title: Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes.
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.
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Kowalska
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Wypijewska del Nogal
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Zbigniew M
authors.initials: ZM
authors.lastname: Darzynkiewicz
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Buck
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany.
authors.forename: Corina
authors.initials: C
authors.lastname: Nicola
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany TRON-Translational Oncology at the University Medical Center Mainz, Germany.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Kuhn
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Lukaszewicz
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Zuberek
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Malwina
authors.initials: M
authors.lastname: Strenkowska
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Ziemniak
authors.affiliation: University of Warmia and Mazury in Olsztyn, Olsztyn, Poland.
authors.forename: Maciej
authors.initials: M
authors.lastname: Maciejczyk
authors.affiliation: Centre of New Technologies, University of Warsaw, Poland.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Bojarska
authors.affiliation: Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Rhoads
authors.affiliation: Division of Biophysics, Institute of Experimental Physics, Faculty of Physics, University of Warsaw, Warsaw, Poland Centre of New Technologies, University of Warsaw, Poland.
authors.forename: Edward
authors.initials: E
authors.lastname: Darzynkiewicz
authors.affiliation: BioNTech RNA Pharmaceuticals GmbH, Mainz, Germany TRON-Translational Oncology at the University Medical Center Mainz, Germany.
authors.forename: Ugur
authors.initials: U
authors.lastname: Sahin
authors.affiliation: 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.
authors.forename: Jacek
authors.initials: J
authors.lastname: Jemielity
mesh_terms: D000818:Animals; D001880:Boranes / Q000737:chemistry*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004722:Endoribonucleases / Q000378:metabolism; D039561:Eukaryotic Initiation Factor-4E / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy; D010710:Phosphates / Q000737:chemistry*; D014176:Protein Biosynthesis / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D011755:Pyrophosphatases / Q000378:metabolism; D012314:RNA Cap Analogs / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D001880:Boranes; D029742:Caenorhabditis elegans Proteins; D039561:Eukaryotic Initiation Factor-4E; D010710:Phosphates; D011500:Protein Synthesis Inhibitors; D012314:RNA Cap Analogs; C510710:boranophosphate; D004722:Endoribonucleases; C485332:DcpS protein, human; D011755:Pyrophosphatases; C509343:dcs-1 protein, C elegans