Organophosphorus Nerve Agents: Types, Toxicity, and Treatments

Abstract

Organophosphorus compounds are extensively used worldwide as pesticides which cause great hazards to human health. Nerve agents, a subcategory of the organophosphorus compounds, have been produced and used during wars, and they have also been used in terrorist activities. These compounds possess physiological threats by interacting and inhibiting acetylcholinesterase enzyme which leads to the cholinergic crisis. After a general introduction, this review elucidates the mechanisms underlying cholinergic and noncholinergic effects of organophosphorus compounds. The conceivable treatment strategies for organophosphate poisoning are different types of bioscavengers which include stoichiometric, catalytic, and pseudocatalytic. The current research on the promising treatments specifically the catalytic bioscavengers including several wild-type organophosphate hydrolases such as paraoxonase and phosphotriesterase, phosphotriesterase-like lactonase, methyl parathion hydrolase, organophosphate acid anhydrolase, diisopropyl fluorophosphatase, human triphosphate nucleotidohydrolase, and senescence marker protein has been widely discussed. Organophosphorus compounds are reported to be the nonphysiological substrate for many mammalian organophosphate hydrolysing enzymes; therefore, the efficiency of these enzymes toward these compounds is inadequate. Hence, studies have been conducted to create mutants with an enhanced rate of hydrolysis and high specificity. Several mutants have been created by applying directed molecular evolution and/or targeted mutagenesis, and catalytic efficiency has been characterized. Generally, organophosphorus compounds are chiral in nature. The development of mutant enzymes for providing superior stereoselective degradation of toxic organophosphorus compounds has also been widely accounted for in this review. Existing enzymes have shown limited efficiency; hence, more effective treatment strategies have also been critically analyzed.

Figure 1

Chemical structure of G-series agents: (a) sarin, (b) soman, (c) tabun, and (d) cyclosarin; (e) V-series agent, VX; (f) VR (substance-33); chemical structures of A-series according to Dr. Mirzayanov: (g) A230, (h) A232, and (i) A234; chemical structures of A-series according Hoenig: (j) A230, (k) A232, and (l) A234; plausible and speculated chemical structures of Novichok: (m) Novichok-5 and (n) Novichok-7. For creating the chemical structures, ChemSketch software was used.

Figure 2

Depiction of cellular interaction of AChE, Ach, and OPCs. (a) Choline released from ACh hydrolysis, moves to axon where it reacts with acetyl moiety of co-acetyl to from ACh by an enzyme ChAT (choline acetyltransferase) and gets stored in vesicles along with cotransmitters such as ATP. (b) The influx of calcium results in the fusion of membranes. (c) Fusion leads to release of ACh into neuron junctions. (d) Interaction of ACh with nAChRs and mAChRs. (e) Signalling to different physiological targets. (f) Excess ACh after signalling, interacts with AChE and degrades into choline and acetate. (g) OPC binds with AChE and leads to increased ACh and endless signalling.

Figure 3

Classification of bioscavengers for organophosphorus compounds. The flowchart represents the classification of OPC hydrolysing enzymes on the basis of their hydrolysing ability into three categories, namely, stoichiometric, catalytic, and pseudocatalytic with their examples. The catalytic bioscavengers are further divided into two groups, bacterial and mammalian.

Figure 4

Diagrammatic representation of toxicity by OPCs and their detoxification. During the toxicity by OPCs, the compounds inhibit AChE and lead to excessive cholinergic effect, whereas the bioscavengers which can act as prophylactic agents neutralize the OPCs before they reach their targets and result in normal physiological hydrolysis of ACh and thus control proper signalling process.

Figure 5

Illustration represents residues important for stereoselectivity of the enzymes: (a) PON1 cartoon structure with different coloured sphere-shaped residues; (b) PON1 residues as sticks; (c) PTE cartoon structure with different coloured sphere-shaped residues; (d) PTE residues as sticks; (e) OPAA cartoon structure with different coloured sphere-shaped residues; (f) OPAA residues as sticks. (For creating the above structures, basic structures were taken from PDB ID: 1V04, 3CAK, and 3L7G, and PyMOL software was used.)