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Statements

Subject Item
n2:RIV%2F00179906%3A_____%2F11%3A10118801%21RIV12-MZ0-00179906
rdf:type
skos:Concept n5:Vysledek
rdfs:seeAlso
http://ac.els-cdn.com/S0378427411012598/1-s2.0-S0378427411012598-main.pdf?_tid=87685fdd2169718a73085c99fcc26252&acdnat=1332850141_53db8f8e1536b2ec4e420045a5eb8b6b
dcterms:description
Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold, Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues. Bioscavengers are molecules able to neutralize neurotoxic organophosphorus compounds (OP) before they can reach their biological target. Human butyrylcholinesterase (hBChE) is a natural bioscavenger each molecule of enzyme neutralizing one molecule of OP. The amount of natural enzyme is insufficient to achieve good protection. Thus, different strategies have been envisioned. The most straightforward consists in injecting a large dose of highly purified natural hBChE to increase the amount of bioscavenger in the bloodstream. This proved to be successful for protection against lethal doses of soman and VX but remains expensive. An improved strategy is to regenerate prophylactic cholinesterases (ChE) by administration of reactivators after exposure. But broad-spectrum efficient reactivators are still lacking, especially for inhibited hBChE. Cholinesterase mutants capable of reactivating spontaneously are another option. The G117H hBChE mutant has been a prototype. We present here the Y124H/Y72D mutant of human acetylcholinesterase; its spontaneous reactivation rate after V-agent inhibition is increased up to 110 fold. Catalytic bioscavengers, enzymes capable of hydrolyzing OP, present the best alternative. Mesophilic bacterial phosphotriesterase (PTE) is a candidate with good catalytic efficiency. Its enantioselectivity has been enhanced against the most potent OP isomers by rational design. We show that PEGylation of this enzyme improves its mean residence time in the rat blood stream 24-fold and its bioavailability 120-fold, Immunogenic issues remain to be solved. Human paraoxonase 1 (hPON1) is another promising candidate. However, its main drawback is that its phosphotriesterase activity is highly dependent on its environment. Recent progress has been made using a mammalian chimera of PON1, but we provide here additional data showing that this chimera is biochemically different from hPON1. Besides, the chimera is expected to suffer from immunogenic issues.
dcterms:title
Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents
skos:prefLabel
Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents Organophosphate hydrolases as catalytic bioscavengers of organophosphorus nerve agents
skos:notation
RIV/00179906:_____/11:10118801!RIV12-MZ0-00179906
n5:predkladatel
n6:ico%3A00179906
n4:aktivita
n16:N
n4:aktivity
N
n4:cisloPeriodika
1
n4:dodaniDat
n15:2012
n4:domaciTvurceVysledku
n13:4185137 n13:4366964
n4:druhVysledku
n17:J
n4:duvernostUdaju
n12:S
n4:entitaPredkladatele
n14:predkladatel
n4:idSjednocenehoVysledku
218903
n4:idVysledku
RIV/00179906:_____/11:10118801
n4:jazykVysledku
n19:eng
n4:klicovaSlova
Paraoxonase; Phosphotriesterase; Acetylcholinesterase; Bioscavenger; Prophylaxis; Organophosphate poisoning
n4:klicoveSlovo
n7:Prophylaxis n7:Paraoxonase n7:Phosphotriesterase n7:Organophosphate%20poisoning n7:Acetylcholinesterase n7:Bioscavenger
n4:kodStatuVydavatele
NL - Nizozemsko
n4:kontrolniKodProRIV
[422D6BFF2CC8]
n4:nazevZdroje
Toxicology Letters
n4:obor
n11:FN
n4:pocetDomacichTvurcuVysledku
2
n4:pocetTvurcuVysledku
14
n4:rokUplatneniVysledku
n15:2011
n4:svazekPeriodika
206
n4:tvurceVysledku
Rochu, Daniel Novotný, Ladislav Jun, Daniel Loiodice, Mélanie Musilová, Lucie Nachon, Florian Trovaslet-Leroy, Marie Gillon, Emilie Masson, Patrick Renault, Fréderique Froment, Mare-Thérése Verdier, Laurent Brazzolotto, Xavier Mišík, Jan
n4:wos
000294940400004
s:issn
0378-4274
s:numberOfPages
10
n18:doi
10.1016/j.toxlet.2011.05.1041