Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: A mini review

Lenz, David E.; Yeung, David T.; Smith, J. Richard; Sweeney, Richard E.; Lumley, Lucille A.; Cerasoli, Douglas M.

doi:10.1016/j.tox.2006.11.066

Cited by 192 publications

(148 citation statements)

References 34 publications

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“…In the absence of oxime reactivation of the inhibited hCE1, it is impossible to experimentally confirm a lack of aging after inhibition by soman or tabun. Additional work to identify an oxime that can reactivate hCE1 might allow this protein to function as a "pseudo-catalytic" scavenger (49).…”

Section: Discussionmentioning

confidence: 99%

“…As such, the use of a human enzyme for such a purpose would be expected to avoid potentially harmful immune responses that may arise from protein-based therapies derived from nonhuman sources. Extensive work has been conducted toward this goal with a recombinant form of BuChE purified from the milk of transgenic goats (49,53). While this enzyme has been shown to confer a level of protection up to 5.5 × LD 50 for VX and soman in guinea pigs (49), it acts purely as a stoichiometric bioscavenger and binds to, but does not catalytically inactivate, nerve agents.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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 stoichiometric scavengers are enzymes which bind stoichiometrically and irreversibly to the OPC (such as the cholinesterases themselves), while the catalytic scavengers hydrolyze the molecules of OPCs (such as OPC hydrolases and anhydrases). 134,135 Several enzymes are being evaluated for use as scavengers, such as human serum BChE, recombinant human BChE expressed in the milk of transgenic goats, genetic variants of AChE and human paraoxonase. [134][135][136][137][138] Oximes can be employed for pretreatment, improving the post-treatment by atropine and other oximes 132,139 (see below), but some questions should be addressed for their use, such as timing, duration and achievement of adequate concentrations after administration.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

“…134,135 Several enzymes are being evaluated for use as scavengers, such as human serum BChE, recombinant human BChE expressed in the milk of transgenic goats, genetic variants of AChE and human paraoxonase. [134][135][136][137][138] Oximes can be employed for pretreatment, improving the post-treatment by atropine and other oximes 132,139 (see below), but some questions should be addressed for their use, such as timing, duration and achievement of adequate concentrations after administration. 132,133 The chemotherapy employed for the treatment of intoxication with OPCs includes the use of three types of drugs: 1,3,13,128 (i) an anticholinergic substance, to antagonize the effects of ACh accumulation in the cholinergic receptors; (ii) a central nervous system (CNS) depressor, which acts as an anticonvulsive; and (iii) an oxime to reactivate inhibited AChE.…”

Section: Treatment and Antidotes For Nerve Agentsmentioning

confidence: 99%

Organophosphorus compounds as chemical warfare agents: a review

Delfino¹,

Ribeiro²,

Figueroa‐Villar³

2009

J. Braz. Chem. Soc.

228

178

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Os agentes de guerra química constituem uma das maiores ameaças do mundo moderno. Dentre estes, destacam-se os agentes neurotóxicos, em virtude de sua alta letalidade e periculosidade. Eles são compostos organofosforados que atuam pela inibição da enzima acetilcolinesterase, a qual é fundamental no processo de transmissão de impulsos nervosos. Existem várias formas de tratamento para a intoxicação por organofosforados, mas nenhuma delas é eficaz contra todos os agentes conhecidos ou contra todos os seus efeitos. Esta revisão tem como foco o uso de compostos organofosforados como agentes neurotóxicos de guerra química. Após uma breve introdução histórica, será feita uma discussão sobre as principais características estruturais e biológicas da acetilcolinesterase, seguida por uma revisão das propriedades dos compostos organofosforados e da sua aplicação como agentes de guerra química. Por fim, serão discutidas as formas de tratamento contra estes agentes, com ênfase nas oximas usadas para reativar a acetilcolinesterase inibida.Chemical warfare agents constitute one of the greatest threats in the modern world. Among them, the neurotoxic agents are of special interest due to their high lethality and danger. Neurotoxic agents are organophosphorus compounds that act by inhibiting the enzyme acetylcholinesterase, which is fundamental for the control of transmission of nervous impulses. There are several ways of treating intoxication by organophosphorus compounds, but none of them is efficient against all the known neurotoxic agents or against all of their effects. This review focus on the use of organophosphorus compounds as neurotoxic chemical warfare agents. After a brief historical introduction, it will be done a discussion about the structural and biological characteristics of acetylcholinesterase, followed by a review of the properties of organophosphorus compounds and their application as chemical warfare agents. Finally, the ways of treatment against intoxication with these agents will be discussed, with emphasis on the oximes used for reactivating the inhibited acetylcholinesterase.

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“…14 More recently, enzymes that can inactivate OP without being consumed are being investigated for their potential as catalytic bioscavengers. 15 An ideal candidate would be a stable, non-immunogenic or minimally immunogenic, non-toxic enzyme with a long halflife in the circulation that has high catalytic efficiency for OP hydrolysis. 16 Human paraoxonase1 (hPON1) has the potential to become such a candidate.…”

Section: Introductionmentioning

confidence: 99%

Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon

et al. 2010

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Human paraoxonase1 (hPON1) is a potential therapeutic against the toxicity of organophosphorus (OP) pesticides and chemical warfare nerve agents. We tested whether PON1 gene transfer using adenovirus provides protection against the toxicity of the OP diazoxon. Using an adenovirus construct containing hPON1 gene, we showed elevated levels of recombinant hPON1 in vitro in 293A cells and in vivo in mice. The recombinant enzyme was secreted by 293A cells into culture medium and into the systemic circulation of mice. Western blotting revealed that the virally expressed hPON1 had the expected molecular weight of 45 kDa. Recombinant hPON1 in mice was in complex with mouse high-density lipoprotein (HDL) and migrated more slowly than endogenous hPON1 in the human HDL complex. Mice injected with adenovirus expressed PON1 at 600-3480 U ml -1 on day 5 post-treatment, which is 8-50-fold above endogenous. Six mice expressing hPON1 survived 2LD 50 doses of diazoxon. Four of the six mice survived a second dose of diazoxon (for a total of 4LD 50 ) administered 24 h later. In contrast, none of the three mice in the control group survived one 2LD 50 dose. These results show that hPON1 in mice functions as a prophylactic and offers significant protection against lethal doses of diazoxon.

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Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: A mini review

Cited by 192 publications

References 34 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^,

Organophosphorus compounds as chemical warfare agents: a review

Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon

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Stoichiometric and catalytic scavengers as protection against nerve agent toxicity: A mini review

Cited by 192 publications

References 34 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,

Organophosphorus compounds as chemical warfare agents: a review

Adenovirus-mediated human paraoxonase1 gene transfer to provide protection against the toxicity of the organophosphorus pesticide toxicant diazoxon

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Product

Resources

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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^,