The Development of Highly Effective BNA-based Antisense Oligonucleotides

近年来，由于桥接核酸等高亲和力修饰核酸的发展，反义药物取得了很大进展，但仍存在疗效和安全性问题。首先，为了验证反义分子的周转能力增加与药效增加相关的假设，设计了无细胞周转检测系统并估计了周转率。正如预期的那样，具有缓慢周转率的反义寡核苷酸在体内没有表现出明显的沉默。另一方面，为了增加剂量反义分子的可用性，从药物库中筛选了激活细胞摄取反义分子或通过未知机制增加沉默作用的小分子，并发现了非常有吸引力的分子。正确的是，高周转率的反义寡核苷酸与小分子结合将使当前的反义治疗复杂化。

Despite recent great progress in antisense drugs coming from the development of high-affinity modified nucleic acids such as Bridged Nucleic Acids (BNAs), there still remain efficacy and safety issues. First, to test the hypothesis that increase of turnover ability of antisense molecules is associated with the increase of efficacy, cell-free turnover detection system was devised and turnover rates were estimated. As expected, antisense oligonucleotides with slow turnover rates showed no significant silencing in vivo. On the other hand, to increase the availability of dosed antisense molecules, small molecules that activate cellular uptake of antisense molecules or increase silencing effect via unknown mechanisms were screened from a drug library and very attractive molecules were found. Correctively, high-turnover antisense oligonucleotide in combination with a small molecule would sophisticate a current antisense therapy.