Naslov
Catalytic soman scavenging by Y337A/F338A acetylcholinesterase mutant assisted with novel site-directed aldoximes

Autori
Kovarik, Zrinka ; Hrvat Maček, Nikolina ; Katalinić, Maja ; Sit, Rakesh K. ; Paradyse, Alexander ; Žunec, Suzana ; Musilek, Kamil ; Fokin, Valery V. ; Taylor, Palmer ; Radić, Zoran

Izvornik
Chemical research in toxicology (0893-228X) 28 (2015), 5; 1036-1044

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
nerve agent toxicity ; fresh-frozen plasma ; in-vitro ; pyridinium oximes ; serum paraoxonase ; active-center ; reactivation ; protection ; butyrylcholinesterase ; organophosphates

Sažetak
Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of the soman-acetylcholinesterase (AChE) conjugate known as. aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE ate ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE Mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown, in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, satin, and paraoxon, inhibition. We here demonstrate that ex vivo, in whole human blood, 1 mu M somari was detoxified within 30 min when supplemented with 04 mu M Y337A/F338A AChE and 100 yM HI-6. This combination was further tested in vivo, Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of 42 pyridinium aldoximes, and 5 imidazole 2-aldoxime N-propylpyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2-3-fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA