Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets,ACS Omega

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Chemical Modification of the siRNA Seed Region Suppresses Off-Target Effects by Steric Hindrance to Base-Pairing with Targets
ACS Omega ( IF 3.7 ) Pub Date : 2017-05-12 00:00:00 , DOI: 10.1021/acsomega.7b00291
Hanna Iribe ₁ , Kengo Miyamoto ₂ , Tomoko Takahashi ₃ , Yoshiaki Kobayashi ₃ , Jastina Leo _{3,

4} , Misako Aida ₂ , Kumiko Ui-Tei _{1,

3}

Affiliation

Chemical modifications of 2′-O-methyl (2′-OMe) and locked nucleic acid (LNA) of the nucleotides in the seed region (positions 2–8) of the small interfering RNA (siRNA) guide strand significantly reduced seed-matched (SM) off-target effects. The siRNA with 2′-OMe modifications inhibited the expression of a completely-matched (CM) target gene, whereas that with LNA modifications did not inhibit the expression of the CM target. By computational predictions of conformational changes of siRNA by these modifications, we revealed that both modifications in the siRNA seed region reduce SM off-target effects by steric hindrance to base-pairing with target transcripts but LNA modifications also disturb the association of the siRNA guide strand with the Argonaute (AGO) protein by altering RNA conformation. Thus, chemical modifications of the siRNA guide strand, which alter steric conformation to disturb base-pairing with target transcripts but do not disturb the association with the AGO protein, may successfully suppress off-target effects without substantial loss of RNA silencing activity.

中文翻译：

siRNA种子区域的化学修饰通过立体抑制抑制与靶标碱基配对的脱靶效应。

对2'-O-甲基（2'-OMe）的化学修饰和小干扰RNA（siRNA）引导链的种子区域（位置2-8）中核苷酸的锁定核酸（LNA）大大降低了种子匹配（SM）脱靶效果。具有2'-OMe修饰的siRNA抑制了完全匹配的（CM）靶基因的表达，而具有LNA修饰的siRNA却没有抑制CM靶的表达。通过这些修饰对siRNA构象变化的计算预测，我们发现siRNA种子区域中的两个修饰都通过与目标转录本碱基配对的空间位阻降低了SM脱靶效应，但LNA修饰也干扰了siRNA导链的缔合。通过改变RNA构象与Argonaute（AGO）蛋白结合。因此，

更新日期：2017-05-12

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