At the Ohio State Center for Catalytic Bioscavenger Medical Defense Research II, chemists Thomas J. Magliery and Christopher M. Hadad lead a team that employs sophisticated methods of protein engineering, high-throughput screening and computational chemistry. Their goal: harness the body’s own defenses to counteract nerve agents and create new types of antidotes for exposure to pesticides and other poisons.
Nerve agents are chemicals that attack the nervous system, causing paralysis and seizures and – ultimately – killing the victim through asphyxiation. They do so by bonding with the enzyme acetylcholinesterase, thereby destroying its activity so that chemical messages from the brain to the rest of the body are transmitted without regulation.
Once attached to the enzyme, nerve agents can’t be removed. So the researchers are focusing on ways to stop the deadly chemicals before they can attach in the first place.
“Fortunately, there are enzymes already in human blood that can deactivate these agents,” said Magliery, co-leader of the Ohio State center. “We just have to engineer them to be more efficient, and we have to be able to produce and formulate them as drugs.”
Hadad, who leads an effort to model the chemical structure of candidate enzymes on the powerful parallel supercomputer systems at OSC, described one of the main challenges. “In nature, each enzyme generally has only one function – one thing that it does very well,” he said. “But we need an enzyme that will deactivate many different nerve agents. We need one molecule that can do it all.”
The ideal enzyme would remain active for days or weeks at a time, pulling toxic agents from the body over and over again. It could be administered as an antidote immediately after an attack, or as an inoculation against future attacks.
Soldiers and first responders are among the likely recipients of such a preventive dose, but so are people whose jobs regularly expose them to nerve agents, such as pesticides. Household pesticides pose the same dangers, so an enzymatic drug could save lives in poison control centers as well.
The Center, funded by a $7.5 million award from the National Institutes of Health, is a collaboration between The Ohio State University, the U.S. Army Medical Research Institute of Chemical Defense at Aberdeen Proving Ground, Md., and the Weizmann Institute of Science in Israel.
Project Lead: Thomas Magliery and Christopher Hadad, The Ohio State University
Research Title: Computational modeling of human paraoxonase activity
Funding Source: National Institutes of Health