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Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential
Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175369/ https://www.ncbi.nlm.nih.gov/pubmed/27903882 http://dx.doi.org/10.1093/nar/gkw896 |
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author | Strenkowska, Malwina Grzela, Renata Majewski, Maciej Wnek, Katarzyna Kowalska, Joanna Lukaszewicz, Maciej Zuberek, Joanna Darzynkiewicz, Edward Kuhn, Andreas N. Sahin, Ugur Jemielity, Jacek |
author_facet | Strenkowska, Malwina Grzela, Renata Majewski, Maciej Wnek, Katarzyna Kowalska, Joanna Lukaszewicz, Maciej Zuberek, Joanna Darzynkiewicz, Edward Kuhn, Andreas N. Sahin, Ugur Jemielity, Jacek |
author_sort | Strenkowska, Malwina |
collection | PubMed |
description | Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5′ end of mRNA (m(7)Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization. |
format | Online Article Text |
id | pubmed-5175369 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-51753692016-12-27 Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential Strenkowska, Malwina Grzela, Renata Majewski, Maciej Wnek, Katarzyna Kowalska, Joanna Lukaszewicz, Maciej Zuberek, Joanna Darzynkiewicz, Edward Kuhn, Andreas N. Sahin, Ugur Jemielity, Jacek Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry Along with a growing interest in mRNA-based gene therapies, efforts are increasingly focused on reaching the full translational potential of mRNA, as a major obstacle for in vivo applications is sufficient expression of exogenously delivered mRNA. One method to overcome this limitation is chemically modifying the 7-methylguanosine cap at the 5′ end of mRNA (m(7)Gppp-RNA). We report a novel class of cap analogs designed as reagents for mRNA modification. The analogs carry a 1,2-dithiodiphosphate moiety at various positions along a tri- or tetraphosphate bridge, and thus are termed 2S analogs. These 2S analogs have high affinities for translation initiation factor 4E, and some exhibit remarkable resistance against the SpDcp1/2 decapping complex when introduced into RNA. mRNAs capped with 2S analogs combining these two features exhibit high translation efficiency in cultured human immature dendritic cells. These properties demonstrate that 2S analogs are potentially beneficial for mRNA-based therapies such as anti-cancer immunization. Oxford University Press 2016-11-16 2016-10-07 /pmc/articles/PMC5175369/ /pubmed/27903882 http://dx.doi.org/10.1093/nar/gkw896 Text en © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Strenkowska, Malwina Grzela, Renata Majewski, Maciej Wnek, Katarzyna Kowalska, Joanna Lukaszewicz, Maciej Zuberek, Joanna Darzynkiewicz, Edward Kuhn, Andreas N. Sahin, Ugur Jemielity, Jacek Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title_full | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title_fullStr | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title_full_unstemmed | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title_short | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
title_sort | cap analogs modified with 1,2-dithiodiphosphate moiety protect mrna from decapping and enhance its translational potential |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175369/ https://www.ncbi.nlm.nih.gov/pubmed/27903882 http://dx.doi.org/10.1093/nar/gkw896 |
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