Naslov
Allosteric interactions in organophosphate inhibition and oxime reactivation of ihibited cholinesteraseses

Autori
Kovalevsky, Andrey ; Blumenthal, Donald ; Cheung, Jonah ; Gerlits, Oksana ; Cheng, Xiaolin ; Fajer, Mikolai ; Kovarik, Zrinka ; Taylor, Palmer ; Radić, Zoran

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

Izvornik
XVth International Symposium on Cholinergic Mechanisms : Abstract book / - , 2016, 83-83

Skup
International Symposium on Cholinergic Mechanisms (15 ; 2016)

Mjesto i datum
Marseille, Francuska, 16.10.2016. - 20.10.2016

Vrsta sudjelovanja
Predavanje

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
x-ray structures, OP biscavengers, room temperature

Sažetak
Acetylcholinesterase (AChE ; EC 3.1.1.7), is a primary target in acute intoxication by nerve agents and organophosphate (OP) pesticides that covalently inhibit its remarkably high catalytic activity. The high worldwide incidence of OP poisoning causing more than 200, 000 fatalities annually obviates a need for more effective therapies of OP intoxication. Our approach is to develop more efficient oxime reactivators of both AChE and butyrylcholinesterase (BChE ; EC 3.1.1.8) inhibited by OPs. Design of novel, accelerated oxime reactivators of OP-conjugated tissue AChE yields reactivation acceleration achieved by improved understanding of human AChE (hAChE) structure at the room temperature and in aqueous solution guided by advanced biophysical studies and computational molecular dynamics simulations. Here, we demonstrate previously undetected changes in hAChE solution structure, remote from the active center, upon OP inhibition and oxime reactivation by using solution small-angle X-ray scattering profiles of hAChE. We have also resolved first room temperature (22 ºC) X-ray crystal structures of hAChE in complex with oximes and other ligands, that reflect their physiological interactions more accurately than X-ray structures conventionally determined at -173 ºC (100 K). Additionally, we focus on catalytic detoxification of offending OP toxicants in exposed tissue by oxime assisted OP bioscavengers before these inhibit tissue AChE. We developed both BChE based and mutant hAChE based, oxime assisted, OP bioscavengers and determined their X-ray structure in order to rationally improve their detoxification efficacy. The advanced hAChE mutant-based and BChE-based bioscavenging, have demonstrated fast in vitro and ex vivo OP detoxification and improvement in survival of nerve agent OP-exposed mice upon treatment with bioscavengers, even in exposure to the fastest-aging nerve agent soman. Allosteric enhancement of the BChE-based oxime assisted OP bioscavenging, accelerated by small molecule allosteric modulators yielded in our hands impressive in vivo improvements of oxime antidotal therapies of OP exposed mice. In conclusion, we provide here the evidence that tertiary structures of both AChE and BChE macromolecules posses’ intrinsic potential for allosteric regulation of significant importance for structure-based developed therapies of OP intoxication. Supported by the NIH CounterACT Program, the NIH Office of the Director, and the National Institute of Neurological Disorders and Stroke, grant numbers 1U01NS083451, R21NS072086 and 1R21NS084904.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA