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Yingting Cai, Shuo Zhou, Madeline J Stewart, Fang Zheng, Chang-Guo Zhan
Human butyrylcholinesterase (BChE) is widely distributed plasma enzyme. For decades, numerous research efforts have been directed at engineering BChE as a bioscavenger of organophosphorus insecticides and chemical warfare nerve agents. However, it has been a grand challenge to cost-efficiently produce BChE in large-scale. Recently reported studies have successfully designed a truncated BChE mutant (with amino-acid substitutions on 47 residues that are far away from the catalytic site), denoted as BChE-M47 for convenience, which can be expressed in E...
July 17, 2019: Chemico-biological Interactions
P Jacquet, L Poirier, D Daudé, E Chabrière
Organophosphorus compounds (OP) are toxic molecules developed as insecticides and chemical warfare nerve agents (CWNAs). Most OP are neurotoxic and act as nervous system disruptors by blocking cholinergic transmission. They are therefore responsible for many poisonings worldwide. OP toxicity may result either from acute or chronic exposure, and their poisoning effect were evaluated using several animal models. These latter were also used for evaluating the efficacy of antidotes. Strategies based on enzymes that can trap (stoichiometric bioscavengers) or degrade (catalytic bioscavengers) OP, were particularly studied since they allow effective decontamination, without toxicity or environmental impact...
June 25, 2019: Annales Pharmaceutiques Françaises
Zrinka Kovarik, Nikolina Maček Hrvat, Jarosław Kalisiak, Maja Katalinić, Rakesh K Sit, Tamara Zorbaz, Zoran Radić, Valery V Fokin, K Barry Sharpless, Palmer Taylor
Tabun represents the phosphoramidate class of organophosphates that are covalent inhibitors of acetylcholinesterase (AChE), an essential enzyme in neurotransmission. Currently used therapy in counteracting excessive cholinergic stimulation consists of a muscarinic antagonist (atropine) and an oxime reactivator of inhibited AChE, but the classical oximes are particularly ineffective in counteracting tabun exposure. In a recent publication (Kovarik et al., 2019), we showed that several oximes prepared by the Huisgen 1,3 dipolar cycloaddition and related precursors efficiently reactivate the tabun-AChE conjugate...
April 9, 2019: Toxicology and Applied Pharmacology
Lorena R Braid, Catherine A Wood, Barry N Ford
Human butyrylcholinesterase (BChE) is a well-characterized bioscavenger with significant potential as a prophylactic or post-exposure treatment for organophosphate poisoning. Despite substantial efforts, BChE has proven technically challenging to produce in recombinant systems. Recombinant BChE tends to be insufficiently or incorrectly glycosylated, and consequently exhibits a truncated half-life, compromised activity, or is immunogenic. Thus, expired human plasma remains the only reliable source of the benchmark BChE tetramer, but production is costly and time intensive and presents possible blood-borne disease hazards...
March 26, 2019: Chemico-biological Interactions
Peng Zhang, Erik J Liu, Caroline Tsao, Shane A Kasten, Michael V Boeri, Thuy L Dao, Sandra J DeBus, C Linn Cadieux, Cetara A Baker, Tamara C Otto, Douglas M Cerasoli, Yantao Chen, Priyesh Jain, Fang Sun, Wenchen Li, Hsiang-Chieh Hung, Zhefan Yuan, Jinrong Ma, Andrew N Bigley, Frank M Raushel, Shaoyi Jiang
Nerve agents are a class of organophosphorus compounds (OPs) that blocks communication between nerves and organs. Because of their acute neurotoxicity, it is extremely difficult to rescue the victims after exposure. Numerous efforts have been devoted to search for an effective prophylactic nerve agent bioscavenger to prevent the deleterious effects of these compounds. However, low scavenging efficiency, unfavorable pharmacokinetics, and immunological problems have hampered the development of effective drugs...
January 2, 2019: Science Translational Medicine
Timothy John Grunkemeyer, David Garcia Mata, Kiran Doddapaneni, Srividya Murali, Thomas J Magliery
The mammalian protein paraoxonase-1 (PON1) has been explored as a promising bioscavenger treatment for organophosphorus (OP) agent poisoning, but it is not active enough to protect against many agents. Engineering is limited because PON1's catalytic mechanism is poorly understood; moreover, its native activity and substrate are unknown. PON1 is a calcium-bound six-bladed β-propeller hydrolase that shares high structural homology, a conserved metal-coordinating active site, and substrate specificity overlap with other members of a superfamily that includes squid diisopropylfluorophosphatase (DFPase), bacterial drug responsive protein 35 (Drp35), and mammalian senescence marker protein 30 (SMP30)...
