Mayo Clinic researcher pioneers new approach to protect humans against chemical warfare agents.
Chemical warfare agents have been used by nations for almost 100 years, and “antidotes” to some of these chemicals have been part of a soldier’s kit for much of the last 60 years. But, given that these antidotes are very limited in their effectiveness, a researcher at the Mayo Clinic campus in Florida has been working to design a new drug that, for the first time, will successfully protect soldiers, as well as civilians, against the deadly agents.
This summer, pharmacologist Terrone Rosenberry, Ph.D., presented research at the 11th International Meeting on Cholinesterases that he says brings him closer to his goal. The biennial meeting, held this year in Kazan, Russia, is devoted in part to decoding the way chemical warfare agents assault the human nervous system.
His work, funded by the Department of Defense and the National Institutes of Health, is leading to a concept in which soldiers would be able to use a prophylactic drug to protect themselves from organophosphates, the active components in most chemical warfare agents, before they are even exposed. Today’s antidotes are used after an attack to try to reverse the toxic effects of the chemical agents and are not very effective, according to Dr. Rosenberry. Several deaths occurred when the agent tabun was used by Iraq in the Iran-Iraq war in 1984, and a number of civilians were killed by the agent sarin in terrorist attacks on the Tokyo subways in 1995.
“As the world continues to stockpile chemical warfare agents, new strategies to diffuse this threat are becoming more and more important,” he says. “A lot of ideas have been pursued over the past half century that have not really panned out to be more useful than what we already have for antidotes. I believe our research points to a new way.”
In his long-standing effort to diffuse the damage these agents cause, Dr. Rosenberry studies a particular enzyme, acetylcholinesterase (AChE), which controls communication between some nerve cells. This communication is inactivated by organophosphates — the active substance in both human chemical warfare agents and some pesticides.
Specifically, AChE helps break down the neurotransmitter acetylcholine, which passes from the end of nerves to muscle cells. Because nerves must stimulate muscle contraction rapidly, signaling by acetylcholine occurs up to 120 times each second, and the job of AChE is to destroy the neurotransmitters as soon as they stimulate muscle cells. The enzyme grabs acetylcholine before it can stimulate another neurotransmitter receptor on muscle, and then breaks it down with water.
Organophosphates function by binding to AChE and stopping the enzyme from degrading acetylcholine, which leads to an overabundance of the neurotransmitter in the nerve synapse — and constant activation of acetylcholine receptors on muscle cells. “What happens then is that the receptors break down because there is too much acetylcholine and, within a few minutes, muscles lose the ability to respond to the neurotransmitter,” Dr. Rosenberry says. “Muscles then become paralyzed, and the brain begins to seize, often resulting in death.”
Antidotes in use today try to soak up the organophosphates that bind to AChE, but too much toxicity and muscle damage has already often occurred, Dr. Rosenberry says.
His research leads to a different strategy. By studying the structure of AChE, he is seeking a way to attach a small molecule “filter” to the enzyme that would block and segregate organophosphate chemicals, which tend to be large, but would still allow AChE to degrade acetylcholine. The chemical warfare agents would be rendered harmless.
Dr. Rosenberry’s presentation at the conference in Russia, as well as his prior research studies, are trying to establish an overall proof of concept that this new strategy is viable. He and his colleagues are now designing potential drugs by computer modeling and looking for natural products that could provide such an organophosphate filter.
“If we can accomplish our goal — and our studies suggest a good possibility for doing that — then it may be possible to administer these new therapies with confidence that you can minimize the effects of chemical nerve agents,” says Dr. Rosenberry.
“Of course, we have much work to do, but we also have a new and exciting avenue with which to defuse the mountains of chemical warfare agents stored around the world,” he says.