In Vitro Interaction of Organophosphono- and Organophosphorothioates with Human Acetylcholinesterase

Abstract

<jats:p>The implementation of the Chemical Weapons Convention (CWC) in 1997 was a milestone in the prohibition of chemical warfare agents (CWA). Yet, the repeated use of CWA underlines the ongoing threat to the population. Organophosphorus (OP) nerve agents still represent the most toxic CWA subgroup. Defensive research on nerve agents is mainly focused on the “classical five”, namely tabun, sarin, soman, cyclosarin and VX, although Schedule 1 of the CWC covers an unforeseeable number of homologues. Likewise, an uncounted number of OP pesticides have been produced in previous decades. Our aim was to determine the in vitro inhibition kinetics of selected organophosphono- and organophosphorothioates with human AChE, as well as hydrolysis of the agents in human plasma and reactivation of inhibited AChE, in order to derive potential structure–activity relationships. The investigation of the interactions of selected OP compounds belonging to schedule 1 (V-agents) and schedule 2 (amiton) of the CWC with human AChE revealed distinct structural effects of the P-alkyl, P-O-alkyl and N,N-dialkyl residues on the inhibitory potency of the agents. Irrespective of structural modifications, all tested V-agents presented as highly potent AChE inhibitors. The high stability of the tested agents in human plasma will most likely result in long-lasting poisoning in vivo, having relevant consequences for the treatment regimen. In conclusion, the results of this study emphasize the need to investigate the biological effects of nerve agent analogues in order to assess the efficacy of available medical countermeasures.</jats:p>

Enzymes, Reacting with Organophosphorus Compounds as Detoxifiers: Diversity and Functions

“…As it was mentioned earlier, OPCs are designed to inhibit serine hydrolases, including cholin- and carboxylesterases [ 77 ]. Nevertheless, it is possible to tune on their activity with OPCs while genetically modifying these enzymes.…”

The Antiviral Drug Tilorone Is a Potent and Selective Inhibitor of Acetylcholinesterase

“…Our docking experiments showed that this inhibition is likely due to active-site interactions similar to that of donepezil, particularly with W286 in the PAS. The results of this study may also be important from both a drug discovery and toxicological perspective as we search for drugs to address pesticide and nerve agent poisoning …”

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