Synthesis, properties, and biological activity of boranophosphate analogs of the mRNA cap: versatile tools for manipulation of therapeutically relevant cap-dependent processes. Issue 16 (22nd August 2014)

• Record Type: Journal Article
• Authors: Kowalska, Joanna; Wypijewska del Nogal, Anna; Darzynkiewicz, Zbigniew M.; Buck, Janina; Nicola, Corina; Kuhn, Andreas N.; Lukaszewicz, Maciej; Zuberek, Joanna; Strenkowska, Malwina; Ziemniak, Marcin; Maciejczyk, Maciej; Bojarska, Elzbieta; Rhoads, Robert E.; Darzynkiewicz, Edward; Sahin, Ugur; Jemielity, Jacek
• Is Part Of: Nucleic acids research. Volume 42:Issue 16(2014)
• Page Start: 10245
• Page End: 10264
• Publication Date: 2014-08-22
• Subjects: Nucleic acids -- Periodicals; Molecular biology -- Periodicals; 572.805
• DOI: 10.1093/nar/gku757
• Languages: English
• ISSNs: 0305-1048

Abstract

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 GppBH3 pG D1 and m2 7, 2′- O GppBH3 pG 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 GppBH3 pG D1 and m2 7, 2′- O GppBH3 pG D2 favorable for anticancer immunization.