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

Bramsen, J. B., Laursen, M. B., Nielsen, A. F., Hansen, T. B., Bus, C., Langkjaer, N., et al. (2009). A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity. Nucleic Acids Research, 37(9), 2867-2881.

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© 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.
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 Creators:
Bramsen, Jesper B., Author
Laursen, Maria B., Author
Nielsen, Anne F., Author
Hansen, Thomas B., Author
Bus, Claus, Author
Langkjaer, Niels, Author
Babu, B. Ravindra, Author
Hojland, Torben, Author
Abramov, Mikhail, Author
Van Aerschot, Arthur, Author
Odadzic, Dalibor, Author
Smicius, Romualdas, Author
Haas, Jens, Author
Andree, Cordula1, Author
Barman, Jharna, Author
Wenska, Malgorzata, Author
Srivastava, Puneet, Author
Zhou, Chuanzheng, Author
Honcharenko, Dmytro, Author
Hess, Simone2, Author              
Müller, Elke2, Author              Bobkov, Georgii V., AuthorMikhailov, Sergey N., AuthorFava, Eugenio1, AuthorMeyer, Thomas F.2, Author              Chattopadhyaya, Jyoti, AuthorZerial, Marino1, AuthorEngels, Joachim W., AuthorHerdewijn, Piet, AuthorWengel, Jesper, AuthorKjems, Jorgen, Author more..
Affiliations:
1Max Planck Society, ou_persistent13              
2Department of Molecular Biology, Max Planck Institute for Infection Biology, Max Planck Society, ou_1664147              

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Free keywords: LOCKED NUCLEIC-ACID; SMALL INTERFERING RNA; MAMMALIAN-CELLS; IN-VIVO;; MODIFIED OLIGONUCLEOTIDES; PASSENGER-STRAND; STRUCTURAL BASIS;; BUILDING-BLOCKS; GUIDE-STRAND; ARGONAUTE2
 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.

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Language(s): eng - English
 Dates: 2009-05
 Publication Status: Published in print
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 Rev. Type: -
 Identifiers: eDoc: 436554
ISI: 000266354600010
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Title: Nucleic Acids Research
Source Genre: Journal
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Pages: - Volume / Issue: 37 (9) Sequence Number: - Start / End Page: 2867 - 2881 Identifier: ISSN: 0305-1048 %R 10.1093/nar/gkp106