| SARS (severe acute respiratory
syndrome) became a part of our lives in the spring of 2003. Healthcare
communities faced incredibly difficult and complex challenges as
they tried to deal with this mysterious and new disease.
The Canadian Protein Engineering Network, or PENCE, reacted quickly
when the SARS epidemic took Toronto, and the world, by surprise. The
Network rapidly mobilized $300,000 in funding for research toward
the identification of validated targets for therapeutics, as well
as lead compounds and libraries of drug candidates.
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SARS Web site has information for researchers
and the public
Early in the fight to characterize the virus and find
effective therapies for SARS, PENCE recognized the need
to have an effective and efficient way to disseminate
the ever-increasing information and data available on
SARS, and to provide access to computer tools for analyzing
the SARS genome and proteins.
Two PENCE researchers, Chris Upton and Rachel Roper
at the University of Victoria, quickly developed the
SARS Bioinformatics Suite based on their work on the
Poxvirus Bioinformatics Resource, which supports researchers
working on vaccines and drugs against smallpox.
The SARS Bioinformatics Suite, available at www.sarsresearch.ca,
is primarily for research purposes but also contains
links to information for the public, including the latest
news on SARS. It provides scientists with a manually
curated and annotated database of all available SARS
genome sequences together with a variety of easy-to-use
integrated tools for comparing and analyzing the genomes.
"The SARS Bioinformatics Suite provides 'one-stop
shopping' for genomic information and analysis tools
for the SARS virus. Its funding by PENCE enables us
to support researchers worldwide and avoid wasteful
duplication of resources," says Dr. Upton.
Funding to continue to maintain and update the site
has been awarded by PENCE in its latest competition
for SARS research.
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"Our ability to quickly commit and deploy almost 10 percent of
our annual research funding highlights how a pre-established network
of researchers, such as PENCE, can rapidly respond to national emergencies,"
says Dr. Stephen Withers, CEO and Scientific Director of PENCE.
Within days of the announcement of the determination of the SARS genome
sequence, PENCE researchers had begun work on key proteins. Within
four weeks, a series of projects had been proposed, peer-reviewed,
and funded. Some of these were in conjunction with the B.C. SARS Vaccine
Initiative (SAVI).
Seed funds from PENCE have led to excellent progress toward the
identification of potential lead drug candidates to treat SARS.
Indeed, in just over a year, several papers have already been published,
and several others submitted.
"The capacity for rapid sequencing of complete pathogen genomes
has changed the face of research into the development of therapeutics
and diagnostics for these diseases. With the sequence information
in hand, research can start immediately in standard labs without
the need for containment facilities," says Dr. Withers.
PENCE held a second SARS funding competition in the spring of 2004.
Through this competition a further $444,500 was committed to fund
successful continuing projects, as well as two new projects.
Characterization of the virus and the problem of developing appropriate
therapies is a continuing global effort. PENCE researchers and others
around the world are developing strategies for targeting the virus
at many different levels.
The main proteinase (an enzyme that cleaves other proteins) of
the SARS virus (3CLpro) plays a crucial role in viral replication
by mediating the cleavage of "polyproteins" into the functional
units required for viral replication. Therefore, 3CLpro represents
an excellent target for therapeutics to treat SARS, much as drugs
targeting the HIV proteinase are used to treat AIDS.
One PENCE group (Eltis, Brown, Vederas, James, Wishart) contributed
to the SARS initiative by employing two strategies to generate novel
leads (potential drugs): high throughput screening (HTS) and rational
design. HTS identified several small molecules that specifically
block 3CLpro. The researchers have made the primary screening data
set publicly available so that it can be used by others, such as
those identifying structure-activity relationships in 3CLpro or
other viral proteinases.
In the second strategy, the group used their knowledge of a related
proteinase to design small molecule inhibitors of 3CLpro. Continuing
studies of these leads and the crystal structures will investigate
how they inhibit 3CLpro and their potential to provide a basis for
innovative antiviral therapies.
"Our small molecule leads combined with emerging structural
information puts us in a unique position to make an exciting contribution
to the development of therapeutics for SARS," says Dr. Lindsay
Eltis, a PENCE researcher at UBC.
Another PENCE group (Seidah and Chrétien) has been studying
the role of proprotein convertases (PCs) in SARS infection. These
host enzymes normally cleave specific cell surface proteins and
enable the virus to fuse with the host membrane. The researchers
have recently demonstrated that the SARS-CoV S protein is processed
by PC-like proteases for the virus to be infectious and that inhibition
of the PCs may represent an alternative strategy beneficial to patients
infected with SARS-CoV. A PC inhibitor could possibly be used along
with vaccination or in conjunction with Interferon treatment.
In view of the widespread implications of the PCs in the processing
of various surface glycoproteins of infectious viruses, development
of a small molecule inhibitor of the convertases is needed, as its
usefulness will likely extend to other emerging infectious agents.
In other work by the Seidah lab, it was shown that chloroquine,
a treatment for malaria, has strong antiviral effects on the SARS-CoV
in specially manufactured cells that are infectable by the SARS-CoV.
To date, no effective therapy has been reported, so these results
are very encouraging. The effects were observed when the cells were
either pretreated with the drug or treated after exposure to the
virus, suggesting both a protective and therapeutic advantage. The
antiviral effect observed may be due to a combination of factors
including the increased pH in the cells and interference with various
required processing of both the viral protein and its receptor.
In these, as well as in the other eight PENCE-funded projects,
exciting and innovative research into SARS continues.
www.pence.ca
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