Scientists Pursue Therapeutics for SARS

A model of a severe acute respiratory syndrome (SARS) coronavirus protease may prove useful in the development of protease inhibitors for SARS therapeutics, according to an article published in the May 13, 2003, issue of Science.

To construct a model of this protease, researchers studied the crystal structures of an enzyme from the human coronavirus 229E, which is one cause of the common cold, and an enzyme from a pig coronavirus in complex with a peptide inhibitor. Based on the resulting model, they suggest that an existing small molecule named AG7088 may be a good starting point for developing therapies for SARS. AG7088, made by Pfizer (New York, NY, USA), was originally developed to treat the common cold but has never been marketed.

Data show that the recombinant SARS coronavirus protease cuts a peptide known to be cut in the same place by the pig coronavirus protease. This confirms predictions about the similarities between the substrate binding sites of the proteases. The coronavirus protease described in the current article is an example of the common cellular enzymes often carried by viruses. These enzymes enable the virus to shut down host processes and convert the infected cell into a virus factory. Specific inhibitors of these enzymes can lead to effective drugs with high safety profiles.

"There are some minor clashes between the inhibitor AG7088 and the structure of SARS coronavirus main protease; therefore, this compound, AG7088, is unlikely to be a drug active against coronavirus infections. It needs to be modified,” said senior author Rolf Hilgenfeld, of the University of Luebeck (Germany). Other German researchers participating were from the Institute of Molecular Biotechnology (Jena), the University of Wurzburg, and the University of Jena.




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