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Discovery of Bird Flu Virus Structure Could Herald Better Drugs


British researchers have taken a step that could lead to more potent drugs against the deadly H5N1 bird flu virus. They have peered inside a key protein on the surface of the virus, obtaining structural information that chemists could use to design new drugs to block it.

To follow this story, it is necessary for a short biology lesson.

The H5N1 virus spreading around the globe has a surface protein whose job is to help the virus enter and infect cells. This protein is called neuraminidase, the N1 in H5N1. This is the enzyme targeted by the drugs Tamiflu and Relenza, which are being stockpiled by some countries in case the H5N1 bird flu becomes a human pandemic.

But the problem is that these drugs were designed on the basis of the atomic structures for two other forms of neuraminidase in other strains of flu, the only two seen so far through x-ray microscopes. So no one knows how well these antivirals would perform against the N1 protein if H5N1 begins to spread easily among people. Tamiflu is the only drug shown to be somewhat effective against H5N1, but there have been several deaths of patients in Asia whose bird flu resisted the drug.

"The reason this is so alarming is that right now, we really don't have a lot of options," said Anna Moscona.

Pediatrician Anna Moscona of the Weill-Cornell Medical College in New York City says new flu drugs are urgently needed.

"So we are really limited to this one drug," she said. "And if we lose the effectiveness of this drug by so many resistant strains that we no longer can use this drug effectively, then we are really in trouble. We have no backup antiviral medication against influenza."

But hope for better drugs now comes from a team led by John Skehel of the British National Institute of Medical Research. The scientists have used the x-ray technology to determine N1's shape as well as that of two other closely related neurominidases. They report in the journal Nature that the enzymes have a key structural difference from the two neurominidases studied earlier.

"It turns out that unlike the previously determined structures, the structure of the N1 and the other members of this group have a cavity next to the active site of the enzyme, which might be able to be used to develop other drugs than the ones that are currently available," said John Skehel.

The cavity in the N1 enzyme closes to lock on to target proteins in a cell so the virus can get a foothold and infect it. But a new drug could be designed so that its atoms bind more snugly into this active site than Tamiflu and Relenza do and prevent the cavity from shutting.

"It would probably be bigger," he said. "I mean, it looks at least from the structure as if it would be possible to add more substituents [atoms], which would then occupy the new cavity specific for this N1 group of neurominidases. In the first instance, those are the sorts of drugs you would try to make."

This kind of drug might avoid the resistance that some influenza viruses have already acquired to Tamiflu.

Skehel says new drugs are at least five years away. Still, a Nature magazine commentary by University of Alabama microbiologist Ming Luo says the work provides valuable intelligence in the war against influenza.

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