Impact of chemical modifications in the structure of isRNA on its antiproliferative and immunostimulatory properties

详细信息    查看全文

• 作者：T. O. Kabilova ; M. I. Meschaninova…
• 关键词：immunostimulatory RNA ; chemical modifications ; cholesterol ; transfection ; pattern recognition receptors
• 刊名：Russian Journal of Bioorganic Chemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：43
• 期：1
• 页码：50-57
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biochemistry, general; Bioorganic Chemistry; Organic Chemistry; Biomedicine general;
• 出版者：Pleiades Publishing
• ISSN：1608-330X
• 卷排序：43

文摘

Short double-stranded RNAs, depending on their structure, sequence, and the method of delivery to cells, can activate the system of innate and adaptive immunity. The immunostimulatory activity of nucleic acids can be used in antitumor and antiviral therapy. We have previously identified a biologically active immunostimulatory 19-bp dsRNA (isRNA) with 3′-nucleotide overhangs, which inhibits the proliferation of tumor cells, stimulates interferon synthesis, and suppresses the growth and metastasis of tumors. Here, we have studied the impact of chemical modifications in the isRNA structure and the type of the transfection agent on the antiproliferative and immunostimulatory properties of isRNA. It has been shown that the attachment of an aminohexyl group or a cholesterol residue to the 5′-terminus of the first strand of the isRNA duplex does not impair its antiproliferative and immunostimulatory properties in vitro and in vivo when it is used in complex with a transfection agent, whereas the modification at the 5′-end of the second strand has an adverse effect on the biological activity of isRNA. It has been found that, when used without the transfection agent, isRNA conjugated with a cholesterol residue does not display antiproliferative and immunostimulatory properties. The use of isRNA in complex with low-toxicity liposomes 2Х3-DOPE enhances its activity: the intravenous injection of the isRNA/2Х3-DOPE complex induces a 55-fold increase in the level of interferon α (INF-α) in the murine blood 6 h after the injection, which is significantly higher than the INF-α level after the injection of the isRNA/Lipofectamine 2000 complex. The cytoplasmic localization of isRNA is crucially important for the manifestation of its antiproliferative activity since the selective inhibition of the dsRNA cytoplasmic sensor PKR (dsRNA-dependent protein kinase R) by 2-aminopurine completely blocks the antiproliferative effect of isRNA.