December 14, 2018: Biochemistry
Thomas W Rösler, Mohamed Salama, Ali S Shalash, Eman M Khedr, Abdelhalim El-Tantawy, Gharib Fawi, Amal El-Motayam, Ehab El-Seidy, Mohamed El-Sherif, Mohamed El-Gamal, Mohamed Moharram, Mohammad El-Kattan, Muhammad Abdel-Naby, Samia Ashour, Ulrich Müller, Astrid Dempfle, Gregor Kuhlenbäumer, Günter U Höglinger
Pesticide exposure is associated with increased risk of Parkinson's disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD...
November 8, 2018: Scientific Reports
Konstantin M Boyko, Timur N Baymukhametov, Yury M Chesnokov, Michael Hons, Sofya V Lushchekina, Petr V Konarev, Alexey V Lipkin, Alexandre L Vasiliev, Patrick Masson, Vladimir O Popov, Michail V Kovalchuk
Human plasma butyrylcholinesterase (BChE) is an endogenous bioscavenger that hydrolyzes numerous medicamentous and poisonous esters and scavenges potent organophosphorus nerve agents. BChE is thus a marker for the diagnosis of OP poisoning. It is also considered a therapeutic target against Alzheimer's disease. Although the X-ray structure of a partially deglycosylated monomer of human BChE was solved 15 years ago, all attempts to determine the 3D structure of the natural full-length glycosylated tetrameric human BChE have been unsuccessful so far...
October 29, 2018: Biochimie
Cédric Touvrey, Charlotte Courageux, Virginia Guillon, Raphael Terreux, Florian Nachon, Xavier Brazzolotto
The efficiency of human butyrylcholinesterase (BChE) as a stoichiometric bioscavenger of nerve agents is well established. However, wide use is currently limited by production and purification costs. Aiming at identifying an alternative human protein bioscavenger, we looked for an original scaffold candidate by virtual screening of the Protein Data Bank for functional similarity using the "Surfing the Molecules" software ( and a search model based on the BChE active site topology...
October 22, 2018: Toxicology
Geoffroy Napon, Alicia J Dafferner, Ashima Saxena, Oksana Lockridge
Drugs to protect against nerve agent toxicity are tested in animals. The current preferred small animal model is guinea pigs because their plasma bioscavenging capacity resembles that of NHP. We stained nondenaturing polyacrylamide slab gels with a variety of substrates, inhibitors, and antibodies to identify the esterases in heparinized guinea pig plasma. An intense band of carboxylesterase activity migrated behind albumin. Minor carboxylesterase bands were revealed after background activity from paraoxonase was inhibited by using EDTA...
October 1, 2018: Comparative Medicine
Alexander Zlobin, Yuliana Mokrushina, Stanislav Terekhov, Arthur Zalevsky, Tatiana Bobik, Anastasiya Stepanova, Maria Aliseychik, Olga Kartseva, Sergey Panteleev, Andrey Golovin, Alexey Belogurov, Alexander Gabibov, Ivan Smirnov
Butyrylcholinesterase (BChE) is considered as an efficient stoichiometric antidote against organophosphorus (OP) poisons. Recently we utilized combination of calculations and ultrahigh-throughput screening (uHTS) to select BChE variants capable of catalytic destruction of OP pesticide paraoxon. The purpose of this study was to elucidate the molecular mechanism underlying enzymatic hydrolysis of paraoxon by BChE variants using hybrid quantum mechanical/molecular mechanical (QM/MM) calculations. Detailed analysis of accomplished QM/MM runs revealed that histidine residues introduced into the acyl-binding loop are always located in close proximity with aspartate residue at position 70...
2018: Frontiers in Pharmacology
Moshe Goldsmith, Yacov Ashani
No abstract text is available yet for this article.
September 25, 2018: Chemico-biological Interactions
Sofya Lushchekina, Patrick Masson
Catalytic bioscavengers are the second-generation bioscavengers. These biopharmaceuticals are intended to degrade toxic organophosphorus agents on the skin for decontamination or in the bloodstream for pre-treatment and post-exposure treatment of organophosphate poisoning. Because catalytic degradation has to be fast, their catalytic efficiency has to be as high as possible (kcat /Km >106 M-1  min-1 ). Certain evolved mammalian paraoxonases and bacterial phosphotriesterases already fulfill this requirement...
November 1, 2018: Toxicology
Moshe Goldsmith, Yacov Ashani
Recent years have seen an increasing number of incidence, in which organophosphate nerve agents (OPNAs) have been used against civilians with devastating outcomes. Current medical countermeasures against OPNA intoxications are aimed at mitigating their symptoms, but are unable to effectively prevent them. In addition, they may fail to prevent the onset of a cholinergic crisis in the brain and its secondary toxic manifestations. The need for improved medical countermeasures has led to the development of bioscavengers; proteins and enzymes that may prevent intoxication by binding and inactivating OPNAs before they can reach their target organs...
