SARS is a respiratory illness that has recently been reported in Asia, North America, and Europe. The illness usually begins with a fever (measured temperature greater than 100.4°F [>38.0°C]). The fever is sometimes associated with chills or other symptoms, including headache, general feeling of discomfort, and body aches. Some people also experience mild respiratory symptoms at the outset.

After 2 to 7 days, SARS patients may develop a dry, nonproductive cough that might be accompanied by or progress to the point where insufficient oxygen is getting to the blood. In 10% to 20% of cases, patients will require mechanical ventilation.

The principal way SARS appears to be spread is through droplet transmission; namely, when someone sick with SARS coughs or sneezes droplets into the air and someone else breathes them in. It is possible that SARS can be transmitted more broadly through the air or from objects that have become contaminated.

D2OL's target is also believed to be critical in the life cycle of the Coronovirus and drugs selected against it our expected to be viralcydal.

With your help we are testing compounds that are readily available, and credible "hits" can be tested in cell and animal models of the disease to confirm potential utility in man.

Structure of coronavirus main proteinase reveals combination of a chymotrypsin fold with an extra α-helical domain

Kanchan Anand, Gottfried J. Palm, Jeroen R. Mesters, Stuart G. Siddell¹,John Ziebur¹,
and Rold Hilgenfeld *
Department of Structural Biology and Crystallography Institute of Molecular Biotechnology, D-07745 Jena ¹Institute of Virology and Immunology, University of Würzburg, D-97078, Würtzburg, Germany

D2OL's target is also believed to be critical in the life cycle of the Coronovirus and drugs selected against it our expected to be viralcydal.

All coronaviruses make a protein called the "Coronavirus Main Protease" or 3CL-PRO , for short. This protein is absolutely essential for the virus to make copies of itself and spread the infection, so stopping this protein from working would very likely stop the virus. This protein is also very sexy from a drug development standpoint. Pharmaceutical companies already know how to make drugs that inhibit proteases made by viruses (e.g., ritonavir and indinavir are major components of anti-HIV drug regimens). It also turns out that the Agouron division of Pfizer has already successfully made drugs against the 3CL-PRO protein found in the virus responsible for the common cold (rhinovirus). The Coronavirus Main Proteinase is, therefore, an excellent drug target for anti-SARS therapy and why we selected this target 4 weeks ago.

As many of the techies already know, to prepare a drug target to work in a docking environment, it is essential that its X-ray crystal structure be solved. This work is typically done by expert biophysicists working in either industrial or academic labs. In order for D2OL to consider drug discovery against 3CL-PRO, we needed the coordinates for the protein as determined by X-ray crystal structure. Four weeks ago, (before the SARS virus was characterized) we were very fortunate to find that a group working in Germany had, a few years back, worked out the X-ray crystal structure for the 3CL-PRO from a coronavirus that causes diarrhea in pigs ( the transmissible gastroenteritis virus, TGEV). Because we knew that all coronaviruses are very similar to each other, we made the basic assumption that since the 3CL-PRO was so essential for the coronavirus to work properly that the 3CL-PRO structure was likely to be very similar if not identical among all members of the coronavirus family. We had some evidence of this from the German group who, in their work from 2001, had shown that the key pieces of the 3CL-PRO protein were identical across all 7 of the coronaviruses they looked at. We thus uploaded to the community the 3CL-PRO identified from the pig coronavirus TGEV as a target that will help us find drugs against SARS. Just yesterday, the same German group that previously worked on the TGEV structure published in the journal Science (if you publish here, you are a star and you are made) that they solved the structure for 3CL-PRO from a coronavirus that causes a variety of the human cold (a.k.a. HCo-V) and based on this structure and that from the TGEV, they were able to deduce the structure of the SARS coronavirus 3CL-PRO. Their conclusions were as follows:

1. As per our assumption, the guts of the 3CL-PRO (the parts that make it work correctly) are the similar enough across all coronaviruses such that drugs that are useful for one type should be useful for all

2. Based on the work done by the Agouron scientists, the German team concluded that 3CL-PRO would be an outstanding target to stop SARS.

But we all already knew this 4 weeks ago.

First and foremost, at The Rothberg Institute, we are scientists. Now that we have spent our 5 minutes patting ourselves on the back for picking the right target in 3CL-PRO, we have been very carefully reading the Science paper from the German group and using it to help us put together an action plan. Details are given in the relevant sections below.

CoronaVirus Main Proteinase(3CL^pro) Structure: Basis for Design of anti-SARS Drugs
Sciencexpress
Kanchan Anand,^1,2 Jonh Ziebur,³ Parvesh Wadhwani³, Jeroen R. Mesters,^1,2 Rolf Hilgenfeld^1,2*
¹Institute of Biochemistry, University Of Lübeck, D-23538 Lübeck, Germany.
²Institute of Molecular Biotechnology, D-07745 Jena, Germany.
³Institute of Virology and Immunology, University of Würzeburg, D-97078 Würzburg, Germany
⁴Institute of Molecular Biology, University of Jena, D-07745 Jena, Germany

We would like to thank the authors for supplying the crystal structures to our laboratories prior to public release.