Catalytic soman scavenging by non-aging acetylcholinesterase mutant assisted with novel site-directed aldoximes (CROSBI ID 651668)
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Podaci o odgovornosti
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Katalinić, Maja ; Sit, Rakesh K. ; Paradyse, Alexander ; Zunec, Suzana ; Fokin, Valery V. ; Taylor, Palmer ; Radic, Zoran.
engleski
Catalytic soman scavenging by non-aging acetylcholinesterase mutant assisted with novel site-directed aldoximes
Poisoning caused by the nerve agent soman calls for immediate treatment, which usually consists of a combined administration of an anticholinergic drug and an oxime as the reactivator of the enzyme acetylcholinesterase (AChE). However, due to the rapid dealkylation of the soman-AChE conjugate known as aging, there are no effective reactivators or satisfactory antidotal therapies for soman exposure. The efficacy of the recommended nerve agent bioscavenger, butyrylcholinesterase, administered intravenously, is limited by strictly stoichiometric scavenging. To over- come this gap, we tested ex vivo in human blood and in vivo in soman-exposed mice, the capacity of the aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a pseudo-catalytic bioscavenger of soman. The pyridinium oxime, HI-6, was previously shown in vitro to be the most efficient reactivator of this mutant following soman, as well as VX, cyclosarin, sarin and paraoxon inhibition. Here, we demonstrated that ex vivo 1 µM of soman was hydrolyzed within 30 minutes when supplemented with 0.5 µM Y337A/F338A and 100 µM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in a delayed onset of poisoning symptoms. Furthermore, to identify a more efficient oxime than HI-6, we screened novel imidazole-pyridinium 2- aldoximes, for reactivation of soman-inhibited Y337A/F338A. Oxime RS2-170B [4-carbamoyl-1-(3- (2-((hydroxyimino)methyl)-1H-imidazol-1- yl)propyl)pyridiniumshowed the reactivation superiority over HI-6. This could be due to the smaller imidazole ring, as indicated by computational molecular models, which may allow a more productive angle of nucleophilic attack.
nerve agents, AChE mutant, human whole blood, bioscavenger, oxime
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Podaci o prilogu
171-171.
2015.
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objavljeno
Podaci o matičnoj publikaciji
The FEBS journal
1742-4658
Podaci o skupu
40th FEBS Congress, The Biochemical Basis of Life
poster
04.06.2015-09.06.2015
Berlin, Njemačka