Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

• Klíčová slova
• acetylcholinesterase, new trends in reactivators, organophosphorus compounds, reactivation process, therapeutic potential,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• GPI-vázané proteiny metabolismus   MeSH
• lidé MeSH
• oximy chemie   terapeutické užití   MeSH
• patenty jako téma MeSH
• reaktivátory cholinesterasy * chemie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• ACHE protein, human MeSH Prohlížeč
• GPI-vázané proteiny MeSH
• oximy MeSH
• reaktivátory cholinesterasy * MeSH

Organophosphorus compounds (OP) are chemicals widely used as pesticides in different applications such as agriculture and public health (vector control), and some of the highly toxic forms have been used as chemical weapons. After application of OPs in an environment, they persist for a period, suffering a degradation process where the biotic factors are considered the most relevant forms. However, to date, the biodegradation of OP compounds is not well understood. There are a plenty of structure-based biodegradation estimation methods, but none of them consider enzymatic interaction in predicting and better comprehending the differences in the fate of OPs in the environment. It is well known that enzymatic processes are the most relevant processes in biodegradation, and that hydrolysis is the main pathway in the natural elimination of OPs in soil samples. Due to this, we carried out theoretical studies in order to investigate the interactions of these OPs with a chosen enzyme-the phosphotriesterase. This one is characteristic of some soils' microorganisms, and has been identified as a key player in many biodegradation processes, thanks to its capability for fast hydrolyzing of different OPs. In parallel, we conducted an experiment using native soil in two conditions, sterilized and not sterilized, spiked with specific amounts of two OPs with similar structure-paraoxon-ethyl (PXN) and O-(4-nitrophenyl) O-ethyl methylphosphonate (NEMP). The amount of OP present in the samples and the appearance of characteristic hydrolysis products were periodically monitored for 40 days using analytical techniques. Moreover, the number of microorganisms present was obtained with plate cell count. Our theoretical results were similar to what was achieved in experimental analysis. Parameters calculated by enzymatic hydrolysis were better for PXN than for NEMP. In soil, PXN suffered a faster hydrolysis than NEMP, and the cell count for PXN was higher than for NEMP, highlighting the higher microbiological toxicity of the latter. All these results pointed out that theoretical study can offer a better comprehension of the possible mechanisms involved in real biodegradation processes, showing potential in exploring how biodegradation of OPs relates with enzymatic interactions.

• Klíčová slova
• bioremediation, molecular modeling, organophosphorus compounds, phosphotriesterase,
• MeSH
• biodegradace * MeSH
• chemická válka MeSH
• hydrolýza MeSH
• insekticidy chemie   metabolismus   MeSH
• lidé MeSH
• organofosforové sloučeniny chemie   metabolismus   MeSH
• paraoxon analogy a deriváty   chemie   MeSH
• pesticidy chemie   toxicita   MeSH
• půda chemie   MeSH
• pyrrolidiny chemie   MeSH
• veřejné zdravotnictví MeSH
• zemědělství MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• ethylparaoxon MeSH Prohlížeč
• insekticidy MeSH
• N-ethylmercapto-3-4-dihydroxy-2-hydroxymethylpyrrolidine MeSH Prohlížeč
• organofosforové sloučeniny MeSH
• paraoxon MeSH
• pesticidy MeSH
• půda MeSH
• pyrrolidiny MeSH

Organophosphorus compounds (OP) are part of a group of compounds that may be hazardous to health. They are called neurotoxic agents because of their action on the nervous system, inhibiting the acetylcholinesterase (AChE) enzyme and resulting in a cholinergic crisis. Their high toxicity and rapid action lead to irreversible damage to the nervous system, drawing attention to developing new treatment methods. The diisopropyl fluorophosphatase (DFPase) enzyme has been considered as a potent biocatalyst for the hydrolysis of toxic OP and has potential for bioremediation of this kind of intoxication. In order to investigate the degradation process of the nerve agents Tabun, Cyclosarin and Soman through the wild-type DFPase, and taking into account their stereochemistry, theoretical studies were carried out. The intermolecular interaction energy and other parameters obtained from the molecular docking calculations were used to construct a data matrix, which were posteriorly treated by statistical analyzes of chemometrics, using the PCA (Principal Components Analysis) multivariate analysis. The analyzed parameters seem to be quite important for the reaction mechanisms simulation (QM/MM). Our findings showed that the wild-type DFPase enzyme is stereoselective in hydrolysis, showing promising results for the catalytic degradation of the neurotoxic agents under study, with the degradation mechanism performed through two proposed pathways.

• Klíčová slova
• DFPase, PCA, QM/MM, cyclosarin, molecular docking, organophosphorus compounds, soman, tabun,
• MeSH
• analýza hlavních komponent MeSH
• biodegradace MeSH
• chemické bojové látky metabolismus   MeSH
• hydrolasy triesterů kyseliny fosforečné metabolismus   MeSH
• organofosfáty metabolismus   MeSH
• organofosforové sloučeniny metabolismus   MeSH
• soman metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chemické bojové látky MeSH
• cyclohexyl methylphosphonofluoridate MeSH Prohlížeč
• diisopropyl-fluorophosphatase MeSH Prohlížeč
• hydrolasy triesterů kyseliny fosforečné MeSH
• organofosfáty MeSH
• organofosforové sloučeniny MeSH
• soman MeSH
• tabun MeSH Prohlížeč