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Issue 22, 2009
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Synthetic dinucleotide mRNA cap analogs with tetraphosphate 5′,5′ bridge containing methylenebis(phosphonate) modification

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Abstract

An effective and facile synthesis of six novel tetraphosphate cap analogs modified with a methylenebis(phosphonate) moiety (1–6) is presented. Analogs have been rationally designed to bind tightly to the eukaryotic initiation factor 4E (eIF4E) responsible for cap binding during the initiation of translation, and have increased stability owing to resistance to enzymatic degradation. Final compounds turned out to have significantly higher association constant values (KAS) for binding to eIF4E (5–9 fold higher than standard). Four of the analogs were resistant towards enzymatic degradation by human Decapping Scavenger enzyme (DcpS). Binding studies of non-hydrolyzable analogs with DcpS revealed a broad range of KAS values for different analogs. All of the analogs were potent inhibitors of translation in a rabbit reticulocyte lysate system (RRL) and those resistant to DcpS turned out to be stable under an elongated time of preincubation while the inhibitory potency of standard was diminished in these conditions. For Anti Reverse Cap Analog (ARCA) dinucleotides (4–6), we have shown that they are effectively incorporated into mRNA and transcripts capped with these analogs undergo translation in vitro.

Graphical abstract: Synthetic dinucleotide mRNA cap analogs with tetraphosphate 5′,5′ bridge containing methylenebis(phosphonate) modification

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Publication details

The article was received on 10 Jun 2009, accepted on 04 Aug 2009 and first published on 07 Sep 2009


Article type: Paper
DOI: 10.1039/B911347A
Citation: Org. Biomol. Chem., 2009,7, 4763-4776
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    Synthetic dinucleotide mRNA cap analogs with tetraphosphate 5′,5′ bridge containing methylenebis(phosphonate) modification

    A. M. Rydzik, M. Lukaszewicz, J. Zuberek, J. Kowalska, Z. M. Darzynkiewicz, E. Darzynkiewicz and J. Jemielity, Org. Biomol. Chem., 2009, 7, 4763
    DOI: 10.1039/B911347A

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