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Title: A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity
Authors: Bramsen, Jesper B ×
Laursen, Maria B
Nielsen, Anne F
Hansen, Thomas B
Bus, Claus
Langkjaer, Niels
Babu, B. Ravindra
Hojland, Torben
Abramov, Mikhail
Van Aerschot, Arthur
Odadzic, Dalibor
Smicius, Romualdas
Haas, Jens
Andree, Cordula
Barman, Jharna
Wenska, Malgorzata
Srivastava, Puneet
Zhou, Chuanzheng
Honcharenko, Dmytro
Hess, Simone
Mueller, Elke
Bobkov, Georgii V
Mikhailov, Sergey N
Fava, Eugenio
Meyer, Thomas F
Chattopadhyaya, Jyoti
Zerial, Marino
Engels, Joachim W
Herdewijn, Piet
Wengel, Jesper
Kjems, Jorgen #
Issue Date: May-2009
Publisher: Oxford univ press
Series Title: Nucleic acids research vol:37 issue:9 pages:2867-2881
Abstract: 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.
URI: 
ISSN: 0305-1048
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Medicinal Chemistry
Associated Section of ESAT - INSYS, Integrated Systems
× corresponding author
# (joint) last author

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