Better flu-fighting models.
SAN DIEGO -- A new computer screening method could help identify existing drugs that target a flu virus's weak spot, researchers reported December 6 at the annual meeting of the American Society for Cell Biology. The work may be especially important in light of health officials' worries that the H1N1 flu virus will develop resistance to antivirals such as Tamiflu.
University of California, San Diego researchers Daniel Dadon, Jacob Durrant and J. Andrew McCammon made a computer movie of slight structural shifts that can occur in the neuraminidase 1 enzyme (the N1 in H1N1), a protein found in avian and swine influenza viruses. Those changes reveal possible target areas that could allow drugs to circumvent a virus's usual means of becoming resistant. All influenza viruses have a neuraminidase enzyme, but the protein comes in several subtypes. Previous work showed that the N1 subtype contains a loop that makes it more nimble than other neuraminidase subtypes, says Rommie Amaro of the University of California, Irvine. Its flexibility may affect the way drugs bind to it.
Analyses of still frames from the movie revealed 27 different conformations that the N1 protein could take on in a host cell. Some parts of the protein change shape readily and some stiffer portions are locked into place, researchers discovered.
Antiviral drugs can wedge into a cavity within an active site of the N1 enzyme (shown), stopping the enzyme's action and blocking the release of new viral particles. But the cavity is prone to shape-altering changes (colored dots show one site of mutation) that can confer drug resistance to the flu virus. Using the simulation to screen a library of FDA-approved drug structures, the team found chemical shapes (green) capable of wedging into a part of the enzyme's active site that doesn't change as easily. That led to the identification of six small-molecule drugs with the desired shape, compounds now being tested against the flu virus. This approach--examining all forms of a protein and then screening a library of drug fragments--could be easily adapted for other molecules, Amaro says.
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|Title Annotation:||Genes & Cells|
|Author:||Saey, Tina Hesman|
|Date:||Jan 2, 2010|
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