Natural enzyme may fight nerve agents, chemical weapons

Biochemist Dan S. Tawfik and his colleagues are working to turn a natural enzyme into a drug that can break down organophosphates and may be able to improve medical responsiveness to chemical disasters.

Organophosphates are chemicals that attack the nervous system by inactivating the enzyme acetylcholinesterase, which helps to regulate muscle contraction, brain function, heartbeat and breathing by controlling levels of acetylcholine. Without regulation, the chemical bombards nerve cells and muscles and can cause many symptoms, including respiratory failure and death in higher levels. Current drug treatments against organophosphates may not prevent against lasting damage to the nervous systems.

"Atropine aims at the symptoms of nerve agent exposure, and oximes minimize the damage after it has already begun," Tawfik said. "Our goal is to develop a drug that can intercept organophosphates before they cause damage."

The enzyme, which is called serum paroxonase, breaks down compounds derived from fats and occasionally hooks up with and destroyed organophosphates. The researchers theorized that they could amplify the behavior to turn PON1 into an organophosphate destroying machine. The research process has been going on for nearly a decade with constant mutation and testing of the enzyme.

Researchers have succeeded in making recombinant PON1 highly reactive against cyclosarin with efficiency 100,000 times higher than that of natural PON1.

In an experiment, mice injected with the enzyme an hour before exposure were more likely to survive than mice given the standard treatments of atropine/oxime.

One drawback of rePON1 is that it has a short time window of effectiveness and it must be made hardier to protect people against a nerve agent attack.

"We would like to see the enzyme sustained in the blood for several days and ideally two weeks," Tawfik said.

The research is supported by the National Institutes of Health Countermeasures Against Chemical Threats program.

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