Cellular Delivery and Photochemical Activation of Antisense Agents through a Nucleobase Caging Strategy
Cellular Delivery and Photochemical Activation of Antisense Agents through a Nucleobase Caging Strategy
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DOI：
10.1021/cb400293e
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发表时间：
2013-10-01
影响因子：
4
通讯作者：
Deiters, Alexander
中科院分区：
文献类型：
--
作者：
Govan, Jeane M.;Uprety, Rajendra;Deiters, Alexander
反义寡核苷酸是调控细胞和模式生物基因表达的有力工具。然而，通常需要转染或显微注射来有效递送反义剂。我们报告的共轭多个HIV达特肽的发夹保护的反义药物通过光可切割的核碱基笼组。这种缀合允许在没有转染试剂的情况下容易地递送反义试剂，并且光化学活化提供对基因表达的精确控制。所开发的方法是高度模块化的，如通过叶酸与笼状反义剂的缀合所证明的。这使得能够通过细胞表面叶酸受体进行靶向细胞递送，然后光化学触发反义活性。重要的是，所提出的策略在光活化后递送天然寡核苷酸，没有任何递送功能或修饰，否则可能损害其反义活性。
Antisense oligonucleotides are powerful tools to regulate gene expression in cells and model organisms. However, a transfection or microinjection is typically needed for efficient delivery of the antisense agent. We report the conjugation of multiple HIV TAT peptides to a hairpin-protected antisense agent through a light-cleavable nucleobase caging group. This conjugation allows for the facile delivery of the antisense agent without a transfection reagent, and photochemical activation offers precise control over gene expression. The developed approach is highly modular, as demonstrated by the conjugation of folic acid to the caged antisense agent. This enabled targeted cell delivery through cell-surface folate receptors followed by photochemical triggering of antisense activity. Importantly, the presented strategy delivers native oligonucleotides after light-activation, devoid of any delivery functionalities or modifications that could otherwise impair their antisense activity.