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.

中文翻译：

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克服无意义的突变相关遗传疾病的化学治疗：纳吉霉素的药物化学。

由框内过早终止密码子（PTC）的存在引起的无意义突变约占基因损伤的10％，这些基因损伤共同导致1800多种遗传性人类疾病。治疗源自PTC的遗传性疾病的一种方法是使用“通读化合物”选择性促进PTC中的翻译通读，这种通读化合物可导致全长功能蛋白表达的部分恢复。（+）-Negamycin，一种天然的二肽类抗生素，可以在患有Duchenne肌营养不良症的小鼠的骨骼肌中恢复某些肌营养不良蛋白的表达，该化合物已被认为是治疗由无意义突变引起的疾病的潜在治疗剂。为了开发具有改进活性的新候选分子，我们使用非手性和手性原料在（+）-新霉素的八个步骤中建立了有效的全合成方法。这些途径提供了一种具有体内通读活性并具有长期治疗潜力的脱氨基衍生物。在另一种方法中，我们发现了两种天然的奈奇霉素类似物3-环氧-脱氧奈奇霉素及其亮氨酸衍生物，它们是有效的通读化合物，可有效对抗真核生物的无意义突变，但对原核生物无效。这些化合物不能显示抗微生物活性。鉴定了更有效的衍生物，其结构衍生自3-表-脱氧新霉素，并在本文中讨论了它们的化学性质。我们发现了两种天然的奈加霉素类似物，3-epi-deoxynegamycin及其亮氨酸衍生物，它们是有效的通读化合物，可有效对抗真核生物的无意义突变，但对原核生物无效。这些化合物不能显示抗微生物活性。鉴定了更有效的衍生物，其结构衍生自3-表-脱氧新霉素，并在本文中讨论了它们的化学性质。我们发现了两种天然的奈加霉素类似物，3-epi-deoxynegamycin及其亮氨酸衍生物，它们是有效的通读化合物，可有效对抗真核生物的无意义突变，但对原核生物无效。这些化合物不能显示抗微生物活性。鉴定了更有效的衍生物，其结构衍生自3-表-脱氧新霉素，并在本文中讨论了它们的化学性质。