There’s a new weapon taking shape in the war on flu, one of the globe’s most dangerous infectious diseases. Scientists have created a designer protein that stops the influenza virus from infecting cells in culture and protects mice from getting sick after being exposed to a heavy dose of the virus. It can also be used as a sensitive diagnostic. And although it isn’t ready as a treatment itself, the protein may point the way to future flu drugs, scientists say.
“It’s impressive,” says James Crowe, an immunologist at Vanderbilt University in Nashville, who was not involved in the study. But because it hasn’t yet been tested in humans, “it [still] has a long way to go,” he says.
Influenza severely sickens 3–5 million people each year, and it kills between 250,000 and 500,000, mostly the elderly and people with weakened immune systems. Every year, public health officials survey the three flu subtypes circulating in humans and design a vaccine for the next winter season that covers them all. But those vaccines are far from perfect: They don't always exactly match the viruses actually going around, and in some people, the shots fail to trigger a vigorous immune response.
Drugs are another line of defense. Most focus on the proteins on the virus’s outer coat, neuraminidase and hemagglutinin (HA). Some drugs that block neuraminidase, which helps the virus escape already infected cells, are starting to bump up against viral resistance. HA is scientists’ next target. The mushroom-shaped protein specializes in infecting cells, first by binding a trio of sites on its head to three separate sugar molecules on the surface of targeted cells. Once the virus latches on, parts of HA’s stem act as a grappling hook to pull the virus in close, allowing it to fuse with the cell membrane and release its contents inside.
In 2011, researchers led by David Baker, a computational biologist at the University of Washington in Seattle, created a designer protein that binds HA’s stem, which prevented viral infection in cell cultures. But because the stem is often shrouded by additional protein, it can be hard for drugs to reach it.
Now, Baker’s team has designed proteins to target HA’s more exposed head group. They started by analyzing x-ray crystal structures that show in atomic detail how flu-binding antibodies in people grab on to the three sugar-binding sites on HA’s head. They copied a small portion of the antibody that wedges itself into one of these binding sites. They then used protein design software called Rosetta to triple that head-binding section, creating a three-part, triangular protein, which the computer calculated would fit like a cap over the top of HA’s head group. Next, they synthesized a gene for making the protein and inserted it into bacteria, which cranked out copies for them to test.
In the test, Baker’s team immobilized copies of the protein on a paperlike material called nitrocellulose. They then exposed it to different strains of the virus, which it grabbed and held. “We call it flu glue, because it doesn’t let go,” Baker says. In other experiments, the protein blocked the virus from infecting cells in culture, and it even prevented mice from getting sick when administered either 1 day before or after viral exposure, they report today in Nature Biotechnology.
Despite these early successes, Baker and Crowe caution that the newly designed protein isn’t likely to become a medicine itself. For starters, Baker says, the protein doesn’t bind all flu strains that commonly infect humans. That means a future drug may require either a cocktail of HA head group binding proteins or work in combination with stem-binding versions. Second, the safety of designer proteins will have to be studied carefully, Crowe says, because they are markedly different than natural HA-binding antibodies. “The further you get away from a natural antibody, the less you can predict what will happen,” Crowe says.
But down the road, Baker says, the new designer protein could serve as the basis for a cheap diagnostic—akin to a pregnancy test—for detecting flu and possibly even medicines able to knock it out.