ReaChE

Poisoning by organophosphorus compounds (OP) is a serious worldwide public and military health issue. OP nerve agents present a threat in terrorist attacks and conflicts (civil war in Syria). The acute toxicity of OP agents results from their irreversible inhibition of acetylcholinesterase (AChE), which regulates cholinergic transmission in the peripheral and centralnervous system (CNS). Emergency treatment consists of administration of pyridiniumoxime antidotes for reactivation of AChE. Yet, none of them are effective reactivators of all OP-inhibited AChE and their efficiency against phosphoramidate (tabun) is limited. Moreover, these oximes do not readily cross the Blood-Brain-Barrier (BBB) to reactivate AChE in the central nervous system. Furthermore, none of them are efficient on OP-inhibited butyrylcholinesterase (BChE), the back-up enzyme to AChE. As a consequence, remediation of both acute and chronic intoxications of civilian and military populations by OP continues to be a challenge of paramount importance. Recent crystallographic studies provided insight into the interactions between reactivator molecules within the AChE active site, revealing that oxime antidotes possessing vastly improved efficiency could be discovered through rational design. Around the world, teams are engaged in the design of new reactivators of OP-inhibited AChE. Teams from the EU, gathered in this consortium, have made the most promising discoveries. Our goal is thus to develop more efficient antidotes and improve the medical treatment of poisoning by highly toxic OP. The objective of this innovative project is to discover new multifunctional reactivators of AChE- and BuChE inhibited by organophosphorus nerve agents. In order to successfully achieve the objective of this exciting and challenging European project, the skills of scientists with skills spanning several disciplines will be required. Critically, the consortium also has access to facilities able to work with OP nerve agents safely.