A5011964055- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- RNA Research and Splicing
- DNA and Nucleic Acid Chemistry
- Neurogenetic and Muscular Disorders Research
- Carbohydrate Chemistry and Synthesis
- Protein Tyrosine Phosphatases
- Adenosine and Purinergic Signaling
- Biochemical and Molecular Research
- Fluorine in Organic Chemistry
- PI3K/AKT/mTOR signaling in cancer
- Cancer-related gene regulation
- Advanced NMR Techniques and Applications
- Genetics and Neurodevelopmental Disorders
- Sulfur Compounds in Biology
- Bacteriophages and microbial interactions
- Sirtuins and Resveratrol in Medicine
- Enzyme Structure and Function
- ATP Synthase and ATPases Research
- Ferrocene Chemistry and Applications
- Click Chemistry and Applications
- Cancer, Hypoxia, and Metabolism
- Synthesis and characterization of novel inorganic/organometallic compounds
- RNA regulation and disease
- HIV/AIDS drug development and treatment
University of Warsaw
2015-2025
Sanford Burnham Prebys Medical Discovery Institute
2025
Discovery Institute
2025
OncoArendi Therapeutics (Poland)
2023-2024
Institute of Experimental Physics of the Slovak Academy of Sciences
2016-2020
Eukaryotic mRNAs undergo cotranscriptional 5′-end modification with a 7-methylguanosine cap. In higher eukaryotes, the cap carries additional methylations, such as m6Am─a common epitranscriptomic mark unique to mRNA 5′-end. This is regulated by Pcif1 methyltransferase and FTO demethylase, but its biological function still unknown. Here, we designed synthesized trinucleotide FTO-resistant N6-benzyl analogue of m6Am-cap–m7GpppBn6AmpG (termed AvantCap) incorporated it into using T7 polymerase....
The human Vaccinia H1-related phosphatase (VHR; DUSP3) is a critical positive regulator of the innate immune response. Recent studies suggest that inhibiting VHR could be beneficial in treating sepsis and septic shock. belongs to superfamily protein tyrosine phosphatases (PTPs), large class enzymes are notoriously difficult target with small molecules. Fragment-based drug discovery (FBDD) has emerged as an effective strategy for generating potent ligands, even challenging targets. Here, we...
The ongoing COVID-19 pandemic exemplifies the general need to better understand viral infections. positive single-strand RNA genome of its causative agent, SARS coronavirus 2 (SARS-CoV-2), encodes all enzymes. In this work, we focused on one particular methyltransferase (MTase), nsp16, which, in complex with nsp10, is capable methylating first nucleotide a capped strand at 2′-O position. This process part capping system and crucial for evasion innate immune reaction. light recently...
To broaden the scope of existing methods based on (19)F nucleotide labeling, we developed a new method for synthesis fluorophosphate (oligo)nucleotide analogues containing an O to F substitution at terminal position (oligo)phosphate moiety and evaluated them as tools NMR studies. Using three efficient comprehensive synthetic approaches phosphorimidazolide chemistry tetra-n-butylammonium fluoride, fluoromonophosphate, or imidazolide fluorine sources, prepared over 30...
Analogues of the mRNA 5'-cap are useful tools for studying translation and degradation, with emerging potential applications in novel therapeutic interventions including gene therapy. We report synthesis mono- dinucleotide cap analogues containing dihalogenmethylenebisphosphonate moiety (i.e. one bridging O atom substituted CCl2 or CF2) their properties context cellular translational decapping machineries, compared to phosphate-unmodified previously reported CH2-substituted caps. The were...
Protected guanosine and adenosine ribonucleosides guanine nucleotides are readily functionalized with CF3 substituents within the nucleobase. is trifluoromethylated at C8 position under radical-generating conditions in up to 95% yield 5′-oligophosphates 35% yield. In case of adenosine, selectivity trifluoromethylation depends heavily on functional group protection strategy leads a set CF3-modified nucleosides different substitution patterns (C8, C2, or both) 37% Further transformations based...
Dinucleotide analogs of the messenger RNA cap (m7GpppN) are useful research tools and have potential applications as translational inhibitors or reagents for modification in vitro transcribed mRNAs. It has been previously reported that replacing methyl group at N7-position with benzyl (Bn) produces a dinucleotide superior properties. Here, we followed up on this finding by synthesizing 17 novel Bn7GpppG determining their structure-activity relationship regarding translation inhibition. The...
