A new antiviral drug that induces mutations in the genetic material of influenza virus is highly effective in treating infection in animals and human airway tissue, a new study shows.

The antiviral drug blocks RNA polymerase, the enzyme that plays a central role in replicating the genome of influenza virus, causing mutations in the viral genome. If enough mutations occur, the genome becomes nonfunctional and the virus cannot replicate.

“The compound is highly efficacious against influenza,” says Richard Plemper, a professor in the Institute for Biomedical Sciences at Georgia State and senior author of the study, published in Science Translational Medicine.

“It’s orally available, it’s broad spectrum against all influenza virus strains tested, and, most important, it establishes a high barrier against viral escape from inhibition.”

THE NEW DRUG VS. INFLUENZA
A contagious respiratory virus causes influenza, which is characterized by fever, cough, headache, muscle and joint pain, severe malaise, sore throat, and sometimes gastrointestinal symptoms.

Patients in higher risk groups, including older adults and people with compromised immune systems, frequently require hospitalization. Each year, seasonal influenza results in 30,000 to 80,000 fatalities in the US. The seasonal flu vaccine is only moderately effective, and licensed antivirals are compromised by rapidly emerging viral resistance to the drugs.

Researchers tested the new antiviral drug in ferrets, the most informative animal model for human influenza disease, against various strains that include seasonal and pandemic viruses, such as the swine-origin influenza virus responsible for a 2009 pandemic.

They found that the antiviral drug efficiently inhibited replication of all of these strains. Virus burden dropped rapidly after treatment, and the duration of fever was significantly shorter in treated ferrets than in control animals that did not receive the drug.

FOCUS ON RESISTANCE
“We think that the next generation of influenza antiviral drugs must not only be efficacious and safe, but also address the resistance problem,” says first author Mart Toots, a research assistant professor associated with Plemper’s lab.

That is where the new drug comes in. Through a combination of conventional and ultra-deep sequencing, Toots, in collaboration with Alex Greninger at the University of Washington, demonstrated that it is very challenging for the virus to find a viable way to avoid the compound.

“We have not identified specific resistance mutations yet and are confident to say that the genetic barrier against viral resistance is high,” Plemper says. “We believe that this compound has high clinical potential as a next-generation influenza drug that combines key antiviral features.”

Additional coauthors are from at Emory University, the University of Washington, and the Paul-Ehrlich-Institute in Germany. The National Institutes of Health/National Institute of Allergy and Infectious Diseases, the Defense Threat Reduction Agency (DTRA), and the Georgia Research Alliance funded the work.

Source: Georgia State University

Original Study DOI: 10.1126/scitranslmed.aax5866