Nerve Agent Antidotes and Novichok Issues

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“Circles appeared before my eyes: red and orange. A ringing in my ears. I caught my breath. And a sense of fear: like something was about to happen. I sat down on a chair and told the guys, ‘It’s got me,'” This was Andrei Zhelenznyakov’s description of his experience, as the first known person to have ever been directly exposed to one of the notorious Novichok Nerve Agents in 1987. While working as a military researcher on a highly classified chemical weapons project for the Soviets, Zheleznyakov’s fume hood malfunctioned, leaving him directly exposed to the dangerous chemical compound which forms a part of a grouping that Russian scientists have called “the deadliest nerve agents ever made.” According to the Guardian, “By 1992 (…) the nerve agent had gutted Zheleznyakov’s central nervous system. Less than a year later he was dead, after battling cirrhosis, toxic hepatitis, nerve damage and epilepsy.”

In more recent times, the UK media has been abuzz with stories regarding the bizarre circumstances surrounding the chemical attack on Yulia Skripal and her father Sergei in March 2018. The two collapsed while eating dinner at a restaurant in the British town of Salisbury and rushed to the hospital where they were treated for presumed nerve agent poisoning. Shortly thereafter, the UK media began publishing an article after article, some claiming that following biological sampling the culprit was Novichok – the same incredibly deadly Soviet nerve agent that Zhelenznyakov was exposed to in 1987.

Following this high profile attack in the UK the deadly agents have re-emerged as premier global chemical threats. Still, despite the media recognition of the Novichok agents as tangible real-world threats, the advancement of antidotes to protect against them has been inadequate. There are a few reasons for this, but one large reason has to do with the uncertainty surrounding the structure of the Novichok agents as well as the belief that, although not precisely known, the Novichok agents likely have a different structure than several of the other well-known organophosphorous nerve agents.

A myriad of potential structures have been proposed for Novichok candidates, with a wide variance among them. However, all of the structures seem to suggest that the Novichok compounds possess a standard organophosphorus core which is seen in the familiar G-series nerve agents that were first synthesized by the Germans starting in 1936. The Novichok agents are believed to have certain substitutions, leading the Novichok compounds to be commonly depicted as a phosphoramidates or phosphonates, usually fluorinated. Due to the mechanism of action of standard oxime antidotes, however, this significant variance in the chemical structure of the Novichok compounds negatively impacts the efficacy of standard treatments. This is a large issue drug developers face in adapting the current nerve agent antidote efforts to the unique idiosyncrasies of a potential phosphoramidate.

Read the full story for free in the NCT Magazine!

Read an article on Novichok facts here!