In the first phase, Tawfik and his team, including research fellow Dr. Moshe Goldsmith and postdoctoral student Dr. Rinkoo Devi Gupta, induced a number of mutations in PON1 some random and others directed at key sites on the enzyme. To identify the most effective PON1 mutants, the scientists joined forces with Yacov Ashani of the Structural Biology Department.
The method that the scientists developed closely mimics what happens in the body upon exposure to nerve agents: They put the acetylcholinesterase in a test tube together with a specific mutant PON1 enzyme that they wanted to test, and added a small amount of nerve agent to it. In cases where the acetylcholinesterase continued to function properly, it could be concluded that PON1 rapidly degraded the nerve agent before it was able to cause damage to the acetylcholinesterase.
After several rounds of scanning, the scientists succeeded in indentifying active mutant enzymes, which are able to break down the nerve agents soman and cyclosarin effectively before any damage is caused to the acetylcholinesterase. These mutant enzymes have been structurally analyzed by a team of scientists from the Structural Biology Department, which included Profs. Joel Sussman and Israel Silman, and research student Moshe Ben-David. Further experiments have shown that when these enzymes were given as a preventative treatment before exposure, they afforded animals near-complete protection against these two types of nerve agents, even when exposed to relatively high levels.
The scientists plan to further expand the scope and develop preventive treatment that provides protection against all types of existing nerve agents. They are also trying to develop enzymes with high enough efficiency to be able to very rapidly break down the nerve agent so they could be used to prevent the lethal effects of nerve agents by injection imme
|Contact: Yivsam Azgad|
Weizmann Institute of Science