Islam Md Ariful, Waki Reiko, Fujisaka Aki, Ito Kosuke Ramon, Obika Satoshi
Graduate School of Pharmaceutical Sciences, Osaka University.
Drug Discov Ther. 2016;10(5):263-270. doi: 10.5582/ddt.2016.01055.
Phosphorothioate modification is one of the most widely investigated and promising chemical modifications in oligonucleotide (ON) based therapeutics. Structurally similar 5'-thio or phosphorothiolate-modified nucleotides, in which a 5'-bridging oxygen is replaced with a sulfur atom, are gaining importance for ON-based research. Several reports have been published describing the synthesis of 5'-thio-modified ONs but no detailed in vitro and in vivo data are available. Here, we report the synthesis of 5'-thio-modified 2'-deoxy-5-methylcytidine. 5'-Thio-modified thymidine and 2'-deoxy-5-methylcytidine were incorporated into target ONs, then we evaluated their binding affinity, nuclease stability, RNase H mediated scission, stability in blood serum, and in vitro and in vivo activity. This is the first report showing the influence of 5'-thio-modified antisense ONs in in vitro and in vivo experiments.
硫代磷酸酯修饰是基于寡核苷酸（ON）的治疗中研究最广泛且最具前景的化学修饰之一。结构相似的5'-硫代或硫代磷酸酯修饰的核苷酸，其中一个5'-桥连氧被硫原子取代，在基于ONs的研究中变得越来越重要。已经发表了几篇描述5'-硫代修饰的ONs合成的报告，但尚无详细的体外和体内数据。在此，我们报告了5'-硫代修饰的2'-脱氧-5-甲基胞苷的合成。将5'-硫代修饰的胸苷和2'-脱氧-5-甲基胞苷掺入目标ONs中，然后我们评估了它们的结合亲和力、核酸酶稳定性、RNase H介导的切割、血清稳定性以及体外和体内活性。这是第一份显示5'-硫代修饰的反义ONs在体外和体内实验中影响的报告。
