Researchers probe enzyme that may lead to new SARS drugs

Researchers at the University of Illinois at Chicago and two other institutions have unraveled the structure of an important new drug target from the virus that causes SARS, severe acute respiratory syndrome.

"By unlocking the three-dimensional structure of this enzyme -- known as papain-like-protease (PLpro) -- we now have a molecular road map to design new drugs that could potentially treat SARS-infected patients, or perhaps patients suffering from other SARS-related illnesses such as the common cold, bronchitis or pneumonia," said Andrew Mesecar, associate professor of pharmaceutical biotechnology in the UIC College of Pharmacy. "We are attempting to use the same approach that has been accomplished in designing effective drugs against HIV protease, which has led to the development of new drugs to fight the AIDS virus."

The research is published in the March 27 issue of the Proceedings of the National Academy of Sciences.

Mesecar said that the knowledge gained from this new atomic structure -- the first-ever reported on this class of proteases -- has the potential to go beyond the treatment of patients infected with the coronavirus that causes SARS.

Coronaviruses, which produce upper respiratory tract infections, were discovered in the late 1960s. The viruses are responsible for 10 percent to 30 percent of all common colds. Recently, two new coronaviruses -- NL63 and HKU1 -- were found to cause many cases of severe pneumonia in children and the elderly throughout the world, he said.

"NL63 and HKU1 infections are severe and often lead to hospitalization," Mesecar said. "It is believed these viruses have been around a long time, but only recently have we developed the technology to identify and detect them. The SARS outbreak and quick response of the scientific community has led to the rapid development of such technology."

SARS was first reported in Asia in early 2003. Over the next several months the illness spread to more than 29 countries in North and South America, Europe and Asia before it was contained. It begins with a high fever, headache and body aches. About 10 percent to 20 percent of patients have diarrhea, and after two to seven days, a dry cough may develop. Most patients develop pneumonia. The infection spreads by close personal contact, often through coughing or sneezing.

According to the World Health Organization, 8,098 people worldwide were diagnosed with SARS during the 2003 outbreak; 774 died. There were 29 cases reported in the United States, with no fatalities.

The papain-like-protease enzyme is essential for viral replication and infection of all of the coronaviruses involved in upper respiratory infections. Eliminating the enzyme should stop the infection, Mesecar said.

During the UIC study, graduate student Kiira Ratia, a member of Mesecar's research team, used X-ray crystallography, a technique that involves bombarding a crystalline form of the enzyme with an intense beam of X-rays that are bent by atoms in the molecules to unlock the details of the molecular structure. The X-ray studies were conducted at Argonne National Laboratory's Advanced Photon Source.

As the X-rays leave the crystal, a unique pattern is created on an ultra-high resolution charge-coupled device camera, a sensor for recording images often used in digital photography and astronomy. The images were then interpreted by computer to reconstruct the positions of all the component atoms.

"We have already discovered compounds that can bind to these pockets and inhibit the activity of this enzyme," Mesecar said. "We have made remarkable progress in a short period of time in generating lead drug-like compounds against the enzyme."

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The research was funded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

In addition to Ratia, other authors included Bernard Santarsiero of UIC; Kumar Saikatendu and Raymond Stevens of the Scripps Research Institute in La Jolla, Calif., and Naina Barretto and Susan Baker of Loyola University Chicago Stritch School of Medicine.


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