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Molecular mechanisms underlying the toxicity of antidotes and potential drugs – CellToxTargets

Croatian Science Foundation

Project head: Maja Katalinić

Project participants:

Sergej Pirkmajer, Ivana Vrhovac Madunić, Antonio Zandona, Josip Madunić, Nikola Maraković, Ana-Marija Lulić

Duration: 1 Mar 2018 – 28 Feb 2023

Funding: 1,693,000.00 HRK

Summary
The project presents the new innovative approach in the field of antidote research for poisoning with organophosphates (OP), having the applications in overall drug discovery. The main goal of the project is to answer how the antidotes and drugs act on cell level and uncover the trigger mechanism leading to the side-effects or even severe effects that could occur in vivo. The specific cell-based screening will be applied to define the mechanism behind such unwanted toxicity of compounds and to aid a more efficient selection of a lead candidate for drug development. Within the proposed project, we will test several defined sets of structurally related antidotes/drugs. This will allow us to use, after obtaining sufficient cell-based data, a structure-activity approach to define the possible structural features of tested compounds triggering certain effects. Thus, features like these could be modified in the early lead compound structure refinement process without performing any in vivo studies. More efficient feedback will be given to studies designing drugs and aid the challenging development of an effective treatment primarily for OP poisoning. We also expect to identify new possible targets on the cell level and explore their therapeutic potential. One such target in treating exposure to OPs, NRE, was identified in our earlier research. Therefore, we will study the role and function of this unexplored enzyme and answer whether it could be considered as a potential target in OP treatment or even has an indication for being a target molecule in treatment of other diseases. Our findings should open up a new perspective with potential impact beyond the original scope. Beside the scientific part, the newly established experienced and skilled research team will stimulate a technology transfer through collaborations, continuous upgrading and improvement of methods and training in specific skills.

Research team

Implementation plan through two main project activities

  • Cell-based research for determining effects of new antidotes and drugs.

  • NRE´s role in the cell and potential to be evaluated as a new target for OP poisoning treatment.

NEWS:

Final Symposium “Cell-Based Research in Toxicology and Drug Design” of the project “Molecular mechanisms underlying the toxicity of antidotes and potential drugs – CellToxTargets”.

The Symposium „Cell–Based Research in Toxicology and Drug Design” was held at the hotel Dubrovnik in Zagreb on January 26th, 2023, with the main objective to disseminate results obtained within the project HrZZ-UIP-05-7260 CellToxTargets and to discuss them with colleagues from different field of research. Organization of the Symposium was supported by the Croatian Science Foundation (grant no. HrZZ-UIP-2017-05-7260, CellToxTargets) and by the Institute for Medical Research and Occupational Health. Also, the organization was sponsored by companies Kefo ltd., Jasika ltd. and Medic ltd.

The Symposium brought together 31 participants including experienced scientists, each expert in a specific field (from kinetics to metabolism and cell-based research), along with the PhD students and postdoctoral fellows, as well as the representatives from the industry, who all presented their recent research achievements.

The scientific programme was divided into five sessions spanning topics from new approaches in drug development, cholinesterase ligand-based drugs and biochemistry in drug-related research, giving the participants floor for fruitful discussion and opening new possibilities for collaborations and ideas for future studies.

We were very pleased that we could host eminent scientists Prof Miguel Castanho and Dr Vera Neves from the Institute of Molecular Medicine Lisbon, Portugal, Prof Pierre-Yves Renard from the Normandie Univ, UNIROUEN, Rouen, France, and Dr Jelena Krstić from the Gottfried Schatz Research Center for Cell Signaling, Metabolism & Aging, Medical University of Graz, Austria, delivering four inspiring lectures presenting new and interesting findings in different areas of biochemistry and molecular biology.

The Symposium has been a rewarding scientific and personal experience for us, and we would like to express our sincere thanks to all of the speakers and participants for sharing their results, and contributing to the excellence of our scientific program. We thank Croatian Science Foundation and the Institute for Medical Research and Occupational Health for their support, and the sponsors whose contribution was invaluable to the overall success of the Symposium.

