New Negamycin-Based Potent Readthrough Derivative Effective against TGA-Type Nonsense Mutations.

ABSTRACT: 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

SUBMITTER: Hamada K 

PROVIDER: S-EPMC6792177 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature