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Nucleic Acids Research Advance Access published online on November 28, 2008
Nucleic Acids Research, doi:10.1093/nar/gkn958
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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.

RNA

RNA major groove modifications improve siRNA stability and biological activity

Montserrat Terrazas and Eric T. Kool*

Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA

*To whom correspondence should be addressed. Tel: +1 650 724 4741; Fax: +1 650 725 0259; Email: kool{at}stanford.edu

Received October 20, 2008. Revised November 10, 2008. Accepted November 11, 2008.

RNA 5-methyl and 5-propynyl pyrimidine analogs were substituted into short interfering RNAs (siRNAs) to probe major groove steric effects in the active RNA-induced silencing complex (RISC). Synthetic RNA guide strands containing varied combinations of propynyl and methyl substitution revealed that all C-5 substitutions increased the thermal stability of siRNA duplexes containing them. Cellular gene suppression experiments using luciferase targets in HeLa cells showed that the bulky 5-propynyl modification was detrimental to RNA interference activity, despite its stabilization of the helix. Detrimental effects of this substitution were greatest at the 5'-half of the guide strand, suggesting close steric approach of proteins in the RISC complex with that end of the siRNA/mRNA duplex. However, substitutions with the smaller 5-methyl group resulted in gene silencing activities comparable to or better than that of wild-type siRNA. The major groove modifications also increased the serum stability of siRNAs.


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