The Sino-European Project on SARS Diagnostics
and Antivirals (SEPSDA) brought together four
European and four Chinese research groups
working on the Severe Acute Respiratory
Syndrome (SARS) Coronavirus. The consortium
determined the three-dimensional structures
of many replicase proteins of the virus by
X-ray crystallography. Based on these target
structures, it discovered about 50 non-toxic
chemical compounds with activity against the
virus; five of these were developed into lead
compounds and are ready for preclinical and
clinical testing in case of a new outbreak of
SARS or another Coronavirus-caused epidemic.
Also, SEPSDA has significantly improved the
existing diagnostics for SARS and introduced
differential diagnostics allowing the rapid and
reliable distinction between the disease and
other forms of viral pneumonia.
When SARS emerged in China, Hong Kong,
Vietnam, Taiwan and Canada in 2003, little
was known about the molecular biology of
Coronaviruses. In particular, reliable diagnosis
was not available (no rapid differential
diagnostics) and no therapy existed.
SEPSDA was set up to achieve breakthroughs in
both the development of better diagnostics of
SARS and structure-based discovery of smallmolecule
compounds with anti-SARS activity.
In order to achieve the latter goal, the threedimensional
structures of many components of
the Coronavirus replicase complex had to be
determined.
Results:
SEPSDA brought together the European
and Chinese research groups that had done
seminal work on the SARS Coronavirus
when this new pathogen emerged in 2003.
During the four years of SEPSDA, these
groups made important contributions to
our understanding of the replication and
transcription mechanisms of the coronaviral
RNA. Furthermore, the knowledge gained
was used for designing drugs that would
interfere with these mechanisms. This was
supported by structure-based drug design;
within SEPSDA, the crystal structures of the
following components of the Coronavirus
replicase complex were determined: X-domain
of Nsp3, SARS-unique domain, Nsp5, Nsp7/8,
Nsp9, Nsp10, and Nsp15.
The main target for anti-SARS drug discovery
was the protease, Nsp5. Many crystal structures
of complexes between Nsp5 and inhibitors
identified within SEPSDA were determined.
SEPSDA researchers elucidated more crystal
structures of coronaviral proteins than any
other consortium working in this field. They
also found about 50 compounds that were
active against the virus. These were either
discovered by virtual screening, by de novo
design, or by screening libraries of Chinese
medicinal compounds. The best of these 'hit
molecules' were then optimised, resulting in
five 'lead compounds', which would be ready
for preclinical and clinical testing in case of a
new outbreak.
In addition to SEPSDA's efforts at discovering
antiviral compounds, the consortium also
worked on improved diagnostics of the virus.
Antibodies against the individual components of
the replicase were raised and a new antibodybased
SARS-CoV assay was developed. Since it
is difficult to quickly decide whether a patient
suffering from pneumonia is infected by the
SARS virus or other respiratory viruses (such
as influenza), advanced differential diagnostics
were developed, allowing this decision to be
taken with confidence. Also, non-infectious
virus-like particles were developed within the
project, for various purposes.
Potential applications:
- Further development into approved drugs
of the anti-SARS lead compounds that were
discovered (in case of a new outbreak).
- Some of the anti-SARS inhibitors that were
discovered also have good activity against
other positive-strand RNA viruses and may
be developed into broad-spectrum antiviral
drugs.
- Differential diagnostics (distinction from
other respiratory viruses)
Coordinator:
Partners:
Dr Peter Kristensen
University of Aarhus
Department of Molecular Biology
Aarhus, Denmark
pk@imsb.au.dk
Dr Leszek Rychlewski
Polish Academy of Science
Bioinformatics Laboratory
Poznan, Poland
leszek@bioinfo.pl
Karin Sonnenberg
Euroimmun AG
Tropical Diagnostics Department
Lübeck, Germany
k.sonnenberg@euroimmun.de
Prof. Zihe Rao
Tsinghua University
Laboratory of Structural Biology
Beijing, People's Republic of China
raozh@xtal.tsinghua.edu.cn
Prof. Hualiang Jiang
Chinese Academy of Science
Shanghai Institute of Materia Medica
Drug Discovery and Design Center
Shanghai, People's Republic of China
hljiang@mail.shcnc.ac.cn
Prof. Jinming Li
National Center for Clinical Laboratory
Division of Immunoassay and Molecular
Diagnosis
Beijing, People's Republic of China
ljm63hn@sina.com
Prof. Huanming Yang
Beijing Genome Institute
Division of Immunoassay and Molecular
Diagnosis
Beijing, People's Republic of China
yanghm@genomics.org.cn
