Article
Chemistry, Organic
Blazej A. Wojtczak, Marcelina Bednarczyk, Pawel J. Sikorski, Anna Wojtczak, Piotr Surynt, Joanna Kowalska, Jacek Jemielity
Summary: Chemical modifications of the mRNA cap structure can improve the therapeutic properties of synthetic mRNA by enhancing stability, translational properties, and half-life. The Suzuki-Miyaura cross-coupling reaction is a useful approach for modifying cap structures, and two methods for synthesizing C8-modified cap structures using this reaction were described. The modified cap structures were successfully used to study the interaction with cap-binding proteins.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Anna Wojtczak, Renata Kasprzyk, Marcin Warminski, Krystian Ubych, Dorota Kubacka, Pawel J. Sikorski, Jacek Jemielity, Joanna Kowalska
Summary: Fluorescence anisotropy (FA) is an effective technique for discovering protein inhibitors in a high-throughput manner. This study developed universal FA-based assays for evaluating compounds targeting therapeutic mRNA 5' cap-binding proteins and confirmed the accuracy of the developed method through competitive binding experiments. The study also extended the applications of promising probes to evaluate allosteric inhibitors and RNA ligands.
SCIENTIFIC REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Mateusz Kozarski, Karolina Drazkowska, Marcelina Bednarczyk, Marcin Warminski, Jacek Jemielity, Joanna Kowalska
Summary: mRNA-based gene delivery is a powerful strategy for vaccines and therapeutics. This study synthesized novel triazole-containing tri- and tetranucleotide cap analogs through copper-catalyzed azide-alkyne cycloaddition. One of the compounds showed translational activity and biochemical properties comparable to natural cap structure, making it a promising mRNA capping reagent.
Article
Pharmacology & Pharmacy
Radoslaw Wojcik, Marek R. Baranowski, Lukasz Markiewicz, Dorota Kubacka, Marcelina Bednarczyk, Natalia Baran, Anna Wojtczak, Pawel J. Sikorski, Joanna Zuberek, Joanna Kowalska, Jacek Jemielity
Summary: This passage discusses the utility of dinucleotide analogs of messenger RNA cap, particularly those with benzyl substitution at N7 position, for potential translational inhibition. The synthesis of novel Bn(7)GpppG analogs and their evaluation in terms of translation and translational inhibition are highlighted, showing promising results for N7-(4-halogenbenzyl) substitutions. Additionally, crystal structures of compounds with eIF4E were determined to gain more molecular insight into N7-benzylation of mRNA cap.
Article
Chemistry, Multidisciplinary
Nils Kloecker, Florian P. Weissenboeck, Melissa van Dulmen, Petr Spacek, Sabine Huewel, Andrea Rentmeister
Summary: Translation of mRNA is a crucial process in gene expression, and a new study introduces FlashCaps, cap analogues with photo-cleavable groups, that can regulate translation of mRNA effectively. These compounds inhibit translation in vitro and in mammalian cells, but can be restored through irradiation for efficient translation. FlashCaps present a promising approach for controlling mRNA expression and dosing mRNA therapeutics with spatial and temporal control.
Article
Chemistry, Multidisciplinary
N. V. Cornelissen, R. Mineikaite, M. Erguven, N. Muthmann, A. Peters, A. Bartels, A. Rentmeister
Summary: mRNAs have potential as modalities for vaccination and protein replacement therapy. By modifying the 5' cap, we demonstrated the potential of an enzymatic cascade for post-synthetic modification of mRNA, which can increase protein production without eliciting an immune response.
Article
Cell Biology
Supratik Das
Summary: Protein translation involves initiation, elongation, and termination events. Trypanosomatids can cause serious diseases, and the conservation of initiation factors in them is beginning to be understood. The cap-binding signatures of eIF4E orthologues in trypanosomatids are compared with human eIF4E1 and Trypanosoma cruzi eIF4E5.
