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Target for potent first-strike influenza drugs identified
Date:8/3/2012

active site. They used X-ray crystallography, a widely employed analytical technique in which X-rays are directed through a crystallized protein, and the pattern of diffracted X-rays analyzed to deduce the structure.

Those studies confirmed that the warhead binds to the active site and also yielded new information on other surrounding pockets into which the compounds fit. The study also revealed which pockets are conserved among different strains.

"By analyzing the structure of the active site with the drugs bound to it, we have identified a number of pockets inside the active site of the protein," said study first author Rebecca DuBois, Ph.D., a postdoctoral research fellow in the St. Jude Structural Biology department. "We can use these structures to develop drugs that will specifically target certain pockets. Now that we know which pockets are really conserved, we can predict the best way to avoid the development of resistance by viral strains." Such resistance arises when a viral strain mutates to change the structure of a pocket, eliminating the ability of a drug to bind and block the active site.

Next, the researchers will use this information to design improved compounds that could be drug candidates for pre-clinical and clinical testing, according to White. The St. Jude team will work with a pharmaceutical company to further develop and test drugs, as part of a collaboration headed by Webb and supported by the National Institutes of Health.

Once in clinical use, the drugs would offer a valuable and widely used first strike against the virus. "You could use these drugs in any situation where a person is hospitalized for influenza," DuBois said. "Whether used alone or in combination with existing influenza medications, we would expect them to be highly effective."

Other viruses, such as Hantavirus and lymphocytic choriomeningitis virus, have polymerases that function like that of the influenza virus, DuBois said. Th
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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