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Nucleic Acids Research Advance Access published online on May 15, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn266
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© 2008 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Computational Biology

Fundamental differences in the equilibrium considerations for siRNA and antisense oligodeoxynucleotide design

Zhi John Lu1 and David H. Mathews1,2,*

1Department of Biochemistry and Biophysics and 2Department of Biostatistics & Computational Biology, University of Rochester Medical Center, Box 712, 601 Elmwood Avenue, Rochester, NY 14642, USA

*To whom correspondence should be addressed. Tel: +01 585 275 1734; Fax: +01 585 275 6007; Email: david_mathews{at}urmc.rochester.edu

Received February 22, 2008. Revised April 11, 2008. Accepted April 21, 2008.

Both siRNA and antisense oligodeoxynucleotides (ODNs) inhibit the expression of a complementary gene. In this study, fundamental differences in the considerations for RNA interference and antisense ODNs are reported. In siRNA and antisense ODN databases, positive correlations are observed between the cost to open the mRNA target self-structure and the stability of the duplex to be formed, meaning the sites along the mRNA target with highest potential to form strong duplexes with antisense strands also have the greatest tendency to be involved in pre-existing structure. Efficient siRNA have less stable siRNA–target duplex stability than inefficient siRNA, but the opposite is true for antisense ODNs. It is, therefore, more difficult to avoid target self-structure in antisense ODN design. Self-structure stabilities of oligonucleotide and target correlate to the silencing efficacy of siRNA. Oligonucleotide self-structure correlations to efficacy of antisense ODNs, conversely, are insignificant. Furthermore, self-structure in the target appears to correlate with antisense ODN efficacy, but such that more effective antisense ODNs appear to target mRNA regions with greater self-structure. Therefore, different criteria are suggested for the design of efficient siRNA and antisense ODNs and the design of antisense ODNs is more challenging.


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