Naslov
Novel (bio)molecules for new organophosphate intoxication treatments

Autori
Radić, Zoran ; Sit, Rakesh K. ; Žunec, Suzana ; Maček Hrvat, Nikolina ; Kovarik, Zrinka ; Fokin, Valery V. ; Taylor, Palmer

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

Izvornik
Book of Abstracts of the Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014 / Katalinić, M. ; Kovarik, Z. - Zagreb : The Croatian Society of Biochemistry and Molecular Biology, 2014

ISBN
978-953-95551-5-1

Skup
The Congress of the Croatian Society of Biochemistry and Molecular Biology "The Interplay of Biomolecules", HDBMB 2014

Mjesto i datum
Zadar, Hrvatska, 24.09.2014. - 27.09.2014

Vrsta sudjelovanja
Pozvano predavanje

Vrsta recenzije
Domaća recenzija

Ključne riječi
alternative and complementary therapeutic approaches; oxime; RS194B; BBB penetration; bioavailability; RS2-33A

Sažetak
Persistent occurrence of potentially fatal human intoxications by pesticide and nerve agent organophosphates (OPs) is at present insufficiently counteracted by combined intramuscularly (i.m.) or intravenously (i.v.) administered therapy of atropine with nucleophilic pyridinium aldoxime acetylcholinesterase (AChE) reactivators. Therapeutic efficacy of pralidoxime (2PAM), obidoxime, and HI-6, the most commonly used reactivator aldoximes, is low in cases of massive OP pesticide or nerve agent exposure due to constant AChE reinhibition by the excess circulating OP. Those oximes do not penetrate Blood Brain Barrier, because of their charge, and can not reactivate OP-inhibited brain AChE. Finally, their bioavailability is generally low, and clearance is rapid, restricting useful administration modes to i.m. or i.v, inconvenient for rapid treatment of larger number of exposed individuals and populations. Owing to discovery and structure-activity refinements of several novel biologically active molecules, we were able, in recent years, to develop several alternative and complementary therapeutic approaches to treatment of OP intoxication. Our uncharged acetamide oxime RS194B shows low intrinsic toxicity, BBB penetration, and high bioavailability and efficacy upon oral administration. Our imidazole aldoxime RS2-33A efficiently reactivates intrinsic, tissue butyrylcholinesterase inhibited by OPs promoting in situ hydrolytic breakdown and removal of offending OPs in the exposed tissue. Finally, combined administration of our aging resistant AChE mutant with suitable novel oxime reactivator provides a useful means of hydrolytic clearing of fast aging nerve agent Soman from the exposed circulation. This research was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS), Grant Numbers U01 NS058046, R21NS072086 and R21NS084904.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA