Novichok Nerve Agents

Nerve agents, also known as nerve gases, are synthetic organic chemicals designed to disrupt the communication between nerves and muscles. Exposure to these agents results in uncontrolled convulsions and, in severe cases, can lead to death due to asphyxiation or cardiac arrest. The disruption is primarily caused by the inhibition of acetylcholinesterase, a crucial enzyme that plays a vital role in nerve function in the body's muscles. At a neuromuscular junction, action potentials release acetylcholine, which binds to receptors on the muscle cell membrane, initiating muscle contraction. Acetylcholinesterase is essential for recycling acetylcholine, preventing its accumulation and maintaining the proper functioning of the neuromuscular junction. Irreversible inhibition of acetylcholinesterase, by for instance nerve gasses, leads to the buildup of acetylcholine, causing impaired neuromuscular junctions, which eventually leads to paralysis or convulsions.

During the Cold War era (1947-1991), heightened geopolitical tensions between the United States and the Soviet Union, and their respective allies, fueled a comprehensive competition. In contrast to the well-publicized race to the moon, the scientific advancements also included the clandestine development of chemical warfare agents by both sides, resulting in various agents targeting acetylcholinesterase. Of particular infamy is the USSR's fourth and final class of neurotoxins, known as newcomers or novichok. In the early 1970s, the State Institute for Scientific Research on Organic Chemistry and Experimental Technologies in the USSR undertook the development of novichok. Their task was to create undetectable, safer-to-use, and highly penetrative poisonous compounds, synthesizable without violating the Chemical Weapons Convention. The novichok program was shrouded in high-level secrecy, and its chemical structure was only revealed in 1995 by Russian scientists Lew Fiodorov and Vil Mirzayanov.

The hydrolysis of acetylcholine by acetylcholinesterase is highly efficient, degrading approximately 25,000 molecules of acetylcholine per second. Noteably, in acetylcholinesterase, substrates are not bound by a negatively charged amino acid in the anionic site, as in some other enzymes, but by interaction of 14 aromatic residues that form a long and narrow gorge leading to the catalytic site. Nerve gases aim to disrupt this hydrolysis through competitive inhibition, where the nerve gas molecule competes with acetylcholine for access to the enzyme's active site. More specifically, novichok agents act through covalent binding which occurs with a serine residue in the catalytic site of acetylcholinesterase. The compounds initially binds to the target enzyme through regular non-covalent bonds, similar to reversible inhibitors, stabilizing the covalent warhead so that it has sufficient reactivity to form a covalent bond with the enzyme's catalytic zone.