A chink in flu’s armor

A protein's structure reveals a target for new drugs

If the avian flu virus were a dragon, scientists have found what would be its soft underbelly.

Flu viruses make a protein that enables the viruses to replicate, and a new study that reveals the nooks and crannies in this protein suggests means of blocking it — and thus of stopping the common and avian forms of the virus from reproducing and spreading.

Existing flu drugs often target parts of the flu virus that can readily mutate, so drug-resistant strains quickly emerge. But because the protein studied, a type of RNA polymerase, is crucial for the virus’s ability to replicate, the protein’s shape is virtually identical among many strains of flu virus and therefore not prone to mutation. So a drug targeting this protein should be resistant to resistance, and it could be effective against the common, seasonal flu as well as a deadly bird flu pandemic.

The hypothetical drug could also be free of major side effects, at least in principle, because the RNA polymerase is made by the virus and unrelated to human proteins.

Sam-Yong Park of Yokohama City University in Japan and his colleagues studied the groove and bump that allow two pieces of the three-part protein to snap together like a jigsaw puzzle.

“This critical interaction [between the two parts] can clearly be used in structure-based anti-influenza drug design,” comments Stephen Cusack, an X-ray crystallographer at the European Molecular Biology Laboratory in Grenoble, France. Once scientists know the shape of a protein’s interaction site, they can search for drugs that would bind with that site and thus interfere with the protein’s function. In this case, a drug would prevent the two subcomponents of the protein from assembling into working RNA polymerases.

The new study, published online July 27 in Nature, expands on research published earlier this month by Yingfang Liu of the ChineseAcademy of Sciences in Beijing and his colleagues. Liu’s team found the shape of the same binding site, but the newer research provides a higher-resolution view.

“These structural studies … are going to revolutionize the understanding of polymerase function and hence influenza virus replication,” Cusack says. “All in all, these are very exciting times in the field, and particularly timely because of the ongoing threat of devastating pandemic flu.”

“Drugging protein-protein interactions have often been attempted, but success rates are very low,” comments Darren Hart, a molecular biologist at EMBL in Grenoble. “But this one looks promising.”

Developing a drug that targets the RNA polymerase could take as long as 10 years, the scientists caution.

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