journal: ACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 2 Pg. 118-22 (Feb 09 2012) ISSN: 1948-5875 [Print] United States
• PMID: 24900441 (Publication Type: Journal Article)