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A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity
Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review
- Jesper B Bramsen
- Maria Bach Laursen
- Anne F Nielsen
- Thomas B Hansen
- Claus Bus
- Niels Langkjær, Nucleic Acid Center, University of Southern Denmark, Denmark
- Bolle Ravindra Babu, Nucleic Acid Center, University of Southern Denmark, Denmark
- Torben Højland, Nucleic Acid Center, University of Southern Denmark, Denmark
- Mikhail Abramov, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
- Arthur Van Aerschot, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium
- Dalibor Odadzic, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Germany
- Romualdas Smicius, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Germany
- Jens Haas, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Germany
- Cordula Andree, Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- Jharna Barman, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Malgorzata Wenska, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Puneet Srivastava, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Chuanzheng Zhou, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Dmytro Honcharenko, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Simone Hess, Department of Molecular Biology, Max Planck Institute for Infection Biology, Germany
- Elke Müller, Department of Molecular Biology, Max Planck Institute for Infection Biology, Germany
- Georgii V Bobkov, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Russian Federation
- Sergey N Mikhailov, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Russian Federation
- Eugenio Fava, Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- Thomas F Meyer, Department of Molecular Biology, Max Planck Institute for Infection Biology, BerlinDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, Germany
- Jyoti Chattopadhyaya, Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Sweden
- Marino Zerial, Max Planck Institute of Molecular Cell Biology and Genetics, Germany
- Joachim W Engels, Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Germany
- Piet Herdewijn, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium
- Jesper Wengel, Nucleic Acid Center, University of Southern Denmark, Denmark
- Jørgen Kjems
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.
| Original language | English |
|---|---|
| Journal | Nucleic Acids Research |
| Volume | 37 |
| Issue | 9 |
| Pages (from-to) | 2867-81 |
| Number of pages | 15 |
| ISSN | 0305-1048 |
| DOIs | |
| Publication status | Published - 2009 |
- Cell Line, Tumor, Cell Survival, Humans, RNA Interference, RNA Stability, RNA, Small Interfering, RNA-Induced Silencing Complex
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ID: 44941532