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Molecules 2015, 20(5), 7602-7619; doi:10.3390/molecules20057602

Modulation of the RNA Interference Activity Using Central Mismatched siRNAs and Acyclic Threoninol Nucleic Acids (aTNA) Units

1
Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), CIBER-BBN Networking Centre on Bioengineering, Biomaterials and Nanomedicine, Jordi Girona 18-26, 08034 Barcelona, Spain
2
Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, 08028 Barcelona, Spain
*
Author to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 13 January 2015 / Revised: 21 April 2015 / Accepted: 22 April 2015 / Published: 24 April 2015
(This article belongs to the Special Issue Frontiers in Nucleic Acid Chemistry)
View Full-Text   |   Download PDF [1604 KB, uploaded 24 April 2015]   |  

Abstract

The understanding of the mechanisms behind nucleotide recognition by Argonaute 2, core protein of the RNA-induced silencing complex, is a key aspect in the optimization of small interfering RNAs (siRNAs) activity. To date, great efforts have been focused on the modification of certain regions of siRNA, such as the 3'/5'-termini and the seed region. Only a few reports have described the roles of central positions flanking the cleavage site during the silence process. In this study, we investigate the potential correlations between the thermodynamic and silencing properties of siRNA molecules carrying, at internal positions, an acyclic L-threoninol nucleic acid (aTNA) modification. Depending on position, the silencing is weakened or impaired. Furthermore, we evaluate the contribution of mismatches facing either a natural nucleotide or an aTNA modification to the siRNA potency. The position 11 of the antisense strand is more permissive to mismatches and aTNA modification, in respect to the position 10. Additionally, comparing the ON-/OFF-target silencing of central mismatched siRNAs with 5'-terminal modified siRNA, we concluded: (i) central perturbation of duplex pairing features weights more on potency rather than silencing asymmetry; (ii) complete bias for the ON-target silencing can be achieved with single L-threoninol modification near the 5'-end of the sense strand. View Full-Text
Keywords: RNAi; siRNA; single-stranded siRNA; L-threoninol; Ago2; RISC; silencing asymmetry; wobble base pair; on-/off-target effects; central mismatched siRNA RNAi; siRNA; single-stranded siRNA; L-threoninol; Ago2; RISC; silencing asymmetry; wobble base pair; on-/off-target effects; central mismatched siRNA
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Alagia, A.; Terrazas, M.; Eritja, R. Modulation of the RNA Interference Activity Using Central Mismatched siRNAs and Acyclic Threoninol Nucleic Acids (aTNA) Units. Molecules 2015, 20, 7602-7619.

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