Marcin Ziemniak | University of Warsaw (original) (raw)

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Papers by Marcin Ziemniak

Research paper thumbnail of Utility of chemically modified cap analogues in studying Dcp1/2 decapping complex mechanism of action

Collection Symposium Series, 2014

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

Nucleic acids research, 2014

Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of n... more 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-...

Research paper thumbnail of m7GTP S is a strong and stable inhibitor of cap-dependent translation

Nucleic Acids Symposium Series, 2008

Two diastereomers of 7-methylguanosine 5&... more Two diastereomers of 7-methylguanosine 5'-O-(1-thiotriphosphate) have been synthesized and resolved by RP HPLC. Preliminary studies revealed that these new analogs of mRNA cap are characterized by high affinity for eIF4E, resistance towards DcpS pyrophosphatase and high potency to inhibit cap-dependent translation.

Research paper thumbnail of Synthesis and evaluation of fluorescent cap analogues for mRNA labelling

We describe the synthesis and properties of five dinucleotide fluorescent cap analogues labelled ... more We describe the synthesis and properties of five dinucleotide fluorescent cap analogues labelled at the ribose of the 7-methylguanosine moiety with either anthraniloyl (Ant) or N-methylanthraniloyl (Mant), which have been designed for the preparation of fluorescent mRNAs via transcription in vitro. Two of the analogues bear a methylene modification in the triphosphate bridge, providing resistance against either the Dcp2 or DcpS decapping enzymes. All these compounds were prepared by ZnCl 2 -mediated coupling of a nucleotide P-imidazolide with a fluorescently labelled mononucleotide. To evaluate the utility of these compounds for studying interactions with cap-binding proteins and cap-related cellular processes, both biological and spectroscopic features of those compounds were determined. The results indicate acceptable quantum yields of fluorescence, pH independence, environmental sensitivity, and photostability. The cap analogues are incorporated by RNA polymerase into mRNA transcripts that are efficiently translated in vitro. Transcripts containing fluorescent caps but unmodified in the triphosphate chain are hydrolysed by Dcp2 whereas those containing a a-b methylene modification are resistant.

Research paper thumbnail of Potential therapeutic applications of RNA cap analogs

Future Medicinal Chemistry, 2013

Cap analogs are chemically modified derivatives of the unique cap structure present at the 5´ end... more Cap analogs are chemically modified derivatives of the unique cap structure present at the 5´ end of all eukaryotic mRNAs and several non-coding RNAs. Until recently, cap analogs have served primarily as tools in the study of RNA metabolism. Continuing advances in our understanding of cap biological functions (including RNA stabilization, pre-mRNA splicing, initiation of mRNA translation, as well as cellular transport of mRNAs and snRNAs) and the consequences of the disruption of these processes - resulting in serious medical disorders - have opened new possibilities for pharmaceutical applications of these compounds. In this review, the medicinal potential of cap analogs in areas, such as cancer treatment (including eIF4E targeting and mRNA-based immunotherapy), spinal muscular atrophy treatment, antiviral therapy and the improvement of the localization of nucleus-targeting drugs, are highlighted. Advances achieved to date, challenges, plausible solutions and prospects for the future development of cap analog-based drug design are described.

Research paper thumbnail of mRNAs containing the histone 3' stem-loop are degraded primarily by decapping mediated by oligouridylation of the 3' end

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

Bioorganic & Medicinal Chemistry Letters, 2009

We report synthesis and properties of a pair of new potent inhibitors of translation, namely two ... more We report synthesis and properties of a pair of new potent inhibitors of translation, namely two diastereomers of 7-methylguanosine 5 0 -(1-thiotriphosphate). These new analogs of mRNA 5 0 cap (referred to as m 7 GTPaS (D1) and (D2)) are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS). The more potent of diastereomers, m 7 GTPaS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate 8−foldand8-fold and 8−foldand15-fold more efficiently than m 7 GTP and m 7 GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.

Research paper thumbnail of Preparation of Synthetically Challenging Nucleotides Using Cyanoethyl P-Imidazolides and Microwaves

Organic Letters, 2012

We describe a general method for the elongation of nucleoside oligophosphate chains by means of c... more We describe a general method for the elongation of nucleoside oligophosphate chains by means of cyanoethyl (CE) phosphorimidazolides. Though the method requires a phosphorylation and subsequent deprotection reaction, both steps could be achieved in one pot without isolation/purification of the initial phosphorylation product. We have also found that pyrophosphate bond formation by this method is significantly accelerated by microwave irradiation.

