Cholesterol Oxime Olesoxime Assessed as a Potential Ligand of Human Cholinesterases
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Olesoxime, a cholesterol derivative with an oxime group, possesses the ability to cross the blood–brain barrier, and has demonstrated excellent safety and tolerability properties in clinical research. These characteristics indicate it may serve as a centrally active ligand of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), whose disruption of activity with organophosphate compounds (OP) leads to uncontrolled excitation and potentially life-threatening symptoms. To evaluate olesoxime as a binding ligand and reactivator of human AChE and BChE, we conducted in vitro kinetic studies with the active metabolite of insecticide parathion, paraoxon, and the warfare nerve agents sarin, cyclosarin, tabun, and VX. Our results showed that both enzymes possessed a binding affinity for olesoxime in the mid-micromolar range, higher than the antidotes in use (i.e., 2-PAM, HI-6, etc.). While olesoxime showed a weak ability to reactivate AChE, cyclosarin-inhibited BChE was reactivated with an overall reactivation rate constant comparable to that of standard oxime HI-6. Moreover, in combination with the oxime 2-PAM, the reactivation maximum increased by 10–30% for cyclosarin- and sarin-inhibited BChE. Molecular modeling revealed productive interactions between olesoxime and BChE, highlighting olesoxime as a potentially BChE-targeted therapy. Moreover, it might be added to OP poisoning treatment to increase the efficacy of BChE reactivation, and its cholesterol scaffold could provide a basis for the development of novel oxime antidotes.Keywords:
Butyrylcholinesterase
Paraoxon
Cholinesterase
Tabun
Huperzine A
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This editorial is written on the occasion of the 25th anniversary of the infamous sarin and VX terrorist attacks in Japan, in order to increase the awareness of the potential terrorist use of nerve agents and to urge the preparedness to cope with its consequences. Nerve agents are extremely toxic organophosphorus acetylcholinesterase inhibitors, divided in three known groups: G-, Vand A-agents. G-agents tabun, sarin and soman were synthesised in Nazi Germany (1938-1944), V-agents including VX by the British in the 1950s and A-agents or Novichok agents between 1971 and 1993 in the Soviet Union. The use or alleged use of tabun and sarin was mentioned in connection with the Iraq-Iran war (1980-1988) and the Syrian conflict in 2013 and 2017. Sarin and VX were used for terrorist purposes by the Japanese religious sect AUM Shinrikyo in 1994 and 1995. The assassination of Kim Jong NAM with VX took place in Kuala Lumpur, Malesia in 2017, while the 2018 Salisbury and Amesbury poisonings in the UK were ascribed to the so-called Novichok agent A234. Milder cases of poisoning with nerve agents is accompanied by predominantly muscarinic symptomatology and more massive intoxications with mainly nicotinic and central symptoms. Treatment consists of use of atropine, oximes and anticonvulsants.
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The therapeutic efficacy of treatments for acute intoxication with highly toxic organophosphorus compounds, called nerve agents, usually involves determination of LD50 values 24 h after nerve agent challenge without and with a single administration of the treatment. Herein, the LD50 values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated intoxication were investigated in mice for experimental end points of 6 and 24 h. The LD50 values of the nerve agents were evaluated by probit-logarithmical analysis of deaths within 6 and 24 h of i.m. challenge of the nerve agent at five different doses, using six mice per dose. The efficiency of atropine alone or atropine in combination with an oxime was practically the same at 6 and 24 h. The therapeutic efficacy of the higher dose of the antinicotinic compound MB327 was slightly higher at the 6 h end point compared to the 24 h end point for soman and tabun intoxication. A higher dose of MB327 increased the therapeutic efficacy of atropine alone for sarin, soman and tabun intoxication, and that of the standard antidotal treatment (atropine and oxime) for sarin and tabun intoxication. The therapeutic efficacy of MB327 was lower than the oxime-based antidotal treatment. To compare the 6 and 24 h end points, the influence of the experimental end point was not observed, with the exception of the higher dose of MB327. In addition, only a negligible beneficial impact of the compound MB327 was observed. Nevertheless, antinicotinics may offer an additional avenue for countering poisoning by nerve agents that are difficult to treat, and synthetic and biological studies towards the development of such novel drugs based on the core bispyridinium structure or other molecular scaffolds should continue.
