scholarly journals Organophosphorus Nerve Agents: Types, Toxicity, and Treatments

2020 ◽  
Vol 2020 ◽  
pp. 1-16 ◽  
Author(s):  
Sudisha Mukherjee ◽  
Rinkoo Devi Gupta
Keyword(s):  
Organophosphorus Compounds ◽  
Treatment Strategies ◽  
Catalytic Efficiency ◽  
High Specificity ◽  
Nerve Agents ◽  
Targeted Mutagenesis ◽  
Organophosphate Poisoning ◽  
Methyl Parathion Hydrolase ◽  
Acetylcholinesterase Enzyme ◽  
Directed Molecular Evolution

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.

scholarly journals A Systematic Review on Nerve Chemical Warfare Agents

2021 ◽  
Vol 9 (10) ◽  
pp. 1329-1333
Author(s):  
Gagan R
Keyword(s):  
Organophosphorus Compounds ◽  
Chemical Warfare Agents ◽  
Nerve Agents ◽  
Nerve Agent ◽  
Chemical Warfare ◽  
The Body ◽  
Warfare Agents ◽  
Pralidoxime Chloride ◽  
Acetylcholinesterase Enzyme ◽  
Neurological System

Abstract: The recent poisoning of Russian opposition figure and critic Alexei Navalny on August 20th , 2020 with a Soviet-era Novichok nerve agent reminded the world of the use of chemical agents, especially nerve agents to eliminate individual targets or for mass destruction. Nerve agents are a class of organophosphorus compounds. Soman, Sarin, Tabun, Cyclosarin, VX are a few examples of nerve agents. Nerve agents affect a person by disrupting the mechanism by which nerve signals are passed in the body. They inhibit the action of acetylcholinesterase enzyme which is responsible for the breakdown of acetylcholine neurotransmitters leading to accumulation of acetylcholine in the body. Nerve agents have a range of chemical effects on the eye, gastro-intestinal (GI) tract, Central nervous system (CNS), Respiratory system, Cardiovascular system and Neurological system. The management of nerve agent poisoning is done by administering Atropine or Pralidoxime chloride or also by administering anticonvulsants like Benzodiazepines or Diazepam. This review presents all such detailed information on this class of chemical Warfare agents. Keywords: Chemical Warfare Weapon, Nerve Agents, Acetylcholinesterase, Toxicity, Instrumentation

scholarly journals Cariogenic Biofilm: Pathology-Related Phenotypes and Targeted Therapy

2021 ◽  
Vol 9 (6) ◽  
pp. 1311
Author(s):  
Xiuqin Chen ◽  
Eric Banan-Mwine Daliri ◽  
Akanksha Tyagi ◽  
Deog-Hwan Oh
Keyword(s):  
Treatment Strategies ◽  
High Specificity ◽  
Low Ph ◽  
Oral Microbiota ◽  
Extracellular Polymers ◽  
Dental Biofilm ◽  
Health And Disease ◽  
Promising Treatment ◽  
Cariogenic Biofilm

The initiation and development of cariogenic (that is, caries-related) biofilms are the result of the disruption of homeostasis in the oral microenvironment. There is a daily accumulation of dental biofilm on the surface of teeth and its matrix of extracellular polymers supports the host in its defense against invading microbes, thus helping to achieve oral microbial homeostasis. However, the homeostasis can be broken down under certain circumstances such as during long-term exposure to a low pH environment which results in the dominance of acidogenic and acid-tolerating species in the dental biofilm and, thus, triggers the shift of harmless biofilm to an acidic one. This work aims to explore microbial diversity and the quorum sensing of dental biofilm and their important contributions to oral health and disease. The complex and multispecies ecosystems of the cariogenic biofilm pose significant challenges for the modulation of the oral microenvironment. Promising treatment strategies are those that target cariogenic niches with high specificity without disrupting the balance of the surrounding oral microbiota. Here, we summarized the recent advances in modulating cariogenic biofilm and/or controlling its pathogenic traits.

scholarly journals Comparative determination of the efficacy of bispyridinium oximes in paraoxon poisoning / Usporedno određivanje učinkovitosti bispiridinijevih oksima pri trovanju paraoksonom

2015 ◽  
Vol 66 (2) ◽  
pp. 129-134 ◽  
Author(s):  
Suzana Žunec ◽  
Božica Radić ◽  
Kamil Kuča ◽  
Kamil Musilek ◽  
Ana Lucić Vrdoljak
Keyword(s):  
Therapeutic Efficacy ◽  
Standard Therapy ◽  
Organophosphorus Compounds ◽  
Nerve Agents ◽  
Therapeutic Efficiency ◽  
Hi 6 ◽  
Comparative Determination

