Self-neutralizing oligonucleotides with enhanced cellular uptake.
Self-neutralizing oligonucleotides with enhanced cellular uptake.
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具有增强细胞摄取的自我中和寡核苷酸。
DOI：
10.1039/c6ob02576e
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发表时间：
2017
影响因子：
3.2
通讯作者：
Tabatadze,DavidR
中科院分区：
文献类型：
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作者：
Yanachkov,Ivan;Zavizion,Boris;Metelev,Valeri;Stevens,LauraJ;Tabatadze,Yekaterina;Yanachkova,Milka;Wright,George;Krichevsky,AnnaM;Tabatadze,DavidR
寡核苷酸(ON)疗法具有巨大的潜力，但由于其多阴离子性质而导致的低细胞渗透率是一个主要障碍。我们开发了一种新的电荷中和方法来解决这个问题，在这种方法中，多个支化的电荷中和套(BCNS)通过磷酸三酯键连接到ON的核苷磷酸盐上。BCNS以带正电荷的氨基终止，并被优化以与邻近的磷酸基团形成离子对。新的改性ONS可以用标准的自动化亚磷酰胺化学方法制备，产率和纯度都很好。它们具有良好的溶解性和杂交性，不参与非标准的分子内聚集，具有低的细胞毒性，足够的化学稳定性，改善的血清稳定性，最重要的是，显示出显著增强的细胞摄取。因此，新的ON衍生物表现出的性质使它们成为开发新的治疗或研究工具以调节靶基因表达的有前景的候选者。
There is tremendous potential for oligonucleotide (ON) therapeutics, but low cellular penetration due to their polyanionic nature is a major obstacle. We addressed this problem by developing a new approach for ON charge neutralization in which multiple branched charge-neutralizing sleeves (BCNSs) are attached to the internucleoside phosphates of ON by phosphotriester bonds. The BCNSs are terminated with positively charged amino groups, and are optimized to form ion pairs with the neighboring phosphate groups. The new modified ONs can be prepared by standard automated phosphoramidite chemistry in good yield and purity. They possess good solubility and hybridization properties, are not involved in non-standard intramolecular aggregation, have low cytotoxicity, adequate chemical stability, improved serum stability, and above all, display significantly enhanced cellular uptake. Thus, the new ON derivatives exhibit properties that make them promising candidates for the development of novel therapeutics or research tools for modulation of the expression of target genes.