Chemical modification patterns compatible with high potency Dicer-substrate small interfering RNAs
Chemical modification patterns compatible with high potency Dicer-substrate small interfering RNAs
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DOI：
10.1089/oli.2008.0123
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发表时间：
2008-06-01
期刊：
影响因子：
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通讯作者：
Behlke, Mark A.
中科院分区：
文献类型：
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作者：
Collingwood, Michael A.;Rose, Scott D.;Behlke, Mark A.
Dicer底物小干扰RNA（DsiRNA）是合成的RNA双链体，其被Dicer加工成21-mer物质，并且显示出作为RNA干扰触发剂的改进的效力，特别是当以低剂量使用时。几个研究小组已经报道了与高效21聚体小干扰RNA相容的化学修饰模式。然而，尚未研究Dicer-底物双链体的修饰模式。因此，我们合成了一系列化学修饰的27-mer DsiRNA，并将修饰模式与功能效力相关联。一些修饰模式深刻地降低了功能，尽管其他模式保持了高效力。观察到序列背景的影响，其中修饰模式的相对效力在位点之间变化。开发了涉及交替的2 '-O-甲基RNA碱基的修饰模式，当在不同基因的不同位点测试时，该修饰模式通常保持高效力，避免先天免疫系统的激活，并提高血清中的稳定性。
Dicer-substrate small interfering RNAs (DsiRNAs) are synthetic RNA duplexes that are processed by Dicer into 21-mer species and show improved potency as triggers of RNA interference, particularly when used at low dose. Chemical modification patterns that are compatible with high potency 21-mer small interfering RNAs have been reported by several groups. However, modification patterns have not been studied for Dicer-substrate duplexes. We therefore synthesized a series of chemically modified 27-mer DsiRNAs and correlated modification patterns with functional potency. Some modification patterns profoundly reduced function although other patterns maintained high potency. Effects of sequence context were observed, where the relative potency of modification patterns varied between sites. A modification pattern involving alternating 2'-O-methyl RNA bases was developed that generally retains high potency when tested in different sites in different genes, evades activation of the innate immune system, and improves stability in serum.