Circular Antisense Oligonucleotides for Specific RNase-H-Mediated microRNA Inhibition with Reduced Off-Target Effects and Nonspecific Immunostimulation,Journal of Medicinal Chemistry

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Circular Antisense Oligonucleotides for Specific RNase-H-Mediated microRNA Inhibition with Reduced Off-Target Effects and Nonspecific Immunostimulation
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-10-21 , DOI: 10.1021/acs.jmedchem.1c01421
Amu Gubu _{1,

2} , Wenbo Su _{1,

2} , Xiaoran Zhao _{1,

2} , Xueli Zhang _{1,

2} , Xinli Fan _{1,

2} , Jing Wang ₁ , Qian Wang ₁ , Xinjing Tang _{1,

2}

Affiliation

Antisense microRNA oligodeoxynucleotides (AMOs) are powerful tools to regulate microRNA functions. Unfortunately, severe off-target effects are sometimes observed. Due to the special topological and enzymatic properties of circular oligodeoxynucleotides (c-ODNs), we rationally designed and developed circular AMOs, which effectively inhibited microRNA functions with high target specificity and low off-target effects. Binding and enzymatic assays indicated that small circular AMOs could selectively bind to and further digest the target mature miR 21, which suggested that the topological properties of circular c-ODNs significantly decreased their off-target effects as microRNA inhibitors. Compared with their linear corresponding phosphorothioated AMOs, circular phosphorothioated AMOs could more effectively reduce the amount of carcinogenic miR 21 and miR 222 and upregulate the expression levels of downstream antitumor proteins of PTEN and PDCD4. In addition, c-PS-antimiRs induced much less nonspecific immunostimulatory effects compared with their linear partner PS-ODNs, further indicating the advantages of circular ODNs in nonspecific immunostimulation.

中文翻译：

用于特定 RNase-H 介导的 microRNA 抑制的环状反义寡核苷酸具有减少的脱靶效应和非特异性免疫刺激

反义 microRNA 寡脱氧核苷酸 (AMO) 是调节 microRNA 功能的强大工具。不幸的是，有时会观察到严重的脱靶效应。由于环状寡核苷酸（c-ODNs）的特殊拓扑和酶学特性，我们合理设计和开发了环状AMOs，它有效地抑制了microRNA的功能，具有高靶向特异性和低脱靶效应。结合和酶促分析表明，小的环状 AMO 可以选择性地结合并进一步消化目标成熟 miR 21，这表明环状 c-ODN 的拓扑特性显着降低了它们作为 microRNA 抑制剂的脱靶效应。与其线性对应的硫代磷酸化 AMO 相比，环状硫代磷酸化AMOs可以更有效地降低致癌性miR 21和miR 222的量，上调下游抗肿瘤蛋白PTEN和PDCD4的表达水平。此外，与线性伙伴 PS-ODN 相比，c-PS-antimiR 诱导的非特异性免疫刺激作用要小得多，进一步表明环状 ODN 在非特异性免疫刺激中的优势。

更新日期：2021-11-11

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