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Cholinesterase
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Organophosphorus nerve agents (OPNAs) are highly toxic compounds inhibiting cholinergic enzymes in the central and autonomic nervous systems and neuromuscular junctions, causing severe intoxications in humans. Medical countermeasures and efficient decontamination solutions are needed to counteract the toxicity of a wide spectrum of harmful OPNAs including G, V and Novichok agents. Here, we describe the use of engineered OPNA-degrading enzymes for the degradation of various toxic agents including insecticides, a series of OPNA surrogates, as well as real chemical warfare agents (cyclosarin, sarin, soman, tabun, VX, A230, A232, A234). We demonstrate that only two enzymes can degrade most of these molecules at high concentrations (25 mM) in less than 5 min. Using surface assays adapted from NATO AEP-65 guidelines, we further show that enzyme-based solutions can decontaminate 97.6% and 99.4% of 10 g∙m−2 of soman- and VX-contaminated surfaces, respectively. Finally, we demonstrate that these enzymes can degrade ethyl-paraoxon down to sub-inhibitory concentrations of acetylcholinesterase, confirming their efficacy from high to micromolar doses.
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Human decontamination
Paraoxon
Cholinesterase
Butyrylcholinesterase
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Tabun
ED50
Cholinesterase
Antidote
Median lethal dose
Pralidoxime
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Tabun
Paraoxon
Enzyme Kinetics
Cholinesterase
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Abstract Construction of Detehit (nerve-agent detector), a colorimetric biosensor of nerve agents, enables its utilization for selective analysis of nerve agents based on the different ability of nucleophilic reagents to reactivate enzyme-inhibitor complexes in the phase before dealkylation. For this purpose mono- and bispyridinium aldoximes, common in treatment of nerve agent poisoning, are used. For a positive identification of a pair of organophosphates, a neural network analysis was used. The analysis was processed based on spectral data of the intensity of color changes of the surface of a cotton cloth reaction zone with immobilized and stabilized enzyme acetylcholinesterase. Color changes are based on Ellman's reaction. Intensity of these changes depends on activity of the enzyme after inhibition and reactivation of enzyme-inhibitor complex. The following nerve agents were identified: sarin, soman, tabun, cyclosarin, VX, and R-33. Keywords: Acetylcholinesterase reactivatorColorimetric biosensorNerve agentNeural analysisAbbreViations: GB, sarinGD, somanGF, cyclosarinGA, tabunVX, agent VXR-33, agent R-33VVPS, multilayer perceptron networkRBF, Radial Basis Function-type network Acknowledgments VOP (Military Repair Plant) Šternberk is a state-owned company. Notes Measurement conditions: HI-6 reactivator at a concentration of 0.05 mg · cm−3 (1.393 × 10−4 M) and 10-minute treatment of acetylcholinesterase-tabun and acetylcholinesterase-VX complexes. Linear: linear network with characterization of the layers; VVPS: multilayer perceptron network with characterization of the layers; RBF: Radial Basis Function-type network with characterization of the layers; GF: cyclosarin; VX: compound VX. GA: tabun; GB: sarin; GD: soman; GF: cyclosarin; R-33: agent R-33; VX: agent VX.
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Enzymes that efficiently hydrolyze highly toxic organophosphorus nerve agents could potentially be used as medical countermeasures. As sufficiently active enzymes are currently unknown, we synthesized twelve fluorogenic analogues of organophosphorus nerve agents with the 3-chloro-7-oxy-4-methylcoumarin leaving group as probes for high-throughput enzyme screening. This set included analogues of the pesticides paraoxon, parathion, and dimefox, and the nerve agents DFP, tabun, sarin, cyclosarin, soman, VX, and Russian-VX. Data from inhibition of acetylcholinesterase, in vivo toxicity tests of a representative analogue (cyclosarin), and kinetic studies with phosphotriesterase (PTE) from Pseudomonas diminuta, and a mammalian serum paraoxonase (PON1), confirmed that the analogues mimic the parent nerve agents effectively. They are suitable tools for high-throughput screens for the directed evolution of efficient nerve agent organophosphatases.
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In last five decades, organophosphorus compounds have become significant because of the widespread uses as pesticides abutting a clear threat to people from the potential use of chemical weapon as nerve agents in the cold wars and terrorist activities. Sarin, tabun, soman, cyclosarin belong to organophosphorus compounds called nerve agents due to their biological interaction as powerful inhibitor of enzyme acetylcholinesterase (AChE) and rendered its neurological function, the underlying mechanism is discussed. The identification and detection of such toxic nerve agents using spectrometry, sensors including enzymatic assays is the prime target of recent researchers. Typically some antidotes like oxime derivatives are most common and are the light of hope for nerve gas exposure. The modern techniques applied for the discovery of new antidote and their way of action by reactivating the blocked nerve enzyme and the hidden mechanism of reactivation of AchE are explained.
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Antidote
Chemical Warfare Agents
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