A new crystallographic study of a protein tail found in all influenza A viruses raises the possibility of prehensile drugs that can grab this protein and prevent viral replication. The protein tail is present in common human influenza A which kills thousands of people every year as well as rare forms such as bird flu.

Jane Tao and colleagues at Rice University and Robert Krug's team at the University of Texas at Austin (UT) have identified the long flexible tail of the influenza virus' nucleoprotein, which is present in all strains of influenza A. They found that even seemingly insignificant changes to the structure of this protein tail prevent it from fulfilling a key role in viral replication. That is, they prevent them from linking together to form structural columns used by the virus to transmit copies of itself.

Their 3.2 Å X-ray structure reveals key features of the protein, that might be exploited in novel drugs to circumvent the issues of drug resistance that have emerged against the well-known anti-flu drugs Tamiflu and Relenza. "There is a small binding pocket for the tail loop of the protein that appears to be a promising target for a new class of antiviral drugs," explains Rice's Tao, "We know from previous genetic studies that this tail loop is almost identical across strains of influenza A, so drugs that target the tail have a high potential of being effective against multiple strains, including the H5N1 [bird flu] strains." New antiviral drugs capable of defending us from strains of influenza A resistant to current drugs such as Tamiflu, will become crucial weapons in efforts to ward off a flu pandemic.

The influenza A nucleoprotein comprises approximately 500 amino acids with thirty of those contained in the tail loop. "We found that a mutation in only one residue out of 30 was enough to prevent the nucleoproteins from coming together to form the building blocks for the columns, and without these columns the virus cannot make copies and infect other cells."

The team used both the Brookhaven National Synchrotron Light Source and the Cornell High Energy Synchrotron Source to collect their X-ray data.

Related links:

• Nature, in press
• Krug's Page
• Tao's Page

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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