New Negamycin-Based Potent Readthrough Derivative Effective against TGA-Type Nonsense Mutations
| Autor: | Masaya Kotake, Kentaro Takayama, Michel Roberge, Noriko Omura, Akihiro Taguchi, Atsuhiko Taniguchi, Alireza Baradaran-Heravi, Keisuke Hamada, Misaki Arai, Yoshio Hayashi |
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| Rok vydání: | 2019 |
| Předmět: |
Drug
viruses media_common.quotation_subject Duchenne muscular dystrophy Nonsense mutation Cell 01 natural sciences Biochemistry chemistry.chemical_compound Drug Discovery medicine media_common chemistry.chemical_classification 010405 organic chemistry Drug candidate fungi Organic Chemistry medicine.disease 0104 chemical sciences Amino acid 010404 medicinal & biomolecular chemistry medicine.anatomical_structure chemistry Premature Termination Codon Derivative (chemistry) |
| Zdroj: | ACS Med Chem Lett |
| ISSN: | 1948-5875 |
| Popis: | [Image: see text] 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. |
| Databáze: | OpenAIRE |
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