Xofluza, the recent 24-hour killing flu drug that was developed by the Japanese pharmaceutical company Shionogi and approved for clinical use in Japan, is now being tested for its efficacy.
Researchers from EMBL Grenoble have examined in detail Xofluza’s mode of action; uncovering possible mechanisms by the possibility of viral resistance which was later published in Scientific Reports.
290,000 to 650,000 individuals die every year due to the flu and over 3 million severe illness cases worldwide are flu-associated. The flu is primarily an infectious disease caused by influenza viruses A and B. Although there is plenty of vaccines and anti-viral drugs to combat the flu, viral strain resistance to flu treatment continue to emerge and the need for a drug with optimum efficacy and novel mechanism of action is at an all-time high.
Xofluza, also known as baloxavir marboxil, is actually an anti-influenza drug approved for clinical use in the 1990s. When patients with the flu are administered Xofluza, their bodies will metabolize it into baloxavir acid. The acid then works to target a key viral enzyme known as influenza polymerase by inactivating its actions. This inactivation causes the influenza virus to be unable to replicate, ultimately halting the progression of an infection. The clinical studies on healthy patients by Shionogi provided evidence that one oral dose of Xofluza holds high efficacy in decreasing viral production and relieving symptoms.
Stephen Cusack, from EMBL Grenoble, examined specifically crystal structures of the drug bound to: 1.) a polymerase of the influenza virus and 2.) a mutant polymerase. The mutant polymerase leads to minor structural changes: one amino acid transforms into another using a single methyl group. "Still, this apparently minor change leads to reduced contact between the polymerase and the drug, weakening the drug's effect. However the virus pays a price for escaping the drug, since we found that the same mutation also lowers the activity of the polymerase, meaning that the mutant virus is less effective at replicating itself. It is therefore uncertain whether this Xofluza-resistant virus would ever spread,” says Cusack, "Only that way can we find out if resistance spreads and becomes a problem. Finding out could take several years, but at least we know what mutations to monitor. In the meantime, in our lab at EMBL Grenoble, we will keep working on influenza polymerase with the aim of supporting the development the next generation of influenza drugs."