Nerve Agent Antidotes and Novichok Issues
Current Efforts To Improve Organophosphate Antidotes may not Immediately Translate to Novichok Solutions
By: Jack J. Fernandes
CEO & Founder of Regenica Biosciences Inc.
"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.
Organophosphate Poisoning, Generally
Exposure to organophosphates, with Novichok being no exception, can lead to the inhibition of acetylcholinesterase (AChE), a build-up of acetylcholine in the body, and potentially even death. Every year there are over two million suicidal cases and over one million accidental cases of organophosphate poisoning from insecticides worldwide. Furthermore, terrorist attacks in the past have involved different nerve agents to induce organophosphate poisoning. Current antidotes can reactivate the organophosphate-inhibited Acetylcholinesterase in the blood and peripheral tissue, but they are often incapable of crossing the blood-brain barrier to reactivate the inhibited AChE in the brain. Thus, there has been a strong need for an antidote capable of efficient reactivation and blood-brain barrier penetration.
My company, Regenica Biosciences, has focused on bringing a response to this call into the market. Our lead compound is a novel antidote that is highly effective and minimally toxic, and most importantly able to cross the blood-brain barrier (BBB) to treat any immediate organophosphate toxicity throughout the brain and body while preventing the persisting seizures that recur following exposure. The hydroxyimino-acetamido alkylamine antidote has a 2.5-fold higher average AChE reactivation rate constant (kobs) compared to the current antidote standard, 2-PAM. In vivo mice results show that the antidote is less toxic than 2-PAM, and comparable to HI-6, which is among the least toxic antidotes available on the market as of 2019. The compound and its analogues are nucleophilic and neutral, specifically designed to rapidly penetrate the blood-brain barrier with sustained half-life and to access the central nervous system. The ionization equilibria of these compounds favor oral bioavailability, making the antidote a versatile solution to protecting against several different nerve agents.
This profile makes our lead antidote ideal for treating organophosphate poisoning from accidental and intentional exposure to insecticides as well as from exposure to nerve agents, such as in terrorist attacks. This is great news, except where Novichok is concerned.
At Regenica, one of our biggest goals has been to tackle the unique issue of Novichok and provide the world with a safe, reliable, and efficient antidote to this tricky threat. As aforementioned, our lead compound has demonstrated antidotal activity against several historically weaponized nerve agents, but it has been primarily meant for protection against a class of nerve agents categorized as methylphosphonates, which include nerve agents such as sarin, soman, VX and cyclosarin. Our lead compound and its analogues have also shown efficacy against phosphorate pesticides that covert to the oxons, such as chlorpyrifos oxon and paraoxon, which could prove useful for agricultural workers who are exposed to these chemicals frequently.
However, traditional nerve agent antidotes and their analogues appear to be not as effective against the phosphoramidate classiciation of organophosphates, such as the nerve agent tabun. The Novichok compounds that were brought in from Russia are classified as phosphoramidates, alongside Tabun, and thus they will require their own uniquely tailored antidotes to provide adequate efficacy.
Since the recent Novichok poisonings occurred near Porton Down in Salisbury, this group has taken the lead in Novichok detection and characterization. As a company, we are in discussions with researchers from Porton Down, hoping to facilitate a robust relationship in order to improve the pace at which our antidotal innovation can occur. It has never before been more clear that private sector companies must work closely and actively engage with public sector organizations to facilitate collaborative research to advance antidotes and defense protocols. Collaboration based on free exchange of information about the Novichoks will be integral to advancing the world’s preparedness and protection efforts and providing new sets of treatments to the uniquely positioned Novichok compounds.