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

Author

Listed:
  • 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
    Suez University, Faculty of Petroleum and Mining Engineering)

  • Tom Brown

    (University of Oxford, Chemistry Research Laboratory)

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.

Suggested Citation

  • 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, 2022. "An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31636-2
    DOI: 10.1038/s41467-022-31636-2
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