Hepatitis C Advance May Help Develop New Treatments

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Hepatitis C Advance May Help Develop New Treatments

A major advance in understanding hepatitis C infection may facilitate the
design of new drugs to treat the disease, which affects nearly 4 million
Americans and 170 million people worldwide. Research in the New York State
Health Department's Wadsworth Center laboratories has shown that hepatitis C
virus hijacks a host cell's protein factory by changing its shape in a way
that favors viral proteins being produced, rather than host proteins. This is
the first time the genetic material of a virus has been captured in the
process of reprogramming the cell in this way. The finding is published in
today's issue of Science.The groundbreaking work was done by Dr. Joachim
Frank, a Howard Hughes Medical Institute investigator at Wadsworth Center, in
collaboration with researchers at Yale University. Dr. Frank studies
ribosomes, cellular machinery that carries out the synthesis of all proteins.
He has pioneered the use of cryo-electron microscopy and his own image
processing software to reconstruct maps of large biological molecules. This
is the first picture of viral genetic material bound to a ribosome at the
start of protein synthesis."Dr. Frank's research epitomizes the quality of
scientific research conducted in New York State and illustrates how
cutting-edge basic science can address a problem of pressing public health
importance," State Health Commissioner Dr. Antonia C. Novello said.The
majority of people infected with hepatitis C (HCV) develop chronic liver
disease, cirrhosis or liver cancer. The Centers for Disease Control and
Prevention estimates that HCV costs the U.S. $600 million a year in
health-care costs and lost wages. Available therapies fail in many cases,
resulting in 10,000 deaths annually in this country. A drug that attacks
molecular targets presented by the virus without harming the tissues and
organs the virus infects would be a significant advance. Ribosomes may be
just such a target.Ribosomes read the genetic code and translate its message
into proteins,the molecular workhorses of life. Ribosomes are themselves
composed of proteins and ribonucleic acid (RNA). Earlier three-dimensional
reconstruction efforts by Dr. Frank and others showed the structure of the
two unequal subunits of this giant macromolecule. In the case of eukaryotes
(organisms whose genetic material is enclosed in a nucleus), these are 40S
and 60S subunits.The present work shows a reconstruction of HCV RNA bound to
the 40S ribosomal subunit from rabbits. The detailed images obtained by the
Frank group show how the virus directs the cell to synthesize its own
proteins for constructing more viruses, leading to the eventual destruction
of the infected cell.In normal cells, messenger RNAs that code for proteins
are recognized by a collection of helper molecules, named initiation factors,
which bind them to ribosomes and instruct the ribosomes where to begin
translating their sequence into proteins.Hepatitis C RNA, by contrast,
contains a complex structure at one end that allows it to directly interact
with ribosomes, dispensing with the need for most initiation factors. This
structure, an internal ribosomal entry site (IRES), gives the viral RNAs an
unfair advantage over normal cellular RNAs, allowing them to subvert the
cell's machinery for their own purpose. The virus gains a competitive edge by
forcing a dramatic change in the shape of the ribosome, placing itself in the
optimal position to then be decoded into a protein."Before, this process was
a complete puzzle," says Dr. Frank. "People knew that viruses would introduce
their messenger RNAs, but how could that be done to the exclusion of host
messenger RNAs being expressed? Our reconstruction shows how the host's
mechanism is completely disabled."Dr. Frank's combination of cryo-electron
microscopy (cryo-EM) and image processing captures ribosomes and other
macromolecular machines in their native, dynamic states. Thousands of
ribosomes are rapidly frozen and their images obtained by an electron
microscope with a low-intensity beam. Using the SPIDER software that he
developed, thousands of the cryo-EM images are transformed into a
three-dimensional map. A complementary structural technique, x-ray
crystallography, provides atomic-level detail of static, biological
molecules. Together, they can point pharmaceutical researchers to a
molecule's active site so that drugs can be developed to initiate or inhibit
activity.Co-authors of the Science paper are Christian Spahn, Robert
Grassucci and Pawel Penczek of the Wadsworth Center and Jeffrey S. Kieft,
Kaihong Zhou and Jennifer Doudna of Yale University. The work was supported
by the Howard Hughes Medical Institute and grants from the National
Institutes of Health and the National Science Foundation.Wadsworth Center is
the public health and research laboratory of the New York State Department of
Health. Wadsworth's role in detecting and responding to disease threats, and
ensuring the quality of laboratories services received by state residents, is
complemented by a long-standing commitment to biomedical and environmental
research. The Center also houses the Resource for the Visualization of
Biological Complexity, a National Institutes of Health-supported
biotechnology facility directed by Dr. Frank. - By Katherine S. Zdeb


"When the way comes to an end, then change - having changed, you pass through."

      I. Ching


 Bruce "Doc". Melson



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