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A Single Amide Linkage in the Passenger Strand Suppresses Its Activity and Enhances Guide Strand Targeting of siRNAs
ACS Chemical Biology ( IF 4 ) Pub Date : 2018-01-03 00:00:00 , DOI: 10.1021/acschembio.7b01012
Travis Hardcastle 1 , Irina Novosjolova 2 , Venubabu Kotikam 2 , Samwel K. Cheruiyot 2 , Daniel Mutisya 2 , Scott D. Kennedy 3 , Martin Egli 4 , Melissa L. Kelley 1 , Anja van Brabant Smith 1 , Eriks Rozners 2
Affiliation  

Potential in vivo applications of RNA interference (RNAi) require suppression of various off-target activities. Herein, we report that replacement of a single phosphate linkage between the first and second nucleosides of the passenger strand with an amide linkage almost completely abolished its undesired activity and restored the desired activity of guide strands that had been compromised by unfavorable amide modifications. Molecular modeling suggested that the observed effect was most likely due to suppressed loading of the amide-modified strand into Ago2 caused by inability of amide to adopt the conformation required for the backbone twist that docks the first nucleotide of the guide strand in the MID domain of Ago2. Eliminating off-target activity of the passenger strand will be important for improving therapeutic potential of RNAi.

中文翻译:

乘客链中的单个酰胺键抑制其活性并增强siRNA的引导链靶向。

体内潜在RNA干扰(RNAi)的应用需要抑制各种脱靶活性。在本文中,我们报道用酰胺键取代过客链的第一和第二核苷之间的单个磷酸酯键几乎完全消除了其不希望的活性,并恢复了由于不利的酰胺修饰而受损的引导链的所需活性。分子模型表明,观察到的效果很可能是由于酰胺无法采用酰胺修饰的链进入Ago2的负载所致,而该修饰是由于酰胺无法采用将引导链的第一个核苷酸停靠在MID结构域中的骨架扭曲所需的构象而引起的。前2。消除过客链的脱靶活性对于提高RNAi的治疗潜力非常重要。
更新日期:2018-01-03
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