An electron microscope image of a flu virus
James Cavallini/Science Source
By Robert F. Service
The flu season is at its height in the Northern Hemisphere, but—as many are discovering—seasonal flu vaccines don’t always provide complete protection, because unexpected flu strains show up unannounced. Now, researchers report they’ve developed an experimental oral medicine that protects mice from a wide range of influenza viruses. If it works in humans, it could lead to a new pill to fight one of the deadliest infections humanity faces.
Every year, influenza causes a severe illness in some 3 million to 5 million people worldwide and kills up to 650,000, according to the World Health Organization. Medicine’s primary defense against the flu is the seasonal flu vaccine, an injected cocktail of killed viruses designed to prod the immune system to produce antibodies. Those antibodies disable the flu strains deemed most likely to circulate that season. But sometimes unforeseen strains end up spreading instead, rendering the vaccine less effective.
Normally, antibodies target an individual strain of flu. But in 2008, researchers discovered a class of so-called broadly neutralizing antibodies (bnAbs) in humans that can bind to and disable multiple flu strains at once. Detailed studies of one the best of these bnAbs, called CR6261, showed it binds to the stem portion of a mushroom-shaped hemagglutinin (HA) protein on the surface of the virus. This portion of the protein is virtually identical in multiple flu strains and is essential for enabling the virus to fuse with the membranes of cells it infects.
Close-up images of CR6261 bound to the HA stem revealed the antibody binds by holding on to five tiny indentations in the stem, much as a rock climber uses minute toe and finger holds to hang onto an otherwise sheer granite cliff face. “CR6261 targets all five pockets up and down the stem,” says Ian Wilson, a structural biologist at Scripps Research in San Diego, California.
In 2011 and 2012, researchers led by Wilson and David Baker at the University of Washington in Seattle used computer design techniques to create a much smaller protein called HB80.4 that binds to HA’s stem using the same holds and blocks viral fusion. But proteins typically don’t work as oral medicines because digestive enzymes break them down in the stomach.
Now, Wilson, Maria van Dongen, a drug discovery expert at the Janssen Pharmaceutical Companies of Johnson & Johnson in Leiden, The Netherlands, and their colleagues have used the previous discovery of HB80.4 to help them find small molecules that do the same thing. Van Dongen and her team created a lab test in which they first bound HB80.4 to the flu virus’s HA stem. They then screened 500,000 small molecules from the company’s proprietary library to see whether any bound to the same site so tightly that they essentially pushed HB80.4 out of the way.
They initially got some 9000 hits, which they whittled down to a top binder. They tweaked this compound further to create JNJ4796, a molecule containing six rings in a line, which not only binds better than HB80.4 to the HA stem’s indentations but has improved properties for acting as a drug, such as increased solubility in blood.
Van Dongen’s team showed the would-be drug blocks a group of flu viruses from infecting mouse and human cells in a petri dish. And studies in mice given the drug orally showed it prevented animals from getting sick after being exposed to lethal doses of multiple strains of the flu, the researchers report today in Science.
“It’s a beautiful story,” showing how scientists have steadily progressed toward coming up with a new antiflu drug, says Yoshihiro Kawaoka, a virologist at the University of Wisconsin in Madison. If the drug proves safe and effective in humans, it would join two approved oral medications—Tamiflu and Xofluza—that can help fight the flu. Unlike JNJ4796, which blocks viruses from entering cells, the approved drugs block viruses from spreading once they have already infected cells. But viruses have already shown signs of developing resistance to the current drugs. “It’s important to have drugs against different targets,” Kawaoka says.
That said, JNJ4796 doesn’t work against all flu viruses. The compound blocks influenza A group 1 viruses, which includes the H1N1 virus that accounts for nearly half of flu infections this season. But it doesn’t block two other classes—influenza A group 2 or influenza B viruses—that account for the rest of this year’s infections.
Nevertheless, Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York City, says the “elegant” screening approach Van Dongen’s team used to identify the initial HA binder could also help find drug leads that bind the other viral classes. The same strategy could even work for finding novel drugs to block other viral diseases, such as Ebola, he says. “This is just the start.”
Source: Science Mag