Abstract The inability of standard therapy to provide adequate protection against poisoning by organophosphorus compounds (pesticides and nerve agents) motivated us to search for new, more effective oximes. We investigated the pharmacotoxicological properties of six experimental K-oximes (K027, K033, K048, K074, K075, and K203) in vivo. The therapeutic efficacy of K-oximes (at doses of 5 or 25 % of their LD50) combined with atropine was assessed in paraoxon-poisoned mice and compared with conventionally used oximes HI-6 and TMB-4. The bisoxime K074 was the most toxic (LD50=21.4 mg kg-1) to mice, while monoxime K027 was the least toxic (LD50=672.8 mg kg-1). With the exception of K033, all of the tested K-oximes showed better therapeutic efficiency than HI-6 and TMB-4. K027 and K048 stood out by demonstrating low acute toxicities and ensuring protective indices ranging from 60.0 to 100.0 LD50 of paraoxon. Taking into account that these two oximes showed a similar therapeutic efficacy regardless of the applied doses, our results suggest that K027 and K048 could be antidotes for paraoxon intoxication.

scholarly journals Saturation Mutagenesis for Phenylalanine Ammonia Lyases of Enhanced Catalytic Properties

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 838 ◽  
Author(s):  
Raluca Bianca Tomoiagă ◽  
Souad Diana Tork ◽  
Ilka Horváth ◽  
Alina Filip ◽  
Levente Csaba Nagy ◽  
...  
Keyword(s):  
Rational Design ◽  
Stereoselective Synthesis ◽  
Catalytic Properties ◽  
Catalytic Efficiency ◽  
High Specificity ◽  
Saturation Mutagenesis ◽  
Petroselinum Crispum ◽  
Natural Substrate ◽  
Whole Cells ◽  
Pal Activity

Phenylalanine ammonia-lyases (PALs) are attractive biocatalysts for the stereoselective synthesis of non-natural phenylalanines. The rational design of PALs with extended substrate scope, highlighted the substrate specificity-modulator role of residue I460 of Petroselinum crispum PAL. Herein, saturation mutagenesis at key residue I460 was performed in order to identify PcPAL variants of enhanced activity or to validate the superior catalytic properties of the rationally explored I460V PcPAL compared with the other possible mutant variants. After optimizations, the saturation mutagenesis employing the NNK-degeneracy generated a high-quality transformant library. For high-throughput enzyme-activity screens of the mutant library, a PAL-activity assay was developed, allowing the identification of hits showing activity in the reaction of non-natural substrate, p-MeO-phenylalanine. Among the hits, besides the known I460V PcPAL, several mutants were identified, and their increased catalytic efficiency was confirmed by biotransformations using whole-cells or purified PAL-biocatalysts. Variants I460T and I460S were superior to I460V-PcPAL in terms of catalytic efficiency within the reaction of p-MeO-Phe. Moreover, I460T PcPAL maintained the high specificity constant of the wild-type enzyme for the natural substrate, l-Phe. Molecular docking supported the favorable substrate orientation of p-MeO-cinnamic acid within the active site of I460T variant, similarly as shown earlier for I460V PcPAL (PDB ID: 6RGS).

scholarly journals Known Evolutionary Paths Are Accessible to Engineered ß-Lactamases Having Altered Protein Motions at the Timescale of Catalytic Turnover

2020 ◽  
Vol 7 ◽  
Author(s):  
Lorea Alejaldre ◽  
Claudèle Lemay-St-Denis ◽  
Carles Perez Lopez ◽  
Ferran Sancho Jodar ◽  
Victor Guallar ◽  
...  
Keyword(s):  
Molecular Evolution ◽  
Synergistic Effect ◽  
Protein Dynamics ◽  
Catalytic Efficiency ◽  
Specific Sequence ◽  
Protein Motions ◽  
Protein Energy ◽  
Protein Functions ◽  
Directed Molecular Evolution

The evolution of new protein functions is dependent upon inherent biophysical features of proteins. Whereas, it has been shown that changes in protein dynamics can occur in the course of directed molecular evolution trajectories and contribute to new function, it is not known whether varying protein dynamics modify the course of evolution. We investigate this question using three related ß-lactamases displaying dynamics that differ broadly at the slow timescale that corresponds to catalytic turnover yet have similar fast dynamics, thermal stability, catalytic, and substrate recognition profiles. Introduction of substitutions E104K and G238S, that are known to have a synergistic effect on function in the parent ß-lactamase, showed similar increases in catalytic efficiency toward cefotaxime in the related ß-lactamases. Molecular simulations using Protein Energy Landscape Exploration reveal that this results from stabilizing the catalytically-productive conformations, demonstrating the dominance of the synergistic effect of the E014K and G238S substitutions in vitro in contexts that vary in terms of sequence and dynamics. Furthermore, three rounds of directed molecular evolution demonstrated that known cefotaximase-enhancing mutations were accessible regardless of the differences in dynamics. Interestingly, specific sequence differences between the related ß-lactamases were shown to have a higher effect in evolutionary outcomes than did differences in dynamics. Overall, these ß-lactamase models show tolerance to protein dynamics at the timescale of catalytic turnover in the evolution of a new function.