August 25, 2018: Chemico-biological Interactions
Laetitia Poirier, Pauline Jacquet, Laure Plener, Patrick Masson, David Daudé, Eric Chabrière
Organophosphorus compounds (OPs) are neurotoxic molecules developed as pesticides and chemical warfare nerve agents (CWNAs). Most of them are covalent inhibitors of acetylcholinesterase (AChE), a key enzyme in nervous systems, and are therefore responsible for numerous poisonings around the world. Many animal models have been studied over the years in order to decipher the toxicity of OPs and to provide insights for therapeutic and decontamination purposes. Environmental impact on wild animal species has been analyzed to understand the consequences of OP uses in agriculture...
June 29, 2018: Environmental Science and Pollution Research International
Emily N Dunn, Teresa M Ferrara-Bowens, Mark E Chachich, Cary L Honnold, Cristin C Rothwell, Heidi M Hoard-Fruchey, Catherine A Lesyna, Erik A Johnson, Douglas M Cerasoli, John H McDonough, C Linn Cadieux
Mice and other rodents are typically utilized for chemical warfare nerve agent research. Rodents have large amounts of carboxylesterase in their blood, while humans do not. Carboxylesterase nonspecifically binds to and detoxifies nerve agent. The presence of this natural bioscavenger makes mice and other rodents poor models for studies identifying therapeutics to treat humans exposed to nerve agents. To obviate this problem, a serum carboxylesterase knockout (Es1 KO) mouse was created. In this study, Es1 KO and wild type (WT) mice were assessed for differences in gene expression, nerve agent (soman; GD) median lethal dose (MLD) values, and behavior prior to and following nerve agent exposure...
October 2018: Toxicology Mechanisms and Methods
Stefano Costanzi, John-Hanson Machado, Moriah Mitchell
Nerve agents are organophosphorus chemical warfare agents that exert their action through the irreversible inhibition of acetylcholinesterase, with a consequent overstimulation of cholinergic transmission followed by its shutdown. Beyond warfare, they have notoriously been employed in acts of terrorism as well as high profile assassinations. After a brief historical introduction on the development and deployment of nerve agents, this review provides a survey of their chemistry, the way they affect cholinergic transmission, the available treatment options, and the current directions for their improvement...
May 16, 2018: ACS Chemical Neuroscience
Sofya V Lushchekina, Lawrence M Schopfer, Bella L Grigorenko, Alexander V Nemukhin, Sergei D Varfolomeev, Oksana Lockridge, Patrick Masson
Organophosphorus agents (OPs) are irreversible inhibitors of acetylcholinesterase (AChE). OP poisoning causes major cholinergic syndrome. Current medical counter-measures mitigate the acute effects but have limited action against OP-induced brain damage. Bioscavengers are appealing alternative therapeutic approach because they neutralize OPs in bloodstream before they reach physiological targets. First generation bioscavengers are stoichiometric bioscavengers. However, stoichiometric neutralization requires administration of huge doses of enzyme...
2018: Frontiers in Pharmacology
Odile Francesca Restaino, Maria Giovanna Borzacchiello, Ilaria Scognamiglio, Luigi Fedele, Alberto Alfano, Elena Porzio, Giuseppe Manco, Mario De Rosa, Chiara Schiraldi
BACKGROUND: Thermostable phosphotriesterase-like lactonases (PLLs) are able to degrade organophosphates and could be potentially employed as bioremediation tools and bioscavengers. But nowadays their manufacturing in high yields is still an issue that limits their industrial applications. In this work we aimed to set up a high yield production and purification biotechnological process of two recombinant PLLs expressed in E. coli, the wild type SacPox from Sulfolobus acidocaldarius and a triple mutated SsoPox C258L/I261F/W263A, originally from Sulfolobus solfataricus...
March 20, 2018: BMC Biotechnology
Jasmine M Corbin, Muchena J Kailemia, C Linn Cadieux, Salem Alkanaimsh, Kalimuthu Karuppanan, Raymond L Rodriguez, Carlito B Lebrilla, Douglas M Cerasoli, Karen A McDonald, Somen Nandi
Recombinant butyrylcholinesterase produced in a metabolically regulated transgenic rice cell culture (rrBChE) was purified to produce a highly pure (95%), active form of enzyme. The developed downstream process uses common manufacturing friendly operations including tangential flow filtration, anion-exchange chromatography, and affinity chromatography to obtain a process recovery of 42% active rrBChE. The purified rrBChE was then characterized to confirm its comparability to the native human form of the molecule (hBChE)...
May 2018: Biotechnology and Bioengineering
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