Results of a new study demonstrate the
feasibility of a novel strategy in drug discovery: screening large numbers of
existing drugs — often already approved for other uses — to see which ones
activate genes that boost natural immunity.
Using
an automated, high-volume screening technique, researchers at Washington
University School of Medicine in St. Louis have identified a cancer drug that enhances an important natural
response to viral infection in human cells.
"Over
many years of research, we have developed a good understanding of the human
body's own mechanisms to fight viruses," says the study's first author
Dhara Patel, PhD, a postdoctoral research scholar at Washington University.
"Instead of targeting the virus itself, which most current antiviral drugs
do, we have designed a strategy to look for chemical compounds that will enhance
this innate antiviral system."
The
results of the study, led by Michael J. Holtzman, MD, the Selma and Herman
Seldin Professor of Medicine, appear May 4 in PLoS ONE.
Of the
2,240 compounds the researchers tested, 64 showed increased activity in the
cells' interferon signaling pathway, an important player in the body's response
to viruses. The 64 compounds included many different classes of drugs treating
conditions as diverse as depression, high blood pressure and ulcers. But the
one that stood out is idarubicin, a cancer drug commonly prescribed to treat
leukemia, lymphoma and breast cancer. Even at low doses, idarubicin
significantly ramps up the interferon signaling system.
In
treating cancer, idarubicin stops cells from dividing by blocking a protein
that unwinds DNA. As long as DNA remains tightly packed, it can't be copied.
And if DNA can't be copied, a cell can't divide. Interestingly, though, the
researchers showed that idarubicin's antiviral effects are totally unrelated to
what makes it a good cancer drug.
"We
tested other cancer drugs that work the
same way as idarubicin but have very different structures," Patel says.
"Although they act the same way that idarubicin does in cancer cells, they
had no effect on the interferon system."
Like
many cancer drugs, idarubicin has toxic side effects, so it is unlikely to ever
be prescribed for patients fighting viral infections. But, its identification
demonstrates that the new strategy works.
"While
idarubicin is not something you would give to a patient who has the flu, we are
continuing to screen more drugs," Patel says. "We're starting to find
compounds from different drug classes that are not so toxic and that have
similar properties in enhancing interferon signaling. We're still validating
them, but we're very excited about what we're finding."
Traditionally,
techniques for drug discovery involve trying to enhance or inhibit a very
specific interaction. To treat a particular disease, scientists might try to
disable a harmful protein, or replace a missing one, for example. But such
approaches assume that altering a specific interaction of interest will result
in the desired effect.
"I
think our technique accepts the fact that we don't understand everything that's
going on in the cell," Patel says. "Instead of looking at one
particular interaction, we measure the downstream effects."
She
compares it to driving a car and trying to make it go faster.
"Traditionally,
we would pick a specific part — a part of the car that we think is responsible
for speed — and then test compounds that alter the part in a way that we think
will make the car go faster," she says.
"With
our approach, we don't assume we know what is responsible for speed. Instead,
we take entire cars, treat them with many different compounds, and just see
which ones go faster."
Patel
says this screening technique is unusual because it can identify drugs that
enhance the body's own immune response to a broad range of viruses, unlike a
vaccine, which only protects against a specific virus.
The
method has also shed light on how some compounds with known antiviral
properties actually fight viruses. In addition to cancer drugs,
antidepressants and blood pressure medications, the initial 64 drugs they
identified with increased interferon activity included some known antiviral
drugs.
"We
already knew some of these compounds had antiviral properties, we just didn't
know why," Patel says. "Now we're starting to find out how they
actually work."
More
information: PLoS
ONE. May 4, 2012. doi: 10.1371/journal.pone.0036594
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