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Structural snapshot hints at new influenza approach

Feb. 21, 2013, 10:29 AM

A careful look at how the body’s natural defenses disarm virulent strains of influenza hints at the possibility of a way to fight the flu.

James Crowe Jr., M.D., professor of Pediatrics and Pathology, Microbiology and Immunology and director of the Vanderbilt Vaccine Center, is a co-author of a recent study in Nature Structural & Molecular Biologydescribing a connection between human antibodies and a well-known structural depression viral influenza uses to hook host cells.

James Crowe Jr., M.D.

“Ideally, we want to mimic the action of antibodies. Now we have been able to view three separate examples of antibodies accessing this particular structural cavity, which is essential for viral access to cells. If we had a drug that could act in a similar way on this place, it would be a new tool to use against the flu,” Crowe said.

This illustration shows the recessed area (red ring) in the viral protein where antibodies have been observed placing a "plug" to impede the virus' ability to attach to host cells.

Drugs have been developed in the past to disrupt the binding of influenza virus proteins called hemagglutinin (HA) to a chemical called sialic acid, found on the surface of many host cells, including those in the upper respiratory system and blood cells. So far this approach to therapy has largely failed.

Together with the other corresponding author of the article, Ian Wilson, D. Phil., D.Sc., chair of the Department of Integrative Structural and Computational Biology at the Scripps Research Institute, Crowe has been working with antibodies found in survivors of the 1957 pandemic flu. The researchers were able to take X-ray snapshots of the antibodies making a unique connection with viral HA on the H2N2 influenza strain.

“We knew where this recessed area was in HA, but there are few antibodies that reach down into this hole. When we got samples from survivors of the 1957 pandemic, we found three different antibodies that all reached into this cavity. All used different angles of approach, but each used a similar mechanism of binding. The antibodies insert a ring-shaped amino acid into this recessed area to bind and block viral attachment to cells,” Crowe said.

Crowe, who has examined pandemic flu antibodies to inform the development of new therapies, says this information can be used in drug discovery. If medications can be developed to mimic this action, targeting this especially vulnerable spot, the influenza virus could be prevented from attaching to host cells, something no current therapy is able to do.

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