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Target for potent first-strike influenza drugs identified
Date:8/2/2012

andidates," said Stephen White, DPhil., chair of the St. Jude Structural Biology department and the study's senior author. "It is a good target because these polymerases are essentially the same across many strains, and also because the virus absolutely needs the polymerase to make copies of itself. The polymerase doesn't have very many similarities to other polymerases in cells, so it should be fairly specific for the flu polymerase."

By contrast, White said, viruses have readily developed resistance to antiviral drugs currently on the market, because they target viral proteins that a virus can readily alter without compromising its viability.

In the study, the scientists drew on previous research that had mapped the molecular structure of the endonuclease, which revealed its active site. This is the region in which the chemical reaction of snipping apart mRNA molecules occurs. To test the compounds, the St. Jude researchers engineered a version of the endonuclease designed to enable them to readily determine whether compounds would block the active site.

They tested inhibition of the active site by six compounds known or predicted to block the active site. Three of the compounds had been developed earlier by Merck as viral inhibitors, and although they had some effectiveness, their properties ruled them out as drug candidates. Three other compounds predicted to block the site were synthesized in the laboratory of study co-author Thomas Webb, Ph.D., a member of the Chemical Biology and Therapeutics department at St. Jude. As a basis for the compounds, Webb constructed a molecule dubbed a warhead, tailored to fit precisely into a central pocket of the active site. This warhead will provide the basis for generating antiviral drug candidates, which will have additional molecular segments designed to fit into neighboring pockets.

After confirming that the six compounds indeed showed activity against the endonuclease, the researchers next per
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SOURCE St. Jude Children's Research Hospital
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