Naslov
The OP Wars - A New Hope: effectiveness of novel oxime antidotes in organophosphate poisoning

Autori
Kolić, Dora ; Kovarik, Zrinka

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

Izvornik
7th Faculty of Science PhD Student Symposium - Book of Abstracts / - Zagreb : Prirodoslovno-matematički fakultet Sveučilišta u Zagrebu, 2023, 48-48

ISBN
978-953-6076-01-7

Skup
7th PhD Student Symposium 2023

Mjesto i datum
Zagreb, Hrvatska, 21.04.2023. - 22.04.2023

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
Organophosphorus compounds ; butyrylcholinesterase ; oxime ; bioscavenger

Sažetak
Organophosphorus (OP) compounds were developed in Germany in the 1930s as pesticides and as warfare nerve agents (NA) since they were found to have a lethal effect on insects and mammals. Although 193 states signed the Chemical Weapons Convention in the 1997, which prohibits the production and use of NA, and they are slowly being replaced as pesticides by newer less hazardous formulations, OP compounds still pose a threat in terrorist attacks and they account for more than three million accidental or deliberate cases of poisoning a year worldwide [1]. OP exert their toxic effect primarily by inhibiting acetylcholinesterase (AChE), an essential enzyme for neurotransmitter acetylcholine (ACh) hydrolysis, and related enzyme butyrylcholinesterase (BChE). AChE inhibition leads to accumulation of ACh in the nerve system and overstimulation of cholinergic receptors in the entire body, which induces symptoms like nausea, convulsions, loss of consciousness, respiratory failure and ultimately death, while poisoning survivors additionally suffer from considerable irreversible neurological complications [2]. Emergency treatment of acute OP poisoning aims to recover the activity of the inhibited enzyme by pyridinium oxime reactivators that displace the phosphorus moiety bound within the enzyme catalytic site. Their disadvantages are that they generally weakly reactivate BChE, do not reactivate AChE in the brain due to their positive charge and the subsequent inability to cross the blood-brain barrier, and they are not universal reactivators of all NA and pesticides [3]. The goal of our study is to identify and kinetically characterize novel oxime antidotes which would efficiently reactivate BChE and potentially establish a pseudocatalytic scavenger system which could detoxify OP in the bloodstream before they reach target tissues [3]. Structurally various novel oximes were tested as reactivators of NA sarin-, cyclosarin-, VX- and tabun-inhibited human AChE and BChE, as well as chosen OP pesticides. For several oximes BChE reactivation potency was showed to be superior when compared to the standard oximes used in medical practice, and binding affinities of phosphylated BChE for some oximes increased up to 1900-fold compared to pyridinium oximes, establishing them as promising candidates for future treatment development.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti, Farmacija

POVEZANOST RADA