Therapy for Nerve Agent Poisoning

Newmark, Jonathan

doi:10.1001/archneur.61.5.649

Cited by 82 publications

(50 citation statements)

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“…The existing treatments for nerve agent exposure must be administered quickly to be effective, and they often do not eliminate long-term toxic side effects (10). Atropine, a muscarinic receptor antagonist, blocks cholinergic parasympathetic neurons to maintain capacity for respiration, and is typically administered as soon as possible after an OP exposure (11).…”

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“…Finally, an anticonvulsant like diazepam is commonly administered to treat seizures that can develop, albeit via unknown mechanisms (13). If this series of compounds is not given within minutes, however, victims quickly succumb (10). In addition, even if rapidly treated, many patients exposed to OP pesticides experience long-term brain damage, permanent electrocardiogram changes, or an "intermediate syndrome" associated with persistent muscle weakness (14).…”

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Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

et al. 2007

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The organophosphorus nerve agents sarin, soman, tabun, and VX exert their toxic effects by inhibiting the action of human acetylcholinesterase, a member of the serine hydrolase superfamily of enzymes. The current treatments for nerve agent exposure must be administered quickly to be effective and they often do not eliminate long-term toxic side effects associated with organophosphate poisoning. Thus, there is significant need for effective prophylactic methods to protect at-risk personnel from nerve agent exposure, and protein-based approaches have emerged as promising candidates. We present the 2.7 Å resolution crystal structures of the serine hydrolase human carboxylesterase 1 (hCE1), a broad-spectrum drug metabolism enzyme, in covalent acylenzyme intermediate complexes with the chemical weapons soman and tabun. The structures reveal that hCE1 binds stereoselectively to these nerve agents; for example, hCE1 appears to react preferentially with the 10 4 -fold more lethal P S stereoisomer of soman relative to the P R form. In addition, structural features of the hCE1 active site indicate that the enzyme may be resistant to deadend organophosphate aging reactions that permanently inactivate other serine hydrolases. Taken together, these data provide important structural details toward the goal of engineering hCE1 into an organophosphate hydrolase and protein-based therapeutic for nerve agent exposure.The organophosphorus (OP) nerve agents sarin, soman, tabun, and VX are among the deadliest man-made chemicals (1). While the military use of OP nerve agents is widely banned, these compounds have been employed in recent decades by rogue states and terrorist groups. In 1988, Iraq employed weaponized sarin against its own Kurdish citizens in Halabja, a town adjacent to the Iranian border, killing an estimated 5,000 (2). Coordinated attacks on the Tokyo subway system by the Japanese Aum Shinrikyo cult in 1995 also employed sarin, killing 12 and injuring † This work was supported, in part, by NIH grants CA98468 and NS58089, and the American Lebanese Syrian Associated Charities. ‡ Protein Data Bank codes are 2HRQ for the hCE1-soman structure and 2HRR for the hCE1-tabun structure. *Corresponding Author: Matthew R. Redinbo, Ph.D., Department of Chemistry, CB #3290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, (919)843-8910; Fax: (919)962-2388, redinbo@unc.edu. 1 Abbreviations: AcChE, Human acetylcholinesterase; BuChE, Human butyrylcholinesterase; CE, carboxylesterase; hCE1, Human carboxylesterase 1; HI-6, 1-(2-hydroxy-iminomethylpyridinium)-1-(4-carboxyamino)-pyridinium dimethylether dichloride; MuAcChE, Mus musculus acetylcholinesterase; OP, organophosphate; Ortho-7, 1,7-heptylene-bis-N,N′-2-pyridiniumaldoxime dichloride; PON1, human serum paraoxonase 1; rmsd, root mean square deviation; Sarin, methylethyl methylphosphonofluoridate; Soman, Tabun, ethyl N, TcAcChE, Torpedo californica acetylcholinesterase; VX, OP toxicity is thought to be mediated through the inhibition of human acety...