Select publications

Book chapters:

  1. Marš, Tomaž; Miš, Katarina; Katalinić, Maja; Pegan, Katarina; Grubič, Zoran; Pirkmajer, Sergej The effects of organophosphates in the early stages of human skeletal muscle regeneration. Handbook of Toxicology of Chemical Warfare Agents (Third Edition), Gupta, Ramesh C. (ed.). London: Academic Press, 2020. pp 829-841.

Journal articles:

  1. Zandona, Antonio; Zorbaz, Tamara; Miš, Katarina; Pirkmajer, Sergej; Katalinić, Maja. Cytotoxicity-related effects of imidazolium and chlorinated bispyridinium oximes in SH-SY5Y cells. Arhiv za higijenu rada i toksikologiju, 73 (2022), 277-284. . [IF=2.078, Q4]
  2. Gašo Sokač, Dajana; Zandona, Antonio; Roca, Sunčica; Vikić-Topić, Dražen; Lihtar, Gabriela; Maraković, Nikola; Bušić, Valentina; Kovarik, Zrinka; Katalinić, Maja. Potential of vitamin B6 dioxime analogues to act as cholinesterase ligands. International journal of molecular sciences, 23 (2022), 21; 13388, 18 doi:10.3390/ijms232113388. [IF=6.208, Q1]
  3. Zorbaz, Tamara; Malinak, David; Hofmanova, Tereza; Maraković, Nikola; Žunec, Suzana; Maček Hrvat, Nikolina; Andrys, Rudolf; Psotka, Miroslav; Zandona, Antonio; Svobodova, Jana et al. Halogen substituents enhance oxime nucleophilicity for reactivation of cholinesterases inhibited by nerve agents. European journal of medicinal chemistry, 238 (2022), 114377, 16 doi:10.1016/j.ejmech.2022.114377. [IF=6.514, Q1]
  4. Matošević, Ana; Radman Kastelic, Andreja; Mikelić, Ana; Zandona, Antonio; Katalinić, Maja; Primožič, Ines; Bosak, Anita; Hrenar, Tomica. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics, 13 (2021), 3; 420, 15 doi:10.3390/pharmaceutics13030420. [IF=5.215, Q1]
  5. Zandona, Antonio; Jagić, Karla; Dvoršćak, Marija; Madunić, Josip; Klinčić, Darija; Katalinić, Maja. PBDEs found in house dust impact human lung epithelial cell homeostasis. Toxics, 10 (2022), 97-112 doi:10.3390/toxics10020097. [IF=4.146, Q2]
  6. Zandona, Antonio; Maraković, Nikola; Mišetić, Petra; Madunić, Josip; Miš, Katarina; Padovan, Jasna; Pirkmajer, Sergej; Katalinić, Maja. Activation of (un)regulated cell death as a new perspective for bispyridinium and imidazolium oximes. Archives of toxicology, 95 (2021), 2737-2754 doi:10.1007/s00204-021-03098-w. [IF=5.153, Q1]
  7. Jurič, Andreja; Zandona, Antonio; Tariba Lovaković, Blanka; Rašić, Dubravka; Pizent, Alica; Kozina, Goran; Katalinić, Maja; Lucić Vrdoljak, Ana; Brčić Karačonji, Irena. Cytotoxic, genotoxic, and oxidative stress-related effects of lysergic acid diethylamide (LSD) and phencyclidine (PCP) in the human neuroblastoma SH- SY5Y cell line. Arhiv za higijenu rada i toksikologiju, 72 (2021), 4; 333-342. [IF=1.948, Q3]
