Novel butyrylcholinesterase reactivators for pseudo-catalytic scavenging of organophoshates

This project focuses on the research into novel butyrylcholinesterase (BChE) reactivators. These small chemical molecules could be used, together with human butyrylcholinesterase, as pseudo-catalytic scavengers for pre-treatment or treatment of organophosphorus intoxications. Various techniques, such as in silico methods, chemical synthesis/analysis, and in vitro or in vivo evaluation will be used. Additionally, the project´s aim is to establish a consortium of five partners from Korea and V4 countries that will collaborate and share their varied expertise to reach anticipated goals and to create mutual cooperation among the partners.

Organophosphorus (OP) compounds are used as insecticides (e.g., chlorpyriphos, parathion) for agricultural purposes. Furthermore, they were used as nerve agents (e.g. sarin, soman, tabun, VX) in armed conflicts (e.g., Syria 2013) and misused for terrorist attacks (e.g., Tokyo 1995). Since the nerve agents and their precursors belong to the classified compounds under the OPCW agreement, the OP pesticides are relatively easily available. Thus, the worldwide use of OPs is estimated to be responsible for 200,000 causes of death, mostly in the case of agricultural workers. From this point of view, the hazard of OP misuse exists, especially sources of food or water supplies are threatened.
Additionally, some OP intoxications (e.g., soman) are known for not responding to standard oxime treatment. For this reason, there is a lack of novel reactivators with improved properties of decreasing OP threat and ensuring the safety of citizens. For such purposes, the combination of a catalytic and human-relevant scavenger (hBChE) with novel (improved) OP reactivators (oximes) may be a step forward. Moreover, the hBChE is readily available from expired human blood samples which may be purified by affinity chromatography for human use in a large amounts. However, the standard oximes are not able to reactivate hBChE, and thus there is a huge lack of small molecules which are able to restore the hBChE function with bound OP under physiological conditions. Furthermore, the standard oximes have a lack of the broad spectrum activity against structurally different OP molecules that might be again resolved for hBChE reactivators. Thus, the desired step in the development of a novel pseudo-catalytic scavenger is the development of a small and human-relevant molecule that would have the broad spectrum ability to restore the hBChE catalytic function.
The participating partners are motivated to carry out highly competitive research in the sphere that is related to international safety and security. If the project strategy is successful, it can enhance the treatment strategy applied in case of life-endangering OP intoxications. This solution would be a global issue of further interest and attention paid by the medical, army, or security specialists.