Naslov
Introduction to the workshop on “Reactivators and Medical Countermeasures against Nerve Agents and Pesticides”

Autori
Kovarik, Zrinka

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

Izvornik
Arhiv za higijenu rada i toksikologiju Vol.69(3) / - , 2018, A33-A33

Skup
Workshop on Reactivators and Medical Countermeasures against Nerve Agents and Pesticides

Mjesto i datum
Zagreb, Hrvatska, 14.05.2018. - 15.05.2018

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
cholinesterase ; nerve agents ; organophosphorus compounds ; poisonings, terrorism

Sažetak
In the last four years we have been focused on realization of the planned research within the HrZZ Cholinesterase project. Our main goal was to develop more efficient antidotes and improve the treatment of highly toxic organophosphorus (OP) compound poisoning. OP compounds used as pesticides account for over 3, 000, 000 cases of poisoning per year worldwide. Furthermore, OPs known as nerve agents (soman, sarin, tabun, VX) present a threat in terrorist attacks and conflicts, as was the case recently in Syria, Malesia and UK. The main targets of OP compounds are acetylcholinesterase (AChE), the essential enzyme in neurotransmission, and butyrylcholinesterase, its back-up enzyme. However, the antidotes currently in use, which act as reactivators of inhibited AChE, were empirically synthesized before the two enzyme’s crystal structures were resolved. Due to structural requirements, their binding affinity and reactivation rate have not been well-balanced. We combined several approaches, including computational and experimental studies of cholinesterase interactions with a wide range of ligands defining favourable characteristic for potential new antidotes, in silico design of novel compounds that direct the subsequent synthesis of selected leads, and thorough in vitro and in vivo experimental evaluation. Moreover, we demonstrated a feasible approach to the development of an oxime-assisted catalytic bioscavengers of soman, tabun and VX based on AChE mutants in combination with its efficient reactivator. Ultimately, the oxime-assisted catalytic scavenging of the nerve agents in mice improved therapeutic outcomes preventing lethality and resulted in a delayed onset of toxicity symptoms.

Izvorni jezik
Engleski

POVEZANOST RADA