  8. Matošević, Ana; Radman Kastelic, Andreja; Mikelić, Ana; Zandona, Antonio; Katalinić, Maja; Primožič, Ines; Bosak, Anita; Hrenar, Tomica. Quinuclidine-Based Carbamates as Potential CNS Active Compounds. Pharmaceutics, 13 (2021), 3; 420, 15 doi:10.3390/pharmaceutics13030420. [IF=6.321, Q1]
  9. Zandona, Antonio; Lihtar, Gabriela; Maraković, Nikola; Miš, Katarina; Bušić, Valentina; Gašo-Sokač, Dajana; Pirkmajer, Sergej; Katalinić, Maja. Vitamin B3-based biologically active compounds as inhibitors of human cholinesterases. International Journal of Molecular Sciences (2020). doi:10.3390/ijms21218088 [IF=4.556, Q1]
  10. Zandona, Antonio; Katalinić Maja. Nicotinic acetylcholine receptors: Diversity and physiological importance for neurodegenerative disorders and development of organophosphate  antidotes. Periodicum Biologorum (2020). U postupku objavljivanja [IF=0.883, Q3]
  11. Zandona, Antonio; Katalinić, Maja; Šinko, Goran; Radman Kastelic, Andreja; Primožič, Ines; Kovarik, Zrinka. Targeting Organophosphorus Compounds Poisoning by Novel quinuclidine-3 Oximes: Development of Butyrylcholinesterase-Based Bioscavengers. Archives of toxicology (2020). doi:10.1007/s00204-020-02811-5 [IF = 5.059, Q1]
  12. Klinčić, Darija; Herceg Romanić, Snježana; Katalinić, Maja; Zandona, Antonio; Čadež, Tena; Matek Sarić, Marijana; Šarić, Tomislav; Aćimov, Dejan. Persistent organic pollutants in tissues of farmed tuna from the Adriatic Sea. Marine Pollution Bulletin (2020), 158:111413, 7 doi:10.1016/j.marpolbul.2020.111413 [IF = 4.049, Q1]
  13. Zorbaz, Tamara; Mišetić, Petra; Probst, Nicolas; Žunec, Suzana; Zandona, Antonio; Mendaš, Gordana; Micek, Vedran; Maček Hrvat, Nikolina; Katalinić, Maja; Braïki, Anissa et al. Pharmacokinetic evaluation of brain penetrating morpholine-3-hydroxy-2-pyridine oxime as an antidote for nerve agent poisoning. ACS Chemical Neuroscience (2020), 11(7):1072-1084. doi:10.1021/acschemneuro.0c00032 [IF = 4.486, Q1]
  14. Zorbaz et al. Pyridinium oximes with ortho-positioned chlorine moiety exhibit improved physico- chemical properties and efficient reactivation of human acetylcholinesterase inhibited by several nerve agents. Journal of Medicinal Chemistry, (2018), 61(23):10753-10766. doi:10.1021/acs.jmedchem.8b01398 [IF = 6.253, Q1].

