Phosphorothioate analogs of m7GTP are enzymatically stable inhibitors of cap-dependent translation

Kowalska, Joanna; Łukaszewicz, Maciej; Zuberek, Joanna; Ziemniak, Marcin; Darżynkiewicz, Edward; Jemielity, Jacek

doi:10.1016/j.bmcl.2009.02.053

Cited by 34 publications

(64 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The most strongly bound compound was the (S P )-isomer characterized by a K as that was twofold higher than for the (R P )-counterpart, and more than fourfold higher than that of its unmodified counterpart (m 7 GpppG). While 7-methylguanosine attached by a 5'À5' b-thiotriphosphate bridge to the first transcribed nucleotide of the mRNA chain enhances the translation process, the phosphorothioate analogs of m 7 GTP (e.g., m 7 GTPaS; 57) occurred to be enzymatically stable inhibitors of cap-dependent translation [185]. Both P-diastereoisomers of m 7 GTPaS are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS).…”

mentioning

confidence: 99%

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

Guga

Koziołkiewicz

2011

Chemistry & Biodiversity

View full text Add to dashboard Cite

We dedicate this work to Prof. Fritz Eckstein (MPI, Gçttingen) and Prof. Wojciech J. Stec (CMMS PAS, Łó dź ), who invented the phosphorothioate modification of nucleic acids, envisioned its many important applications, carefully elucidated its biochemical and stereochemical aspects, and fostered PS-Oligos over decades. We are very grateful to have had the honor and pleasure to develop our understanding of PS-Oligos through guidance by their papers and lectures, and through stimulating scientific discussions with these two great scientists.

show abstract

mentioning

confidence: 99%

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

Guga

Koziołkiewicz

2011

Chemistry & Biodiversity

View full text Add to dashboard Cite

show abstract

“…To measure the luciferase activity, 2.5 μL of the translation reaction was mixed with 40 μL of Luciferase Assay Reagent (Promega), and a luminescence signal was detected in a luminometer (Glomax, Promega). The obtained data were used to determine IC 50 values for inhibition of cap-dependent translation by cap analogs as previously described (Kowalska et al 2009). …”

Section: Inhibition Of Cap-dependent Translation In Vitro In Rrlmentioning

confidence: 99%

“…Reactions were stopped after 60 min after addition of mRNA by chilling on ice. The pre-incubation step was described in Kowalska et al (2009) and was used in all of the further experiments that were performed in our lab. Using the same conditions allows comparison of data obtained for various cap analogs.…”

Section: Inhibition Of Cap-dependent Translation In Vitro In Rrlmentioning

confidence: 99%

“…To evaluate the ability of newly synthesized triazole-containing monophosphates to inhibit cap-dependent translation in a cell-free translation system, the previously reported procedure was used (Kowalska et al 2009). The chosen method, SCHEME 1.…”

Section: Biologymentioning

confidence: 99%

“…An inhibition assay of the cap-dependent translation in vitro in a micrococcal nuclease-treated RRL lysate (Flexi Rabbit Reticulocyte Lysate System, Promega) was performed as previously described (Kowalska et al 2009).…”

Section: Inhibition Of Cap-dependent Translation In Vitro In Rrlmentioning

confidence: 99%

See 2 more Smart Citations

Triazole-containing monophosphate mRNA cap analogs as effective translation inhibitors

Piecyk

Łukaszewicz

Darżynkiewicz

et al. 2014

RNA

Self Cite

View full text Add to dashboard Cite

Synthetic analogs of the 5′ end of mRNA (cap structure) are widely used in molecular studies on mechanisms of cellular processes such as translation, intracellular transport, splicing, and turnover. The best-characterized cap binding protein is translation initiation factor 4E (eIF4E). Recognition of the mRNA cap by eIF4E is a critical, rate-limiting step for efficient translation initiation and is considered a major target for anticancer therapy. Here, we report a facile methodology for the preparation of N2-triazole-containing monophosphate cap analogs and present their biological evaluation as inhibitors of protein synthesis. Five analogs possessing this unique hetero-cyclic ring spaced from the m7-guanine of the cap structure at a distance of one or three carbon atoms and/or additionally substituted by various groups containing the benzene ring were synthesized. All obtained compounds turned out to be effective translation inhibitors with IC 50 similar to dinucleotide triphosphate m 7 GpppG. As these compounds possess a reduced number of phosphate groups and, thereby, a negative charge, which may support their cell penetration, this type of cap analog might be promising in terms of designing new potential therapeutic molecules. In addition, an exemplary dinucleotide from a corresponding mononucleotide containing benzyl substituted 1,2,3-triazole was prepared and examined. The superior inhibitory properties of this analog (10-fold vs. m 7 GpppG) suggest the usefulness of such compounds for the preparation of mRNA transcripts with high translational activity.

show abstract

Application of Phosphoramidate ProTide Technology for the Synthesis of 5’‐mRNA Cap Analogs Modified on the Exocyclic Amine Group

et al. 2023

Self Cite

View full text Add to dashboard Cite

Aryloxy triester phosphoramidate methodology, commonly known as ProTide technology, is one of the most widely used prodrug approaches applied to therapeutic nucleosides. This approach has been used extensively by the pharmaceutical industry and researchers in medicinal chemistry. Herein we report our adaptation of this effective method for the synthesis of bioactive 5'-mRNA cap analogues as inhibitors for targeting cap-dependent translation. The synthesis was performed in two main stages: preparation of N2-modified guanosine analogues and their subsequent transformation into prodrugs using phenylethoxy-l-alaninyl phosphorochloridate. The prepared pro-nucleotide cap analogues were tested for their capacity in enzymatic activation, inhibitory properties in a rabbit reticulocyte lysate system, and passive membrane translocation properties.

show abstract

Phosphorothioate analogs of m7GTP are enzymatically stable inhibitors of cap-dependent translation

Cited by 34 publications

References 18 publications

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

Phosphorothioate Nucleotides and Oligonucleotides – Recent Progress in Synthesis and Application

Triazole-containing monophosphate mRNA cap analogs as effective translation inhibitors

Application of Phosphoramidate ProTide Technology for the Synthesis of 5’‐mRNA Cap Analogs Modified on the Exocyclic Amine Group

Contact Info

Product

Resources

About