ArticleMolecular therapy. Nucleic acids2025
An siRMSD parameter of structural distortion induced by chemical modification is predictive of the off-target effect of siRNA.
Article in Molecular therapy. Nucleic acids, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Working So Hard: Double-Stranded RNAs That Can Perform Both Gene Activation and Gene Silencing.Chembiochem : a European journal of chemical biology · 2026Article
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6 authors.
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Abstract
We developed siRMSD, a predictive parameter for off-target effects induced by chemical modifications, to optimize siRNA therapeutics. In RNA interference, small interfering RNA (siRNA) suppresses gene function by degrading mRNA with perfect sequence complementarity, providing therapeutic potential through the targeted inhibition of disease-related genes. However, off-target effects on unintended mRNAs pose a significant challenge to clinical application. While chemical modifications improve nuclease stability and reduce off-target effects, the underlying mechanisms remain unclear. Here, we show that structural distortions caused by chemical modifications determine off-target effects. Modifications, including 2'-O-methoxyethyl, 2'-O-methyl, and 2'-formamido, at positions 2-5 disrupted the A-form RNA duplex on argonaute 2, preventing stable binding to target mRNA. In contrast, modifications at positions 6-8 had minimal impact on off-target effect resulting from changes in thermodynamic stability.
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