Compound that stops viruses from replicating identified

Washington : Scientists have identified how a naturally occurring enzyme in humans and other mammals prevents viruses from multiplying, an advance that may pave the way for new antiviral drugs. The enzyme viperin, known to have antiviral effects on a wide variety of viruses, including West Nile, hepatitis C, rabies, and HIV, facilitates a reaction that produces the molecule ddhCTP, which prevents viruses from copying their genetic material and thus from multiplying.

The discovery could allow researchers to develop a drug that induces the human body to produce this molecule and could act as a broad-spectrum therapy for a range of viruses. "We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses," said Craig Cameron, a professor at Pennsylvania State University in the US.

Researchers found that viperin catalyses an important reaction that results in the creation of a molecule called ddhCTP. They decoded the effects of ddhCTP on a virus' ability to replicate its genetic material. "The molecule acts in a similar manner to drugs that were developed to treat viruses like HIV and hepatitis C. With a better understanding of how viperin prevents viruses from replicating, we hope to be able to design better antivirals," said Cameron.

A virus co-opts the host's genetic building blocks to copy its own genetic material, incorporating molecules called nucleotides into new strands of RNA. The molecule ddhCTP mimics these nucleotide building blocks and becomes incorporated into the virus' genome. Once incorporated into a new strand of the virus' RNA, these "nucleotide analogues" prevent an enzyme called RNA polymerase from adding more nucleotides to the strand, thus preventing the virus from making new copies of its genetic material. "Long ago, the paradigm was that in order to kill a virus, you had to kill the infected cell," said Cameron.

"Such a paradigm is of no use when the virus infects an essential cell type with limited capacity for replenishment. The development of nucleotide analogues that function without actually killing the infected cell changed everything," he said. Most nucleotide analogues on the market are human-made, but there are often complications with using these synthetic drugs. Since nucleotides are used by many proteins and enzymes of the cell, numerous opportunities exist for analogues to interfere with normal cellular function. The molecule ddhCTP, however, does not appear to have any unintended targets.

The research team suspects that the natural origin of the compound within the human body necessitates that it be nontoxic. To verify the effectiveness of ddhCTP, the research team showed that the molecule inhibited the RNA polymerases of dengue virus, West Nile virus and Zika virus, which are all in a group of viruses called flaviviruses. "The molecule directly inhibited replication of three different strains of Zika virus," said Joyce Jose, an assistant professor at Penn State.