Zhang Jinhao, Jing Nannan, Fan Xinli, Tang Xinjing
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, No. 38 Xueyuan Rd., 100191, Beijing, P.R. China.
Chemistry. 2020 Nov 2;26(61):14002-14010. doi: 10.1002/chem.202003084. Epub 2020 Sep 30.
RNA interference is an essential and powerful tool for targeting and verifying specific gene functions. Conditional control of small interfering RNA (siRNA) activity, especially using light activation, is a potential method for regulating target gene expression and functions. In this study, a series of photolabile siRNAs with amantadine modification have been rationally designed and developed through host-guest interactions between amantadine and β-cyclodextrin derivatives to enhance the blocking effect of siRNA binding and/or RNA-induced silencing complex processing. These caged siRNAs with amantadine modification at the 5' end of antisense-strand RNA were efficiently inactivated through the host-guest interactions between amantadine and β-cyclodextrin. Photomodulation of the gene silencing activity of these amantadine-modified caged siRNAs targeting both exogenous and endogenous genes was successfully achieved, which indicates that host-guest interactions could be a new strategy for developing new caged siRNAs for gene photoregulation with low leaking activity.
RNA干扰是靶向和验证特定基因功能的一种重要且强大的工具。对小干扰RNA（siRNA）活性进行条件控制，尤其是利用光激活，是调节靶基因表达和功能的一种潜在方法。在本研究中，通过金刚烷与β-环糊精衍生物之间的主客体相互作用，合理设计并开发了一系列具有金刚烷修饰的光不稳定siRNA，以增强siRNA结合和/或RNA诱导沉默复合体加工的阻断效果。这些在反义链RNA的5'端具有金刚烷修饰的笼形siRNA通过金刚烷与β-环糊精之间的主客体相互作用被有效灭活。成功实现了对这些靶向外源和内源基因的金刚烷修饰笼形siRNA的基因沉默活性的光调制，这表明主客体相互作用可能是开发具有低泄漏活性的用于基因光调控的新型笼形siRNA的一种新策略。
