Sino-European Project on SARS Diagnostics and Antivirals
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.[+] Read More
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.