Institute of Chemical Biology and Fundamental Medicine, Siberian Branch of the Russian Academy of Sciences (ICBFM SB RAS), 630090 Novosibirsk, Russia.
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520;
Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1229-1234. doi: 10.1073/pnas.1813376116. Epub 2019 Jan 8.
Here we describe a DNA analog in which the mesyl (methanesulfonyl) phosphoramidate group is substituted for the natural phosphodiester group at each internucleotidic position. The oligomers show significant advantages over the often-used DNA phosphorothioates in RNA-binding affinity, nuclease stability, and specificity of their antisense action, which involves activation of cellular RNase H enzyme for hybridization-directed RNA cleavage. Biological activity of the oligonucleotide analog was demonstrated with respect to pro-oncogenic miR-21. A 22-nt anti-miR-21 mesyl phosphoramidate oligodeoxynucleotide specifically decreased the miR-21 level in melanoma B16 cells, induced apoptosis, reduced proliferation, and impeded migration of tumor cells, showing superiority over isosequential phosphorothioate oligodeoxynucleotide in the specificity of its biological effect. Lower overall toxicity compared with phosphorothioate and more efficient activation of RNase H are the key advantages of mesyl phosphoramidate oligonucleotides, which may represent a promising group of antisense therapeutic agents.
在这里，我们描述了一种 DNA 类似物，其中每个核苷酸位置的亚磺酰（甲烷磺酰基）磷酰胺取代了天然的磷酸二酯基团。与经常使用的 DNA 硫代磷酸酯相比，这些寡聚物在 RNA 结合亲和力、核酸酶稳定性和反义作用的特异性方面具有显著优势，反义作用涉及激活细胞内的 RNase H 酶进行杂交指导的 RNA 切割。寡核苷酸类似物的生物学活性已在致癌 miR-21 方面得到证明。22 个碱基对的抗 miR-21 亚磺酰磷酰胺寡脱氧核苷酸可特异性降低黑色素瘤 B16 细胞中的 miR-21 水平，诱导细胞凋亡，降低增殖并阻碍肿瘤细胞迁移，在其生物学效应的特异性方面优于等序硫代磷酸酯寡脱氧核苷酸。与硫代磷酸酯相比，总体毒性更低，并且更有效地激活 RNase H，是亚磺酰磷酰胺寡核苷酸的关键优势，它们可能代表一类有前途的反义治疗剂。
