Projects / Programmes source: ARIS

Design, synthesis, and evaluation of new voltage-gated sodium channels modulators

Research activity

Code Science Field Subfield
1.09.00  Natural sciences and mathematics  Pharmacy   

Code Science Field
B740  Biomedical sciences  Pharmacological sciences, pharmacognosy, pharmacy, toxicology 

Code Science Field
3.01  Medical and Health Sciences  Basic medicine 
voltage-gated sodium channels, subtype-selective modulators, marine alkaloids, antibacterials, drug design, medicinal chemistry
Evaluation (rules)
source: COBISS
Researchers (1)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  28905  PhD Nace Zidar  Pharmacy  Head  2013 - 2015  216 
Organisations (1)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0787  University of Ljubljana, Faculty of Pharmacy  Ljubljana  1626973  17,536 
Voltage-gated sodium channels (VGSC, NaV channels) are integral membrane proteins which play essential roles in the initiation and propagation of action potentials in neurons and other electrically excitable cells. They are composed of a single α-subunit, which forms a voltage-sensing pore, and one or more auxiliary β-subunits. To date, nine different α-subunits (NaV1.1–NaV1.9) and four different β-subunits have been identified. VGSC subtypes have similar structures, but the expression of α-subunits is strongly cell-type- and tissue-specific, therefore each of these subtypes is believed to have unique properties. The abnormally increased activity of sodium channels leads to over-excitation of specific groups of cells which can cause different neurodegenerative diseases, chronic pain, epilepsy, arrhythmias, and spasticity. Although there are several drugs acting at NaV channels, a more rational approach is required to exploit the full therapeutic potential of these drug targets. Current drugs acting on VGSCs have low potency and are relatively non-specific, therefore there is a need for the development of isoform-specific modulators which offer the promise of therapies with a significant advantage over current standard of care.   Recently, the first crystal structure of a NaV channel from Arcobacter butzleri was published. This crystal structure offers key insights into the molecular basis of electrical signaling and provides the template for understanding the action of drugs targeting NaV channels at the atomic level. The given structural information is an excellent starting point for a more rational approach in the design of potent and selective VGSC modulators.   Alkaloids from the Caribbean sponge of the genus Agelas, e.g. clathrodin, oroidin, sceptrin and dibromosceptrin affect NaV channels by influencing channel ion conductance or by modifying the channel inactivation characteristics. In addition to effects on VGSC, some alkaloids from the oroidin class also possess antibacterial activity. Natural oroidin-like compounds possess favorable physicochemical properties and are thus excellent candidates for medicinal chemistry optimization.   The ultimate goals of the project are (i) to develop compounds selectively acting on different VGSC subtypes for possible further development to drug candidates, and (ii) to identify and develop substances with potential antibacterial activity, both based on synthetic oroidin analogs and related starting compounds. We will search for a possible connection of the antibacterial activity of compounds to their effects on NaV channels. In order to achieve these goals we will design and synthesize series of analogs and biologically evaluate them on different VGSC subtypes using electrophysiological assays. X-ray structure of the bacterial NaV channel will be used for the prediction of 3D structures of human isoforms and the predicted homology models will be used for the design of novel VGSC modulators. The essential structural elements required for biological activity will be identified and, applying structure-based design in several iterative cycles, new generations of drug-like compounds will be designed, synthesized and biologically evaluated. Structural information, together with advanced computer-aided drug design methods offers good prospect for the development of potent and selective NaV modulators within the proposed project.   Despite the tremendous therapeutic potential of VGSC modulators, NaV channels remain significantly under-exploited as therapeutic targets. Selective VGSC modulators prepared within the proposed project will be of paramount scientific, economical and healthcare importance. In addition, development of compounds with antibacterial activity would be a big step forward in the fight against resistant bacterial strains. New led compounds developed during the project lifetime will be a valuable contribution in a permanent quest for new and better drugs for human health ca
Significance for science
NaV channels have an immense therapeutic potential which remains significantly under-exploited. Within the family of NaV channels there are many therapeutically highly relevant targets and the design of modulators of specific NaV channel subtypes might turn out as a key step towards new drugs for currently incurable diseases. Current drugs acting on NaV channels are neither very potent nor subtype-selective. NaV1.3 channel selective inhibitors that were discovered within this project are of invaluable importance to the development of this scientific field. The results are of potential importance for science and human health care. New compounds developed during this project are an important and valuable scientific contribution to medicinal chemistry and health science in general, and represent a good basis for further development towards more potent and more selective inhibitors of NaV channels. Because of the widespread occurrence of resistant bacterial strains the search for new drugs with novel mechanisms of action is of great scientific importance. New oroidin analogues possessing activity on different bacterial strains identified during this project are relevant to health and life sciences. On the basis of the discovered structures, the development of improved antibacterials is possible. We have discovered also that some of the prepared oroidin analogues inhibit the bacterial biofilm formation and thus represent good basis for further development of more effective inhibitors of S. aureus and S. mutans biofilm formation. We have discovered also, that some of the prepared analogues possess proapoptotic activity on selected mammalian cell lines which is a potentially relevant to the discovery of anticancer agents. A selected subset of compounds was evaluated also against different isoforms of voltage-gated potassium channels where some of the compounds displayed good inhibitory activities. The results obtained during this project were disseminated in form of contributions at scientific conferences, oral communications and in seven scientific publications. Three more publications are currently in preparation. New scientific concepts and findings emerging from this project were made available to the worldwide scientific community and will hopefully stimulate creative research in different scientific fields.
Significance for the country
Worldwide sales of ion channel-targeted drugs is estimated to be approximately US$12 billion (Wickenden, A. et al., Future Med. Chem. 2012, 4, 661–679) so it is not surprising that this has prompted a high degree of interest from the pharmaceutical industry, resulting in numerous patent applications and patents. NaV channels offer a huge pool of opportunities for developing new drugs in different therapeutic areas, but nevertheless remain significantly under-exploited as therapeutic targets. Selective NaV1.3 channel modulators prepared during this project are of relevance for the society and its economy and are potentially important for the development of Slovenia. Later development and launching of a successful drug would have an immense positive effect on health and economy. In addition, the widespread occurrence of bacterial strains resistant to currently used antibiotics presents a great health threat for the society. Our contribution to the identification of new compounds with antibacterial activity could have a positive impact on health and society. The project had a positive impact for the development of Slovenia also through generation and dissemination of new knowledge through presentations at conferences and in scientific publications. These activities were important to promote science inside the country and also to promote Slovenian science and country worldwide. The project was very important for reinforcing the cooperation in interdisciplinary, interinstitutionary and international scientific environment.
Most important scientific results Annual report 2013, 2014, final report, complete report on dLib.si
Most important socioeconomically and culturally relevant results Annual report 2013, 2014, final report, complete report on dLib.si
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