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.