Scientists Identify New Leads for Treating Parasitic Worm Disease
Compounds May Provide Much-Needed New Weapons In Worldwide Battle Against Schistosomiasis
A research team supported by the National Institutes of Health
(NIH) Roadmap and the National Institute of Allergy and Infectious
Diseases (NIAID) has identified chemical compounds that hold promise
as potential therapies for schistosomiasis, a parasitic disease
that afflicts more than 200 million people worldwide. The findings
were reported today in the advance online publication of the journal Nature
Medicine.
In their paper, researchers from Illinois State University (ISU)
in Normal, Ill., and NIH's Chemical Genomics Center (NCGC) report
that chemical compounds known as oxadiazoles can inhibit an enzyme
vital to survival of Schistosoma, a group of parasitic
flatworms that cause schistosomiasis. The NCGC, established in
2004 by the NIH Roadmap for Medical Research, includes a set of
strategic initiatives drawing collectively from the agency-wide
research resources of NIH.
"New therapeutic agents are sorely needed if we hope to
ease the burden of schistosomiasis on the world's health," said
NIH Director Elias A. Zerhouni, M.D. "These findings exemplify
what academic researchers can accomplish with access to translational
infrastructure and technologies that have previously been beyond
their reach."
Schistosomiasis, also known as bilharzia or snail fever, affects
an estimated 207 million people, most of whom live in developing
nations in tropical areas. About 20 million of those people with
the disease become seriously disabled due to severe anemia, diarrhea,
internal bleeding and/or organ damage. In addition, another 280,000
die of the disease each year.
People become infected with Schistosoma when they wade,
swim or bathe in fresh water inhabited by snails, which serve as
the worms' intermediate hosts. The microscopic worms enter
the human body by boring through the skin and migrate into the
blood vessels that supply the intestinal and urinary systems. After
the worms mature and reproduce, their eggs are eliminated in human
urine and feces. If human waste contaminated by worm eggs finds
its way into fresh water, the cycle begins again.
Currently, people living in more than 70 tropical nations require
annual or semi-annual drug treatment to rid their bodies of the
parasite. Since the 1980s, praziquantel has effectively been the
sole drug used for this purpose. Public health experts are concerned
that the Schistosoma parasites will become resistant to
praziquantel and the drug will lose its effectiveness, as has been
the case for agents used to combat many other infectious diseases
such as malaria and tuberculosis.
"The search for new drugs for schistosomiasis is imperative
if we are to control this devastating disease that exacts an enormous
toll, both in terms of human suffering and economic development," said
NIAID Director Anthony S. Fauci, M.D.
The new research, which was conducted with Schistosoma maintained
in laboratory conditions, shows that an oxadiazole compound was
effective in inhibiting a crucial worm enzyme, called thioredoxin
glutathione reductase (TGR). Furthermore, in tests of laboratory
mice infected with Schistosoma, this compound killed
the parasite in all of its stages, from larva to adult. The results
exceeded all benchmarks set by the World Health Organization for
potential new compounds to treat schistosomiasis. Importantly,
the researchers also showed that the compound was active against
all three major species of Schistosoma worms that infect
humans.
"This builds upon my lab's previous findings that Schistosoma worms
survive in the host due to a protective enzyme TGR. By teaming
with NCGC, we were able to move our research one step closer to
the clinic by identifying a class of compounds that specifically
target that enzyme," said the study's lead researcher,
David L. Williams, Ph.D., a professor of biology at ISU and NIAID
grantee. "Still, much remains to be done. Our ultimate goal
is to see our basic biological findings translated into help for
people with schistosomiasis."
The TGR project submitted to NCGC by Dr. Williams' group
was the first one officially accepted for screening by the NIH
Roadmap Molecular Libraries Initiative. The results of that collaboration
underscore the value of a new paradigm established by the NCGC,
which is administered by the National Human Genome Research Institute
(NHGRI). The high-tech center offers academic researchers, such
as the ISU team, the opportunity to tap into a robotic system for
quickly screening large numbers of chemical compounds for biological
activity.
"Chemical genomic advances are being used to develop a new
approach to a parasite that has afflicted countless generations
of humankind," said NHGRI Director Francis S. Collins, M.D.,
Ph.D. "This study showcases the beauty of high-throughput
chemical screening for biomedical applications."
NCGC Director Christopher P. Austin, M.D., who is a co-author
of the Nature Medicine paper, said "Our center has
brought pharmaceutical-scale chemical screening, informatics and
medicinal chemistry to bear on neglected diseases that affect millions
globally, but are not worked on by the pharmaceutical industry
since they cannot generate the needed financial returns. This study
demonstrates the wonderful things that can happen when the NCGC's
scientific capabilities and infrastructure are combined with the
biological expertise of individual academic investigators."
For more information on schistosomiasis, go to: http://www.cdc.gov/ncidod/dpd/parasites/schistosomiasis/default.htm
A diagram depicting the life cycle of the Schistosoma parasite
can be found at genome.gov/pressDisplay.cfm?photoID=20042.
Micrographs of Schistosoma parasites can be found at: genome.gov/pressDisplay.cfm?photoID=20041, genome.gov/pressDisplay.cfm?photoID=20043,
and genome.gov/pressDisplay.cfm?photoID=20044.
Full-resolution video clips of NCGC's chemical screening
facility in action are available at http://genome.gov/pressDisplay.cfm?photoID=20030.
NHGRI is one of the 27 institutes and centers at the NIH, an agency
of the Department of Health and Human Services. The NHGRI Division
of Intramural Research develops and implements technology to understand,
diagnose and treat genomic and genetic diseases. Additional information
about NHGRI can be found at its Web site, www.genome.gov.
NIAID is a component of the NIH. NIAID supports basic and applied
research to prevent, diagnose and treat infectious diseases such
as HIV/AIDS and other sexually transmitted infections, influenza,
tuberculosis, malaria and illness from potential agents of bioterrorism.
NIAID also supports research on basic immunology, transplantation
and immune-related disorders, including autoimmune diseases, asthma
and allergies. News releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at www.niaid.nih.gov.
NCGC is an ultra-high-throughput screening center
that generates chemical probes of gene and cell functions in
health and disease, and catalyzes for drug development for neglected
rare and orphan diseases. It is part of the NIH Roadmap
for Medical Research. The Roadmap is a series of initiatives
designed to pursue major opportunities and gaps in biomedical
research that no single NIH institute could tackle alone, but
which the agency as a whole can address to make the biggest impact
possible on the progress of medical research. Additional information
about the NIH Roadmap can be found at www.nihroadmap.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.
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