More than 65,000 Americans have been victims of influenza A H3N2 this season, according the Centers for Disease Control. And this particular strain of the flu virus has proven to be remarkably resistant to vaccination, because it frequently mutates after the vaccine has been formulated. Could antiviral treatments help tamp down the virus after infection?
A research team led by the University of California at San Diego has developed a small molecule that they believe could weaken or even stop H3N2 in its tracks. It works by exploiting a flaw in the mechanism the virus uses to replicate, according to the team, which presented their research at the 255th National Meeting & Exposition of the American Chemical Society (ACS) in New Orleans.
Many pathogens replicate by using their hosts’ DNA, but not H3N2. Instead it uses its own enzyme called RNA-dependent RNA polymerase. That enzyme consists of three subunits, one of which is vital for replication and dependent on manganese metal ions, the scientists reported. They figured if they could develop a drug that binds to two of those ions, they could shut down the virus’ ability to reproduce and spread.
They developed a small molecule that binds to both manganese ions at the same time and tested it on the RNA polymerase enzyme. It demonstrated potency, they reported, and they are now planning to test it on the whole flu virus.
“This enzyme is completely ubiquitous across all flu strains,” said Seth Cohen, Ph.D., a professor at UCSD, during a press conference at the ACS event Monday. He believes the drug could eliminate the virus or at least slow its reproduction enough so the immune system can take over and eliminate it. Cohen is also co-founder of Forge Therapeutics, a company developing drugs that target metalloenzymes.
This year’s deadly flu outbreak has revived interest in improving vaccines and treatments that target the virus. In January, scientists at UCLA described a vaccine they’re developing that interferes with the ability of the flu virus to block immune proteins called interferons. Last year, scientists at St. Jude Children’s Research Hospital discovered that an experimental cancer drug, BEZ235, decreased the ability of the flu to replicate.
The UCSD researchers had previously developed small-molecule anti-flu drugs that could bind to one manganese atom, Cohen explained during the ACS conference. The team realized that “even just a small tweak—adding two atoms—we thought could enhance it. To our surprise, it enhanced it far more than we ever expected,” binding both ions and boosting its potency, he said.
A similar approach is being pursued by Shionogi, which recently won approval in Japan for an anti-flu drug that also targets RNA polymerase. The drug, Xofluza (baloxavir marboxil), effectively killed the flu virus in 24 hours—as compared to the 72 hours that’s required for Roche’s Tamiflu to kick in—which Cohen hailed as “quite a good validation” of the approach. Shionogi plans to file for FDA approval this year.
Cohen envisions a compound such as his complementing flu vaccination, particularly in young, the elderly and immuno-compromised, who proved to be particularly susceptible to complications of the virus over the last few months. “This was a good year to highlight” the need for more effective antiviral treatments, he said during the conference. “The vaccine wasn’t very effective this year.”