Identification and characterization of novel catalytic bioscavengers of organophosphorus nerve agents

Otto, Tamara C.; Scott, J; Kauffman, Monika A; Hodgins, Sean M.; diTargiani, Robert C.; Hughes, James H.; Sarricks, Erin P; Saturday, Greg; Hamilton, Tracey A.; Cerasoli, Douglas M.

doi:10.1016/j.cbi.2012.09.009

Cited by 18 publications

(12 citation statements)

References 10 publications

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“…So, insects and birds lack paraoxonase, whereas mammals contain high concentrations of this PTE making them more resistant to paraoxone toxicity [163]. For the strong potency to degrade the toxic insecticides, exogenous purified PTEs exert protective effects against OPs poisoning and can be used as prophylactics and antidotes in the therapeutic treatment of OPs intoxication [164-166]. Besides, these decomposing enzymes exhibit promising applications in other biotechnology fields: bioremediation of wasted materials, biodegradation of insecticide residues, detoxifying warfare arsenals, development of biosensors for OPs [167, 168].…”

Section: Detoxification Of Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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Acetylcholinesterase is involved in the termination of impulse transmission by rapid hydrolysis of the neurotransmitter acetylcholine in numerous cholinergic pathways in the central and peripheral nervous systems. The enzyme inactivation, induced by various inhibitors, leads to acetylcholine accumulation, hyperstimulation of nicotinic and muscarinic receptors, and disrupted neurotransmission. Hence, acetylcholinesterase inhibitors, interacting with the enzyme as their primary target, are applied as relevant drugs and toxins. This review presents an overview of toxicology and pharmacology of reversible and irreversible acetylcholinesterase inactivating compounds. In the case of reversible inhibitors being commonly applied in neurodegenerative disorders treatment, special attention is paid to currently approved drugs (donepezil, rivastigmine and galantamine) in the pharmacotherapy of Alzheimer’s disease, and toxic carbamates used as pesticides. Subsequently, mechanism of irreversible acetylcholinesterase inhibition induced by organophosphorus compounds (insecticides and nerve agents), and their specific and nonspecific toxic effects are described, as well as irreversible inhibitors having pharmacological implementation. In addition, the pharmacological treatment of intoxication caused by organophosphates is presented, with emphasis on oxime reactivators of the inhibited enzyme activity administering as causal drugs after the poisoning. Besides, organophosphorus and carbamate insecticides can be detoxified in mammals through enzymatic hydrolysis before they reach targets in the nervous system. Carboxylesterases most effectively decompose carbamates, whereas the most successful route of organophosphates detoxification is their degradation by corresponding phosphotriesterases.

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Section: Detoxification Of Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

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“…All of the OP hydrolyzing enzymes belong to the phosphotriesterase class (PTE, EC 3.1.8) subdivided into two groups. Enzymes with a preference for P-O bond cleavage are referred to as OP hydrolases (e.g., paraoxonase and bacterial phosphotriesterase, EC 3.1.8.1) and those with a preference for P-F or P-CN bonds are termed diisopropylfluorophosphatases (e.g., DFPase; EC 3.1.8.2) In the meantime, research focused on human paraoxonase (PON1) and bacterial PTE as potential catalytic bioscavengers (Masson and Rochu, 2009), although other enzymes, e.g., prolidase, laccase and other bacterial enzymes, are under investigation as well (Amitai et al, 1998;Rezk et al, 2015;Otto et al, 2013). In fact, the prophylactic administration of OP hydrolases in different animal species provided protection against various OP compounds in different species (Ashani et al, 1991;Bird et al, 2008;Gresham et al, 2010;Valiyaveettil et al, 2011;Worek et al, 2014a;Raveh et al, 1992).…”

Section: Catalytic Bioscavengersmentioning

confidence: 99%

Catalytic bioscavengers in nerve agent poisoning: A promising approach?

Worek¹,

Thiermann²,

Wille³

2016

Toxicology Letters

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“…Inhibition of AChE leads to a buildup of acetylcholine in the central and peripheral nervous system, resulting in a cholinergic syndrome consisting of respiratory and oral secretions, diarrhea and vomiting, sweating, altered mental status, autonomic instability, general weakness, and progression to paralysis and respiratory arrest [2,3]. In the United States the standard of care for OP poisoning is treatment with atropine, which reduces binding of acetylcholine to muscarinic receptors, and pyridinium-2-aldoxime (2-PAM Cl), which can reactivate inhibited AChE [2][3][4][5]. If administered shortly after intoxication, these medical countermeasures are successful in preventing death, but do not alleviate performance deficits in the warfighter caused by the symptoms of OP poisoning [4,6].…”

Section: Introductionmentioning

confidence: 99%

“…In the United States the standard of care for OP poisoning is treatment with atropine, which reduces binding of acetylcholine to muscarinic receptors, and pyridinium-2-aldoxime (2-PAM Cl), which can reactivate inhibited AChE [2][3][4][5]. If administered shortly after intoxication, these medical countermeasures are successful in preventing death, but do not alleviate performance deficits in the warfighter caused by the symptoms of OP poisoning [4,6]. This, in addition to the side-effects from the therapeutics themselves, can leave units temporarily depleted and vulnerable to future attack.…”

Section: Introductionmentioning

confidence: 99%

Targeting of organophosphorus compound bioscavengers to the surface of red blood cells

McCranor¹,

Hofstetter²,

Moorad-Doctor³

et al. 2016

Chemico-Biological Interactions

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To develop a prophylactic for organophosphorus (OP) poisoning utilizing catalytic bioscavengers, the circulatory stability of the enzymes needs to be increased. One strategy for increasing the bioavailability of OP bioscavengers is to target them to the surface of red blood cells (RBCs). Given the circulatory lifespan of 120 days for human RBCs, this strategy has the potential for creating a persistent pool of bioscavenger. Here we report the development of fusion proteins with a single chain variable fragment (scFv) of Ter119, a molecule that associates with glycophorin A on the surface of RBCs, and the VIID11 variant of paraoxonase 1 (scFv-PON1). We show that scFv-PON1 variants expressed by Trichoplusia ni larvae are catalytically active and that one variant in particular can successfully bind to the surface of murine RBCs both in vitro and in vivo. This study represents a proof of concept for targeting catalytic bioscavengers to the surface of RBCs and is an early step in developing catalytic bioscavengers that can remain in circulation for an extended period of time.

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Identification and characterization of novel catalytic bioscavengers of organophosphorus nerve agents

Cited by 18 publications

References 10 publications

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Catalytic bioscavengers in nerve agent poisoning: A promising approach?

Targeting of organophosphorus compound bioscavengers to the surface of red blood cells

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