Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties
Mesyl phosphoramidate antisense oligonucleotides as an alternative to phosphorothioates with improved biochemical and biological properties
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DOI：
10.1073/pnas.1813376116
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发表时间：
2019-01-22
影响因子：
11.1
通讯作者：
Stetsenko, D. A.
中科院分区：
文献类型：
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作者：
Miroshnichenko, S. K.;Patutina, O. A.;Stetsenko, D. A.
在这里，我们描述了一种DNA类似物，其中甲酰基（甲磺酰基）酰胺基在每个核苷酸间位置取代天然磷酸二酯基。与常用的DNA硫代酸盐相比，低聚物在RNA结合亲和力、核酸酶稳定性和反义作用特异性方面具有显著优势，反义作用涉及激活细胞RNase H酶进行杂交定向RNA切割。寡核苷酸类似物对促癌miR-21的生物活性得到证实。22-nt anti-miR-21 mesyl phospamidate oligodeoxynucleotide特异性降低黑色素瘤B16细胞中miR-21水平，诱导细胞凋亡，减少增殖，阻碍肿瘤细胞迁移，在生物学效应特异性上优于同序列phosp硫代寡脱氧核苷酸。与硫代磷酸酯相比，低总毒性和更有效的RNase H活化是甲酰基磷酰胺寡核苷酸的主要优势，可能是一组有前途的反义治疗剂。
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.