Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes
| Autor: | Edward Darzynkiewicz, Corina Nicola, Malwina Strenkowska, Elzbieta Bojarska, Zbigniew M. Darzynkiewicz, Maciej Lukaszewicz, Maciej Maciejczyk, Andreas Kuhn, Anna Wypijewska del Nogal, Jacek Jemielity, Joanna Zuberek, Joanna Kowalska, Ugur Sahin, Marcin Ziemniak, Robert E. Rhoads, Janina Buck |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
RNA Cap Analogs
Eukaryotic Initiation Factor-4E DCPS Biology 010402 general chemistry 01 natural sciences Phosphates 03 medical and health sciences Neoplasms Endoribonucleases Genetics Protein biosynthesis Animals Humans Pyrophosphatases Boranes Caenorhabditis elegans Proteins 030304 developmental biology Boranophosphate Protein Synthesis Inhibitors 0303 health sciences Messenger RNA EIF4E Translation (biology) Stereoisomerism Dendritic Cells 0104 chemical sciences Biochemistry Protein Biosynthesis Synthetic Biology and Chemistry |
| Zdroj: | Nucleic Acids Research |
| ISSN: | 1362-4962 0305-1048 |
| Popis: | Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of novel therapeutic interventions. We report the synthesis and properties of 11 dinucleotide cap analogs bearing a single boranophosphate modification at either the α-, β- or γ-position of the 5',5'-triphosphate chain. The compounds can potentially serve either as inhibitors of translation in cancer cells or reagents for increasing expression of therapeutic proteins in vivo from exogenous mRNAs. The BH3-analogs were tested as substrates and binding partners for two major cytoplasmic cap-binding proteins, DcpS, a decapping pyrophosphatase, and eIF4E, a translation initiation factor. The susceptibility to DcpS was different between BH3-analogs and the corresponding analogs containing S instead of BH3 (S-analogs). Depending on its placement, the boranophosphate group weakened the interaction with DcpS but stabilized the interaction with eIF4E. The first of the properties makes the BH3-analogs more stable and the second, more potent as inhibitors of protein biosynthesis. Protein expression in dendritic cells was 2.2- and 1.7-fold higher for mRNAs capped with m2 (7,2'-O)GppBH3pG D1 and m2 (7,2'-O)GppBH3pG D2, respectively, than for in vitro transcribed mRNA capped with m2 (7,3'-O)GpppG. Higher expression of cancer antigens would make mRNAs containing m2 (7,2'-O)GppBH3pG D1 and m2 (7,2'-O)GppBH3pG D2 favorable for anticancer immunization. |
| Databáze: | OpenAIRE |
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