scholarly journals Assessment of four organophosphorus pesticides as inhibitors of human acetylcholinesterase and butyrylcholinesterase

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Tena Čadež ◽  
Dora Kolić ◽  
Goran Šinko ◽  
Zrinka Kovarik
Keyword(s):  
Organophosphorus Compounds ◽  
Organophosphorus Pesticides ◽  
Nerve Agents ◽  
Acute Poisoning ◽  
Health Concern ◽  
Common Mechanism ◽  
Standard Medical Therapy ◽  
Further Development ◽  
Kinetics Of

AbstractToxicity of organophosphorus compounds (OPs) remains a major public health concern due to their widespread use as pesticides and the existence of nerve agents. Their common mechanism of action involves inhibition of enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) which are crucial for neurotransmission. Both chronic and acute poisoning by OPs can leave long-lasting health effects even when the patients are treated with standard medical therapy. Therefore, an increasing urgency exists to find more effective oxime reactivators for compounds which are resistant to reactivation, especially phosphoramidates. Here, we investigated in silico and in vitro interactions and kinetics of inhibition for human cholinesterases with four organophosphate pesticides—ethoprophos, fenamiphos, methamidophos and phosalone. Overall, ethoprophos and fenamiphos displayed higher potency as inhibitors for tested cholinesterases. Our results show that methamidophos-inhibited hAChE was more susceptible to reactivation than hAChE inhibited by fenamiphos by selected oximes. Molecular modelling enabled an evaluation of interactions important for specificity and selectivity of both inhibition and reactivation of cholinesterases. Two newly developed reactivators—bispyridinium triazole oxime 14A and zwitterionic oxime RS194B possess remarkable potential for further development of antidotes directed against pesticides and related phosphoramidate exposures, such as nerve agents tabun or Novichoks.

scholarly journals Kinetics of a nucleoside release from lactide-caprolactone and lactide-glycolide polymers in vitro.

2000 ◽  
Vol 47 (1) ◽  
pp. 59-64
Author(s):  
T Kryczka ◽  
P Grieb ◽  
M Bero ◽  
J Kasperczyk ◽  
P Dobrzynski
Keyword(s):  
Formation Rate ◽  
Local Treatment ◽  
Extracellular Fluid ◽  
Brain Extracellular Fluid ◽  
Artificial Cerebrospinal Fluid ◽  
Fluid Formation ◽  
Further Development ◽  
Kinetics Of ◽  
The Brain

We assessed the rate of release of a model nucleoside (adenosine, 5%, w/w) from nine different lactide-glycolide or lactide-caprolactone polymers. The polymer discs were eluted every second day with an artificial cerebrospinal fluid at the elution rate roughly approximating the brain extracellular fluid formation rate. Adenosine in eluate samples was assayed by HPLC. Three polymers exhibited a relatively constant release of adenosine for over four weeks, resulting in micromolar concentrations of nucleoside in the eluate. This points to the necessity of further development of polymers of this types as intracerebral nucleoside delivery systems for local treatment of brain tumors.

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.

scholarly journals Characterization of the Global Stabilizing Substitution A77V and Its Role in the Evolution of CTX-M β-Lactamases

2015 ◽  
Vol 59 (11) ◽  
pp. 6741-6748 ◽  
Author(s):  
Meha P. Patel ◽  
Bartlomiej G. Fryszczyn ◽  
Timothy Palzkill
Keyword(s):  
Antibiotic Resistance ◽  
Adaptive Mutation ◽  
Common Mechanism ◽  
Antibiotic Hydrolysis ◽  
The Stability ◽  
Kinetics Of ◽  
M 14

