New drug forces flu virus into ‘error catastrophe,’ overwhelming it with mutations

New drug forces flu virus into ‘error catastrophe,’ overwhelming it with mutations

Scientists often warn about the dangers of pandemic pathogens spreading quickly around the globe. But one virus already sweeps across the world every year, causing tens of millions of infections and hundreds of thousands of deaths: influenza. Now, a new drug that has shown promise in ferrets may help drive down that toll, researchers report today. The drug appears to be more effective than the most commonly used treatment, oseltamivir, and there are hints that it won’t prompt easy resistance in the virus.

Scientists have long been frustrated by the constant shapeshifting of the flu virus, which necessitates an annual reformulation of flu vaccines to reflect commonly circulating strains. When that match is bad, vaccine protection can be low, especially for elderly people who are most at risk. Meanwhile, new influenza drugs have been slow to develop, and those that exist are often inadequate. Oseltamivir, for instance, provides a moderate benefit at best, and only when given early in the infection; whether it prevents hospitalizations and deaths is controversial.

What’s more, the flu virus has developed resistance to oseltamivir and to an older drug, amantadine. And there are already reports of flu strains resistant to baloxavir, a drug approved by the U.S. Food and Drug Administration just last year.

To come up with an alternative, scientists at Georgia State University and Emory University, both in Atlanta, investigated a compound named N-hydroxycytidine (NHC), which has been known for years to inhibit a broad range of RNA viruses like the flu. Previously, the researchers had shown that NHC is active against influenza; but in tests on macaques, they found the drug is not taken up well by the body, “a potential deal breaker” for human use, says Georgia State molecular virologist Richard Plemper, one of the researchers leading the new work.

The researchers tweaked NHC’s structure to create a new compound named EIDD-2801, which converts back into NHC inside the body. They then tested it in ferrets, the most widely used animal model for influenza. If the ferrets received the compound 12 hours after infection, they did not develop disease at all. Those that received it after 24 hours, when fever had started, produced less virus than control animals that received oseltamivir or no treatment at all. The fever also ended faster in treated animals, the researchers write in Science Translational Medicine .

“It’s important that they showed a reduction in symptoms in ferrets, because it gets much closer to predicting what happens in people,” says Andrew Pavia, an infectious disease expert at the University of Utah in Salt Lake City. “It’s a major step towards developing a drug for humans.”

The scientists also investigated how NHC blocks influenza by sequencing the genomes of flu viruses exposed to the compound. They found that the virus incorporates the drug into its RNA when it replicates, instead of a molecule named cytosine, leading to a cascade of mistakes that virologists call “error catastrophe”—essentially overwhelming the virus with mutations.

To test how easily flu becomes resistant to EIDD-2801, the researchers also grew the virus while keeping it exposed to sublethal doses of NHC or slowly increasing the concentration of NHC—methods that typically don’t kill the virus, but give it a chance to evolve resistance. Even though sequencing clearly shows the virus trying to resist the drug, no resistant strains developed. That bodes well, Pavia says, because oseltamivir and other older drugs all eventually fail the test.

Still, it doesn’t mean resistance cannot develop, says Albert Osterhaus, a virologist at the University of Veterinary Medicine in Hanover, Germany. Favipiravir, a drug approved in 2014 in Japan for pandemic flu viruses resistant to all other drugs, was thought to have a similarly high barrier to resistance before resistant strains developed.

Plemper says additional toxicity tests in animals have not thrown up any red flags, and the first trials of EIDD-2801 in humans are likely to start next spring. Pavia says the new drug could eventually be used in combination with other drugs to stave off resistance, a strategy already in use for HIV and hepatitis B treatments.