The high sensitivity of 19F nucleus to changes in the chemical environment has promoted use fluorine-labeled molecular probes study structure and interactions nucleic acids by NMR. So far, most efforts have focused on incorporating fluorine atom into nucleobase ribose moieties using either monomer building blocks for solid-phase synthesis, or nucleoside triphosphates enzymatic synthesis. Here, we report a simple efficient synthesis 5'-fluoromonophosphorylated 5'-fluorodiphosphorylated...
Several nucleotide-specific phosphohydrolases can cleave P-F bonds in substrate analogues containing a fluorophosphate moiety to release fluoride ions. In this work, by employing fluoride-sensitive molecular sensor, we harnessed cleavage reaction develop fluorescence assay screen for phosphohydrolase inhibitors. The is rapid, sensitive, and based on simple synthetically available reagents. was adapted the high-throughput screening (HTS) format its utility demonstrated an 'in-house' library...
Abstract The recent COVID-19 pandemics have demonstrated the great therapeutic potential of in vitro transcribed (IVT) mRNAs, but improvements their biochemical properties, such as cellular stability, reactogenicity and translational activity, are critical for further practical applications gene replacement therapy anticancer immunotherapy. One strategies to overcome these limitations is chemical modification a unique mRNA 5′-end structure, 5′-cap, which responsible regulating translation at...
Abstract The ongoing COVID-19 pandemic exemplifies the general need to better understand viral infections. positive single strand RNA genome of its causative agent, SARS coronavirus 2 (SARS-CoV-2) encodes all enzymes. In this work, we focus on one particular methyltransferase (MTase), nsp16, which in complex with nsp10 is capable methylating first nucleotide a capped at 2′-O position. This process part capping system and crucial for evasion innate immune reaction. light recently discovered...
Sulfotransferases (STs) are ubiquitous enzymes that participate in a vast number of biological processes involving sulfuryl group (SO3) transfer. 3′-phosphoadenosine 5′-phosphosulfate (PAPS) is the universal ST cofactor, serving as "active sulfate" source cells. Herein, we report synthesis three fluorinated PAPS analogues bear fluorine or trifluoromethyl substituents at C2 C8 positions adenine and their evaluation substitute cofactors enable activity to be quantified real-time-monitored by...
Adenylate kinase (AK) plays a crucial role in the metabolic monitoring of cellular adenine nucleotide homeostasis by catalyzing reversible transfer phosphate group between ATP and AMP, yielding two ADP molecules. By regulating levels energy metabolism, enzyme is considered disease modifier potential therapeutic target for various human diseases, including malignancies inflammatory neurodegenerative disorders. However, lacking approved drugs targeting AK hinders broad studies on this enzyme's...
Cytosolic nucleotidases (cNs) catalyze dephosphorylation of nucleoside 5'-monophosphates and thereby contribute to the regulation nucleotide levels in cells. cNs have also been shown dephosphorylate several therapeutically relevant analogues. cN-IIIB has vitro a distinctive activity towards 7-mehtylguanosine monophosphate (m7GMP), which is one key metabolites mRNA cap. Consequently, it proposed that participates cap turnover prevents undesired accumulation salvage m7GMP. Here, we sought...
Abstract The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia H1-related (VHR) was reported to exhibit elevated protein level in cervix cancer cell lines compared normal keratinocytes implicating VHR a novel target for cervical therapeutic. belongs the superfamily of tyrosine phosphatases (PTPs), large class human enzymes that is notoriously difficult with small molecules. Recent studies have demonstrated some PTP functions oncogenes promote tumor development including SHP2...
Abstract Eukaryotic mRNAs undergo co-transcriptional 5’-end modification with a 7-methylguanosine cap. In higher eukaryotes, the cap carries additional methylations, such as m6 A m – common epitranscriptomic mark unique to mRNA 5’-end. This is regulated by Pcif1 methyltransferase and FTO demethylase, but its biological function still unknown. Here, we designed synthesized trinucleotide FTO-resistant N 6-benzyl analog of -cap 7 Gppp Bn6 pG (termed AvantCap ) incorporated it into using T7...