Structure-activity relationship study of leucyl-3-epi-deoxynegamycin for potent readthrough activity to premature termination codon
Structure-activity relationship study of leucyl-3-epi-deoxynegamycin for potent readthrough activity to premature termination codon
复制标题
亮氨酰-3-表脱氧霉素的构效关系研究对提前终止密码子的有效通读活性
DOI：
10.1021/acsmedchemlett.7b00269
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发表时间：
2017
影响因子：
4.2
通讯作者：
Yoshio Hayashi
中科院分区：
文献类型：
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作者：
Akihiro Taguchi;Keisuke Hamada;Masataka Shiozuka;Misaki Kobayashi;Saori Murakami;Kentaro Takayama;Atsuhiko Taniguchi;Takeo Usui;Ryoichi Matsuda;Yoshio Hayashi
(+)-Negamycin 是从紫褐链霉菌 (Streptomyces purpeofuscus) 中分离出来的，具有针对革兰氏阴性菌的抗菌活性和针对无义突变的通读活性。此前，我们报道了两种天然的负霉素类似物，5-脱氧-3-表负霉素及其亮氨酸加合物，在真核细胞（COS-7细胞）中比负霉素具有更强的通读活性，但不具有抗菌活性，并且在原核系统中没有体外通读活性。在本研究中，对亮氨酰-3-表-脱氧负霉素进行了结构-活性关系研究，以开发更有效的通读剂。在基于细胞的通读测定中，带有硝基溴苄酯的衍生物 13b 作为前药发挥作用，并且对 TGA 型 PTC 表现出比氨基糖苷类 G418 更高的通读活性。该酯 (13b) 显示出低毒性的体内通读活性，表明它具有治疗无义突变引起的遗传性疾病的潜力。
(+)-Negamycin, isolated fromStreptomyces 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-epi-deoxynegamycin, a structure–activity relationship study was performed to develop more potent readthrough agents. In a cell-based readthrough assay, the derivative13bwith ano-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.