Yanachkov Ivan, Zavizion Boris, Metelev Valeri, Stevens Laura J, Tabatadze Yekaterina, Yanachkova Milka, Wright George, Krichevsky Anna M, Tabatadze David R
ZATA Pharmaceuticals, Inc., 60 Prescott St., Worcester, MA 01605, USA.
GLSynthesis, Inc., One Innovation Drive, Worcester, MA 01605, USA.
Org Biomol Chem. 2017 Feb 7;15(6):1363-1380. doi: 10.1039/c6ob02576e.
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.
寡核苷酸（ON）疗法具有巨大潜力，但因其多阴离子性质导致细胞穿透性低是一个主要障碍。我们通过开发一种新的ON电荷中和方法来解决这个问题，即在ON的核苷间磷酸上通过磷酸三酯键连接多个分支电荷中和套筒（BCNS）。BCNS以带正电荷的氨基结尾，并经过优化以与相邻的磷酸基团形成离子对。新的修饰寡核苷酸可以通过标准的自动化亚磷酰胺化学方法以良好的产率和纯度制备。它们具有良好的溶解性和杂交特性，不参与非标准的分子内聚集，具有低细胞毒性、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衍生物展现出的特性使其成为开发新型治疗药物或用于调节靶基因表达的研究工具的有前景的候选物。
