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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| Veröffentlicht in: | Nucleic acids research 2016-11, Vol.44 (20), p.9578-9590 |
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| creator | Strenkowska, Malwina Grzela, Renata Majewski, Maciej Wnek, Katarzyna Kowalska, Joanna Lukaszewicz, Maciej Zuberek, Joanna Darzynkiewicz, Edward Kuhn, Andreas N Sahin, Ugur Jemielity, Jacek |
| 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
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. |
| doi_str_mv | 10.1093/nar/gkw896 |
| format | Article |
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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.</description><identifier>ISSN: 0305-1048</identifier><identifier>EISSN: 1362-4962</identifier><identifier>DOI: 10.1093/nar/gkw896</identifier><identifier>PMID: 27903882</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Chemical Biology and Nucleic Acid Chemistry ; Dendritic Cells ; Diphosphates - chemistry ; DNA-Binding Proteins - metabolism ; Humans ; Molecular Structure ; Protein Binding ; Protein Biosynthesis ; RNA Cap Analogs - chemical synthesis ; RNA Caps ; RNA, Messenger - chemistry ; RNA, Messenger - genetics ; Transcription Factors - metabolism</subject><ispartof>Nucleic acids research, 2016-11, Vol.44 (20), p.9578-9590</ispartof><rights>The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.</rights><rights>The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research. 2016</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c378t-456a77d3594400b118d5d5014d5db13cac12f70584e52f1b045a2711fd5cc92c3</citedby><cites>FETCH-LOGICAL-c378t-456a77d3594400b118d5d5014d5db13cac12f70584e52f1b045a2711fd5cc92c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175369/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175369/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27903882$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Strenkowska, Malwina</creatorcontrib><creatorcontrib>Grzela, Renata</creatorcontrib><creatorcontrib>Majewski, Maciej</creatorcontrib><creatorcontrib>Wnek, Katarzyna</creatorcontrib><creatorcontrib>Kowalska, Joanna</creatorcontrib><creatorcontrib>Lukaszewicz, Maciej</creatorcontrib><creatorcontrib>Zuberek, Joanna</creatorcontrib><creatorcontrib>Darzynkiewicz, Edward</creatorcontrib><creatorcontrib>Kuhn, Andreas N</creatorcontrib><creatorcontrib>Sahin, Ugur</creatorcontrib><creatorcontrib>Jemielity, Jacek</creatorcontrib><title>Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential</title><title>Nucleic acids research</title><addtitle>Nucleic Acids Res</addtitle><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
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.</description><subject>Chemical Biology and Nucleic Acid Chemistry</subject><subject>Dendritic Cells</subject><subject>Diphosphates - chemistry</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Humans</subject><subject>Molecular Structure</subject><subject>Protein Binding</subject><subject>Protein Biosynthesis</subject><subject>RNA Cap Analogs - chemical synthesis</subject><subject>RNA Caps</subject><subject>RNA, Messenger - chemistry</subject><subject>RNA, Messenger - genetics</subject><subject>Transcription Factors - metabolism</subject><issn>0305-1048</issn><issn>1362-4962</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkV1rFDEYhYNY7Fq98QdILkWcNp8zmRuhLH5BqSB6Hd5NMjvRmSQmWUv99Ua2Fnt1Qt4n57zhIPSCknNKRn4RIF_sf9yosX-ENpT3rBNjzx6jDeFEdpQIdYqelvKdECqoFE_QKRtGwpViG_R7CwlDgCXuC16j9ZN3Ft_4OmP6hnW2HXy7TXMsaYbqGuNdvcUpx-pMxeuX60s85bhi6wyk5MO-2VnswgzBOOxrwTVDKAtUH1sOTu1hqB6WZ-hkgqW453d6hr69f_d1-7G7-vzh0_byqjN8ULUTsodhsFyOQhCyo1RZaWX7SpMd5QYMZdNApBJOsonuiJDABkonK40ZmeFn6O3RNx12q7OmpWdYdMp-hXyrI3j9cBL8rPfxl5Z0kLwfm8GrO4Mcfx5cqXr1xbhlgeDioWiqhGSS0VE19PURNTmWkt10H0OJ_luWbmXpY1kNfvn_Yvfov3b4H27fk6o</recordid><startdate>20161116</startdate><enddate>20161116</enddate><creator>Strenkowska, Malwina</creator><creator>Grzela, Renata</creator><creator>Majewski, Maciej</creator><creator>Wnek, Katarzyna</creator><creator>Kowalska, Joanna</creator><creator>Lukaszewicz, Maciej</creator><creator>Zuberek, Joanna</creator><creator>Darzynkiewicz, Edward</creator><creator>Kuhn, Andreas N</creator><creator>Sahin, Ugur</creator><creator>Jemielity, Jacek</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161116</creationdate><title>Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential</title><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></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c378t-456a77d3594400b118d5d5014d5db13cac12f70584e52f1b045a2711fd5cc92c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Chemical Biology and Nucleic Acid Chemistry</topic><topic>Dendritic Cells</topic><topic>Diphosphates - chemistry</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Humans</topic><topic>Molecular Structure</topic><topic>Protein Binding</topic><topic>Protein Biosynthesis</topic><topic>RNA Cap Analogs - chemical synthesis</topic><topic>RNA Caps</topic><topic>RNA, Messenger - chemistry</topic><topic>RNA, Messenger - genetics</topic><topic>Transcription Factors - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Strenkowska, Malwina</creatorcontrib><creatorcontrib>Grzela, Renata</creatorcontrib><creatorcontrib>Majewski, Maciej</creatorcontrib><creatorcontrib>Wnek, Katarzyna</creatorcontrib><creatorcontrib>Kowalska, Joanna</creatorcontrib><creatorcontrib>Lukaszewicz, Maciej</creatorcontrib><creatorcontrib>Zuberek, Joanna</creatorcontrib><creatorcontrib>Darzynkiewicz, Edward</creatorcontrib><creatorcontrib>Kuhn, Andreas N</creatorcontrib><creatorcontrib>Sahin, Ugur</creatorcontrib><creatorcontrib>Jemielity, Jacek</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Nucleic acids research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Strenkowska, Malwina</au><au>Grzela, Renata</au><au>Majewski, Maciej</au><au>Wnek, Katarzyna</au><au>Kowalska, Joanna</au><au>Lukaszewicz, Maciej</au><au>Zuberek, Joanna</au><au>Darzynkiewicz, Edward</au><au>Kuhn, Andreas N</au><au>Sahin, Ugur</au><au>Jemielity, Jacek</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential</atitle><jtitle>Nucleic acids research</jtitle><addtitle>Nucleic Acids Res</addtitle><date>2016-11-16</date><risdate>2016</risdate><volume>44</volume><issue>20</issue><spage>9578</spage><epage>9590</epage><pages>9578-9590</pages><issn>0305-1048</issn><eissn>1362-4962</eissn><abstract>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
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.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>27903882</pmid><doi>10.1093/nar/gkw896</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; Oxford Journals Open Access Collection; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Chemical Biology and Nucleic Acid Chemistry Dendritic Cells Diphosphates - chemistry DNA-Binding Proteins - metabolism Humans Molecular Structure Protein Binding Protein Biosynthesis RNA Cap Analogs - chemical synthesis RNA Caps RNA, Messenger - chemistry RNA, Messenger - genetics Transcription Factors - metabolism |
| title | Cap analogs modified with 1,2-dithiodiphosphate moiety protect mRNA from decapping and enhance its translational potential |
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