The Development of Highly Effective BNA-based Antisense Oligonucleotides

尽管近年来由于高亲和力修饰核酸如桥接核酸（BNAs）的开发而在反义药物方面取得了很大进展，但仍然存在有效性和安全性问题。首先，为了检验反义分子的转换能力的增加与功效的增加相关的假设，设计了无细胞转换检测系统并估计了转换率。正如预期的那样，具有慢转换速率的反义寡核苷酸在体内没有显示出显著的沉默。另一方面，为了提高反义分子的利用率，从药物库中筛选出了能够激活细胞摄取反义分子或通过未知机制增加沉默效应的小分子，并发现了非常有吸引力的分子，正确地，高转换反义寡核苷酸与小分子的组合将取代当前的反义治疗。

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.