Researchers Publish Model of SARS Protein;
Suggest It May Prove Useful in Therapeutics

All Information Freely Available Through Science / AAAS

Scientists built a model of a SARS coronavirus "protease" which may prove useful in the development of protease inhibitors for SARS therapeutics according to a paper being released today, 13 May 2003, by the AAAS journal Science.

To construct a model of this protease — an enzyme involved in viral replication — the researchers studied the crystal structures of an enzyme from human coronavirus 229E (one cause of the common cold) and an enzyme from a pig coronavirus in complex with a peptide inhibitor.

After modeling the SARS coronavirus protease, Kanchan Anand and his German colleagues suggest that an existing small molecule, named "AG7088," may be a good starting point for developing SARS therapeutics. AG7088 is currently in clinical trials as a treatment for "rhinovirus" a bug that can cause the common cold.

The authors propose AG7088 as one initial starting point for the creation of SARS coronavirus protease inhibitors because of similarities between the rhinovirus and SARS coronavirus proteases.

"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. However, the new crystal structures, together with the modeled inhibitor, provide a good starting point for the design of such modifications," said Rolf Hilgenfeld, the senior author on the paper from the University of Luebeck in Luebeck, Germany.

The authors also provide data demonstrating that the recombinant SARS coronavirus protease cuts a peptide that is known to be cut in the same place by the pig coronavirus protease. This data confirms predictions about similarities between the substrate binding sites of the proteases.

The SARS coronavirus protease described in this study is an example of the common cellular enzymes that viruses often carry. These enzymes enable the virus to shut down host processes and to convert the infected cell into a virus factory. Specific inhibitors of these virus-encoded enzymes can lead to effective drugs with high safety factors.

Download the complete article, "Coronavirus Main Proteinase (3CLpro) Structure: Basis for Design of anti-SARS Drugs."

More information about SARS can be found here:

Toward SARS Therapeutics:
www.eurekalert.org/pub_releases/science/2003-05/
sars-anand-5-03-public.html

First Peer-reviewed SARS Genome Sequence Appears in Science:
www.eurekalert.org/pub_releases/science/2003-05/
sars-5-03-public.html

Science tracks progress on SARS:
www.sciencemag.org/feature/data/sars

EurekAlert!:
www.eurekalert.org

Latest information on SARS from the Centers for Disease Control and Prevention (CDC):
www.cdc.gov/ncidod/sars

Latest information on SARS from the World Health Organization (WHO):
www.who.int/csr/sars/en

ProMED-mail, the Program for Monitoring Emerging Diseases, from the International Society for Infectious Diseases:
www.promedmail.org/pls/askus/f?p=2400:1000

—Daniel Kane

13 May 2003