ABSTRACTThe widespread use of oxyimino-cephalosporin antibiotics drives the evolution of the CTX-M family of β-lactamases that hydrolyze these drugs and confer antibiotic resistance. Clinically isolated CTX-M enzymes carrying the P167S or D240G active site-associated adaptive mutation have a broadened substrate profile that includes the oxyimino-cephalosporin antibiotic ceftazidime. The D240G substitution is known to reduce the stability of CTX-M-14 β-lactamase, and the P167S substitution is shown here to also destabilize the enzyme. Proteins are marginally stable entities, and second-site mutations that stabilize the enzyme can offset a loss in stability caused by mutations that enhance enzyme activity. Therefore, the evolution of antibiotic resistance enzymes can be dependent on the acquisition of stabilizing mutations. The A77V substitution is present in CTX-M extended-spectrum β-lactamases (ESBLs) from a number of clinical isolates, suggesting that it may be important in the evolution of antibiotic resistance in this family of β-lactamases. In this study, the effects of the A77V substitution in the CTX-M-14 model enzyme were characterized with regard to the kinetic parameters for antibiotic hydrolysis as well as enzyme expression levelsin vivoand protein stabilityin vitro. The A77V substitution has little effect on the kinetics of oxyimino-cephalosporin hydrolysis, but it stabilizes the CTX-M enzyme and compensates for the loss of stability resulting from the P167S and D240G mutations. The acquisition of global stabilizing mutations, such as A77V, is an important feature in β-lactamase evolution and a common mechanism in protein evolution.

scholarly journals Studies of the acetylcholinesterase from houseflies (Musca domestica L.) resistant and susceptible to organophosphorus insecticides

1975 ◽  
Vol 149 (2) ◽  
pp. 463-469 ◽  
Author(s):  
A L Devonshire
Keyword(s):  
Musca Domestica ◽  
Rate Constants ◽  
Gel Electrophoresis ◽  
Organophosphorus Compounds ◽  
Organophosphorus Insecticides ◽  
Triton X ◽  
Kinetics Of ◽  
Kinetics Of Inhibition ◽  
Single Enzyme

Acetylcholinesterase from the heads of insecticide-resistant and -susceptible houseflies (Musca domestica L.) was studied in vitro. The enzymes could not be distinguished electrophoretically, and their behaviour on polyacrylamide-disc-gel electrophoresis was influenced by the presence of Triton X-100 in both the homogenate and the gels. In the absence of detergent, the acetylcholinesterase was heterogeneous, but behaved as a single enzyme when it was present. By analogy with studies of acetylcholinesterase from other sources, these observations were attributed to aggregation of the enzyme when not bound by membranes. The enzyme from resistant flies was more slowly inhibited than the susceptible enzyme, bimolecular rate constants (ki) differing by approx. 4-20-fold for a range of organophosphorus compounds. The kinetics of inhibition of acetylcholinesterase were consistent with the results of electrophoresis, i.e. they corresponded to those of a single enzyme in the presence of Triton X-100, but a mixture of enzymes in its absence. The susceptibility of the more sensitive components in these mixtures was determined.

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.

scholarly journals Interactions of cyclodextrins and their derivatives with toxic organophosphorus compounds

2016 ◽  
Vol 12 ◽  
pp. 204-228 ◽  
Author(s):  
Sophie Letort ◽  
Sébastien Balieu ◽  
William Erb ◽  
Géraldine Gouhier ◽  
François Estour
Keyword(s):  
Organophosphorus Compound ◽  
Organophosphorus Compounds ◽  
Organophosphorus Pesticides ◽  
Nerve Agents ◽  
Cyclic Structure ◽  
Biological Target

The aim of this review is to provide an update on the current use of cyclodextrins against organophosphorus compound intoxications. Organophosphorus pesticides and nerve agents play a determinant role in the inhibition of cholinesterases. The cyclic structure of cyclodextrins and their toroidal shape are perfectly suitable to design new chemical scavengers able to trap and hydrolyze the organophosphorus compounds before they reach their biological target.

scholarly journals Novel Nucleoside Analogues as Effective Antiviral Agents for Zika Virus Infections

Molecules ◽  
2020 ◽  
Vol 25 (20) ◽  
pp. 4813
Author(s):  
Marcella Bassetto ◽  
Cecilia M. Cima ◽  
Mattia Basso ◽  
Martina Salerno ◽  
Frank Schwarze ◽  
...  
Keyword(s):  
Zika Virus ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Antiviral Effect ◽  
Health Concern ◽  
Virus Infections ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Further Development

