PDF(Pubmed)
Abstract：
This investigation addresses the challenge of suboptimal unnatural amino acid (UAA) utilization in the site-specific suppression of nonsense mutations through genetic code expansion, which is crucial for protein restoration and precise property tailoring. A facile and economical oral liquid formulation is developed by converting UAAs into ionic liquids, significantly enhancing their bioavailability and tissue accumulation. Empirical data reveal a 10-fold increase in bioavailability and up to a 13-fold rise in focal tissue accumulation, alongside marked improvements in UAA incorporation efficiency. A 4-week oral administration in mdx mice, a model for Duchenne muscular dystrophy (DMD), demonstrates the formulation\'s unprecedented therapeutic potential, with up to 40% dystrophin expression restoration and 75% recovery of normal fiber functions, surpassing existing treatments and exhibiting substantial long-term safety. This study presents a potent oral dosage form that dramatically improves UAA incorporation into target proteins in vivo, offering a significant advance in the treatment of nonsense mutation-mediated disorders and holding considerable promise for clinical translation.
摘要：
这项研究解决了通过遗传密码扩展在无义突变的位点特异性抑制中利用次优非天然氨基酸（UAA）的挑战，这对于蛋白质修复和精确的属性定制至关重要。通过将UAA转化为离子液体，开发了一种简便且经济的口服液体制剂。显着提高其生物利用度和组织积累。经验数据显示生物利用度增加10倍，局灶性组织积累增加13倍，以及UAA注册效率的显著提高。在mdx小鼠中口服4周，杜氏肌营养不良症（DMD）的模型，展示了该配方前所未有的治疗潜力，高达40%的肌营养不良蛋白表达恢复和75%的正常纤维功能恢复，超越现有的治疗方法，并表现出实质性的长期安全性。这项研究提出了一种有效的口服剂型，可以显着改善体内UAA掺入靶蛋白，在无义突变介导的疾病的治疗方面取得了重大进展，并为临床翻译提供了可观的希望。
