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

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.

Select publications

  1. 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; 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.
  2. 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. 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/
  2. 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/#!
  3. 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/
  4. 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/
  5. 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/
  6. 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

  7. 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. Zandona Antonio: Poster Award on Congress of Croatian Society of Biochemistry and Molecular Biology, Lovran, Hrvatska (25.-28.9.2019.)
  2. 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.)
  3. 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.)
  4. Zandona Antonio: Fellowship for attend on 13thInternational Meeting on Cholinesterases and the 7th International Conference on Paraoxonases, Hradec Králové, Czech Republic (9.-14.09.2018.)

 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

Zandona Antonio:
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-)

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

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