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21 June 2018, 13:03
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Properties of protein viperin will help to create a universal drug for HIV and hepatitis С treatment

Properties of protein viperin will help to create a universal drug for HIV and hepatitis С treatment - picture 1

A group of researchers in the United States has identified the mode of action of an interferon-inducible protein viperin, also known as RSAD2, that has antiviral effects on a wide range of different viruses such as influenza, hepatitis C, HIV, human cytomegalovirus and West Nile virus. Scientists believe, that this discovery, can help to develop a universal drug that may effectively fight a number of viruses, including Zika virus.

According to the research results published on June 20 in Nature, viperin acts as a kind of "catalyst" for the reaction that generates the ddhCTP molecule, which prevents the copying of the genetic material of the viruses and, therefore, their replication.

This discovery can be a first step towards creating a drug that can induce the body to produce this molecule and provide a universal virologic response.

“We knew viperin had broad antiviral effects through some sort of enzymatic activity, but other antivirals use a different method to stop viruses,” - said the author of the discovery, Craig Cameron, professor and holder of the Eberly Chair in Biochemistry and Molecular Biology at the University of Pennsylvania. “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.”

As the authors of the study explain, the virus usually co-opts (incorporate) the host’s genetic building blocks (nucleotides) into new RNA strands to copy its own genetic material. The ddhCTP molecule mimics these nucleotide building blocks and becomes incorporated into the virus’s genome. After that, the "nucleotide analogs" prevent an enzyme called RNA polymerase from adding more nucleotides to the RNA strand, thereby preventing the appearance of new copies of the virus’s genetic material.

“Long ago, the paradigm was that in order to kill a virus, you had to kill the infected cell,” says 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.”

“The major obstacle to developing therapeutically useful antiviral nucleotides is unintended targets,” said co-author Jamie Arnold from the University of Pennsylvania.

“For example, a few years ago we discovered that a nucleotide analog under development for 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.”

The experts found out that The ddhCTP molecule has no "side effects". The research team believes that the natural origin of the compound requires that it be non-toxic.

“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.”

To prove the effectiveness of ddhCTP, the research team showed that the molecule inhibited RNA polymerase of the dengue virus, West Nile virus and the Zika virus (flaviviruses).

However, as it turned out, RNA polymerases of rhinovirus and human poliovirus (picornaviruses) were not sensitive to the molecule.

In order to better understand the causes of this, the researchers plan to study the polymerase structures of these viruses more closely.

Author: Marina Shegay