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Títol:	Rational design of novel N-alkyl-N capped biostable RNA nanostructures for efficient long-term inhibition of gene expression
Autor/a:	Terrazas, Montserrat; Ivani, Ivan; Villegas, Núria; Paris, Clément; Salvans, Cándida; Brun-Heath, Isabelle; Orozco, Modesto
Altres autors:	Barcelona Supercomputing Center
Abstract:	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.
Abstract:	Instituto de Salud Carlos III [Miguel Servet Program, CP13/00211, 205024141 to M.T.]; Spanish MINECO [BIO2012–32869 and BIO2015-64802-R toM.O.]; AGAUR (toM.O.); ERCCouncil (SimDNA, grant 291433, to M.O.). M.O. is an ICREA Academia fellow. Funding for open access charge: ERC Council [grant 291433 (simDNA)].
Abstract:	Peer Reviewed
Matèries:	-Àrees temàtiques de la UPC::Enginyeria biomèdica -RNA -Molecular dynamics -DNA--Analysis -RNA -Breast cancer cells -RNA interference (RNAi) -Oligonucleotide sequences -ADN -Dinàmica molecular
Drets:	Attribution-NonCommercial-NoDerivs 4.0 Spain http://creativecommons.org/licenses/by-nc-nd/4.0/es/
Tipus de document:	Article - Versió publicada Article
Publicat per:	Oxford University Press (OUP)
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