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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	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 , Tom Brown Nature Communications 13 DOI: 10.1038/s41467-022-31636-2 Diamond Proposal Number(s): [18069, 23459] Open Access Show 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.	Jul 2022

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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography

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