The risk associated with organophosphorus nerve agents: from their discovery to their unavoidable threat, current medical countermeasures and perspectives

Abstract

The first organophosphorus nerve agent was discovered accidently during the de-velopment of pesticides, shortly after the first use of chemical weapons (chlorine, phosgene) on the battlefield during World War I. Despite the Chemical Weapons Convention banning these substances, they have still been employed in wars, ter-rorist attacks or political assassinations. Characterised by their high lethality, they target the nervous system by inhibiting the acetylcholinesterase (AChE) enzyme, preventing neurotransmission, which, if not treated rapidly, inevitably leads to seri-ous injury or the death of the person intoxicated. The limited efficacy of current anti-dotes, known as AChE reactivators, pushes research towards new treatments. Nu-merous paths have been explored, from modifying the original pyridinium oximes to developing hybrid reactivators seeking a better affinity for the inhibited AChE. An-other crucial approach resides in molecules more prone to cross the blood-brain bar-rier: uncharged compounds, bio-conjugated reactivators or innovative formulations. Our aim is to raise awareness on the threat and toxicity of organophosphorus nerve agents and to present the main synthetic efforts deployed since the first AChE reac-tivator, to tackle the task of efficiently treating victims of these chemical warfare agents.

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ORCID for Richard C.D. Brown: orcid.org/0000-0003-0156-7087

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