Rational design of novel N-alkyl-N capped biostable RNA nanostructures for efficient long-term inhibition of gene expression.

Autor:	Terrazas M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain montserrat.terrazas@irbbarcelona.org., Ivani I; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain., Villegas N; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain., Paris C; Department of Organic Chemistry and IBUB, University of Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain., Salvans C; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain., Brun-Heath I; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain., Orozco M; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Joint IRB-BSC Program in Computational Biology, Baldiri Reixac 10-12, 08028 Barcelona, Spain Barcelona Supercomputing Center, Jordi Girona 29, 08034 Barcelona, Spain Department of Biochemistry and Molecular Biology, University of Barcelona, 08028 Barcelona, Spain modesto.orozco@irbbarcelona.org.
Jazyk:	angličtina
Zdroj:	Nucleic acids research [Nucleic Acids Res] 2016 May 19; Vol. 44 (9), pp. 4354-67. Date of Electronic Publication: 2016 Mar 14.
DOI:	10.1093/nar/gkw169
Abstrakt:	Computational techniques have been used to design a novel class of RNA architecture with expected improved resistance to nuclease degradation, while showing interference RNA activity. The in silico designed structure consists of a 24-29 bp duplex RNA region linked on both ends by N-alkyl-N dimeric nucleotides (BCn dimers; n = number of carbon atoms of the alkyl chain). A series of N-alkyl-N capped dumbbell-shaped structures were efficiently synthesized by double ligation of BCn-loop hairpins. The resulting BCn-loop dumbbells displayed experimentally higher biostability than their 3'-N-alkyl-N linear version, and were active against a range of mRNA targets. We studied first the effect of the alkyl chain and stem lengths on RNAi activity in a screen involving two series of dumbbell analogues targeting Renilla and Firefly luciferase genes. The best dumbbell design (containing BC6 loops and 29 bp) was successfully used to silence GRB7 expression in HER2+ breast cancer cells for longer periods of time than natural siRNAs and known biostable dumbbells. This BC6-loop dumbbell-shaped structure displayed greater anti-proliferative activity than natural siRNAs. (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)
Databáze:	MEDLINE
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