Chemotherapeutics Overcoming Nonsense Mutation-Associated Genetic Diseases : Medicinal Chemistry of Negamycin
Chemotherapeutics Overcoming Nonsense Mutation-Associated Genetic Diseases : Medicinal Chemistry of Negamycin
复制标题
克服无义突变相关遗传病的化疗：负霉素的药物化学
DOI：
10.1038/ja.2017.112
复制
发表时间：
2017
影响因子：
3.3
通讯作者：
and Yoshio Hayashi
中科院分区：
文献类型：
--
作者：
Akihiro Taguchi;Keisuke Hamada;and Yoshio Hayashi
由帧内过早终止密码子（PTC）引起的无义突变占基因病变的约10%，这些基因病变共同导致1800多种遗传性人类疾病。治疗由PTC引起的遗传疾病的一种方法是使用“读透化合物”选择性地促进PTC的翻译读透，这可以导致全长功能蛋白表达的部分恢复。（+）-负霉素是一种天然的二肽样抗生素，可恢复杜氏肌营养不良小鼠骨骼肌中部分肌营养不良蛋白的表达，该化合物已被认为是无义突变引起疾病的潜在治疗剂。为了开发具有更高活性的新候选分子，我们利用手性和非手性原料建立了8步高效的(+)-负霉素全合成方法。这些途径提供了具有体内读出活性的脱氨基衍生物，具有长期治疗的潜力。在另一种方法中，我们发现了两种天然负霉素类似物，3-外延脱氧负霉素及其亮氨酸衍生物，它们是有效的读通化合物，对真核生物无义突变有效，但对原核生物无效。这些化合物不能显示抗菌活性。本文还鉴定了一些结构由3-表-脱氧内霉素衍生的强效衍生物，并对其化学性质进行了讨论。
Nonsense mutations caused by the presence of an in-frame premature termination codon (PTC) account for~ 10% of gene lesions that together cause over 1800 inherited human diseases. One approach to treating genetic diseases that stem from PTCs is selective promotion of translational readthrough in a PTC using ‘readthrough compounds’ that can lead to partial restoration of full-length functional protein expression.(+)-Negamycin, a natural dipeptide-like antibiotic, may restore some dystrophin expression in the skeletal muscles of mice with Duchenne muscular dystrophy, and this compound has been recognized as a potential therapeutic agent for diseases caused by nonsense mutations. In an effort to develop new candidate molecules with improved activities, we established the efficient total synthesis in eight steps of (+)-negamycin using both achiral and chiral starting material. These routes provided a deamino derivative with in vivo readthrough activity with potential for long-term treatment. In a separate approach, we discovered two natural negamycin analogs, 3-epi-deoxynegamycin and its leucine derivative, which are potent readthrough compounds effective against nonsense mutations of eukaryotes but not prokaryotes. These compounds fail to display antimicrobial activity. More potent derivatives, whose structure is derived from 3-epi-deoxynegamycin, were identified and their chemistry is discussed in this review.