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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...

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Autores principales: Strenkowska, Malwina, Grzela, Renata, Majewski, Maciej, Wnek, Katarzyna, Kowalska, Joanna, Lukaszewicz, Maciej, Zuberek, Joanna, Darzynkiewicz, Edward, Kuhn, Andreas N., Sahin, Ugur, Jemielity, Jacek
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2016
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.
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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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