Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, 565-0871, Japan.
Future Med Chem. 2011 Mar;3(3):339-65. doi: 10.4155/fmc.11.2.
Numerous chemically modified oligonucleotides have been developed so far and show their own unique chemical properties and pharmacodynamic/pharmacokinetic characteristics. Among all non-natural nucleotides, to the best of our knowledge, only five chemistries are currently being tested in clinical trials: phosphorothioate, 2´-O-methyl RNA, 2´-O-methoxyethyl RNA, 2´,4´-bridged nucleic acid/locked nucleic acid and the phosphorodiamidate morpholino oligomer. Since phosphorothioate modification can improve the pharmacokinetics of oligonucleotides, this modification is currently used in combination with all other modifications except phosphorodiamidate morpholino oligomer. For the treatment of metabolic, cardiovascular, cancer and other systemic diseases, the phosphorothioate class of drugs is obviously helpful, while superior efficacies can be observed in phosphorodiamidate morpholino oligomer compared to other classes of oligonucleotides for the treatment of Duchenne muscular dystrophy. Which properties of antisense molecules are actually essential for clinical applications? In this article, we provide an overview of the medicinal chemistry of existing non-natural antisense molecules, as well as their clinical applications, to discuss which properties of antisense oligonuculeotides affect therapeutic potency.
迄今为止，已经开发出了许多化学修饰的寡核苷酸，并展示出了它们各自独特的化学性质和药效学/药代动力学特征。在所有非天然核苷酸中，据我们所知，目前只有五种化学物质正在临床试验中进行测试：硫代磷酸酯、2´-O-甲基 RNA、2´-O-甲氧基乙基 RNA、2´,4´-桥接核酸/锁核酸和磷酰胺二酯吗啉代寡核苷酸。由于硫代磷酸酯修饰可以改善寡核苷酸的药代动力学，因此这种修饰目前与除磷酰胺二酯吗啉代寡核苷酸以外的所有其他修饰结合使用。对于代谢、心血管、癌症和其他全身性疾病的治疗，硫代磷酸酯类药物显然是有帮助的，而对于杜氏肌营养不良症的治疗，与其他寡核苷酸类药物相比，磷酰胺二酯吗啉代寡核苷酸可以观察到更优越的疗效。反义分子的哪些特性实际上对临床应用是必不可少的？本文综述了现有非天然反义分子的药物化学及其临床应用，以探讨反义寡核苷酸的哪些特性影响治疗效果。
