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 journalArticle

1 Citation (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 languageEnglish
Pages (from-to)1060-1065
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume8
Issue number10
DOIs
Publication statusPublished - Oct 12 2017
Externally publishedYes

Fingerprint

Nonsense Codon
Structure-Activity Relationship
Esters
Inborn Genetic Diseases
Factor IX
COS Cells
Prodrugs
Streptomyces
Aminoglycosides
Gram-Negative Bacteria
Leucine
Toxicity
Assays
Bacteria
Derivatives
negamycin
epi-deoxynegamycin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

Cite this

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 journalArticle

Taguchi, A, Hamada, K, Shiozuka, M, Kobayashi, M, Murakami, S, Takayama, K, Taniguchi, A, Usui, T, Matsuda, R & Hayashi, Y 2017, 'Structure-Activity Relationship Study of Leucyl-3-epi-deoxynegamycin for Potent Premature Termination Codon Readthrough', ACS Medicinal Chemistry Letters, vol. 8, no. 10, pp. 1060-1065. https://doi.org/10.1021/acsmedchemlett.7b00269
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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