TY  - JOUR
A1  - Bramsen, Jesper B.
A1  - Laursen, Maria B.
A1  - Nielsen, Anne F.
A1  - Hansen, Thomas B.
A1  - Bus, Claus
A1  - Langkjaer, Niels
A1  - Babu, B. Ravindra
A1  - Hojland, Torben
A1  - Abramov, Mikhail
A1  - Van Aerschot, Arthur
A1  - Odadžić, Dalibor
A1  - Smicius, Romualdas
A1  - Haas, Jens
A1  - Andree, Cordula
A1  - Barman, Jharna
A1  - Wenska, Malgorzata
A1  - Srivastava, Puneet
A1  - Zhou, Chuanzheng
A1  - Honcharenko, Dmytro
A1  - Hess, Simone
A1  - Müller, Elke
A1  - Bobkov, Georgii V.
A1  - Mikhailov, Sergey N.
A1  - Fava, Eugenio
A1  - Meyer, Thomas F.
A1  - Chattopadhyaya, Jyoti
A1  - Zerial, Marino
A1  - Engels, Joachim W.
A1  - Herdewijn, Piet
A1  - Wengel, Jesper
A1  - Kjems, Jørgen
T1  - A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity
T2  - Nucleic Acids Research
N2  - 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.
KW  - LOCKED NUCLEIC-ACID
KW  - SMALL INTERFERING RNA
KW  - MAMMALIAN-CELLS
KW  - IN-VIVO
KW  - MODIFIED OLIGONUCLEOTIDES
KW  - PASSENGER-STRAND
KW  - STRUCTURAL BASIS
Y1  - 2009
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/7469
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30-74453
N1  - © 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.
VL  - 37
IS  - 9
SP  - 2867
EP  - 2881
ER  -