Nano-Intercalated Organophosphorus-Hydrolyzing Enzymes in Organophosphorus Antagonism

Petrikovics, Ilona; Wales, Melinda E.; Budai, Marianna; Yu, Jorn C. C.; Szilasi, Mária

doi:10.1208/s12249-011-9728-5

Cited by 15 publications

(9 citation statements)

References 31 publications

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“…In MAFP, the C20 alkyl chain on the fluorophosphonate might more easily target TesA catalytic site than the less lipophilic organophosphorus malathion, giving a possible explanation to their different TesA inhibition abilities, despite common ability to attack a nucleophilic serine catalytic residue. Furthermore, MAFP has been reported to be a broad-spectrum Ser active site inhibitor compared to malathion [45][46][47]. Indeed, the serine-reactive fluorophosphonate (FP) of MAFP inhibited more M. tuberculosis esterases than the E-600, THL, and PMSF inhibitors [48].…”

Section: Discussionmentioning

confidence: 99%

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

et al. 2019

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Edited by Peter BrzezinskiPhthiocerol dimycocerosates and phenolic glycolipids (PGL) are considered as major virulence elements of Mycobacterium tuberculosis, in particular because of their involvement in cell wall impermeability and drug resistance. The biosynthesis of these waxy lipids involves multiple enzymes, including thioesterase A (TesA). We observed that purified recombinant M. tuberculosis TesA is able to dimerize in the presence of palmitoyl-CoA and our 3D structure model of TesA with this acyl-CoA suggests hydrophobic interaction requirement for dimerization. Furthermore, we identified that methyl arachidonyl fluorophosphonate, which inhibits TesA by covalently modifying the catalytic serine, also displays a synergistic antimicrobial activity with vancomycin further warranting the development of TesA inhibitors as valuable antituberculous drug candidates.

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Section: Discussionmentioning

confidence: 99%

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

et al. 2019

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“…In the present study, the optimal OPH activity towards DFP has been assessed by k cat / K m 541.7 ± 12.6 mM -1 s -1 (approximately 5.4 × 10 5 M -1 s -1 ) at 300 mM TEA condition (Table 6), desirably higher than DFPase and reaching at the level of OPAA, the best DFP-degrading enzyme ever reported. OPAA has been well exploited to detoxify fluoride-containing OPs and successfully encapsulated as dentritic-enzyme complexes with pralidoxime and/or atropine to protect AChE and/or cholinesterase against DFP [47–49]. In contrast, despite of having a wide OPs spectrum, OPH has been not so good to degrade organophosphofluoridates including DFP, somewhat reducing the practical value of this enzyme.…”

Section: Discussionmentioning

confidence: 99%

Aminoalcohol-Induced Activation of Organophosphorus Hydrolase (OPH) towards Diisopropylfluorophosphate (DFP)

Zhang

Song

et al. 2017

PLoS ONE

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Aminoalcohols have been addressed as activating buffers for alkaline phosphatase. However, there is no record on the buffer activation regarding organophosphorus hydrolase (OPH). Here we reported the activating effects of aminoalcohols on OPH-catalyzed hydrolysis of diisopropylfluorophosphate (DFP), an analog molecule of G-type warfare agents. The kinetic parametors kcat, Vmax and kcat/Km in the OPH reaction were remarkably increased in the buffers (pH 8.0, 25°C) containing aminoalcohols with C2 between nitrogen (N) and oxygen (O) in their structures, including triethanolamine (TEA), diethanolamine, monoethanolamine, 1-amino-2-propanol, 2-amino-2-methyl-1-propanol, and triisopropanolamine. In contrast, much lower or no rate-enhancing effects were observed in the adding of amines, alcohols, amine/alcohol mixtures, or 3-amino-1-propanol (C3 between N and O). The 300 mM TEA further increased DFP-degrading activities of OPH mutants F132Y and L140Y, the previously reported OPH mutants with desirable activities towards DFP. However, the treatment of ethylenediaminetetraacetate (EDTA) markedly abolished the TEA-induced activation of OPH. The product fluoride effectively inhibited OPH-catalyzed hydrolysis of DFP by a linear mixed inhibition (inhibition constant Ki ~ 3.21 mM), which was partially released by TEA adding at initial or later reaction stage. The obtained results indicate the activation of OPH by aminoalcohol buffers could be attributed to the reduction of fluoride inhibition, which would be beneficial to the hydrolase-based detoxification of organophosphofluoridate.

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“…Owing to their void core, DPs could also provide higher loading capacity than several traditional enzyme delivery systems, such as liposomes. In the studies of Petrikovics and coworkers, OP-hydrolyzing recombinant enzymes, OP acid anhydrolase and OP hydrolase were encapsulated in poly(2-alkyloxazoline)-based dendritic nanocarriers (Petrikovics, Wales, Budai, Yu, & Szilasi, 2012). Therapeutic effect of the antidote-DP NPs against two model OP compounds, paraoxon (PO) and diisopropylfluorophosphate (DFP) was investigated both in vitro on AChE activity essays and in vivo on male BALB/C mice treated with sublethal doses of either PO or DFP.…”

Section: Organophosphorus Exposurementioning

confidence: 99%

Brain delivery of antidotes by polymeric nanoparticles

Manek

Petroianu

2020

J of Applied Toxicology

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Accidental intoxications from environmental pollutants, as well as intentional selfand chemical warfare-related poisonings affect millions of people worldwide each year. While many toxic agents can readily enter the central nervous system (CNS), the blood-brain barrier (BBB) prevents the brain uptake of most pharmaceuticals. Consequently, poisoning antidotes usually cannot reach their site of action in the CNS in therapeutically relevant concentrations, and thus only provide effective protection to the peripheral nervous system. This limitation can be overcome by encapsulating the antidotes in nanoparticles (NP), which can enhance their CNS accumulation without damaging the integrity of the BBB. Among nanocarriers, polymerbased drug delivery systems exhibit remarkable benefits, such as bioavailability, cell uptake and tissue retention. Furthermore, due to their capacity to mask unfavorable physicochemical properties of cargo drugs, polymeric NPs were able to improve BBB transport of various pharmaceuticals. However, while polymer NP-mediated treatment of various pathological brain conditions, such as glioma and Alzheimer's disease were exhaustively studied, the application of polymeric nanocarriers for braintargeted delivery of antidote molecules has not been adequately examined. To display its therapeutic potential, we review the state of the art of polymer NP-assisted CNS delivery of antidotes for various poisonings, including heavy metal and organophosphorus intoxications.

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Nano-Intercalated Organophosphorus-Hydrolyzing Enzymes in Organophosphorus Antagonism

Cited by 15 publications

References 31 publications

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

Methyl arachidonyl fluorophosphonate inhibits Mycobacterium tuberculosis thioesterase TesA and globally affects vancomycin susceptibility

Aminoalcohol-Induced Activation of Organophosphorus Hydrolase (OPH) towards Diisopropylfluorophosphate (DFP)

Brain delivery of antidotes by polymeric nanoparticles

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