ArticleJournal of the American Chemical Society2013
Short interfering RNA guide strand modifiers from computational screening.
Article in Journal of the American Chemical Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Clickable RNA via 4'-Bioconjugate chemistry · 2025Article
- Improving the potency prediction for chemically modified siRNAs through insights from molecular modeling of individual sequence positions.Molecular therapy. Nucleic acids · 2025Article
- siRNA potency enhancement via chemical modifications of nucleotide bases at the 5'-end of the siRNA guide strand.RNA (New York, N.Y.) · 2021Article
- Ester modification at the 3' end of anti-microRNA oligonucleotides increases potency of microRNA inhibition.Bioorganic & medicinal chemistry · 2021Article
- Investigation of Strand-Selective Interaction of SNA-Modified siRNA with AGO2-MID.International journal of molecular sciences · 2020Article
- A Bump-Hole Approach for Directed RNA Editing.Cell chemical biology · 2019Article
- A Single Amide Linkage in the Passenger Strand Suppresses Its Activity and Enhances Guide Strand Targeting of siRNAs.ACS chemical biology · 2018Article
- Evaluation and control of miRNA-like off-target repression for RNA interference.Cellular and molecular life sciences : CMLS · 2018Review
- Exploring PAZ/3'-overhang interaction to improve siRNA specificity. A combined experimental and modeling study.Chemical science · 2018Article
- Controlling miRNA-like off-target effects of an siRNA with nucleobase modifications.Organic & biomolecular chemistry · 2017Article
- Guide Strand 3'-End Modifications Regulate siRNA Specificity.Chembiochem : a European journal of chemical biology · 2016Article
- SMEpred workbench: A web server for predicting efficacy of chemicallymodified siRNAs.RNA biology · 2016Article
- Structure-Guided Control of siRNA Off-Target Effects.Journal of the American Chemical Society · 2016Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
Short interfering RNAs (siRNAs) are promising drug candidates for a wide range of targets including those previously considered "undruggable". However, properties associated with the native RNA structure limit drug development, and chemical modifications are necessary. Here we describe the structure-guided discovery of functional modifications for the guide strand 5'-end using computational screening with the high-resolution structure of human Ago2, the key nuclease on the RNA interference pathway. Our results indicate the guide strand 5'-end nucleotide need not engage in Watson-Crick (W/C) H-bonding but must fit the general shape of the 5'-end binding site in MID/PIWI domains of hAgo2 for efficient knockdown. 1,2,3-Triazol-4-yl bases formed from the CuAAC reaction of azides and 1-ethynylribose, which is readily incorporated into RNA via the phosphoramidite, perform well at the guide strand 5'-end. In contrast, purine derivatives with modified Hoogsteen faces or N2 substituents are poor choices for 5'-end modifications. Finally, we identified a 1,2,3-triazol-4-yl base incapable of W/C H-bonding that performs well at guide strand position 12, where base pairing to target was expected to be important. This work expands the repertoire of functional nucleotide analogues for siRNAs.
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Registered trials
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