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Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

et al. 2007

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“…43 Nerve agents are subdivided into G-type and V-type agents. G agents include sarin, soman, tabun, and cyclosarin and are so named due to their discovery in Germany in the 1930s and 40s.…”

Section: Ion Mobility Spectrometrymentioning

confidence: 99%

“…A CWA is considered persistent if it remains hazardous for over 24 hours. 43 The common names, chemical names, toxicity, and volatility of several common nerve agents are shown in …”

Section: Ion Mobility Spectrometrymentioning

confidence: 99%

The application of single particle aerosol mass spectrometry for the detection and identification of high explosives and chemical warfare agents

Martin

2006

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were also analyzed, and peaks due to the explosive components of each sample were present in each spectrum. Mass spectral variability with laser fluence is discussed. The ability of the SPAMS system to identify explosive components in a single complex explosive particle (~1 pg) without the need for consumables is demonstrated.SPAMS was also applied to the detection of Chemical Warfare Agent (CWA) simulants in the liquid and vapor phases. Liquid simulants for sarin, cyclosarin, tabun, and VX were analyzed; peaks indicative of each simulant were identified. Vapor phase CWA simulants were adsorbed onto alumina, silica, Zeolite, activated carbon, and metal powders which were directly analyzed using SPAMS. The use of metal powders as adsorbent materials was especially useful in the analysis of triethyl phosphate (TEP), a VX stimulant, which was undetectable using SPAMS in the liquid phase. The capability of SPAMS to detect high explosives and CWA simulants using one set of operational conditions is established.iii ACKNOWLEDGEMENTS

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“…The medical management of an OP victim includes drugs such as atropine (a muscarinic receptor antagonist that artificially maintains the respiration capacity), diazepam (or similar anticonvulsant drug, commonly administered to treat seizure) and oxime reactivators [34][35][36][37][38][39][40][41][42][43][44][45][46] (which liberate the inhibited enzyme). Since aging of an inhibited enzyme occurs within minutes to hours and results in the permanent disability of the enzymatic activity of AChE, the victim should be administered these drugs as soon as possible [49] .…”

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confidence: 99%

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

et al. 2010

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Aim: To performe a time-dependent topographical delineation of protein-drug interactions to gain molecular insight into the supremacy of Ortho-7 over HI-6 in reactivating tabun-conjugated mouse acetylcholinesterase (mAChE). Methods: We conducted all-atom steered molecular dynamics simulations of the two protein-drug complexes. Through a host of protein-drug interaction parameters (rupture force profiles, hydrogen bonds, water bridges, hydrophobic interactions), geometrical, and orientation ordering of the drugs, we monitored the enzyme's response during the release of the drugs from its active-site. Results: The results show the preferential binding of the drugs with the enzyme. The pyridinium ring of HI-6 shows excellent complementary binding with the peripheral anionic site, whereas one of two identical pyridinium rings of Ortho-7 has excellent binding compatibility in the enzyme active-site where it can orchestrate the reactivation process. We found that the active pyridinium ring of HI-6 undergoes a complete turn along the active site axis, directed away from the active-site region during the course of the simulation. Conclusion: Due to excellent cooperative binding of Ortho-7, as rendered by several cation-π interactions with the active-site gorge of the enzyme, Ortho-7 may be a more efficient reactivator than HI-6. Our work supports the growing body of evidence that the efficacy of the drugs is due to the differential bindings of the oximes with AChE and can aid to the rational design of oxime drugs.

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Therapy for Nerve Agent Poisoning

Cited by 82 publications

References 11 publications

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

The application of single particle aerosol mass spectrometry for the detection and identification of high explosives and chemical warfare agents

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

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Therapy for Nerve Agent Poisoning

Cited by 82 publications

References 11 publications

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun,

The application of single particle aerosol mass spectrometry for the detection and identification of high explosives and chemical warfare agents

Differential binding of bispyridinium oxime drugs with acetylcholinesterase

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Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,

Crystal Structures of Human Carboxylesterase 1 in Covalent Complexes with the Chemical Warfare Agents Soman and Tabun^,