Influenza virus variants resistant to new antiviral drug candidate lose pathogenicity, study finds

Influenza A viruses with induced resistance to a new antiviral drug candidate were found to be impaired in cell culture and weakened in animals, according to a study led by researchers at the Center for Translational Antiviral Research at Georgia State University.

In a study published in PLOS Pathogens, the authors explored the potential for developing 4′-fluorouridine (4′-FlU), a clinical drug candidate, for the treatment of influenza. They profiled the compound’s resistance against influenza viruses and mapped possible pathways of viral evasion, specifically looking at whether resistance affects the pathogenicity and transmission capacity of the virus.

In previous studies, 4′-FlU demonstrated broad oral efficacy against seasonal, pandemic and highly pathogenic avian influenza viruses in cell cultures, human airway epithelial cells and two animal models, ferrets and mice.

Seasonal influenza viruses pose a major threat to public health, infecting nearly a billion people worldwide each year and forcing millions to require hospitalization and advanced care. Annual flu vaccines provide moderate protection, but the benefit is marginal when vaccines do not match circulating virus strains or when new pandemic virus strains emerge.

Although three different classes of antivirals are approved by the U.S. Food and Drug Administration for use against influenza, they each have a weak genetic barrier to viral resistance. One of these classes is no longer recommended by the Centers for Disease Control and Prevention due to the widespread presence of resistance mutations in circulating strains of human and animal influenza A virus. Resistance has also been frequently observed to the other two classes of antivirals in human viruses.

“Developing new treatments to mitigate seasonal influenza and improve preparedness for future influenza pandemics is an urgent priority due to pre-existing or emerging resistance of influenza viruses to approved antivirals,” said Carolin Lieber, first author of the study. study and postdoctoral fellow at the Center for Translational Antiviral Research at the Georgia State Institute of Biomedical Sciences.

“In this study, we tested the potential of 4′-FlU as an influenza drug and found that resistant variants of the influenza A virus are severely weakened in mice. In ferrets, these resistant variants are impaired in their ability to invade the lower respiratory tract and cause viral pneumonia, in addition to being defective or compromised in terms of transmission,” Lieber said.

In cell culture, six different escape lines with distinct mutations were found. The mutations adhered to three distinct structural clusters that are all predicted to affect the active site of the viral RNA-dependent RNA polymerase complex, leading to moderately reduced viral sensitivity to the drug, according to the study results.

The study also found that oral 4′-FlU administered at either the lowest effective dose (2 mg/kg) or the high dose (10 mg/kg) overcame moderate resistance when mice were infected with an amount lethal influenza virions. This was demonstrated by significantly reduced viral load and complete survival, the authors reported.

“We found that we could completely attenuate lethal infection by resistant variants and viral spread with a standard or five times higher oral dose of 4′-FlU,” said Richard Plemper, lead author of the study, Regents Professor at the Research Institute. Biomedical Sciences and Director of the Antiviral Translational Research Center at Georgia State. “These results demonstrate that partial CA09 escape from 4′-FlU is achievable in principle, but clusters of escape mutations are unlikely to reach clinical significance or persist in circulation.”