Other publications are available at
https://www.bib.irb.hr/pregled/projekti/HRZZ-UIP-2017-05-7260

Lectures

  1. Katalinić, Maja. Where we are going from here? Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  2. Vrhovac Madunić, Ivana. Interaction of renal and hepatic organic cation transporters (OCT) with oximes. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  3. Žunec, Suzana; Katalinić Maja. Metabolic stability as a challenge facing drug oriented research. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  4. Lulić, Ana-Marija. Characterization of lysophospholipase PNPLA7 as a potential target for drug development. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  5. Zandona, Antonio. Structure – cytotoxicity relationship of cholinesterase-based ligands Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  6. Katalinić, Maja. Molecular mechanisms underlying the toxicity of antidotes and potential drugs – HrZZ-UIP-2017-05-7260. Symposium Cell-Based Research in Toxicology and Drug Design. 2023.
  7. Zandona, Antonio; Maraković, Nikola; Katalinić Maja. Oximes developed as antidotes for organophosphates present a scaffold for new research(es) candidates. Book of abstracts of 6th Mini Symposium of Section of Medicinal and Pharmaceutical Chemistry. Zagreb, 2022. str. 2-2.
  8. Žunec, Suzana; Vadlja, Donna; Zandona, Antonio; Ramić, Alma; Primožič, Ines; Katalinić, Maja. Cell response to N-alkyl quaternary quinuclidine oxime treatment. 11th International Congress of the Turkish Society of Toxicology : Abstract Book, Basran, Nursen (ur.). Antalya, 2022. str. 64-64.
  9. Maja Katalinić: Activation of (un)regulated cell death as a new perspective for oxime research. 7th Symposium Apoptosis and Neoplasms, Zagreb, 2021.
  10. Zandona, Antonio; Miš, Katarina Miš; Pirkmajer, Sergej; Katalinić, Maja. Cytotoxic effects of vitamin B3 derivatives in cultured cells. 6th Croatian Congress of Toxicology with International Participation CROTOX 2021
  11. Katalinić, Maja; Zandona, Antonio; Madunić, Josip; Vrhovac Madunić, Ivana; Miš, Katarina; Pirkmajer, Sergej. 3rd SYMPOSIUM & WORKSHOP “Skeletal muscle research – from cell to human 2019”: Neural and muscle cells in organophosphorus compound antidote research“, 26-28.05.2019. Ljubljana, Slovenia.
  12. Katalinić Maja. Molecular mechanisms underlying the toxicity of antidotes and potential drugs. Workshop: „Reactivators and Medical Countermeasures against Nerve Agents and Pesticides“, 14-16.05.2018., Zagreb, Croatia. Arhiv za higijenu rada i toksikologiju 2018; 69:A32-A43.

Science Popularization

  1. Zandona Antonio, (Bio)chemistry of antidotes, 30.1.2023., učenici 3. i 4. razreda gimnazije Srednja Škola Pakrac, Pakrac.

2. Lulić Ana-Marija i Zandona Antonio, Dan karijera na PMF-u, WorkIn’ Science – WISe, 03.11.20121., PMF, Zagreb., http://wise.pmf.unizg.hr/

3. Katalinić Maja, Challenges in antidote research in organophosphorus poisoning (warfare agents), Professional meeting AZOO, prezentation, 8.7.2020. Zagreb, Croatia.

4. Katalinić Maja, From phosphoric acid to warfare agents, IMIMobil 2019, presentation, IMI Open Doors 2019, 22.3.2018. Karlovac, Croatia. https://www.imi.hr/hr/2019/04/04/imimobil-je-krenuo/

5. Ivana Vrhovac Madunić, Molecular toxicology on IMROH, presentation, University Career Week at J. J. Strossmayer Department of Biology, University of Osijek 14.05.2019. Osijek, Croatia. https://www.imi.hr/hr/2019/20/05/imi-na-sveucilisnom-tjednu-karijera/#!

6. Katalinić Maja, Sarin, VX, Novichok – why are they still a threat? II. Vocational Teacher Days, 22-24.10.2018. Šibenik, Croatia. https://danistrukovnihnastavnika2018.weebly.com/

7. Zandona Antonio, Mechanism of toxicity of xenobiotics and potential drugs, WorkIn’ Science – WISe, 07.11.2018., Faculty of science Zagreb, Croatia http://wise.pmf.unizg.hr/

8. Zandona Antonio, Molecular mechanism of toxicity of antidotes and potential drugs, Youth Science Talks, IMROH Mini Symposium, 21.11.2018., Zagreb, Croatia, https://www.imi.hr/hr/2018/13/11/znanstveni-razgovori-mladih/

9- Zandona Antonio, Katalinić Maja, Molecular mechanism of toxicity of antidotes and potential drugs, Guest appearance in a science show “Treći element” on HTV3, 12.12.2018. in episode called “Pazi otrov!” https://www.youtube.com/watch?v=QcRg3gCQpG4

