nucleobase, nucleoside, nucleotide, oligonucleotide, oligoribonucleotide, DNA, RNA, poliaminonucleoside, poliaminooligonucleotide, protecting group, bifunctional protecting group, silyl protecting group, chemical synthesis, sequencing, combinatorial library, methylation, epigenetics, i-PSC, molecular dynamics simulation, modeling of molecular structure of RNA, proteins and their complexes, parameterizations and evaluation of force-fields, rational drug design
Chemical synthesis of nucleic acids fragments (oligonucleotides), their components and analogues allow to determine their physicochemical properties and structure. These studies are necessary for understanding a relationship between structure and biological activity of the studied materials.
Low molecular weight compounds are modeled and synthesized as inhibitors of epigenetic enzymes: methylases of DNA and histones and histone deacetylases. These studies are carried in order to select new small molecules able to induce pluripotency of cells (i-PSC) and their transformation into cardiomyocytes.
Our research group apply 3D modeling, quantum mechanics, molecular dynamics simulations, docking and visualization of biomacromolecular structures in order to understand their dynamics, molecular recognition processes and biological functioning. We apply different computational approaches for in silico prediction of structure, interactions and dynamic properties of biomolecules and its complexes. To get insight into the structure-activity relationship of the new inhibitors –potential therapeutics, we employ molecular modeling, docking, QM and MD simulations methods.
Chemical synthesis of oligonucleotides containing modified units requires elaboration of appropriate protecting groups. New protecting groups allowing for a functionalisation of ribonucleosides are sought in a systematic manner, especially amongst bifunctional silyl derivatives, as well as protecting groups and new approaches for their introduction into nucleoside 2’-hydroxyl position as required in RNA synthesis.
Properties of oligonucleotides and their analogues and components are studied with spectroscopic methods, using combinatorial chemistry approach as well as biochemical/biological in vitro/vivo experiments. Dispersed combinatorial libraries of oligonucleotides on polymer beaded support media are synthesized and used.
Current research activity:
- synthesis of small molecules for induction pluripotent cells (i-PSC)
- synthesis of inhibitors of DNA methyltransferases
- quantum mechanical reactivity and transition states studies
- analysis of non canonical interactions stabilizing RNA structure of CCUG repeats by QM-MM calculations.
- synthesis and structure of polyaminooligonucleotides
- oligonucleotide combinatorial libraries
- new protecting groups of 2’-OH for chemical synthesis of RNA
Most important research achievements:
- Development of the synthesis of cytosine derivatives - a new type of inhibitors of DNA methyltransferase.
- Development of the synthesis of polyaminonucleosides and polyaminooligonucleotides and elucidation of their structure with NMR spectroscopy.
- Development of the synthesis and analysis of oligonucleotide combinatorial libraries and methods of sequencing the elements of libraries with MALDI-TOF mass spectrometry.
- Development of new bifunctional silyl protecting group - tetraisopropyldisilane-1,2-diyl.
QM-MM potential energy calculations of structural models of duplexes with non canonical C-U and U-U base pairs involving tautomeric or protonated forms of nucleobases based on crystallographic structures of duplexes
Actual research projects:
- Low molecular weight epigenetic modulators for activation of pluripotency o f cells for regenerative medicine purposes– Consortium EpiCell in the Programme StrategMed 1, 2015 – 2017, NCBiR
- E. Fadrna, N. Spackova, J. Sarzynska, J. Koca, M. Orozco, T.E.III. Cheatham, T. Kulinski, J. Sponer, Single Stranded Loops of Quadruplex DNA As Key Benchmark for Testing Nucleic Acids Force Fields, J. Chem. Theory Comp. 5(9), 5(9), 2514-2530 (2009).
- J. Sarzyńska, A. Mickiewicz, M. Milostan, P. Lukasiak, J. Blazewicz, M. Figlerowicz, T. Kuliński, Flexibility of dicer studied by implicit solvent molecular dynamics simulations, Computational Methods in Science and Technology, 16(1), 97-104 (2010).
- Rulka, W.T. Markiewicz, Sequencing of combinatorial libraries with mass spectrometry.Collection Symposium Series 12, 388-389 (2011).
