Engineered Enzymes: A New Way to Detox

Courtesy Photo | Image courtesy of U.S. Army RDECOM  

FORT BELVOIR, VA, UNITED STATES

08.21.2018

Courtesy Story

Defense Threat Reduction Agency's Chemical and Biological Technologies Department

GERMANY, 1936 – Dr. Gerhard Schrader was developing pesticides to reduce the Third Reich’s reliance on food imports. Instead, the mixture he synthesized sent him to the hospital and killed not only insects, but mice, rats and other primates. As a pesticide, the organophosphorus (OP) compound was a failure, but to the German military, he discovered a game-changing chemical weapon. Now, as these weapons continue to threaten our warfighters, the Defense Threat Reduction Agency’s Chemical and Biological Technologies Department is leading efforts to mitigate these deadly agents.

Once an OP nerve agent enters the body, it binds to a critical enzyme called acetylcholinesterase. Acetylcholinesterase regulate muscle and nerve function, causing both seizures and vomiting. Current therapies are only symptomatic treatments, leaving our warfighters vulnerable.

With DTRA support, researchers from the U.S. Army RDECOM engineered a new version of the organophosphorus acid anhydrolase (OPAA) enzyme to prevent and treat nerve agent poisoning. These new catalytic enzymes detoxify the agents on the skin or in the blood before they bind to acetylcholinesterase, thereby preventing poisoning. OPAA is fast-acting, and a single molecule can detoxify more than 1,000 molecules of agent per second under physiological conditions. Mark Guelta, Melissa Dixon and Steve Harvey of U.S. Army RDECOM recently received a U.S. patent for the engineered enzyme.

There are, however, challenges associated with the use of enzymes as countermeasures, which the U.S. Army RDECOM team is currently addressing. Enzymes tend to be very specific in their activity, working well on one compound and not as effectively on variations of the compound. Nerve agents are chiral molecules, which means they are a mixture of two or more mirror-image structures, half of which are more toxic than the other. OPAA enzymes are naturally-occurring and typically prefer the less toxic structures. Therefore, they need to be engineered in order to efficiently detoxify all structures.

As shown in the figure, an engineered version of OPAA (OPAA-FL) has between two and 10 times the catalytic efficiency of the original, making it the most efficient enzyme reported for several of these agents.
In conjunction to the U.S. Army RDECOM effort, researchers from Texas A&M University are focusing efforts on developing the phosphotriesterase (PTE) enzyme. The PTE enzyme is particularly efficient at catalyzing the detoxification of other types of nerve agents, providing a new treatment method.

For more than 80 years, OP nerve agents have been a danger to both warfighters and civilians. DTRA, in partnership with U.S. Army RDECOM and Texas A&M University, is on the horizon of bringing new countermeasures for nerve agent exposure. This will allow for building a more lethal force while ensuring U.S. troops can quickly restore readiness in the event of exposure.

DTRA CB POC: Alison E. Director-Myska, Ph.D.; [e-mail] ECBC POC: Steve Harvey, Ph.D.; [e-mail]

• Date Taken: 08.21.2018
• Date Posted: 08.21.2018 10:30
• Story ID: 289621
• Location: FORT BELVOIR, VA, US