Projects / Programmes
Chemistry and structure of biologically active compounds
January 1, 2022
- December 31, 2027
| Code |
Science |
Field |
Subfield |
| 1.04.00 |
Natural sciences and mathematics |
Chemistry |
|
| 1.03.00 |
Natural sciences and mathematics |
Biology |
|
| Code |
Science |
Field |
| 1.04 |
Natural Sciences |
Chemical sciences |
| 1.06 |
Natural Sciences |
Biological sciences |
structure, dynamics, folding, preorganization, DNA, RNA, non-canonical structures, G-quadruplex, i-motif, tandem repeats, non-coding RNA, microRNA, mitochondrial transfer RNA, proteins, interactions, NMR, nanodevices, natural substance, disease, pest control
Data for the last 5 years (citations for the last 10 years) on
April 25, 2024;
A3 for period
2018-2022
| Database |
Linked records |
Citations |
Pure citations |
Average pure citations |
| WoS |
420 |
9,024 |
7,930 |
18.88 |
| Scopus |
420 |
9,605 |
8,480 |
20.19 |
Researchers (18)
Organisations (2)
Abstract
Research program P1-242 is focused on studies of structure and dynamics of (bio)(macro)molecules as well as their interactions, NMR method development for studies of small and larger systems in solution and solid state, and natural products. Understanding the roles of nucleic acids and proteins in living organisms requires insights into intricate relationships between their biological function and structure. NMR is an excellent tool for studies of structure and conformational changes of DNA, RNA and proteins as well as their interactions with ligands and cations under conditions which are close to physiological states. Guanine-rich DNA and RNA sequences have been shown to form G-quadruplexes (G4), while different tandem repeat sequences may form other noncanonical structures. They are frequent in telomeric ends, in promoters of oncogenes and have also been utilized as nanodevices and as artificial ion channels in lipid bilayers. Indeed, G4-forming DNA and RNA sequences are not confined to the human genome, but are also found in other organisms including plants, bacteria, viruses, etc. This opens many opportunities to exploit their unique structural features for the development of new therapeutic strategies. Indeed, structural details of G4 are a basis for identification of highly selective ligands applicable in anticancer and antiviral treatments. The vast majority of G4 ligands employ rigid aromatic heterocyclic frameworks that are designed to stack onto the large surface of G-quartets. Structural studies of G4-ligand interactions provide insights beyond potential of ligands to simply bind to G4 with the aim of enhancing their stability or extending their lifetime in vivo. Innovative approaches open new ways to design G4 ligands that exert different kinds of control that could be exploited toward biosensor, biological and therapeutic ends. Such approaches harness the selectivity of G4-binding chemotypes to trigger a further molecular event, such as modification of the G4 by oxidation or epigenetic marks. Short non-coding RNAs play an essential role in the regulation of gene expression through targeting messenger RNAs for post-transcriptional gene silencing. Deregulation of microRNA levels may be a cause of many human diseases, including cancer. Structure-function relationships uncover insights into biogenesis processes and interactions with target mRNAs which is crucial for controlling and using miRNAs for therapeutic purposes in design of novel and potent miRNA drugs. Mitochondrial transfer RNAs are essential for maintaining the normal function of mitochondria, which generate the majority of energy in cells. Modern analytical methods enable insights into composition and identity of compounds in various medicinal and aromatic plants that contain bioactive substances with potential for medicinal and agricultural use in treatments of plant diseases and pests control.
Significance for science
Expected results of our research will help to broaden and deepen knowledge of structures and folding of DNA, RNA and proteins involved in several important biological processes as well as their mutual interactions and interactions with small molecules and cations. Understanding of processes in living organisms is based on knowledge of the relationship between structure and function, which recently also includes knowledge of the dynamic properties of bio-molecules. Here, we accentuate the power of NMR in providing information on conformational exchange and dynamic processes across a large span of timescales. So far, very little is known about the structural motifs of G-quadruplexes and other noncanonical structures, which are taken up by G-rich and other tandem repeat sequences in the promoter regions of oncogenes. Such knowledge is important for the understanding of the regulation of gene expression and in the design of new organic molecules, which can specifically stabilize a particular G-quadruplex or alternative non-B-type structures. Novel ligands will help in the fight against various forms of cancer and viral diseases. Novel media for determination of RDC coupling constants are expected to extend possibilities for partial alignment of small organic molecules and contribute to determination of stereochemistry in systems with chiral centers. So far, anisotropic media created by assembly of G-quartet based systems and G-quadruplexes forming liquid crystalline media have been exploited poorly. New methods will facilitate studies of complex biological mixtures, such as metabolites or peptidoglycans. Up till now, very little is known about structural features of G-quadruplexes, which are made of guanine and cytosine residues only, as well as hybrid DNA:RNA quadruplexes. New data on prefolded structures and new quadruplex structural features is important for the design of new organic molecules that could specifically stabilize certain G-quadruplex structure or its preorganized form and thus help in fight against various forms of cancer, viral diseases, frontotemporal dementia and amyotrophic lateral sclerosis. We will also contribute to the development of experimental methods for oligonucleotide structure elucidation. A strong correlation between RNA G-quadruplex structures and their biological activity is expected to be developed. Results of our studies will uncover biological relevance of RNA G-quadruplexes and help in the design stage of new selective ligands for G-quadruplex stabilization and development of potential anticancer drugs. Onset and prolongation of amyloid neuronal diseases (Parkinson's disease, Alzheimer's disease, Transmissible spongiform encephalopathy, etc.) still represent an unsolved problem. Knowledge about the identity and composition of bioactive substances in the tissues of medicinal plants will enable their further studies towards finding their natural resources. At the same time, identification of compounds is a starting point for further research on their effectiveness and possible use. In the case of use of hops in brewing, the obtained information will help to understand hops role in the persistence and stability of beer, as is already known that it is a component, which plays a decisive role.