MOLECULAR AND CELLULAR BIOCHEMISTRY
(2021)
Article
Neurosciences
Iva Salamon, Geeta Palsule, Xiaobing Luo, Alfonso Roque, Shawn Tucai, Ishan Khosla, Nicole Volk, Wendy Liu, Huijuan Cui, Valentina Dal Pozzo, Petronio Zalamea, Xinfu Jiao, Gabriella D'Arcangelo, Ronald P. Hart, Mladen-Roko Rasin, Megerditch Kiledjian
Summary: Mutations in the gene encoding the scavenger mRNA-decapping enzyme DcpS have been linked to developmental delay and intellectual disability, affecting neuronal differentiation and neurite outgrowth in both human and mouse models. These findings suggest that DcpS plays a crucial role in neural development and further support the association between mRNA metabolism, neocortical pathologies, and intellectual disability.
Article
Chemistry, Multidisciplinary
Xue Tian, Lloyd C. Murfin, Luling Wu, Simon E. Lewis, Tony D. James
Summary: Small-molecule based fluorescent probes play an increasingly important role in detecting and imaging biological signaling molecules due to their simplicity, high selectivity, and real-time analysis capabilities. Various sensing mechanisms, including FRET, ICT, PeT, ESIPT, AIE, as well as dual/triple sensing mechanisms, are highlighted, but challenges remain. Future development should focus on improving small-molecule fluorescent probes for biosensing applications.
Article
Endocrinology & Metabolism
Crystal S. Conn, Haojun Yang, Harrison J. Tom, Kenji Ikeda, Juan A. Oses-Prieto, Hieu Vu, Yasuo Oguri, Supna Nair, Ryan M. Gill, Shingo Kajimura, Ralph J. DeBerardinis, Alma L. Burlingame, Davide Ruggero
Summary: This study reveals the translational control of lipid processing as a driver of high-fat-diet-induced weight gain and provides a pharmacological target to treat obesity.
Review
Oncology
Yuejun Luo, Yuxin Yao, Peng Wu, Xiaohui Zi, Nan Sun, Jie He
Summary: N-7-methylguanosine (m7G) is a prevalent RNA modification that actively participates in biological and pathological functions. It plays a critical role in cancer development and is closely associated with tumorigenesis and progression. The underlying molecular mechanisms of m7G in cancer are not fully understood.
JOURNAL OF HEMATOLOGY & ONCOLOGY
(2022)
Review
Cell Biology
Jerry Pelletier, T. Martin Schmeing, Nahum Sonenberg
Summary: This article discusses the significance of adding the 5' cap structure during RNA transcription, the role of cap binding proteins in gene expression regulation, and the recognition mechanism of the cap. Studying the biological properties of the cap and key points of interaction with CBPs is important for guiding drug development.
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2021)
Article
Biochemistry & Molecular Biology
Jake C. Swartzel, Michael J. Bond, Andreas P. Pintado-Urbanc, Mehana Daftary, Mackenzie W. Krone, Todd Douglas, Evan J. Carder, Joshua T. Zimmer, Takahiro Maeda, Matthew D. Simon, Craig M. Crews
Summary: The RNA decapping scavenger protein DcpS has been identified as a dependency in acute myeloid leukemia (AML), and its inhibition or knockdown shows antiproliferative effects on AML cells. The non-essential nature of DcpS in normal human hematopoietic cells suggests potential for therapeutic intervention in AML by modulating DcpS activity. JCS-1, a PROTAC developed in this study, effectively degrades DcpS in nanomolar concentrations, offering a new strategy for AML and other DcpS-dependent genetic disorders.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Zihao Dai, Haining Liu, Junbin Liao, Cheng Huang, Xiaoxue Ren, Wanjie Zhu, Shenghua Zhu, Baogang Peng, Shaoqiang Li, Jiaming Lai, Lijian Liang, Lixia Xu, Sui Peng, Shuibin Lin, Ming Kuang
Summary: Intrahepatic cholangiocarcinoma (ICC) shows upregulation of N-7-methylguanosine (m(7)G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, which are associated with poor prognosis. METTL/WDR4 play a critical role in promoting ICC cell survival and progression by selectively regulating the translation of oncogenic transcripts through m(7)G-tRNA-decoded codon-frequency-dependent mechanisms. Studies with overexpression and knockout mouse models demonstrate the crucial oncogenic function of Mettl1-mediated m(7)G tRNA modification in promoting ICC tumorigenesis and progression in vivo.
