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DRUG DISCOVERY
Using crystal structures of a crucial enzyme from two related coronaviruses as a guide, German scientists claim to have identified a promising starting point for the design of a drug to combat severe acute respiratory syndrome. Many viruses, including the coronavirus that causes SARS, rely on a protein-cleaving enzyme called main proteinase to activate replication. Such viruses must replicate themselves in order to cause infection, making this enzyme a prime target for drug development. Rolf Hilgenfeld, director of the Institute for Biochemistry at the University of Lübeck, in Germany, and his coworkers determined X-ray crystal structures of the main proteinases produced by a human coronavirus and a pig coronavirus. Hilgenfeld's team used their structures to create a structural model of the SARS coronavirus main proteinase [Science, published online May 13, http://www.sciencemag.org/cgi/rapidpdf/1085658v1]. Eidogen, based in Pasadena, Calif., made public its own model of the same enzyme on May 14.
On the basis of its model, Hilgenfeld's team suggests that AG7088--a main proteinase inhibitor that Pfizer has tested against the virus that causes the common cold--would be a good jumping-off point for the design of inhibitors of the SARS main proteinase. AG7088 doesn't fit perfectly, Hilgenfeld notes, but the model suggests how the compound can be modified to bind better. Following release of the German group's findings, Pfizer confirmed that it has given AG7088 and other compounds to the U.S. Army Medical Research Institute of Infectious Diseases and the National Institute of Allergy & Infectious Diseases to test for efficacy against SARS. |
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