engleski

Neural and muscle cells in organophosphorus compound antidote research

A better selection of a lead candidate for preclinical drug development has become an unconditional requirement in recent years. For that reason, early, rapid and robust results that unambiguously rank compounds according to their desirable and undesirable effects placed cell-based in vitro toxicology in major focus, overcoming the criticised use of animals in toxicological studies. The focus of our research has been set on the early safety evaluation of potential antidotes for organophosphorus compounds (OPs), which still attract great attention due to their continuous use in modern industrial society (as in agriculture and chemical industry), but unfortunately also due to their use as chemical agents (soman, satin, tabun, VX) in the battlefield or in terrorist attacks. The therapeutically approved antidotes (i.e. oximes 2-PAM or HI-6) have several major limitations, and the search for new, more efficient ones is still ongoing. Until now, hundreds of new oximes have been tested but none passed to the final step of approval even if they acted efficiently on their main target in the organism. Their crucial drawback is always linked to the observed side effects like neuropathy or myopathy or toxicity in general. Therefore, by a simple addition of a cell-based assay identification of specific molecular targets of the tested compounds’ unwanted action at the beginning of research could help reduce the risk of missing this critical information, which often proves costly in later stages of development. We selected two cell types as the two main targets of OP poisoning and antidote therapy in vivo: skeletal muscle cells (myoblasts and myotubes) and neuronal cells SH-SY5Y. We tested several defined sets of structurally related compounds, marked as potent OP antidotes in Current research. The selected compounds showed a different cell toxicity profile and the myoblasts were more sensitive to exposure. However, compounds that were toxic to muscle cells were toxic to neuronal cells as well, and the obtained results could be linked to the structure of the compounds itself. Thus, defining the structural features probably responsible for a negative effect enabled us to give efficient feedback to the designers of these compounds who could then modify them in the early lead compound structure refinement process without performing any in vivo studies. Moreover, the results obtained here could be useful and applied to any of the drug design and developmental studies, as the determined cell effects of specific compound structural features are general.

organophosphorus compound

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