Significance for the country
Research within the program group P1-242 represents an important part of the activities of the Slovenian NMR Centre, which as a core partner of the EN-FIST Centre of Excellence connects academic users and industrial partners. New NMR methods will be available to the widest range of users. NMR spectroscopy is being extensively used to solve both structural and conformational problems of smaller molecules, including organic compounds, active pharmaceutical ingredients and macromolecules such as proteins, nucleic acids and carbohydrates. We expect to contribute to the dissemination and expansion of knowledge in the field of modern NMR spectroscopy to the broader Slovenian scientific and research communities. We wish to emphasize our longstanding collaboration with pharmaceutical and chemical companies in Slovenia, particularly Krka, Lek, Helios, Bia Separations, Melamin and AciesBio. Novel NMR methods for partial alignment and RDC measurements could be used in pharmaceutical and chemical industry in determination of relative stereochemistry. Structural, conformational and stereochemical features of molecules of natural origin and potential active pharmaceutical ingredients could be studied by means of NMR spectroscopy. Objectives of the program group involve wide range of socio-economic, societal and cultural challenges. Innovative solutions are following the European Green deal objectives, where our expertise and studies can contribute to lowering of carbon footprint and pollution prevention, climate change adaptation, transition into circular economy and protection and restoration of biodiversity and ecosystems. Search for correlations between the structure and function is highly relevant for pharmaceutical industry. We expect that our results will contribute to the understanding of various structural features of DNA, RNA and hybrid DNA:RNA quadruplex structures as well as their prefolded forms. These systems could be used as targets for development of new drugs as well as in the design of nanomachines based on dynamic folding of oligonucleotides. Results of our studies will be very important for future determination of NMR solution state RNA G-quadruplex structures. Furthermore, studies of binding interfaces will help to explain possible roles of RNA G-quadruplexes and will be attractive for pharmaceutical companies since we will focus on RNA G-quadruplexes located in the 5'UTRs of certain mRNAs involved also in cancer. By identifying structural anomalies of prion proteins, we hope to better understand the initial stages of transmissible spongiform encephalopathy and prion disease in particular. The acquired knowledge will enable us to screen for compounds that could prevent further stages of the disease. Our goal is to transfer knowledge into pharmaceutical industry that is highly developed in Slovenia. Our internationally recognized high-level expertise has led to intensive cooperation in the medical field in recent years. Studies are underway in cooperation with University Medical Centers in Ljubljana and Maribor. The program team is strongly involved in educational process. Topics and mentoring by the members of the program group are subject of B. Sc. and M. Sc. as well as Ph. D. theses. The P.I. of the program is lecturer of several courses at UL FCCT and at the interdisciplinary doctoral programs of Biomedicine and Biosciences. Important aspect of education and development of human resources involves spreading knowledge about the usefulness of NMR spectroscopy in addressing a wide range of professional challenges. As NMR spectroscopy plays a key role in identifying materials at the atomic level, we can make an important contribution in the field of preservation and protection of historical objects and artefacts of great national as well as global importance. We can make a key contribution to the quality of conservation procedures, which in turn will improve the sustainability of our cultural heritage. Studies are ongoing in colaboration with National museum of Slovenia and National and University Library of Ljubljana. Knowledge about the possible effectiveness of medicinal plants provides a starting point for the diversification of agricultural production in Slovenia in the field of cultivation of these plants. A strong interest in agriculture and related processing industries is reflected in search of new possibilities for the production and processing while achieving a higher added value. At the same time, such programs create new 'green' jobs and with the displacement of monocultures enrich the natural landscape. Optimization of processes in brewing and their deeper understanding provide potential technological improvements and higher competing demands in the brewing industry in Slovenia and on export markets.
