New discovery may lead to treatments for lethal Ebola virus

The Ebola virus - one of the deadliest
diseases known to man - has been
appearing throughout the world with
increasing frequency over the last two
years. There is no cure and no vaccines
exist for the disease, which has a fatality
rate of up to 90 percent.
However, in a new study published in the
journal Cell , scientists are revealing a
breakthrough discovery regarding the
molecular mechanism behind the Ebola
virus, possibly paving the way for
effective treatments in the future.
For the past 10 years, researchers
believed they had a good understanding
of this mechanism. Yet certain questions
about how the virus operated and spread
remained, prompting study author Erica
Ollmann Saphire and her colleagues to
examine the virus further.
"We'd been looking at other proteins in
the virus and how they work. It's a
fascinating virus and only has seven genes - compared to a human with 20,000
genes," Saphire, professor in the
department of immunology and microbial
science at the Scripps Research Institute
in La Jolla, Calif., said. "How does this
virus do everything it needs to do with
only a couple of tools in its tool kit?"
Ebola is highly virulent, spreading rapidly
when a person comes into contact with
bodily fluids of an infected person or
animal. People who contract the infection
initially come down with a high fever,
headache and body aches. But the disease
progresses quickly and soon begins to
replicate in extremely high concentrations
within the blood.
"The virus replication causes tissue
destruction, and the virus protein causes
you to clot where you aren't supposed to
and bleed where you aren't supposed to,"
Saphire said. "You get disseminated
intravascular coagulation, which causes
vomiting, diarrhea and essentially you die
from shock."
Upon examining the Ebola VP40 protein,
the biological mechanism at the root of
the lethal disease, Saphire and her
colleagues discovered something shocking:
the protein which was previously thought
to be a monomer, or single molecule, was
actually a dimer, a pair of molecules.
"We'd thought that the structure of the
protein was solved," Saphire said. "That
the structure available must resemble how
the protein builds the virus, because a
central dogma that we all learn as
biochemistry students is that the
sequence of a protein dictates its fold and
the fold dictates its function. A one-way
destiny of sequence to function. It was a
surprise that this sequence makes so
many structures for so many functions."
Thanks in part to improved technologies,
Saphire and her team were able to see the
Ebola VP40 protein with more clarity than
previous researchers. They ultimately
found its structure and behavior were
different when compared to typical
monomer proteins.
"The virus life cycle is it's floating around,
finds a cell, dives in, makes copies of all
the protein and then those assemble into
new viruses and bud out," Saphire said.
However, researchers noticed that the
Ebola VP40 protein was shifting shapes as
it made its way through the various stages
of virus assembly before branching out
and spreading to other cells, in a way
never before seen.
"The analogy we like to use is (that it's
like) a transformer. It has all the right
parts, but one stage is born as a robot...
Then...it unfolds and refolds," Saphire
said. "What we need to do is design drugs
to prevent it from changing."
Currently, no treatments exist for the
Ebola virus and patients can only be
offered supportive care as the disease
makes its way through their bodies. Yet,
this discovery opens up the possibility of
developing treatment options that could
kill the virus before it spreads.
"In terms of practical use, we see it uses
structures A, B and C, and now we know
that a drug that inhibits A can kill it, B
can kill it or C can kill it," Saphire said.
"So we now have all of these opportunities
to kill the virus."
Saphire says this knowledge could
someday be used to cure people infected
with the virus. Additionally, prophylactic
drugs could be developed, which would
prove useful to people frequently sent to
high-risk outbreak areas, such as
employees of the Centers for Disease
Control and Prevention (CDC).
Furthermore, now that researchers have
discovered this protein, they are
interested in exploring whether it exists in
other viruses or diseases as well.
"With cancer, where the state of the cell
goes from healthy to cancerous, could
that change be because of the protein
adopting a different structure and we
have never thought to look for that
before?" Saphire asked. "This speaks to
how information can be encoded and
proteins can do more than we ever
thought."