Human enzyme makes antiviral small molecule

The quest to design new antiviral drugs may have missed an important source: the human body. A team of researchers has discovered that humans express an enzyme that produces a small molecule that inhibits the replication of several viruses, including Zika virus. The molecule could provide a scaffold for new drugs against infectious diseases, the researchers say (Nature 2018, DOI: 10.1038/s41586-018-0238-4).

When fish, birds, and mammals get infected by a virus, one of the genes that turns on to help fight off the invader is Viperin. But scientists didn’t know the source of the gene’s antiviral activity. Although they were aware that the gene encodes an enzyme, little was known about the reactions it catalyzed.

Tyler Grove and Steven Almo at Albert Einstein College of Medicine decided to collaborate with Jamie Arnold and Craig Cameron at Pennsylvania State University to investigate the enzyme’s activity. The enzyme uses S-adenosyl methionine (SAM) to catalyze electron transfers and make radical species. The team found that one reaction it catalyzes is the dehydration of cytidine triphosphate (CTP).

The resulting small molecule, 3′-deoxy-3′,4′-didehydro-CTP (ddhCTP), looks like existing antiviral drugs that disrupt the replication of some viruses’ RNA genomes. In experiments in test tubes, the researchers determined that ddhCTP inhibits the RNA polymerases of Zika virus, West Nile virus, dengue virus, and hepatitis C. It also blocked replication of the Zika virus in monkey cells.

RNA polymerases are responsible for synthesizing RNA for both viruses and other organisms, including humans. ddhCTP looks like a molecule a viral polymerase would use to add to a growing RNA chain, but once it’s added it blocks further synthesis, terminating the RNA chain and resulting in an incomplete viral genome. The researchers are now trying to figure out why ddhCTP doesn’t interfere with humans’ or other organisms’ polymerases.

Peter Cresswell of Yale University, who studies the Viperin gene, says the work is “amazing.” But it doesn’t explain all of the antiviral effects of Viperin, he adds, such as how it disrupts viral DNA replication.

Although drugmakers have designed inhibitors of viral polymerases, biologists weren’t previously aware of organisms producing such antiviral small molecules, says Priscilla Yang, a virologist at Harvard University. The study will stimulate the field to consider the function of naturally produced small molecules, she says.

The team has filed a U.S. provisional patent application and wants to partner with a pharmaceutical company to develop a version of ddhCTP that could get into cells more easily. The researchers are also studying why the viperin enzyme uses CTP to make the antiviral molecule. There might be more clues that could help design even better antiviral compounds, Einstein’s Almo says.