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dc.contributor.author
Jahns, Hartmut
dc.contributor.author
Roos, Martina
dc.contributor.author
Imig, Jochen
dc.contributor.author
Baumann, Fabienne
dc.contributor.author
Wang, Yuluan
dc.contributor.author
Gilmour, Ryan
dc.contributor.author
Hall, Jonathan
dc.date.accessioned
2018-09-07T15:29:32Z
dc.date.available
2017-06-11T16:34:22Z
dc.date.available
2018-09-07T15:29:32Z
dc.date.issued
2015
dc.identifier.issn
2041-1723
dc.identifier.other
10.1038/ncomms7317
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/99092
dc.identifier.doi
10.3929/ethz-b-000099092
dc.description.abstract
An established means of improving the pharmacokinetics properties of oligoribonucleotides (ORNs) is to exchange their phosphodiester linkages for phosphorothioates (PSs). However, this strategy has not been pursued for small interfering RNAs (siRNAs), possibly because of sporadic reports that PS siRNAs show reduced inhibitory activity. The PS group is chiral at phosphorous (Rp/Sp centres), and conventional solid-phase synthesis of PS ORNs produces a population of diastereoisomers. Here we show that the choice of the activating agent for the synthesis of a PS ORN influences the Rp/Sp ratio of PS linkages throughout the strand. Furthermore, PS siRNAs composed of ORNs with a higher fraction of Rp centres show greater resistance to nucleases in serum and are more effective inhibitors in cells than their Sp counterparts. The finding that a stereochemically biased population of ORN diastereoisomers can be synthesized and exploited pharmacologically is important because uniform PS modification of siRNAs may provide a useful compromise of their pharmacokinetics and pharmacodynamics properties in RNAi therapeutics.
en_US
dc.format
application/pdf
en_US
dc.language.iso
en
en_US
dc.publisher
Nature Publishing Group
en_US
dc.rights.uri
http://creativecommons.org/licenses/by/4.0/
dc.title
Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs
en_US
dc.type
Journal Article
dc.rights.license
Creative Commons Attribution 4.0 International
dc.date.published
2015-03-06
ethz.journal.title
Nature Communications
ethz.journal.volume
6
en_US
ethz.journal.abbreviated
Nat Commun
ethz.pages.start
6317
en_US
ethz.size
9 p.
en_US
ethz.version.deposit
publishedVersion
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.identifier.nebis
007044158
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.leitzahl
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03760 - Hall, Jonathan / Hall, Jonathan
en_US
ethz.leitzahl.certified
ETH Zürich::00002 - ETH Zürich::00012 - Lehre und Forschung::00007 - Departemente::02020 - Dep. Chemie und Angewandte Biowiss. / Dep. of Chemistry and Applied Biosc.::02534 - Institut für Pharmazeutische Wiss. / Institute of Pharmaceutical Sciences::03760 - Hall, Jonathan / Hall, Jonathan
ethz.date.deposited
2017-06-11T16:34:41Z
ethz.source
ECIT
ethz.identifier.importid
imp593653030155375964
ethz.ecitpid
pub:155030
ethz.eth
yes
en_US
ethz.availability
Open access
en_US
ethz.rosetta.installDate
2017-07-20T16:58:07Z
ethz.rosetta.lastUpdated
2020-02-15T14:54:02Z
ethz.rosetta.versionExported
true
ethz.COinS
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