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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Boranes / chemistry*
  • Caenorhabditis elegans Proteins / metabolism
  • Dendritic Cells / metabolism
  • Endoribonucleases / metabolism
  • Eukaryotic Initiation Factor-4E / metabolism
  • Humans
  • Neoplasms / drug therapy
  • Phosphates / chemistry*
  • Protein Biosynthesis / drug effects
  • Protein Synthesis Inhibitors / chemistry*
  • Protein Synthesis Inhibitors / pharmacology
  • Pyrophosphatases / metabolism
  • RNA Cap Analogs / chemical synthesis
  • RNA Cap Analogs / chemistry*
  • RNA Cap Analogs / metabolism
  • RNA Cap Analogs / pharmacology
  • Stereoisomerism


  • Boranes
  • Caenorhabditis elegans Proteins
  • Eukaryotic Initiation Factor-4E
  • Phosphates
  • Protein Synthesis Inhibitors
  • RNA Cap Analogs
  • boranophosphate
  • Endoribonucleases
  • DcpS protein, human
  • Pyrophosphatases
  • dcs-1 protein, C elegans