Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough

Akihiro Taguchi; Keisuke Hamada; Masataka Shiozuka; Misaki Kobayashi; Saori Murakami; Kentaro Takayama; Atsuhiko Taniguchi; Takeo Usui; Ryoichi Matsuda; Yoshio Hayashi

doi:10.1021/acsmedchemlett.7b00269

Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough

Akihiro Taguchi, Keisuke Hamada, Masataka Shiozuka, Misaki Kobayashi, Saori Murakami, Kentaro Takayama, Atsuhiko Taniguchi, Takeo Usui, Ryoichi Matsuda, Yoshio Hayashi

Research output: Contribution to journal › Article

3 Citations (Scopus)

Abstract

(+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure-activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.

Original language	English
Pages (from-to)	1060-1065
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	8
Issue number	10
DOIs	https://doi.org/10.1021/acsmedchemlett.7b00269
Publication status	Published - Oct 12 2017
Externally published	Yes

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All Science Journal Classification (ASJC) codes

Biochemistry
Drug Discovery
Organic Chemistry

Cite this

Taguchi, A., Hamada, K., Shiozuka, M., Kobayashi, M., Murakami, S., Takayama, K., ... Hayashi, Y. (2017). Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough. ACS Medicinal Chemistry Letters, 8(10), 1060-1065. https://doi.org/10.1021/acsmedchemlett.7b00269

Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough. / Taguchi, Akihiro; Hamada, Keisuke; Shiozuka, Masataka; Kobayashi, Misaki; Murakami, Saori; Takayama, Kentaro; Taniguchi, Atsuhiko; Usui, Takeo; Matsuda, Ryoichi; Hayashi, Yoshio.

In: ACS Medicinal Chemistry Letters, Vol. 8, No. 10, 12.10.2017, p. 1060-1065.

Research output: Contribution to journal › Article

Taguchi, Akihiro ; Hamada, Keisuke ; Shiozuka, Masataka ; Kobayashi, Misaki ; Murakami, Saori ; Takayama, Kentaro ; Taniguchi, Atsuhiko ; Usui, Takeo ; Matsuda, Ryoichi ; Hayashi, Yoshio. / Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough. In: ACS Medicinal Chemistry Letters. 2017 ; Vol. 8, No. 10. pp. 1060-1065.

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abstract = "(+)-Negamycin, isolated from Streptomyces purpeofuscus, shows antimicrobial activity against Gram-negative bacteria and readthrough activity against nonsense mutations. Previously, we reported that two natural negamycin analogues, 5-deoxy-3-epi-negamycin and its leucine adduct, have more potent readthrough activity in eukaryocytes (COS-7 cells) than negamycin but possess no antimicrobial activity and no in vitro readthrough activity in prokaryotic systems. In the present study, on leucyl-3-epi-deoxynegamycin, a structure-activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative 13b with an o-bromobenzyl ester functions as a prodrug and exhibits a higher readthrough activity against TGA-type PTC than the aminoglycoside G418. This ester (13b) shows an in vivo readthrough activity with low toxicity, suggesting that it has the potential for treatment of hereditary diseases caused by nonsense mutations.",

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AU - Takayama, Kentaro

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Access to Document

10.1021/acsmedchemlett.7b00269