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          Institute: MPI für Infektionsbiologie     Collection: Department of Molecular Biology     Display Documents



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ID: 436554.0, MPI für Infektionsbiologie / Department of Molecular Biology
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; Müller, 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
Language:English
Date of Publication (YYYY-MM-DD):2009-05
Title of Journal:Nucleic Acids Research
Volume:37
Issue / Number:9
Start Page:2867
End Page:2881
Copyright:© 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.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
Free Keywords:LOCKED NUCLEIC-ACID; SMALL INTERFERING RNA; MAMMALIAN-CELLS; IN-VIVO;; MODIFIED OLIGONUCLEOTIDES; PASSENGER-STRAND; STRUCTURAL BASIS;; BUILDING-BLOCKS; GUIDE-STRAND; ARGONAUTE2
External Publication Status:published
Document Type:Article
Communicated by:Hilmar Fünning
Affiliations:MPI für Infektionsbiologie/Department of Molecular Biology
MPI für molekulare Zellbiologie und Genetik
External Affiliations:Department of Molecular Biology, University of Aarhus, Århus; Nucleic Acid Center, University of Southern Denmark, Odense, Denmark; Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium; Institute of Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Frankfurt am Main; Department of Bioorganic Chemistry, Biomedical Center, Uppsala University, Uppsala, Sweden; Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
Identifiers:ISSN:0305-1048 %R 10.1093/nar/gkp106 [ID No:1]
ISI:000266354600010 [ID No:2]
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