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Military personnel in Salisbury, U.K., investigating the poisoning of Sergei Skripal by an exquisitely toxic Russian nerve agent.

Chris J Ratcliffe/Getty Images

U.K. attack shines spotlight on deadly nerve agent developed by Soviet scientists

One of the world’s deadliest poisons has emerged from the shadows after the audacious attempt earlier this month to murder a former Russian spy on U.K. soil. Scientists are racing to unravel why the mysterious nerve agent, concocted by Soviet chemists in the 1970s, is so potent. They fear its chemical structure will make finding an antidote unusually difficult, and that the compound could cause long-lasting health effects in those who survive exposure.

The drama began on 4 March, when Sergei Skripal and his daughter Yulia were discovered gravely ill on a park bench in Salisbury, U.K. In 2006, a Russian military tribunal had convicted Skripal, a former colonel in Russia’s foreign intelligence service, of treason. He settled in Salisbury after a spy swap in 2010.

U.K. investigators say they recovered residues of a nerve agent on clothing and belongings in Skripal’s home and at a pizzeria in which he and Yulia dined just before taking ill. U.K. officials accused Russia of perpetrating the crime, sparking a diplomatic row in which the United Kingdom expelled 23 Russian diplomats, drawing a reciprocal response from Russia. Meanwhile, as Science went to press, Skripal and his daughter remained in critical condition, and a responding police officer who was exposed was in serious condition.

The poison, U.K. investigators have revealed, is one of the Novichok, or “newcomer,” class of nerve agents the Soviet Union began developing nearly 50 years ago. In 1992, a former Soviet military chemist, Vil Mirzayanov, blew the lid off the clandestine program, claiming that the hitherto-unknown chemicals are several times more toxic than VX—until then, the deadliest known nerve agent. Even for an experienced chemist, “it would be extremely dangerous to try to make these compounds. You could easily get yourself killed,” says Mohamed Abou-Donia, a neurobiologist at Duke University in Durham, North Carolina.

The assassination attempt has thrust the Novichok agents back into the spotlight, but few experts in the rarefied area of chemical weapons defense are willing—or able—to shed further light on them. Information about the Novichok nerve agents is classified, says one U.S. military scientist who, like other U.S. government scientists, declined to speak with Science.

Mirzayanov’s 2008 memoir, State Secrets: An Insider’s Chronicle of the Russian Chemical Weapons Program, still gives the fullest picture of the Novichok agents. He writes that the compounds—perhaps five phosphoramidates in all, he told Science in an interview last week—are similar in structure to other nerve agents such as sarin, soman, and tabun (also a phosphoramidate). Like their cousins, they bind to acetylcholinesterase (AChE), an enzyme that dismantles the neurotransmitter acetylcholine when it is released into synapses. Without medical intervention, acetylcholine builds up in synapses, eroding muscle function and altering signals from the brain that control respiration and maintain blood pressure

Using data in the open literature, Zoran Radić, a chemist at the University of California, San Diego (UCSD), in recent days has explored how a Novichok named A-232, which is similar in structure to tabun and soman, forms a conjugate with AChE. (Some news reports have speculated that A-232 was used in the Skripal attack.) His modeling found that A-232 would nestle snugly in AChE’s active center, a narrow gorge in the enzyme. Like other nerve agents, it would form a stable covalent bond with a serine group in the cleft. All of the Novichok compounds would likely bind to AChE “in a very similar way,” based on structural information in Mirzayanov’s book, Radić says.

But, he notes, the compound has a structural feature that traditional nerve agents lack: an amine group studded with an extra proton. That’s bad news in two respects. For one, it could make it harder to identify the right antidote. All nerve agent victims are given atropine, which blocks muscarinic acetylcholine receptors. They are also given an oxime, a compound that can pry an agent out of AChE’s active center before the agent has “aged,” or bound irreversibly to the enzyme. An oxime’s effectiveness depends on a nerve agent’s structure and how it sits in the gorge. The exact configuration of the bond between A-232 and AChE might “compromise” oximes now approved for use in Europe and the United States, Radić says. Experimental oximes might be more effective, he says.

The second concern, Radić says, is that A-232’s alkyl amine group could enable it to target other enzymes in addition to AChE—and that raises the specter of severe symptoms arising months or years after exposure. Sarin and other organophosphates that lack an amine group may trigger a lasting neurotoxic syndrome with symptoms such as nightmares, memory deficits, muscle weakness, and depression.

New modeling studies of the nerve agent A-232 (ball and stick) depict its descent from acetylcholinesterase’s gorge opening (left) to a tight fit in the enzyme’s deep active center.

Z. Radic, using NanoPro VR by Nanome, Inc.

An observation in Mirzayanov’s memoir supports the possibility of lasting effects. He worked for 26 years in the Soviet Union’s premier chemical weapons lab, the State Scientific Research Institute for Organic Chemistry and Technology in Moscow. One day, he recounts, a rubber tube that piped A-232 into a spectrometer ruptured, exposing his colleague, Andrei Zheleznyakov, to minute amounts. Zheleznyakov felt dizzy and his vision blurred, and he collapsed on the way home that day—but survived. Months later, Mirzayanov says, Zheleznyakov developed difficulties concentrating and became withdrawn.

The amine group could also explain an intriguing detail about the Novichok compounds, says UCSD pharmacologist Palmer Taylor. Whereas other nerve agents are manufactured as liquids and dispersed as aerosols or vapors, these compounds, as ionized alkylamines, are thought to form a fine powder, a picture supported by reports of a powdery residue on personal belongings of Skripal and his daughter.

For terrorists, sarin would be the nerve agent of choice to inflict mass casualties because of its high volatility and rapid uptake in the body. But the Novichok compounds would be a formidable weapon for an assassin. Given their reported toxicity, ingesting or inhaling minuscule amounts could be fatal. On 18 March, U.K. Foreign Secretary Boris Johnson alleged that Russia has stockpiled Novichok agents precisely for use in assassinations.

If that’s true, whoever made the attempt on Skripal’s life botched the job. Investigators have hypothesized that the nerve agent was either introduced into Yulia’s suitcase before she boarded a flight from Moscow to London on 3 March, or blown into the air vents of Skripal’s BMW. Either way, the Skripals “were accumulating a very low dose,” presumably through the skin, Taylor says. “Not much blood is coming from the skin back to the heart.” The Skripals and the ill police officer may have survived thus far because they didn’t inhale or ingest larger doses of the agent.

Taylor says “it would be far too dangerous” for UCSD and other academic labs to make Novichok compounds. But they could safely study the nerve agent–AChE conjugate—if military labs were willing to share samples. Until that happens, any further insights into the Novichok compounds are likely to remain a secret guarded closely by both the Russian weaponeers and the Western military chemists seeking to counter them.