An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides
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. W...
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Springer Nature
2022
|
| _version_ | 1826309443365634048 |
|---|---|
| author | Baker, YR Thorpe, C Chen, J Poller, LM Cox, L Kumar, P Lim, WF Lie, L McClorey, G Epple, S Singleton, D McDonough, MA Hardwick, JS Christensen, KE Wood, MJA Hall, JP El-Sagheer, AH Brown, T |
| author_facet | Baker, YR Thorpe, C Chen, J Poller, LM Cox, L Kumar, P Lim, WF Lie, L McClorey, G Epple, S Singleton, D McDonough, MA Hardwick, JS Christensen, KE Wood, MJA Hall, JP El-Sagheer, AH Brown, T |
| author_sort | Baker, YR |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:34:15Z |
| format | Journal article |
| id | oxford-uuid:feee29f6-4738-4016-8b23-b76c5088be6a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:34:15Z |
| publishDate | 2022 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:feee29f6-4738-4016-8b23-b76c5088be6a2023-02-21T11:46:06ZAn LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotidesJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:feee29f6-4738-4016-8b23-b76c5088be6aEnglishSymplectic ElementsSpringer Nature2022Baker, YRThorpe, CChen, JPoller, LMCox, LKumar, PLim, WFLie, LMcClorey, GEpple, SSingleton, DMcDonough, MAHardwick, JSChristensen, KEWood, MJAHall, JPEl-Sagheer, AHBrown, TOligonucleotides 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. |
| spellingShingle | Baker, YR Thorpe, C Chen, J Poller, LM Cox, L Kumar, P Lim, WF Lie, L McClorey, G Epple, S Singleton, D McDonough, MA Hardwick, JS Christensen, KE Wood, MJA Hall, JP El-Sagheer, AH Brown, T An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title | An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title_full | An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title_fullStr | An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title_full_unstemmed | An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title_short | An LNA-amide modification that enhances the cell uptake and activity of phosphorothioate exon-skipping oligonucleotides |
| title_sort | lna amide modification that enhances the cell uptake and activity of phosphorothioate exon skipping oligonucleotides |
| work_keys_str_mv | AT bakeryr anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT thorpec anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT chenj anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT pollerlm anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT coxl anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT kumarp anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT limwf anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT liel anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT mccloreyg anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT epples anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT singletond anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT mcdonoughma anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT hardwickjs anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT christensenke anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT woodmja anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT halljp anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT elsagheerah anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT brownt anlnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT bakeryr lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT thorpec lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT chenj lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT pollerlm lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT coxl lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT kumarp lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT limwf lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT liel lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT mccloreyg lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT epples lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT singletond lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT mcdonoughma lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT hardwickjs lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT christensenke lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT woodmja lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT halljp lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT elsagheerah lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides AT brownt lnaamidemodificationthatenhancesthecelluptakeandactivityofphosphorothioateexonskippingoligonucleotides |