- B. Uszczyńska, T. Ratajczak, E. Frydrych, H. Maciejewski, M. Figlerowicz, W.T. Markiewicz, M.K. Chmielewski, The application of click chemistry to the production of DNA microarrays.Lab on a Chip, 12, 1151-1156 (2012).
- M.K. Chmielewski, E. Tykarska, W.T. Markiewicz, W.R. Rypniewski, Engineering N-(2-pyridyl)aminoethyl alcohols as potential precursor of thermolabile protection groups. New J. Chem. 36 (3), 603-612 (2012).
- B. Plitta, E. Adamska, M. Giel-Pietraszuk, A. Fedoruk-Wyszomirska, M. Naskręt-Barciszewska, W.T. Markiewicz, J. Barciszewski, New cytosine derivatives as inhibitors of DNA methylation. European Journal of Medicinal Chemistry, 55, 243-254 (2012).
- E. Adamska, J. Barciszewski, W.T. Markiewicz, Convenient and Efficient Syntheses of N 6 - and N 4 - Substituted Adenines and Cytosines and their 2'-Deoxyribosides.Nucleosides, Nucleotides and Nucleic Acids, 31, 861-871 (2012).
- M. Chmielewski, W.T. Markiewicz, Novel Method of Synthesis of 5’’-Phosphate 2’-O-ribosyl-ribonucleosides and Their 3’-Phosphoramidites. Molecules, 18, 14780–14796 (2013).
- J. Brzezinska, Z. Gdaniec, , L. Popenda, W.T. Markiewicz, Polyaminooligonucleotide: NMR structure of duplex DNA containing a nucleoside with spermine residue, N-[4,9,13-triazatridecan-1-yl]-2’-deoxycytidine. Biochim. Biophys. Acta - Gen. Subj., 1840, 1163–1170 (2014).
- A. Krajczyk, K. Kulinska, T. Kulinski, B.L. Hurst, C.W. Day, D.F. Smee, T. Ostrowski, P. Januszczyk, J. Zeidler, Antivirally active ribavirin analogues--4,5-disubstituted 1,2,3-triazole nucleosides: biological evaluation against certain respiratory viruses and computational modelling. Antivir. Chem. Chemother., 23, 161–71 (2014).
- J. Brzezinska, W.T. Markiewicz, Non-Nucleosidic Analogues of Polyaminonucleosides and Their Influence on Thermodynamic Properties of Derived Oligonucleotides. Molecules, 20, 12652–12669 (2015).
- J., Barciszewski, V.E., Marquez, , J.-J. Vasseur, , W.T. Markiewicz, Chemical Biology of Nucleic Acids. ACS Chem. Biol., 10, 1358–1361 (2015).
- W. Rypniewski, K. Banaszak, T. Kuliński, A. Kiliszek, Watson–Crick-like pairs in CCUG repeats: evidence for tautomeric shifts or protonation. RNA, 22, 22–31 (2016).
- K. Malczewska-Jaskóła, B. Jasiewicz, L. Mrówczyńska, Nicotine alkaloids as antioxidant and potential protective agents against in vitro oxidative haemolysis. Chem. Biol. Interact., 243, 62–71 (2016).
- M. Baranek, W.T. Markiewicz, J. Barciszewski, Selected small molecules as inducers of pluripotency. Acta Biochim. Pol., 63,000.(2016).
- M. Baranek, A. Belter, M.Z. Barciszewska, M. Stobiecki, W.T. Markiewicz, J. Barciszewski Effect of small molecules on cell reprogramming. Mol. BioSyst., DOI: 10.1039/C6MB00595K.(2016)
- A. Mickiewicz, J. Sarzyńska , M. Miłostan, A. Kurzyńska-Kokorniak, A. Rybarczyk, P. Łukasiak, T. Kuliński, M. Figlerowicz, J. Błażewicz, Modeling of the catalytic core of Arabidopsis thaliana Dicer-like 4 protein and its complex with double-stranded RNA. Computational Biology and Chemistry DOI: 10.1016/j.compbiolchem.2016.11.003 (2016)