Article
Chemistry, Multidisciplinary
Ines J. Marques, Pedro D. Vaz, Ana V. Girao, Mariela M. Nolasco, Carla D. Nunes
Summary: Silica-coated iron oxide and silica nanoparticles were prepared and derivatized with a europium complex to yield magneto-fluorescent and fluorescent nanomaterials. The fluorescence was enhanced by the anchored europium complex and maintained in cellular medium. These nanomaterials have potential applications as biosensors and in imaging.
NEW JOURNAL OF CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Agnieszka Mlynarska-Cieslak, Mikolaj Chrominski, Tomasz Spiewla, Marek R. Baranowski, Marcelina Bednarczyk, Jacek Jemielity, Joanna Kowalska
Summary: In this study, we synthesized three fluorinated PAPS analogues and evaluated their performance as ST cofactors using fluorine-19 nuclear magnetic resonance (19F NMR) spectroscopy. These analogues showed complementary properties in enzyme recognition and working pH range, making them attractive tools for studying STs. Additionally, we developed an F-19 NMR assay for screening potential inhibitors against SULT1A3, highlighting the potential use of fluorinated PAPS analogues for drug discovery in ST-related diseases.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Jessica K. Peters, Ryan W. Tibble, Marcin Warminski, Jacek Jemielity, John D. Gross
Summary: Poxviruses encode decapping enzymes that remove the 5' cap from mRNA to inhibit protein synthesis and limit accumulation of viral dsRNA. The structure of vaccinia virus decapping enzyme D9 reveals a unique domain organization and a bipartite active site for cap binding. The specificity for methylated guanosine cap is achieved through stacking with conserved aromatic residues.
Article
Chemistry, Medicinal
Dorota Kubacka, Mateusz Kozarski, Marek R. Baranowski, Radoslaw Wojcik, Joanna Panecka-Hofman, Dominika Strzelecka, Jerome Basquin, Jacek Jemielity, Joanna Kowalska
Summary: This study aimed to develop molecular tools for advanced studies on the cellular role of cytosolic nucleotidase cN-IIIB. Through substrate and inhibitor property profiling of a library of 41 substrate analogs, several 7-benzylguanosine 5'-monophosphate derivatives were identified as potent, unhydrolyzable inhibitors of cN-IIIB. The inhibitory mechanism was elucidated using X-ray crystallography and molecular docking, and it was demonstrated that these compounds can inhibit m(7)GMP decay in cell lysates.
Article
Chemistry, Organic
Kamil Ziemkiewicz, Marcin Warminski, Radoslaw Wojcik, Joanna Kowalska, Jacek Jemielity
Summary: Here, a straightforward one-step procedure for modifying N-nucleophilic groups in commercially available nucleoside phosphoramidites is reported. This involves deprotonating amide groups under phase-transfer conditions and reacting with electrophilic molecules such as alkyl halides or organic isocyanates. Ten different classes of modified nucleoside phosphoramidites suitable for oligonucleotide synthesis, including noncanonical nucleotides found in natural RNA or DNA, were obtained using this approach. Such modifications of nucleobases are common mechanisms for post-transcriptional regulation of RNA stability and translational activity.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Letter
Chemistry, Organic
Mikolaj Chrominski, Kamil Ziemkiewicz, Joanna Kowalska, Jacek Jemielity
Summary: A reaction between ribonucleosides and ex situ generated sulfonyl fluoride has been developed, leading to nucleosides equipped with a sulfamoyl fluoride moiety. These nucleosides undergo a selective sulfur fluoride exchange (SuFEx) reaction with various amines to form sulfamide-functionalized derivatives. The study also demonstrates the scope and examples of further functionalization to nucleotides, oligonucleotides, and peptide-nucleoside conjugates.
