Naslov
Structural analogs of the HI-6 oxime are the most potent reactivators of the soman-inhibited AChE mutant that resists ageing

Autori
Maček, Nikolina ; Radić, Zoran ; Taylor, Palmer ; Kuča, Kamil ; Kovarik, Zrinka

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

Izvornik
14th Medical Chemical Defence Conference 2013 "Translation of experimental research for improved treatment of chemical warfare agent poisoning" : abstracts / - , 2013, 60-60

Skup
Medical Chemical Defence Conference "Translation of experimental research for improved treatment of chemical warfare agent poisoning" (14 ; 2013)

Mjesto i datum
München, Njemačka, 23.04.2013. - 25.04.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
AChE; soman; reactivators; oximes; mutants

Sažetak
The toxicity of organophosphorus compounds (OPs) caused by the phosphylation of AChE active center serine results in the accumulation of the neurotransmitter acetylcholine (ACh), consequently causing seizures and in severe cases even death. Immediate therapeutic treatment usually consists of a combined administration of anticholinergic drugs and an oxime as the reactivator of AChE. The nerve agent soman is an extremely toxic OP and acts almost instantaneously. AChE inhibited by soman is less accessible to reactivation due to the rapid dealkylation phenomenon of the soman- AChE conjugate called ˝ageing˝. Earlier studies have shown that amino acid substitutions in the AChE active center could slow down ageing and enable oximes to reactivate the soman-AChE conjugate prior to its ageing. The human AChE mutant hY337A/F338A combines the increase in the active center accessibility of the Y337A mutant to oximes with the ageing resistance of the F338A mutation. Therefore, its administration to potentially exposed individuals in the form of a pre-treatment is suggested so that it acts as a pseudo catalytic bioscavenger. Nevertheless, apart from ageing, the oxime reactivation of the soman- AChE conjugate is effected by the steric hindrance of the soman’s alkoxy side chain which limits the effectiveness of pyridinium oximes. In the 1970s, it was found that potential reactivators have an oxime group in the ortho position on the pyridinium ring and/or a CH2-O-CH2 linking chain between two pyridinium rings. Oxime HI-6, containing both characteristics, especially stood out. The search for novel oxime reactivators is still ongoing. We tested a number of novel and some previously known oximes in order to challenge the 1970s findings. Nevertheless, among all the tested oximes, HI-6 and its structural analogs, when taking kobs as the main criterion, have proven to be the most potent reactivators of the soman-Y337A/F338A conjugate. Acknowledgments: This work was supported by the NIH (Grant No. U01 NS058046) and by the Croatian Ministry of Science, Education and Sports (Grant No.022-0222148-2889).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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