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Nucleic Acids Res. 2014;42(16):10245-64. doi: 10.1093/nar/gku757. Epub 2014 Aug 22.

Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes.

Author information

1
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
2
BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
3
BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany TRON-Translational Oncology at the University Medical Center Mainz, Germany.
4
University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
5
Centre of New Technologies, University of Warsaw, Poland.
6
Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA.
7
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland Centre of New Technologies, University of Warsaw, Poland.
8
Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland Centre of New Technologies, University of Warsaw, Poland jacekj@biogeo.uw.edu.pl.

Abstract

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.

PMID:
25150148
PMCID:
PMC4176373
DOI:
10.1093/nar/gku757
[Indexed for MEDLINE]
Free PMC Article

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