Research paper thumbnail of Utility of chemically modified cap analogues in studying Dcp1/2 decapping complex mechanism of action

Collection Symposium Series, 2014

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

Nucleic acids research, 2014

Modified mRNA cap analogs aid in the study of mRNA-related processes and may enable creation of n... more 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-...

Research paper thumbnail of m7GTP S is a strong and stable inhibitor of cap-dependent translation

Nucleic Acids Symposium Series, 2008

Two diastereomers of 7-methylguanosine 5&... more Two diastereomers of 7-methylguanosine 5'-O-(1-thiotriphosphate) have been synthesized and resolved by RP HPLC. Preliminary studies revealed that these new analogs of mRNA cap are characterized by high affinity for eIF4E, resistance towards DcpS pyrophosphatase and high potency to inhibit cap-dependent translation.

Research paper thumbnail of Synthesis and evaluation of fluorescent cap analogues for mRNA labelling

We describe the synthesis and properties of five dinucleotide fluorescent cap analogues labelled ... more We describe the synthesis and properties of five dinucleotide fluorescent cap analogues labelled at the ribose of the 7-methylguanosine moiety with either anthraniloyl (Ant) or N-methylanthraniloyl (Mant), which have been designed for the preparation of fluorescent mRNAs via transcription in vitro. Two of the analogues bear a methylene modification in the triphosphate bridge, providing resistance against either the Dcp2 or DcpS decapping enzymes. All these compounds were prepared by ZnCl 2 -mediated coupling of a nucleotide P-imidazolide with a fluorescently labelled mononucleotide. To evaluate the utility of these compounds for studying interactions with cap-binding proteins and cap-related cellular processes, both biological and spectroscopic features of those compounds were determined. The results indicate acceptable quantum yields of fluorescence, pH independence, environmental sensitivity, and photostability. The cap analogues are incorporated by RNA polymerase into mRNA transcripts that are efficiently translated in vitro. Transcripts containing fluorescent caps but unmodified in the triphosphate chain are hydrolysed by Dcp2 whereas those containing a a-b methylene modification are resistant.

Research paper thumbnail of Potential therapeutic applications of RNA cap analogs

Future Medicinal Chemistry, 2013

Cap analogs are chemically modified derivatives of the unique cap structure present at the 5´ end... more Cap analogs are chemically modified derivatives of the unique cap structure present at the 5´ end of all eukaryotic mRNAs and several non-coding RNAs. Until recently, cap analogs have served primarily as tools in the study of RNA metabolism. Continuing advances in our understanding of cap biological functions (including RNA stabilization, pre-mRNA splicing, initiation of mRNA translation, as well as cellular transport of mRNAs and snRNAs) and the consequences of the disruption of these processes - resulting in serious medical disorders - have opened new possibilities for pharmaceutical applications of these compounds. In this review, the medicinal potential of cap analogs in areas, such as cancer treatment (including eIF4E targeting and mRNA-based immunotherapy), spinal muscular atrophy treatment, antiviral therapy and the improvement of the localization of nucleus-targeting drugs, are highlighted. Advances achieved to date, challenges, plausible solutions and prospects for the future development of cap analog-based drug design are described.

Research paper thumbnail of mRNAs containing the histone 3' stem-loop are degraded primarily by decapping mediated by oligouridylation of the 3' end

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

Bioorganic & Medicinal Chemistry Letters, 2009

We report synthesis and properties of a pair of new potent inhibitors of translation, namely two ... more We report synthesis and properties of a pair of new potent inhibitors of translation, namely two diastereomers of 7-methylguanosine 5 0 -(1-thiotriphosphate). These new analogs of mRNA 5 0 cap (referred to as m 7 GTPaS (D1) and (D2)) are recognized by translational factor eIF4E with high affinity and are not susceptible to hydrolysis by Decapping Scavenger pyrophosphatase (DcpS). The more potent of diastereomers, m 7 GTPaS (D1), inhibited cap-dependent translation in rabbit reticulocyte lysate 8−foldand8-fold and 8−foldand15-fold more efficiently than m 7 GTP and m 7 GpppG, respectively. Both analogs were also significantly more stable in RRL than unmodified ones.

Research paper thumbnail of Preparation of Synthetically Challenging Nucleotides Using Cyanoethyl P-Imidazolides and Microwaves

Organic Letters, 2012

We describe a general method for the elongation of nucleoside oligophosphate chains by means of c... more We describe a general method for the elongation of nucleoside oligophosphate chains by means of cyanoethyl (CE) phosphorimidazolides. Though the method requires a phosphorylation and subsequent deprotection reaction, both steps could be achieved in one pot without isolation/purification of the initial phosphorylation product. We have also found that pyrophosphate bond formation by this method is significantly accelerated by microwave irradiation.