A team of Stanford researchers is developing approaches to thwart a family of deadly viruses called flaviviruses, by targeting the human cells that host these invading pathogens.
Flaviviruses include the dengue-fever, yellow-fever, West Nile and Zika viruses transmitted to humans by mosquitos, as well as encephalitis transmitted by ticks. Unfortunately, approved antiviral drugs for these diseases aren’t currently available.
So, instead of traditional approach of attacking an individual virus directly, the researchers focused on the cellular factors of their human hosts that are essential to many viral infections.
“Generally, when you develop a drug against a specific protein in dengue virus, for instance, it won’t work for yellow fever or Zika, and you have to develop new antivirals for each,” said Stanford virologist Jan Carette, PhD, in a news release. “Here, by targeting the host rather than a specific virus, we’ve been able to take out multiple viruses at once.”
Earlier, the team genetically profiled human cells to identity the host factors necessary for the viruses to replicate inside the cells — revealing new candidate targets for antiviral drug development. Specifically, they demonstrated the importance of the oligosaccharyltransferase (OST) complex that attaches sugar molecules to proteins. They found flaviviruses did not infect their genetically engineered cells without OST.
In the new study, published today in Cell Reports, the Stanford researchers collaborated with scientists at Yale University to test the effectiveness of a drug called NGI-1, which inhibits the activity of the OST complex.
They showed that low concentrations of NGI-1 could be used to block the viruses from replicating without harming the host cells — successfully reducing the infection by 99 percent when treating cells immediately after they were infected by Zika or dengue virus, and by 80 percent when administered 24 hours after infection.
Their study also indicated that the viruses are unlikely to become resistant to NGI-1. “When you target a host function rather than a viral protein, it’s usually much more difficult for a virus to develop resistance,” Carette said in the release.
The researchers are now busy with follow-up studies to test NGI-1 in small animal models of dengue fever and are also developing similar drugs with improved specificity.
Previously: Study reveals human genes, non-essential to us, that dengue, Zika, hepatitis C viruses depend on and Talking about the Zika virus and Global pandemics affect us all, Stanford health policy researchers write
Photo of Jan Carette by Paul Sakuma