An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides

Ysobel R. Baker, Cameron Thorpe, Jinfeng Chen, Laura M. Poller, Lina Cox, Pawan Kumar, Wooi F. Lim, Lillian Lie, Graham McClorey, Sven Epple, Daniel Singleton, Michael A. McDonough, Jack S. Hardwick, Kirsten E. Christensen, Matthew J. A. Wood, James P. Hall, Afaf H. El-Sagheer and Tom Brown ()
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Ysobel R. Baker: University of Oxford, Chemistry Research Laboratory
Cameron Thorpe: University of Oxford, Chemistry Research Laboratory
Jinfeng Chen: University of Oxford, Chemistry Research Laboratory
Laura M. Poller: University of Oxford, Chemistry Research Laboratory
Lina Cox: University of Oxford, Chemistry Research Laboratory
Pawan Kumar: University of Oxford, Chemistry Research Laboratory
Wooi F. Lim: University of Oxford
Lillian Lie: University of Oxford, Chemistry Research Laboratory
Graham McClorey: University of Oxford
Sven Epple: University of Oxford, Chemistry Research Laboratory
Daniel Singleton: University of Southampton
Michael A. McDonough: University of Oxford, Chemistry Research Laboratory
Jack S. Hardwick: University of Oxford, Chemistry Research Laboratory
Kirsten E. Christensen: University of Oxford, Chemistry Research Laboratory
Matthew J. A. Wood: University of Oxford
James P. Hall: University of Reading
Afaf H. El-Sagheer: University of Oxford, Chemistry Research Laboratory
Tom Brown: University of Oxford, Chemistry Research Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Oligonucleotides that target mRNA have great promise as therapeutic agents for life-threatening conditions but suffer from poor bioavailability, hence high cost. As currently untreatable diseases come within the reach of oligonucleotide therapies, new analogues are urgently needed to address this. With this in mind we describe reduced-charge oligonucleotides containing artificial LNA-amide linkages with improved gymnotic cell uptake, RNA affinity, stability and potency. To construct such oligonucleotides, five LNA-amide monomers (A, T, C, 5mC and G), where the 3′-OH is replaced by an ethanoic acid group, are synthesised in good yield and used in solid-phase oligonucleotide synthesis to form amide linkages with high efficiency. The artificial backbone causes minimal structural deviation to the DNA:RNA duplex. These studies indicate that splice-switching oligonucleotides containing LNA-amide linkages and phosphorothioates display improved activity relative to oligonucleotides lacking amides, highlighting the therapeutic potential of this technology.

Date: 2022
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DOI: 10.1038/s41467-022-31636-2

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