Previously considered a neglected flavivirus, Zika virus has recently emerged as a public health concern due to its ability to spread rapidly and cause severe neurological disorders, such as microcephaly in newborn babies from infected mothers, and Guillain-Barré syndrome in adults. Despite extensive efforts towards the identification of effective therapies, specific antivirals are still not available. As part of ongoing medicinal chemistry studies to identify new antiviral agents, we screened against Zika virus replication in vitro in a targeted internal library of small-molecule agents, comprising both nucleoside and non-nucleoside agents. Among the compounds evaluated, novel aryloxyphosphoramidate prodrugs of the nucleosides 2′-C-methyl-adenosine, 2-CMA, and 7-deaza-2′C-methyl-adenosine, 7-DMA, were found to significantly inhibit the virus-induced cytopathic effect in multiple relevant cell lines. In addition, one of these prodrugs exhibits a synergistic antiviral effect against Zika virus when applied in combination with an indirect antiviral agent, a l-dideoxy bicyclic pyrimidine nucleoside analogue, which potently inhibits vaccinia and measles viruses in vitro by targeting a host pathway. Our findings provide a solid basis for further development of an antiviral therapy for Zika virus infections, possibly exploiting a dual approach combining two different agents, one targeting the viral polymerase (direct-acting antiviral), the second targeting a host-directed autophagy mechanism.

scholarly journals In vitro release of cytotoxic nucleoside analogs from lactide-caprolactone and lactide-glycolide copolymers.

2002 ◽  
Vol 49 (1) ◽  
pp. 205-210 ◽  
Author(s):  
Tomasz Kryczka ◽  
Maciej Bero ◽  
Janusz Kasperczyk ◽  
Piotr Dobrzyński ◽  
Barbara Marciniec ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Gamma Radiation ◽  
Local Treatment ◽  
In Vitro Release ◽  
Nucleoside Analogs ◽  
Further Development ◽  
Kinetics Of ◽  
Vitro Release ◽  
Observation Period

The aims of our study were to assess the release of cytotoxic nucleoside analogs 5-fluorouracil and 2-chloro-2'-deoxyadenosine from different lactide-glycolide or lactide-caprolactone biodegradable copolymers and the effects of sterilization on this release. The polymers were sterilized either with ethylene oxide at 37 degrees C, or with gamma radiation (15 kGy, 20 kGy, or 25 kGy). The kinetics of nucleoside release from the copolymers were measured over 50 days. Four copolymers exhibited relatively constant release of nucleosides in micromolar concentrations during the entire observation period. Sterilization with either ethylene oxide or gamma radiation only slightly influenced nucleoside release. Further development of these copolymers as an intracerebral nucleoside delivery system for local treatment of brain tumors is indicated.

scholarly journals The novel bis-1,2,4-triazine MIPS-0004373 demonstrates rapid and potent activity against all blood stages of the malaria parasite

2021 ◽  
Author(s):  
Katherine M. Ellis ◽  
Leonardo Lucantoni ◽  
Marina Chavchich ◽  
Matthew Abraham ◽  
Amanda De Paoli ◽  
...  
Keyword(s):  
Drug Exposure ◽  
De Novo ◽  
The Novel ◽  
Excellent Activity ◽  
Transmission Stage ◽  
Emergence Of Resistance ◽  
Further Development ◽  
Kinetics Of

Novel bis-1,2,4-triazine compounds with potent in vitro activity against Plasmodium falciparum parasites were recently identified. The bis-1,2,4-triazines represent a unique antimalarial pharmacophore, and are proposed to act by a novel, but as-yet-unknown mechanism of action. This study investigated the activity of the bis-1,2,4-triazine, MIPS-0004373, across the mammalian lifecycle stages of the parasite, and profiled the kinetics of activity against blood and transmission-stage parasites in vitro and in vivo . MIPS-0004373 demonstrated rapid and potent activity against P. falciparum , with excellent in vitro activity against all asexual blood stages. Prolonged in vitro drug exposure failed to generate stable resistance de novo , suggesting a low propensity for the emergence of resistance. Excellent activity was observed against sexually-committed ring stage parasites, but activity against mature gametocytes was limited to inhibiting male gametogenesis. Assessment of liver stage activity demonstrated good activity in an in vitro P. berghei model, but no activity against P. cynomolgi hypnozoites or liver schizonts. The bis-1,2,4-triazine, MIPS-0004373, efficiently cleared an established P. berghei infection in vivo , with efficacy similar to artesunate and chloroquine, and a recrudescence profile comparable to chloroquine. This study demonstrates the suitability of bis-1,2,4-triazines for further development towards a novel treatment for acute malaria.

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