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Nucleic Acids Research 2004 32(20):5991-6000; doi:10.1093/nar/gkh936
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Published online 15 November 2004

Nucleic Acids Research, Vol. 32 No. 20 © Oxford University Press 2004; all rights reserved

RNA interference using boranophosphate siRNAs: structure–activity relationships

Allison H. S. Hall1, Jing Wan2, Erin E. Shaughnessy3, Barbara Ramsay Shaw2 and Kenneth A. Alexander1,4,*

1 Department of Molecular Genetics and Microbiology, Box 3020, Duke University Medical Center, Durham, NC 27710, USA, 2 Department of Chemistry, Box 90354, Duke University, Durham, NC 27708, USA, 3 School of Medicine, Duke University Medical Center, Durham, NC 27710, USA and 4 Division of Pediatric Infectious Disease, Department of Pediatrics, Box 3461, Duke University Medical Center, Durham, NC 27710, USA

* To whom correspondence should be addressed. Tel: +919 684 9590; Fax: +919 684 8735; Email: alexa005{at}mc.duke.edu
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors

Received February 24, 2004; Revised May 20, 2004; Accepted October 25, 2004

In RNA interference (RNAi), short double-stranded RNA (known as siRNA) inhibits expression from homologous genes. Clinical or pre-clinical use of siRNAs is likely to require stabilizing modifications because of the prevalence of intracellular and extracellular nucleases. In order to examine the effect of modification on siRNA efficacy and stability, we developed a new method for synthesizing stereoregular boranophosphate siRNAs. This work demonstrates that boranophosphate siRNAs are consistently more effective than siRNAs with the widely used phosphorothioate modification. Furthermore, boranophosphate siRNAs are frequently more active than native siRNA if the center of the antisense strand is not modified. Boranophosphate modification also increases siRNA potency. The finding that boranophosphate siRNAs are at least ten times more nuclease resistant than unmodified siRNAs may explain some of the positive effects of boranophosphate modification. The biochemical properties of boranophosphate siRNAs make them promising candidates for an RNAi-based therapeutic.


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