Study of medicinal chemistry of nonsense mutation disease therapeutics focused on negamycin with readthrough activity
| Project/Area Number |
25893258
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| Research Category |
Grant-in-Aid for Research Activity Start-up
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| Allocation Type | Single-year Grants |
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| Research Field |
Drug development chemistry
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| Research Institution | Tokyo University of Pharmacy and Life Science |
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Principal Investigator |
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| Project Period (FY) |
2013-08-30 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | リードスルー / ネガマイシン / デュシェンヌ型筋ジストロフィー / 創薬化学 / 抗生物質 |
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| Outline of Final Research Achievements |
(+)-Negamycin, a natural dipeptidic antibiotic, exhibits a readthrough activity toward the nonsense mutation. We performed a structure activity relationship study for development of nonsense mutation disease therapeutics. As a result, we successful obtained that TCP-112 shows a higher readthrough activity than negamycin. In this study, further derivatization at the carboxylic acid part of TCP-112 demonstrates that m-chlorobenzyl ester derivative exhibits a more potent readthrough activity than TCP-112 in cell-based assay. However, in the cell-free protein expression system, the readthrough activity of m-chlorobenzyl ester derivative drastically decreases compared to that in the cell-based assay. These results suggest that benzyl ester-type derivatives enhance the hydrophobicity and function as prodrugs to produce TCP-112 in living cell systems.
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Report
(3 results)
Research Products
(9 results)
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[Journal Article] Discovery of Natural Products Possessing Selective Eukaryotic Readthrough Activity: 3-epi-Deoxynegamycin and Its Leucine Adduct2014
Author(s)
Akihiro Taguchi, Keisuke Hamada, Masaya Kotake, Masataka Shiozuka, Hidemasa Nakaminami, Thanigaimalai Pillaiyar, Kentaro Takayama, Fumika Yakushiji, Norihisa Noguchi, Takeo Usui, Ryoichi Matsuda, Yoshio Hayashi
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Journal Title
ChemMedChem
Volume: 9
Issue: 10
Pages: 2233-2237
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Presentation] Structure activity relationship study of (+)- negamycin derivatives at the C-terminal part as a readthrough drug2014
Author(s)
Keisuke Hamada, Akihiro Taguchi, Masaya Kotake, Suguru Aita, Shuntaro Ikezawa, Masataka Shiozuka, Yoshiaki Nonomura, Kentaro Takayama, Fumika Yakushiji, Takeo Usui, Ryoichi Matsuda, Yoshio Hayashi
Organizer
18th Korean Peptide Protein Symposium
Place of Presentation
Busan, South Korea
Year and Date
2014-07-07 – 2014-07-08
Related Report
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