The dengue virus, which like the prominent Zika virus is a flavivirus, has no vaccine or cure, but a Dutch research team has identified a protein that would make a promising potential drug target. The team have evidence that a protein named NS4B would make a promising antiviral drug target, data they uncovered by screening the National Institutes of Health Clinical Collection (CA, USA), a library of small molecules that have been used clinically in humans.
The researchers found that AM404, a metabolite of common pain reliever acetaminophen, inhibited the dengue virus from replicating. They determined this by using a derivative of the dengue virus that expresses luciferase, a bioluminescent molecule, during replication. Ronald van Rij, corresponding author of the study, explained: "This system provides an easy and rapid read-out of virus replication, and is therefore very useful for screening purposes.”
The team then tried to generate resistance mutations by culturing the virus in the presence of AM404, in an effort to identify the compounds target, but these attempts were unsuccessful. They then tested three dengue virus mutants that had proven resistance to other antiviral compounds for cross-resistance.
"Surprisingly, all three amino acid substitutions rendered [dengue virus] insensitive to AM404, whereas the mutants remained sensitive to ribavirin [another antiviral compound]," the research team wrote. "These mutations are located in the viral NS4B protein, indicating that aNS4B is the direct or indirect target of AM404.”
Unfortunately, AM404's antiviral activity against dengue is rather modest. Van Rij concluded: "However, insights into the mechanism behind AM404's antiviral activity will teach us a lot about the infection."
Van Cleef KWR, Overheul GJ, Thomassen MC, Marjakangas JM, van Rij RP. Escape mutations in NS4B render dengue virus insensitive to the antiviral activity of the paracetamol metabolite AM404. Antimicrobial Agents and Chemotherapy. (2016); https://www.asm.org/index.php/journal-press-releases/94016-new-research-identifies-drug-target-for-dengue-virus