Naslov
Cholesterol oxime olesoxime (TRO19622) as a potential reactivator of nerve agent-inhibited cholinesterases

Autori
Kolić, Dora ; Šinko, Goran ; Jean, Ludovic ; Chioua, Mourad ; Dias, José ; Marco-Contelles, José ; Kovarik, Zrinka

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

Izvornik
FEBS Open Bio, 12 (Suppl. S1) / - : FEBS Press, 2022, 132-132

Skup
The Biochemistry Global Summit

Mjesto i datum
Lisabon, Portugal, 06.07.2022. - 14.07.2022

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Nerve agents, acetylcholinesterase, butyrylcholesterase, cholesterol oxime

Sažetak
Olesoxime (cholest-4-en-3-one) is a cholesterol derivative originally developed in 2007 as an experimental drug for treatment of a neurodegenerative disorder amyotrophic lateral sclerosis (ALS). Olesoxime exhibited broad neuroprotective effects in a number of cell and animal models, prompting further preclinical studies for other neurodegenerative diseases and phase II/III clinical trials for treatment of ALS and spinal muscular atrophy (SMA). Although olesoxime failed to achieve relevant therapeutic effects in clinical studies, its ability to cross blood-brain barrier, excellent safety and tolerability properties and presence of an oxime group reveal it as a potential antidote and centrally active reactivator for nerve agent-inhibited cholinesterases. Nerve agents (NA) are organophosphate compounds which irreversibly inhibit enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), serine esterases which hydrolize neurotransmitter acetylcholine. Disruption of their activity leads to uncontrolled signal transduction in synapses, cholinergic crisis and potentially life-threathening symptoms. In this work we evaluated the potency of olesoxime to reactivate AChE and BChE inhibited by NAs sarin, cyclosarin, tabun and VX and determined the binding affinity for the enzymes in terms of IC50 value. Molecular modelling enabled evaluation of oxime-enzyme interactions important for specificity and selectivity of both inhibition and reactivation. Olesoxime showed reactivation potential for cyclosarin-inhibited BChE, with the overall reactivation rate constant (kr) of 476 ± 12 M-1 min-1 comparable to that of standard oxime HI-6 (780 ± 30 M-1 min-1). We also tested the ability of olesoxime to assisst a clinically used standard oxime 2-PAM and the promising results highlight the undiscovered capability of olesoxime as a novel NA poisoning antidote.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Interdisciplinarne prirodne znanosti, Farmacija

POVEZANOST RADA