A gene called RSAD2 is well-known among scientists who study virology, because it codes for an enzyme that stops several viruses from replicating. Now, researchers at Albert Einstein College of Medicine and Pennsylvania State University have gained new insight into RSAD2 that they believe could be used to create new antiviral therapies.
The enzyme that RSAD2 makes is called viperin, and it naturally creates a compound that stops a range of viruses from replicating. That compound, called ddhCTP, inhibits a virus’s ability to copy its genetic material, the researchers reported in the journal Nature. They believe their discoveries could help in the design of new antiviral treatments inspired by ddhCTP, and they generated early evidence that such a molecule could be effective against three strains of Zika.
"We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses," said co-author Craig Cameron, Ph.D., professor of biochemistry and molecular biology at Penn State, in a release.
The team discovered that ddhCTP blocks viral replication by incorporating itself into the genome of the virus. It becomes part of the virus’s RNA, then prevents the enzyme RNA polymerase from adding nucleotides to that strand of RNA. That cripples the ability of the virus to copy its genetic material.
There are antiviral treatments on the market known as “nucleotide analogs” that achieve the same feat, but they can also interfere with the functioning of normal cells, which can cause unintended side effects. The researchers believe that because ddhCTP is naturally created in the human body, it may avoid those toxic effects.
To examine the potential of ddhCTP as a treatment, the researchers tested it in samples of dengue, West Nile and Zika, which are all part of a family known as flaviviruses. Then they tested whether it could stop the replication of three different strains of Zika in cells. It worked. And it was as effective in two strains of Zika that were implicated in the 2016 outbreak as it was in the original 1947 strain, they reported.
The most recent Zika outbreak inspired several research teams to search for attacks against flaviviruses. For example, a team at Stanford University led an effort to develop a compound that targets the part of the host cell that adds sugar molecules to proteins. Inhibiting that process could prevent cells from becoming infected by Zika and other flaviviruses, they believe.
A team at Harvard Medical School has tested several potential Zika vaccines, and found last year that one dose of a vaccine based on an adeno-associated virus (AAV) protected monkeys against Zika for a year.
The Einsten and Penn State scientists believe the appeal of ddhCTP lies not only in its natural origins but also in its potential to combat several different diseases. The flavivirus family also includes West Nile, yellow fever and hepatitis C.
Steven Almo, Ph.D., professor and chair of biochemistry said in a statement that ddhCTP is “a completely novel drug scaffold" that could be used to create new antiviral therapies. "We are hoping we can generate variants of this molecule that will be even more effective," he said.