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

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9 Citations (Scopus)


(+)-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
Issue number10
Publication statusPublished - Oct 12 2017
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry


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