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

Autor: Baker YR; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Thorpe C; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Chen J; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Poller LM; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Cox L; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Kumar P; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Lim WF; Department of Paediatrics, University of Oxford, LGC building, South Parks Road, Oxford, OX1 3QX, UK., Lie L; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., McClorey G; Department of Paediatrics, University of Oxford, LGC building, South Parks Road, Oxford, OX1 3QX, UK., Epple S; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Singleton D; ATDBio Ltd, School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK., McDonough MA; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Hardwick JS; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Christensen KE; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK., Wood MJA; Department of Paediatrics, University of Oxford, LGC building, South Parks Road, Oxford, OX1 3QX, UK., Hall JP; Department of Pharmacy, Chemistry and Pharmacy Building, University of Reading, Whiteknights, Reading, RG6 6AD, UK., El-Sagheer AH; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK.; Department of Science and Mathematics, Suez University, Faculty of Petroleum and Mining Engineering, Suez, 43721, Egypt., Brown T; Department of Chemistry, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, Oxford, OX1 3TA, UK. tom.brown@chem.ox.ac.uk.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Jul 12; Vol. 13 (1), pp. 4036. Date of Electronic Publication: 2022 Jul 12.
DOI: 10.1038/s41467-022-31636-2
Abstrakt: 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.
(© 2022. Crown.)
Databáze: MEDLINE
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