Article
Chemistry, Analytical
Anna Pepanian, Paul Sommerfeld, Renata Kasprzyk, Toni Kuehl, F. Ayberk Binbay, Christoph Hauser, Reik Loeser, Robert Wodtke, Marcelina Bednarczyk, Mikolaj Chrominski, Joanna Kowalska, Jacek Jemielity, Diana Imhof, Markus Pietsch
Summary: This study presents a reliable fluorescence anisotropy-based method to determine ligands' affinity at the GTP-binding site and quantify the fraction of active G alpha i1 protein. It contributes a novel approach for future investigations of G alpha i and other G alpha protein subunits, exploring their signal transduction systems and potential biomedical applications.
ANALYTICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Karolina Drazkowska, Rafal Tomecki, Marcin Warminski, Natalia Baran, Dominik Cysewski, Anais Depaix, Renata Kasprzyk, Joanna Kowalska, Jacek Jemielity, Pawel J. Sikorski
Summary: This study explores the impact of nucleotide modifications in mRNA capping on protein production levels and immune response. The researchers find that 2'-O-methylation of the second transcribed nucleotide can significantly affect protein synthesis in a cell-specific manner and is linked to transcript escape from the host immune response.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemistry & Molecular Biology
Anais Depaix, Ewa Grudzien-Nogalska, Bartlomiej Fedorczyk, Megerditch Kiledjian, Jacek Jemielity, Joanna Kowalska
Summary: Many non-canonical caps, including NAD-linked, FAD-linked, and UDP-glucose-linked RNAs, have been identified recently. However, the study of these caps is limited by the difficulties in obtaining high-quality in vitro transcribed RNA probes. To address this issue, researchers have developed new capping reagents and transcription conditions to improve the quality of unconventionally capped RNAs. This method provides easy access to chemical probes for investigating the biological roles of non-canonical RNA 5' capping.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Organic
Blazej A. Wojtczak, Marcelina Bednarczyk, Pawel J. Sikorski, Anna Wojtczak, Piotr Surynt, Joanna Kowalska, Jacek Jemielity
Summary: Chemical modifications of the mRNA cap structure can improve the therapeutic properties of synthetic mRNA by enhancing stability, translational properties, and half-life. The Suzuki-Miyaura cross-coupling reaction is a useful approach for modifying cap structures, and two methods for synthesizing C8-modified cap structures using this reaction were described. The modified cap structures were successfully used to study the interaction with cap-binding proteins.
JOURNAL OF ORGANIC CHEMISTRY
(2023)
Review
Chemistry, Multidisciplinary
Marcin Warminski, Adam Mamot, Anais Depaix, Joanna Kowalska, Jacek Jemielity
Summary: mRNA serves as a universal instruction for ribosomes to produce proteins, and its instability has been a major challenge in the development of RNA-based therapeutics. After years of trial and error, researchers have successfully developed the first mRNA vaccines during the SARS-CoV-2 pandemic. Chemical modifications at the ends of mRNA, such as the cap and poly(A) tail, have been used to improve its biological properties and stability.
ACCOUNTS OF CHEMICAL RESEARCH
(2023)
Article
Chemistry, Multidisciplinary
Mateusz Kozarski, Karolina Drazkowska, Marcelina Bednarczyk, Marcin Warminski, Jacek Jemielity, Joanna Kowalska
Summary: mRNA-based gene delivery is a powerful strategy for vaccines and therapeutics. This study synthesized novel triazole-containing tri- and tetranucleotide cap analogs through copper-catalyzed azide-alkyne cycloaddition. One of the compounds showed translational activity and biochemical properties comparable to natural cap structure, making it a promising mRNA capping reagent.
Article
Chemistry, Organic
Kamil Ziemkiewicz, Marcin Warminski, Radoslaw Wojcik, Joanna Kowalska, Jacek Jemielity
Summary: The study presents a method for modifying nucleobases in nucleoside phosphoramidites, resulting in 10 different classes of modified nucleoside phosphoramidites suitable for oligonucleotide synthesis, including noncanonical nucleotides found in natural RNA or DNA. This approach can help in understanding the post-transcriptional regulation of RNA stability and translational activity. Further research requires identification and characterization of relevant cellular recognition partners, though limited access to molecular tools with modified nucleotides remains a challenge.
JOURNAL OF ORGANIC CHEMISTRY
(2022)