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Issue 1, 2013
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Conjugation of PEG and gold nanoparticles to increase the accessibility and valency of tethered RNA splicing enhancers

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Abstract

Since alternative splicing patterns are exhibited by most mammalian genes, the functional properties of a gene may be changed for therapeutic purposes by nudging splicing from one pattern to another. Splicing to a refractory exon can be enhanced using bifunctional targeted oligonucleotide enhancers of splicing (TOES), which anneal to a target exon and carry additional sequence motifs to recruit activator proteins. We have tested here the effectiveness of increasing the availability of the activating domain by using click chemistry to insert spacers of hexaethylene glycol (HEG) or abasic DNA between the activating and annealing domains of the oligonucleotide. We show that the presence of one or two HEG spacers can increase the effectiveness of an oligonucleotide, but the inclusion of 11 or 20 reduced the activity. To increase the valency of the oligonucleotides further, the annealing and activating domains were conjugated to gold nanoparticles (GNPs). We show that activity of these GNP–RNA conjugates in splicing assays depended on the size of the GNP conjugates, the RNA sequence and the directionality (i.e. attachment to GNP at either the 5′ or 3′-ends) of the RNA strands conjugated to the GNP surface. Strikingly, only the activating domains were required.

Graphical abstract: Conjugation of PEG and gold nanoparticles to increase the accessibility and valency of tethered RNA splicing enhancers

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Publication details

The article was received on 11 Jul 2012, accepted on 20 Oct 2012 and first published on 22 Oct 2012


Article type: Edge Article
DOI: 10.1039/C2SC20937C
Citation: Chem. Sci., 2013,4, 257-265
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    Conjugation of PEG and gold nanoparticles to increase the accessibility and valency of tethered RNA splicing enhancers

    A. J. Perrett, R. L. Dickinson, Ž. Krpetić, M. Brust, H. Lewis, I. C. Eperon and G. A. Burley, Chem. Sci., 2013, 4, 257
    DOI: 10.1039/C2SC20937C

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