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Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides
The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in t...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450106/ https://www.ncbi.nlm.nih.gov/pubmed/34417625 http://dx.doi.org/10.1093/nar/gkab718 |
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author | Anderson, Brooke A Freestone, Graeme C Low, Audrey De-Hoyos, Cheryl L III, William J Drury Østergaard, Michael E Migawa, Michael T Fazio, Michael Wan, W Brad Berdeja, Andres Scandalis, Eli Burel, Sebastien A Vickers, Timothy A Crooke, Stanley T Swayze, Eric E Liang, Xuehai Seth, Punit P |
author_facet | Anderson, Brooke A Freestone, Graeme C Low, Audrey De-Hoyos, Cheryl L III, William J Drury Østergaard, Michael E Migawa, Michael T Fazio, Michael Wan, W Brad Berdeja, Andres Scandalis, Eli Burel, Sebastien A Vickers, Timothy A Crooke, Stanley T Swayze, Eric E Liang, Xuehai Seth, Punit P |
author_sort | Anderson, Brooke A |
collection | PubMed |
description | The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect. |
format | Online Article Text |
id | pubmed-8450106 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-84501062021-09-20 Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides Anderson, Brooke A Freestone, Graeme C Low, Audrey De-Hoyos, Cheryl L III, William J Drury Østergaard, Michael E Migawa, Michael T Fazio, Michael Wan, W Brad Berdeja, Andres Scandalis, Eli Burel, Sebastien A Vickers, Timothy A Crooke, Stanley T Swayze, Eric E Liang, Xuehai Seth, Punit P Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect. Oxford University Press 2021-08-20 /pmc/articles/PMC8450106/ /pubmed/34417625 http://dx.doi.org/10.1093/nar/gkab718 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Anderson, Brooke A Freestone, Graeme C Low, Audrey De-Hoyos, Cheryl L III, William J Drury Østergaard, Michael E Migawa, Michael T Fazio, Michael Wan, W Brad Berdeja, Andres Scandalis, Eli Burel, Sebastien A Vickers, Timothy A Crooke, Stanley T Swayze, Eric E Liang, Xuehai Seth, Punit P Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title | Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title_full | Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title_fullStr | Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title_full_unstemmed | Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title_short | Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
title_sort | towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450106/ https://www.ncbi.nlm.nih.gov/pubmed/34417625 http://dx.doi.org/10.1093/nar/gkab718 |
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