Naslov
Catalytic soman scavenging by non-aging acetylcholinesterase mutant assisted with novel site-directed aldoximes

Autori
Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Katalinić, Maja ; Sit, Rakesh K. ; Paradyse, Alexander ; Zunec, Suzana ; Fokin, Valery V. ; Taylor, Palmer ; Radic, Zoran.

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
The FEBS Journal Volume 282, Supplement 1 ; Special issue, 40th FEBS Congress, The Biochemical Basis of Life / - , 2015, 171-171

Skup
40th FEBS Congress, The Biochemical Basis of Life

Mjesto i datum
Berlin, Njemačka, 04.06.2015. - 09.06.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
nerve agents, AChE mutant, human whole blood, bioscavenger, oxime

Sažetak
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.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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