Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

Musílek, Kamil; Holas, Ondřej; Horova, Anna; Pohanka, Miroslav; Karasová, Jana Žďárová; Jun, Daniel; Kuča, Kamil

doi:10.5772/17287

Cited by 6 publications

(4 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…On the contrary, bisquaternary oximes, trimedoxime and obidoxime exhibited very good abilities in the treatment of OP insecticides poisoning, whereas asoxime was found to be effective for nerve agent induced intoxication and without the meaningful reactivation of the inhibited AChE by OP insecticides. Moreover, obidoxime, combined with atropine and diazepam, has demonstrated positive results in the clinical trials [150, 151]. Furthermore, among 300 synthesized and evaluated oxime reactivators, some novel compounds ( e.g.…”

Section: Detoxification Of Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

View full text Add to dashboard Cite

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.

show abstract

Section: Detoxification Of Acetylcholinesterase Inhibitorsmentioning

confidence: 99%

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Apparently, the interaction of ligand moieties by cation-π or π-π with AChE aromatic residues s(His, Phe, Trp, Tyr) plays an important role in the reactivation 16 . The major role of the indole ring of Trp 286 displays a variety of interaction modes, including stacking, aromatic-aromatic and p-cation, which basically depends upon the nature of the ligand.…”

Section: Fig 1: Active Site Residues Of Ache Enzyme (Pdb Id: 2whp) Amentioning

confidence: 99%

Untitled

2020

IJPSR

View full text Add to dashboard Cite

Organophosphorus (OP) nerve agents blocks acetylcholinesterase and do not allow the degradation of acetylcholine. Post-treatment of organophosphate poisoning involves the treatment with oxime reactivators as an antidote, which will dephosphorylate the phosphate bond between enzyme and nerve agent. Due to CNS permeability failure of these oximes, the introduction of low molecular non-oximes has become a challenging role for reactivation of inhibited acetylcholinesterase. In-silico high-throughput structure-based virtual screening and docking by using LOPAC database targeting CNS for inhibited acetylcholinesterase reactivation. For the identification of an active site of AChE enzyme and high throughput virtual screening, Inventus™ software was being used. ADME analysis for the selection of leads which can follow up Lipinski rule of 5 and CNS parameters for permeation. Further docking studies of selected lead candidates was done using Schrodinger software. By taking various CNS parameters into consideration hits were selected. For further refinement docking was performed, and the best lead obtained with glide XP docking score-11.656 Kcal/mol. The best lead candidates passed CNS permeation parameters range and have shown well binding with Acetylcholinesterase enzyme as that of standards. INTRODUCTION: Acetylcholinesterase (AChE) enzyme (serine hydrolase) notably responsible for the deterioration of acetylcholine and termination of neurotransmission 1. AChE enzyme mainly consists of active (Ser203, His447, and Glu334) and peripheral sites (aromatic residues Tyr72, Tyr124, Trp286, and Tyr341 and acidic Asp74) for binding inhibitors and other allosteric molecules 2 .

show abstract

“…Commercial reactivators have been widely applied in AChE recovery using traditional approaches, but these are plagued by unstable recovery percentages affected by many different factors such as the concentration of inhibitors, different types of neurotoxins, and so forth. 26,27 Therefore, it is important to explore practical, simple, and reliable approaches that allow the regeneration of inhibitionbased enzymatic biosensing systems in multiple analytical applications.…”

Section: ■ Introductionmentioning

confidence: 99%

“…A large number of reports have described AChE biosensors possessing good speed and sensitivity, high selectivity, and miniaturization. ,− However, the regeneration of biofunctional interfaces is not well documented, and most reports of inhibition-based detection neglect the restoration of enzyme activity, although usually a correlation between activity loss (inhibition) and analyte concentration can be found. − Another important reason that such a regenerative system has not been realized is the lack of simple, reliable, cost-effective regeneration methods. Commercial reactivators have been widely applied in AChE recovery using traditional approaches, but these are plagued by unstable recovery percentages affected by many different factors such as the concentration of inhibitors, different types of neurotoxins, and so forth. , Therefore, it is important to explore practical, simple, and reliable approaches that allow the regeneration of inhibition-based enzymatic biosensing systems in multiple analytical applications.…”

Section: Introductionmentioning

confidence: 99%

Layer-by-Layer Assembled Carbon Nanotube-Acetylcholinesterase/Biopolymer Renewable Interfaces: SPR and Electrochemical Characterization

et al. 2015

View full text Add to dashboard Cite

Developing simple, reliable, and cost-effective methods of renewing an inhibited biocatalyst (e.g., enzymatic interfaces) on biosensors is needed to advance multiuse, reusable sensor applications. We report a method for the renewal of layer-by-layer (LbL) self-assembled inhibition-based enzymatic interfaces in multiwalled carbon nanotube (MWCNT) armored acetylcholinesterase (AChE) biosensors. The self-assembly process of MWCNT dispersed enzymes/biopolymers was investigated using surface plasmon resonance (SPR). The LbL fabrication consisted of alternating cushion layers of positively charged CNT-polyethylenimine (CNT-PEI) and negatively charged CNT-deoxyribonucleic acid (CNT-DNA) and a functional interface consisting of alternating layers of CNT-PEI and negatively charged CNT-acetylcholine esterase (CNT-AChE, pH 7.4). The observed SPR response signal increased while assembling the different layers, indicating the buildup of multiple layers on the Au surface. A partial desorption of the top enzymatic layer in the LbL structure was observed with a desorption strategy employing alkaline treatment. This indicates that the strong interaction of CNT-biopolymer conjugates with the Au surface was a result of both electrostatic interactions between biopolymers and the surface binding energy from CNTs: the closer the layers are to the Au surface, the stronger the interactions. In contrast, a similar LbL assembly of soluble enzyme/polyelectrolytes resulted in stronger desorption on the surface after the alkaline treatment; this led to the investigation of AChE layer removal, permanently inhibited after pesticide exposure on glassy carbon (GC) electrodes, while keeping the cushion layers intact. The desorption strategy permitted the SPR and electrochemical electrode surfaces to be regenerated multiple times by the subsequent self-assembly of fresh PEI/AChE layers. Flow-mode electrochemical amperometric analysis demonstrated good stability toward the determination of acetylcholine with 97.1 ± 2.7% renewability. Our simple, inexpensive approach shows the potential of renewable LbL self-assembled functional interfaces for multiple uses in a wide field of applications such as biosensing, various biotechnological processes, and the food and health industries.

show abstract

Progress in Antidotes (Acetylcholinesterase Reactivators) Against Organophosphorus Pesticides

Cited by 6 publications

References 69 publications

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Acetylcholinesterase Inhibitors: Pharmacology and Toxicology

Untitled

Layer-by-Layer Assembled Carbon Nanotube-Acetylcholinesterase/Biopolymer Renewable Interfaces: SPR and Electrochemical Characterization

Contact Info

Product

Resources

About