scholarly journals Catalytic Degradation of Nerve Agents

Catalysts ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 881
Author(s):  
Agatino Zammataro ◽  
Rossella Santonocito ◽  
Andrea Pappalardo ◽  
Giuseppe Trusso Sfrazzetto
Keyword(s):  
World War Ii ◽  
Acute Toxicity ◽  
Organophosphorus Compounds ◽  
Organophosphorus Pesticides ◽  
Lethal Effect ◽  
Nerve Agents ◽  
Catalytic Degradation ◽  
World War ◽  
Degradation Reactions ◽  
Chemical Hydrolysis

Nerve agents (NAs) are a group of highly toxic organophosphorus compounds developed before World War II. They are related to organophosphorus pesticides, although they have much higher human acute toxicity than commonly used pesticides. After the detection of the presence of NAs, the critical step is the fast decontamination of the environment in order to avoid the lethal effect of these organophosphorus compounds on exposed humans. This review collects the catalytic degradation reactions of NAs, in particular focusing our attention on chemical hydrolysis. These reactions are catalyzed by different catalyst categories (metal-based, polymeric, heterogeneous, enzymatic and MOFs), all of them described in this review.

An OPAA enzyme mutant with increased catalytic efficiency on the nerve agents sarin, soman, and GP

2018 ◽  
Vol 112 ◽  
pp. 65-71 ◽  
Author(s):  
Sue Y. Bae ◽  
James M. Myslinski ◽  
Leslie R. McMahon ◽  
Jude J. Height ◽  
Andrew N. Bigley ◽  
...  
Keyword(s):  
Catalytic Efficiency ◽  
Nerve Agents

scholarly journals Effect of organophosphorus compounds on the external respiratory function in rats during intratracheal and intraperitoneal administration

2021 ◽  
Author(s):  
Anastasiya A. Kryazhevskikh ◽  
Aleksey A. Kryazhevskikh ◽  
Svetlana N. Subbotina ◽  
Nataliia A. Sklyarova
Keyword(s):  
Respiratory Failure ◽  
Respiratory Function ◽  
Organophosphorus Compounds ◽  
Intraperitoneal Administration ◽  
Toxic Chemicals ◽  
Organophosphate Poisoning ◽  
Toxic Chemical ◽  
Intratracheal Administration ◽  
Chemical Factors ◽  
Lethal Doses

Due to the increasing influence of chemical factors on the human body, the experiment has been conducted using organophosphorus compounds (OPC) to stimulate poisoning cases in the production facilities. Given that the development of respiratory failure is a specific organophosphate poisoning symptom, a comparative analysis of external respiratory function (ERF) in rats with intratracheal and intraperitoneal administration of diisopropyl fluorophosphates (DFP) has been carried out. During the research, the average lethal doses of the toxic chemicals have been established, the conditions of DFP intoxication have been modeled. Thus, LD16 was 0.284 mg/kg by intratracheal administration, 1.6 mg/kg by intraperitoneal administration. Experimental data have shown that the intratracheal intake of OPC causes the development of respiratory failure in the first minutes after poisoning. The return of the ERF indicators to the background values was noted a day after poisoning. With the intraperitoneal administration of the toxic chemical, the rate of development of ERF disorders was lower, toxic effects persisted for two days. The data obtained can be used to make appropriate recommendations for the prevention of accidents and non-emergency cases in a production facility.

scholarly journals Enzymatic Degradation of Organophosphorus Pesticides and Nerve Agents by EC: 3.1.8.2

Catalysts ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1365
Author(s):  
Marek Matula ◽  
Tomas Kucera ◽  
Ondrej Soukup ◽  
Jaroslav Pejchal
Keyword(s):  
Catalytic Activity ◽  
Organophosphorus Compounds ◽  
Organophosphorus Pesticides ◽  
Chemical Warfare Agents ◽  
Enzyme Commission Number ◽  
Nerve Agents ◽  
Organophosphorus Acid Anhydrolase ◽  
Warfare Agents ◽  
Heavy Burden ◽  
Medical Countermeasures

The organophosphorus substances, including pesticides and nerve agents (NAs), represent highly toxic compounds. Standard decontamination procedures place a heavy burden on the environment. Given their continued utilization or existence, considerable efforts are being made to develop environmentally friendly methods of decontamination and medical countermeasures against their intoxication. Enzymes can offer both environmental and medical applications. One of the most promising enzymes cleaving organophosphorus compounds is the enzyme with enzyme commission number (EC): 3.1.8.2, called diisopropyl fluorophosphatase (DFPase) or organophosphorus acid anhydrolase from Loligo Vulgaris or Alteromonas sp. JD6.5, respectively. Structure, mechanisms of action and substrate profiles are described for both enzymes. Wild-type (WT) enzymes have a catalytic activity against organophosphorus compounds, including G-type nerve agents. Their stereochemical preference aims their activity towards less toxic enantiomers of the chiral phosphorus center found in most chemical warfare agents. Site-direct mutagenesis has systematically improved the active site of the enzyme. These efforts have resulted in the improvement of catalytic activity and have led to the identification of variants that are more effective at detoxifying both G-type and V-type nerve agents. Some of these variants have become part of commercially available decontamination mixtures.

Sign in / Sign up

Export Citation Format

Share Document