2014 Fiscal Year Final Research Report
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
|
| 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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| Free Research Field |
医歯薬学
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