10. Zandona Antonio, Katalinić Maja, Vrhovac Madunić Ivana, Travel by stations, Scientific Cookies, presentation, Open Doors IMI 2018, 27. and 28.3.2018. https://www.imi.hr/dov2018/program/

Awards

  1. Lulić Ana-Marija: Fellowship to attend on Congress of Croatian Society of Biochemistry and Molecular Biology, Brela, Croatia (2022)
  2. Zandona Antonio: FEBS Bursary for the 25th IUBMB Congress, the 46th FEBS Congress and the 15th PABMB Congress, Lisbon, Portugal (2022)
  3. Zandona Antonio: Fellowship to attend onthe 6th Croatian Congress of Toxicology with International Participation, Rabac, Hrvatska (2021)
  4. Zandona Antonio: IMI Award for at least 3 original scientific papers on which the employee is the first author, and which were published in the previous calendar year in journals indexed in the Web of Science database, Zagreb (2020)
  5. Zandona Antonio: EMBO Short Term Fellowship, Institute for Molecular Medicine, Lisbon, Portugal (2020)
  6. Zandona Antonio: Best Poster Award on „Symposium of PhD students of the Faculty of Science 2020.“, Zagreb, Hrvatska (28.2.2020.)
  7. Zandona Antonio: Poster Award on Congress of Croatian Society of Biochemistry and Molecular Biology, Lovran, Hrvatska (25.-28.9.2019.)
  8. Zandona Antonio: 2nd Prize for the Communication Challenge presentation on FEBS Network in the callange 19th FEBS Young Scientists’ Forum (YSF), Krakow, Poland (3.-6.7.2019.)
  9. Zandona Antonio: Fellowship to attend on 19thFEBS Young Scientists’ Forum (YSF) and 44nd FEBS Congress “From molecules to cells and back”, Krakow, Poland (3.-11.7.2019.)
  10. Zandona Antonio: Fellowship for attend on 13th International Meeting on Cholinesterases and the 7th International Conference on Paraoxonases, Hradec Králové, Czech Republic (9.-14.09.2018.)

Doctoral thesis

  1. Antonio Zandona: Structure – cytotoxicity relationship of oxime reactivators of phosphylated acetylcholinesterase. Faculty of Science, Zagreb (14.6.2021.)

Graduation thesis

  1. Gabriela Lihtar: Effect of nicotinamide structure change on cholinesterase inhibition and cytotoxicity. Faculty of Science, Zagreb (28.2.2020.)
  2. Dunja Kureljak: Cytotoxic effect of imidazole compounds on prostate cancer cells. Faculty of Science, Zagreb (29.9.2021.)

 Poster Award on Congress of Croatian Society of Biochemistry and Molecular Biology, Lovran, Croatia (25.-28.9.2019.)

A brief research presentation on 19th FEBS Young Scientists’ Forumu and attendance on 44nd FEBS Congress “From molecules to cells and back”, Krakow, Poland (3.-11.7.2019.)

Additional activities during the project

Katalinić Maja:
Secretary of Croatian Society of Biochemistry and Molecular Biology, HDBMB (2017-)
Member of the Committee on Science and Society, HDBMB (2017-)
Member of the Organisation Committee FEBS2020, Ljubljana, Slovenia
Chair FEBS Young Scientits’ Forum 2020, Lovran, Croatia

Lulić Ana-Marija:
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2021)
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2022)

Zandona Antonio:
Training at Institute for Molecular Medicine, Lisabon, Portugal (2021)
Training at Institute for Pathophysiology, MF, Ljubljana, Slovenia (2019)
Training at Institute for Anatomy, MF, Ljubljana, Slovenia (2019)
Representative of Assistants to the Scientific Council of the Institute (2018-2020)

Madunić Josip:
Postdoc at UCONN, Connecticut, USA (2019-2020)

Vrhovac Madunić Ivana:
Postdoc at UCONN, Connecticut, USA (2019-2020)
Training at Nacional Institute for Biology, Ljubljana, Slovenija (2022.)