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A large-scale chemical modification screen identifies design rules to generate siRNAs with high activity, high stability and low toxicity
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2009 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 37, no 9, 2867-2881 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Oxford University Press , 2009. Vol. 37, no 9, 2867-2881 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-106722DOI: 10.1093/nar/gkp106ISI: 000266354600010OAI: oai:DiVA.org:uu-106722DiVA: diva2:225942
Available from: 2009-06-29 Created: 2009-06-29 Last updated: 2017-12-13Bibliographically approved
In thesis
1. Conformationally Constrained Nucleic Acids as Potential RNA Targeting Therapeutics
Open this publication in new window or tab >>Conformationally Constrained Nucleic Acids as Potential RNA Targeting Therapeutics
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Publisher
67 p.
National Category
Organic Chemistry
Research subject
Chemistry with specialization in Bioorganic Chemistry
Identifiers
urn:nbn:se:uu:diva-113680 (URN)
Public defence
2010-03-31, C10:301, BMC, Husargatan 3, Uppsala, 14:00 (English)
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Supervisors
Available from: 2010-03-10 Created: 2010-02-02 Last updated: 2010-03-11

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Srivastava, PuneetZhou, ChuanzhengHoncharenko, DmytroChattopadhyaya, Jyoti

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Srivastava, PuneetZhou, ChuanzhengHoncharenko, DmytroChattopadhyaya, Jyoti
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