in Large-Scale Screen of Existing Drugs
Johns Hopkins researchers join collaborative group to screen 6,000 existing drugs in hopes of finding treatments for Zika Virus infection
August
29, 2016 -- Scientists report that a specialized drug screen test using
lab-grown human cells has revealed two classes of compounds already in the
pharmaceutical arsenal that may work against mosquito-borne Zika virus
infections.
In a
summary of their work, published in Nature Medicine on Aug. 29, the
investigators say they screened 6,000 existing compounds currently in
late-stage clinical trials or already approved for human use for other
conditions, and identified several compounds that showed the ability to hinder
or halt the progress of the Zika virus in lab-grown human neural cells.
The
research collaboration includes teams from the Johns Hopkins University School
of Medicine, the National Institutes of Health and Florida State
University
“It
takes years if not decades to develop a new drug,” says Hongjun Song, Ph.D.,
director of the Stem Cell Program in the Institute of Cell
Engineering
“So
instead of using new drugs, we chose to screen existing drugs,” adds Guo-li
Ming, M.D., Ph.D., professor of neurology at the Johns Hopkins University
School of Medicine. “In this way, we hope to create a therapy much more
quickly.”
The new
findings are an extension of previous work by the research team, which found
that Zika mainly targets specialized stem cells that give rise to neurons in
the brain’s outer layer, the cortex. The researchers observed Zika’s effects in
two- and three-dimensional cell cultures called “mini-brains,” which share
structures with the human brain and allow researchers to study the effects of
Zika in a more accurate model for human infection.
In the
current study, the research team exposed similar cell cultures to the Zika
virus and the drugs one at a time, measuring for indicators of cell death,
including caspase-3 activity, a chemical marker of cell death, and ATP, a
molecule whose presence is indicative of cell vitality.
Typically,
after Zika infection, the damage done to neural cells is “dramatic and
irreversible,” says Hengli Tang, Ph.D., professor of biological sciences at Florida State University
Further
analysis of the surviving cells, says Ming, showed that the promising drugs
could be divided into two classes: neuroprotective drugs, which prevent the
activation of mechanisms that cause cell death, and antiviral drugs, which slow
or stop viral infection or replication. Overall, Song says, three drugs showed
robust enough results to warrant further study: PHA-690509, an investigational
compound with antiviral properties; emricasan, now in clinical trials to reduce
liver damage from hepatitis C virus and shown to have neuroprotective effects;
and niclosamide, a drug already used in humans and livestock to combat
parasitic infections, which worked as an antiviral agent in these experiments.
Song
cautioned that the three drugs “are very effective against Zika in the dish,
but we don’t know if they can work in humans in the same way.” For example, he
says, although niclosamide can safely treat parasites in the human
gastrointestinal tract, scientists have not yet determined if the drug can even
penetrate the central nervous system of adults or a fetus inside a carrier’s
womb to treat the brain cells targeted by Zika.
Nor, he
says, do they know if the drugs would address the wide range of effects of Zika
infection, which include microcephaly in fetuses and temporary paralysis from
Guillain-Barre syndrome in adults.
“To
address these questions, additional studies need to be done in animal models as
well as humans to demonstrate their ability to treat Zika infection,” says
Ming. “So we could still be years away from finding a treatment that works.”
The
researchers say their next steps include testing the efficacy of these drugs in
animal models to see if they have the ability to combat Zika in vivo.
Zika was
first identified in 1947 and garnered little scientific interest until an
outbreak began in South America in mid-2015.
This outbreak is now known to be responsible for an increase in cases of microcephaly
— a severe birth defect in which afflicted infants are born with underdeveloped
brains. In the continental United
States Florida ,
in the Miami Puerto Rico has reported
7,855 locally transmitted cases, spurring the Obama administration to declare a
public health emergency in the territory on Aug. 12. From these reports, the Centers
for Disease Control and Prevention (CDC) estimates that up to 270 babies may be
born with microcephaly by 2017. The CDC is advising preventive measures for
people in these areas, including eliminating standing water where mosquitos
breed and creating a barrier from bites with clothing and wearing insect
repellents. The Florida Department of Health has a robust mosquito-borne
illness surveillance system. It has partnered with local groups and the CDC to
fight Zika infections, and is providing free Zika testing to all pregnant
women. The Puerto Rico Department of Health has put an active Zika surveillance
system in place to coordinate reporting from health care providers and weekly
mosquito spraying in many areas.
The Zika
virus is commonly transmitted from mosquito bites or from an infected person to
an uninfected person through sexual contact. Despite the potential effects of
infection, only one in four infected people will present symptoms if Zika
infection, allowing the virus to spread rapidly in areas with local
transmission. Because of this, the CDC recommends all pregnant women with
ongoing risk of Zika infection, including residence or frequent travel to areas
with active Zika virus transmission, receive screening throughout their
pregnancy.
Many
research groups are fast tracking the development of vaccines, treatments and
mosquito control measures to combat further spread of the virus.
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