The human body can make a compound with a special power to fight viruses; viperin is an enzyme made naturally in many mammals. Scientists have found that it has an antiviral effect on a variety of pathogens including hepatitis C, rabies and West Nile viruses. The enzyme aids the chemical reaction that generates ddhCTP, a molecule that can prevent viruses from replicating their genetic material, halting the expansion of the viral population. This work, which was reported in Nature, could have important implications in antiviral drug development.
"We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses," explained study author Craig Cameron, a professor and the Eberly Chair in Biochemistry and Molecular Biology at Penn State. "Our collaborators at the Albert Einstein College of Medicine, led by senior authors Tyler Grove and Steven Almo, revealed that viperin catalyzes an important reaction that results in the creation of a molecule called ddhCTP.
“Our team at Penn State then showed the effects of ddhCTP on a virus's ability to replicate its genetic material. Surprisingly, 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."
Viruses usually have small genomes and lack critical cell components found in normal cells, so they hijack the cellular machinery they lack, using nucleotide bases from their host to build new genetic material - viral RNA. The ddhCTP chemical can mimic nucleotides, the foundations of DNA and RNA, and these 'nucleotide analogs' get incorporated into the new viral RNA that is made. Then they can interfere with the extension of the genetic strand, which stops the virus from making new copies of itself.
"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 analogs that function without actually killing the infected cell changed everything."
Usually, nucleotide analogs are synthetic and come with risks. Nucleotides are important in many ways, so they can have dangerous side effects.
"The major obstacle to developing therapeutically useful antiviral nucleotides is unintended targets," noted study author Jamie Arnold, associate research professor of biochemistry and molecular biology at Penn State. "For example, a few years ago we discovered that a nucleotide analog under development for [the] treatment of hepatitis C could interfere with the production of RNA in mitochondria, subcellular organelles important for energy production in the patient's own cells. That meant people with mitochondrial dysfunction are predisposed to any negative effects of this unintended interference."
However, ddhCTP appears to be safe so far; it does not seem to have unintended targets.
"Unlike many of our current drugs, ddhCTP is encoded by the cells of humans and other mammals," said Cameron. "We have been synthesizing nucleotide analogs for years, but here we see that nature beat us to the punch and created a nucleotide analog that can deal with a virus in living cells and does not exhibit any toxicity to date. If there's something out there that's going to work, nature has probably thought of it first. We just have to find it."
The researchers tested ddhCTP against West Nile, Zika and dengue viruses, and found that the ddhCTP could stop the replication of Zika in live cells.
"The molecule directly inhibited replication of three different strains of Zika virus," said study author Joyce Jose, assistant professor of biochemistry and molecular biology at Penn State. "It was equally effective against the original strain from 1947 as it was against two strains from the recent 2016 outbreak. This is particularly exciting because there are no known treatments for Zika. This study highlights a new avenue of research into natural compounds like ddhCTP that could be used in future treatments."
The researchers have shown that ddhCTP has a lot of potential as a therapeutic, although it was not effective against a class of viruses called picornaviruses; that group includes polio and rhinovirus. The researchers would like to find out why, and determine if a vulnerable virus might gain resistance against ddhCTP.
"Development of resistance to an antiviral agent is always an issue," said Cameron, "Having some idea of how resistance happens, or being able to prevent it from happening, will be critical if this is to be used as a broad-spectrum therapy."