Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
Oligonucleotides are rapidly emerging as powerful therapeutics for hard to treat diseases. Short single-stranded oligonucleotides can base pair with target RNA and alter gene expression, providing an attractive therapeutic approach at the genetic level. Whilst conceptually appealing, oligonucleotides require chemical modification for clinical use. One emerging approach is to substitute the phosphodiester backbone with other chemical linkages such as triazole. The triazole linkage is inherently resistant to enzymatic degradation, providing stability in vivo, and is uncharged, potentially improving cell-penetration and in vivo distribution. Triazole linkages, however, are known to reduce RNA target binding affinity. Here we show that by attaching pyrene or anthraquinone to the ribose sugar on the 5′-side of the triazole, it is possible to recover duplex stability and restore the splice switching ability of triazole-containing oligonucleotides.
765-772
Sysko, Anna
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Baker, Ysobel
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McClorey, Graham
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Wood, Matthew J.A.
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Fenner, Sabine
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Williams, Glynn
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El-Sagheer, Afaf H
05b8295a-64ad-4fdf-ad57-c34934a46c04
Brown, Tom
a64aae36-bb30-42df-88a2-11be394e8c89
8 June 2022
Sysko, Anna
8d0c418f-a01f-4713-89b2-d480bea961da
Baker, Ysobel
4fceec1f-89ed-4a32-a753-8967daf6763a
McClorey, Graham
063a9904-49c3-4837-81a0-47d4ac35a5ed
Wood, Matthew J.A.
67653744-b581-4981-9ed4-d1fd73cb4241
Fenner, Sabine
79b55fcb-d5e3-43ac-8ebd-a519f6f120e2
Williams, Glynn
15157baa-89be-453c-b800-857072600533
El-Sagheer, Afaf H
05b8295a-64ad-4fdf-ad57-c34934a46c04
Brown, Tom
a64aae36-bb30-42df-88a2-11be394e8c89
Sysko, Anna, Baker, Ysobel, McClorey, Graham, Wood, Matthew J.A., Fenner, Sabine, Williams, Glynn, El-Sagheer, Afaf H and Brown, Tom
(2022)
Covalently attached intercalators restore duplex stability and splice-switching activity to triazole-modified oligonucleotides.
RSC Chemical Biology, 2022 (3), .
(doi:10.1039/D2CB00100D).
Abstract
Oligonucleotides are rapidly emerging as powerful therapeutics for hard to treat diseases. Short single-stranded oligonucleotides can base pair with target RNA and alter gene expression, providing an attractive therapeutic approach at the genetic level. Whilst conceptually appealing, oligonucleotides require chemical modification for clinical use. One emerging approach is to substitute the phosphodiester backbone with other chemical linkages such as triazole. The triazole linkage is inherently resistant to enzymatic degradation, providing stability in vivo, and is uncharged, potentially improving cell-penetration and in vivo distribution. Triazole linkages, however, are known to reduce RNA target binding affinity. Here we show that by attaching pyrene or anthraquinone to the ribose sugar on the 5′-side of the triazole, it is possible to recover duplex stability and restore the splice switching ability of triazole-containing oligonucleotides.
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More information
Accepted/In Press date: 15 May 2022
e-pub ahead of print date: 16 May 2022
Published date: 8 June 2022
Additional Information:
Funding Information:
This work was supported by UK BBSRC grants BB/J001694/2 (Extending the boundaries of nucleic acid chemistry), BB/R008655/1 (New and versatile chemical approaches for the synthesis of mRNA and tRNA) and BB/S018794/1 (New oligonucleotide analogues for therapeutic applications). The authors would like to thank Dr Samir El-Andaloussi for the HeLa pLuc/705 cell line and Dr Susan Merrihew for valuable discussions. This research utilised equipment funded by the John Fell Oxford University Press Research Fund and an EPSRC Strategic Equipment Grant (EP/T019190/1).
Publisher Copyright:
© 2022 The Author(s).
Identifiers
Local EPrints ID: 476817
URI: http://eprints.soton.ac.uk/id/eprint/476817
ISSN: 2633-0679
PURE UUID: 1afddd1d-9329-4678-ae69-d081136047b5
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Date deposited: 16 May 2023 17:01
Last modified: 28 Aug 2024 02:12
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Contributors
Author:
Anna Sysko
Author:
Ysobel Baker
Author:
Graham McClorey
Author:
Matthew J.A. Wood
Author:
Sabine Fenner
Author:
Glynn Williams
Author:
Afaf H El-Sagheer
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