Naslov
Oxime-assisted detoxification of nerve agents by a human AChE mutant

Autori
Maček Hrvat, Nikolina ; Radić, Zoran ; Taylor, Palmer ; Kovarik, Zrinka

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

Izvornik
Knjiga Sažetaka Mini simpozija Sekcije za medicinsku i farmaceutsku kemiju. Zagreb, Hrvatska, 2017. / - , 2017, 3-3

Skup
Mini simpozij Sekcije za medicinsku i farmaceutsku kemiju

Mjesto i datum
Zagreb, Hrvatska, 17.10.2017

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
cholinesterases, antidotes, bioscavengers, nerve agents

Sažetak
In the event of nerve agent poisoning immediate medical intervention is vital due to the deadly effects caused by acetylcholinesterase (AChE, EC 3.1.1.7) inhibition. The outcome is especially adverse in case of soman, owing to the very rapid dealkylation (ageing) of the soman-AChE conjugate. Nowadays, exogenously administered human enzymes like butyrylcholinesterase or AChE mutants are investigated as supplemental bioscavengers with the intention of developing prophylaxis for first responder use. Our in vitro studies have shown that HI-6 is an efficient reactivator of the human AChE mutant Y337A/F338A upon VX and soman inhibition and that the soman-Y337A/F338A conjugate has a 50 min half time of aging (vs. 2 min for wild-type human AChE). Along these lines, we tested the bioscavenging potential of the Y337A/F338A AChE mutant when combined with HI-6 for samples of whole human blood treated with VX or soman. Our findings indeed indicated that blood cholinesterase activity was completely restored by this catalytic oxime- assisted scavenging system within 10 min in case of exposure to a 10-fold VX excess (with regard to the mutant) and treatment with 1 mM HI-6. A similar bioscavenging action was also noticeable in case of soman exposure. Therefore, we have shown that VX and soman detoxification is possible and effective in whole human blood by turnover cycles of Y337A/F338A inhibition and reactivation by HI- 6. This combination scavenging system affords a potentially significant improvement in the treatment of VX and soman exposure. Moreover, further in vivo experiments on mice supported the ex vivo results showing that catalytic VX and soman scavenging improved therapeutic outcomes by delaying the onset of toxicity symptoms and preventing lethality. Supported by the NIH (Grants: U01 NS058046, R21NS072086, R21NS084904) and by the Croatian Science Foundation (Project 4307).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA