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Nucleic Acids Research Advance Access originally published online on March 12, 2009
Nucleic Acids Research 2009 37(9):2867-2881; doi:10.1093/nar/gkp106
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Nucleic Acids Research, 2009, Vol. 37, No. 9 2867-2881
© 2009 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

A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity

Jesper B. Bramsen1,*, Maria B. Laursen1, Anne F. Nielsen1, Thomas B. Hansen1, Claus Bus1, Niels Langkjær2, B. Ravindra Babu2, Torben Højland2, Mikhail Abramov3, Arthur Van Aerschot3, Dalibor Odadzic4, Romualdas Smicius4, Jens Haas4, Cordula Andree5, Jharna Barman6, Malgorzata Wenska6, Puneet Srivastava6, Chuanzheng Zhou6, Dmytro Honcharenko6, Simone Hess7, Elke Müller7, Georgii V. Bobkov8, Sergey N. Mikhailov8, Eugenio Fava5, Thomas F. Meyer7, Jyoti Chattopadhyaya6, Marino Zerial5, Joachim W. Engels4, Piet Herdewijn3, Jesper Wengel2 and Jørgen Kjems1

1Department of Molecular Biology, University of Aarhus, Århus, 2Nucleic Acid Center, University of Southern Denmark, Odense, Denmark, 3Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium, 4Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Frankfurt am Main, 5Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany, 6Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden, 7Department of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany and 8Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia

*To whom correspondence should be addressed. Tel: +45 8942 2668; Fax: +45 8619 6500; Email: jebb{at}mb.au.dk

Received November 26, 2008. Revised February 9, 2009. Accepted February 9, 2009.

The use of chemically synthesized short interfering RNAs (siRNAs) is currently the method of choice to manipulate gene expression in mammalian cell culture, yet improvements of siRNA design is expectably required for successful application in vivo. Several studies have aimed at improving siRNA performance through the introduction of chemical modifications but a direct comparison of these results is difficult. We have directly compared the effect of 21 types of chemical modifications on siRNA activity and toxicity in a total of 2160 siRNA duplexes. We demonstrate that siRNA activity is primarily enhanced by favouring the incorporation of the intended antisense strand during RNA-induced silencing complex (RISC) loading by modulation of siRNA thermodynamic asymmetry and engineering of siRNA 3'-overhangs. Collectively, our results provide unique insights into the tolerance for chemical modifications and provide a simple guide to successful chemical modification of siRNAs with improved activity, stability and low toxicity.


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