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."
Source: https://www.labroots.com/trending/microbiology/11860/antiviral-compound-found-human-body
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