BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

• Keywords
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes metabolism   MeSH
• Cholinesterase Inhibitors metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Brain enzymology   MeSH
• Organophosphates metabolism   MeSH
• Oximes metabolism   MeSH
• Pyridinium Compounds metabolism   MeSH
• Cholinesterase Reactivators metabolism   MeSH
• Molecular Docking Simulation MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

Chemical weapons are a major worldwide problem, since they are inexpensive, easy to produce on a large scale and difficult to detect and control. Among the chemical warfare agents, we can highlight the organophosphorus compounds (OP), which contain the phosphorus element and that have a large number of applications. They affect the central nervous system and can lead to death, so there are a lot of works in order to design new effective antidotes for the intoxication caused by them. The standard treatment includes the use of an anticholinergic combined to a central nervous system depressor and an oxime. Oximes are compounds that reactivate Acetylcholinesterase (AChE), a regulatory enzyme responsible for the transmission of nerve impulses, which is one of the molecular targets most vulnerable to neurotoxic agents. Increasingly, enzymatic treatment becomes a promising alternative; therefore, other enzymes have been studied for the OP degradation function, such as phosphotriesterase (PTE) from bacteria, human serum paraoxonase 1 (HssPON1) and diisopropyl fluorophosphatase (DFPase) that showed significant performances in OP detoxification. The understanding of mechanisms by which enzymes act is of extreme importance for the projection of antidotes for warfare agents, and computational chemistry comes to aid and reduce the time and costs of the process. Molecular Docking, Molecular Dynamics and QM/MM (quantum-mechanics/molecular-mechanics) are techniques used to investigate the molecular interactions between ligands and proteins.

• Keywords
• computational methods, enzymatic biodegradation, oximes, warfare nerve agents,
• Publication type
• Journal Article MeSH