Open AccessNew Negamycin-Based Potent Readthrough Derivative Effective against TGA-Type Nonsense Mutations
Author(s) -
Keisuke Hamada,
Noriko Omura,
Akihiro Taguchi,
Alireza BaradaranHeravi,
Masaya Kotake,
Misaki Arai,
Kentaro Takayama,
Atsuhiko Taniguchi,
Michel Roberge,
Yoshio Hayashi
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00273
Subject(s) - nonsense mutation , nonsense , derivative (finance) , type (biology) , computer science , combinatorial chemistry , computational biology , chemistry , mutation , genetics , biology , missense mutation , gene , business , ecology , finance
We report a novel negamycin derivative TCP-1109 ( 13x ) which serves as a potent readthrough drug candidate against nonsense-associated diseases. We previously demonstrated that TCP-112 ( 7 ), a nor-compound of native 3- epi -deoxynegmaycin, showed a higher readthrough activity than (+)-negamycin. In the present study, we performed a structure-activity relationship (SAR) study of compound 7 focused on its 3-amino group in an effort to develop a more potent readthrough compound. Introduction of a variety of natural or unnatural amino acids to the 3-amino group gave us the more potent derivative 13x which has about four times higher readthrough activity than 7 in a cell-based assay using a premature termination codon of TGA derived from Duchenne muscular dystrophy. The activity was dose-dependent and relatively selective for TGA. However, the activities for TAG and TAA were also higher than those of (+)-negamycin and 7 . Moreover, compound 13x showed significant cell-based readthrough activity for several nonsense mutations derived from other nonsense-associated diseases. It is suggested that 13x has the potential to be a readthrough drug useful for the treatment of many kinds of nonsense-associated diseases.