Journal
ACS MEDICINAL CHEMISTRY LETTERS
Volume 8, Issue 10, Pages 1060-1065Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.7b00269
Keywords
Duchenne muscular dystrophy; Leucyl-3-epi-deoxynegamycin; (+)-Negamycin; Readthrough
Categories
Funding
- Japan Society for the Promotion of Science (JSPS)
- Ministry of Education, Culture, Sports, Science and Technology [16J08454, 23390029, 25860092, 25893258]
- Intramural Research Grant for Neurological and Psychiatric Disorders of NCNP [29-4]
- MEXT
- Platform for Drug Discovery, Informatics and Structural Life Science
- KAKENHI
- Grants-in-Aid for Scientific Research [16J08454, 25893258, 25860092, 23390029] Funding Source: KAKEN
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(+)-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-epideoxynegamycin, 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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