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

Akihiro Taguchi; Shigenobu Nishiguchi; Masataka Shiozuka; Takao Nomoto; Mayuko Ina; Shouta Nojima; Ryoichi Matsuda; Yoshiaki Nonomura; Yoshiaki Kiso; Yuri Yamazaki; Fumika Yakushiji; Yoshio Hayashi

doi:10.1021/ml200245t

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

Akihiro Taguchi, Shigenobu Nishiguchi, Masataka Shiozuka, Takao Nomoto, Mayuko Ina, Shouta Nojima, Ryoichi Matsuda, Yoshiaki Nonomura, Yoshiaki Kiso, Yuri Yamazaki, Fumika Yakushiji, Yoshio Hayashi

Research Center for Math and Science Education

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18 Citations (Scopus)

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.

Original language	English
Pages (from-to)	118-122
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	2
DOIs	https://doi.org/10.1021/ml200245t
Publication status	Published - 9 Feb 2012

Keywords

Duchenne muscular dystrophy
Negamycin
genetic disease
hydrazino dipeptide
nonsense mutations
readthrough-promoting activity

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10.1021/ml200245t

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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.",

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T1 - Negamycin analogue with readthrough-promoting activity as a potential drug candidate for Duchenne muscular dystrophy

AU - Taguchi, Akihiro

AU - Nishiguchi, Shigenobu

AU - Shiozuka, Masataka

AU - Nomoto, Takao

AU - Ina, Mayuko

AU - Nojima, Shouta

AU - Matsuda, Ryoichi

AU - Nonomura, Yoshiaki

AU - Kiso, Yoshiaki

AU - Yamazaki, Yuri

AU - Yakushiji, Fumika

AU - Hayashi, Yoshio

PY - 2012/2/9

Y1 - 2012/2/9

N2 - 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.

AB - 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.

KW - Duchenne muscular dystrophy

KW - Negamycin

KW - genetic disease

KW - hydrazino dipeptide

KW - nonsense mutations

KW - readthrough-promoting activity

UR - https://www.scopus.com/pages/publications/84856913604

U2 - 10.1021/ml200245t

DO - 10.1021/ml200245t

M3 - Article

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ER -

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

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Keywords

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