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Synthesis and properties of mRNA cap analogs containing imidodiphosphate moiety—fairly mimicking natural cap structure, yet resistant to enzymatic hydrolysis
Bioorganic & Medicinal Chemistry (2012)
  • Anna M. Rydzik
  • Marta Kulis
  • Maciej Lukaszewicz
  • Joanna Kowalska
  • Joanna Zuberek
  • Zbigniew M. Darzynkiewicz
  • Edward Darzynkiewicz
  • Jacek Jemielity
Abstract

We describe synthesis and properties of eight dinucleotide mRNA 5′ cap analogs containing imidodiphosphate moiety within 5′,5′-tri- or tetraphosphate bridge (NH-analogs). The compounds were obtained by coupling an appropriate nucleoside 5′-imidodiphosphate with nucleotide P-imidazolide mediated by divalent metal chloride in anhydrous DMF. To evaluate the novel compounds as tools for studying cap-dependent processes, we determined their binding affinities for eukaryotic translation initiation factor 4E, susceptibilities to decapping pyrophosphatase DcpS and, for non-hydrolysable analogs, binding affinities to this enzyme. The results indicate that the O to NH substitution in selected positions of oligophosphate bridge ensures resistance to enzymatic decapping and suggest that interactions of NH-analogs with cap binding proteins fairly mimic interactions of unmodified parent compounds. Finally, we identified NH-analogs as potent inhibitors of cap-dependent translation in cell free system, and evaluated their utility as reagents for obtaining 5′ capped mRNAs in vitro to be rather moderate.

Keywords
  • Bioorganic chemistry,
  • Nucleotides,
  • mRNA cap,
  • Enzymatic resistance,
  • Translation inhibition,
  • Imidodiphosphate
Publication Date
Spring March 1, 2012
Citation Information
Anna M. Rydzik, Marta Kulis, Maciej Lukaszewicz, Joanna Kowalska, et al.. "Synthesis and properties of mRNA cap analogs containing imidodiphosphate moiety—fairly mimicking natural cap structure, yet resistant to enzymatic hydrolysis" Bioorganic & Medicinal Chemistry Vol. 20 Iss. 15 (2012)
Available at: http://works.bepress.com/joanna_kowalska/11/