The SARS Virus Yields Up Its Secrets

The SARS coronavirus that sparked a global panic three years ago uses a key coat protein, called S2, to gain entry into human host cells. Now, a team of biochemists at the Weill Medical College of Cornell University in New York City has identified four important steps in this process -- each of which could be a potent new target for drugs or vaccines aimed at stopping SARS, should it reappear.

"S2-mediated entry into the host cell is vital to infection. By identifying mechanisms important to infection, we're a step closer to pharmaceuticals that can break that chain of events," explains senior researcher Dr. Min Lu, associate professor of biochemistry at WeillCornellMedicalCollege.

His team published their findings in the May 16, 2006 issue of Structure.

Severe acute respiratory syndrome (SARS) was first reported in Asia in February 2003. Over the next few months, the illness spread to more than two dozen countries in North America, South America, Europe and Asia before the global outbreak was contained.

According to the World Health Organization, 8,098 people worldwide became sick with SARS during the outbreak, and 774 died. Since that time, there has not been another SARS outbreak.

The threat remains, however, and scientists have raced to discover some kind of viral Achilles' heel that will both give them a better understanding of how SARS spreads, and how it might be controlled.

"Because of years of research into HIV, scientists already know a lot about how these types of viruses gain entry into cells," Lu notes.

In the case of SARS, the S2 protein lying on the virus' outer membrane is the "fusion machine" that allows the virus to fuse its outer membrane with that of the host cell. Once this fusion occurs, the virus can insert its genome into the host cell, where it replicates, bursts forth, and spreads to new cells.

"So, understanding how S2 works is key to stopping infection," Lu says. "The molecule's heptad-repeat regions have unusual structural and thermodynamic features."

Using biophysical methods, his team has discovered and described the conformations of four distinct S2 "domains" -- structures and polymorphic interactions of the two heptad-repeat regions that are released and then refolded as membrane fusion occurs.

"This process occurs in a series of steps the virus has devised over time to protect itself as it penetrates the cell," Lu explains.

Identifying these steps is crucial to the development of antiviral drugs that might fight SARS.

"HIV research has already proved the concept that various stages in membrane fusion can be useful targets for drug therapy, and many powerful antivirals are focused on inhibiting one of these intermediate steps," Lu observes.

Already, agents called C-peptides look promising in their ability to block one of the four domains outlined in the study.

The identification and structural determination of the four distinct conformations of S2 also suggest a potential strategy for SARS vaccine development.

"Because it lies on the outer membrane, S2 is really the prime target for neutralizing antibodies," Lu says. "Right now, development of a SARS vaccine remains a long shot, but this kind of research at least gives us a place to start."

According to Lu, the stabilized forms of a soluble coat protein complex might lead to useful immunogens in efforts to elicit neutralizing antibodies. "That's our next challenge. Once we have the structural model of the complex, we can build on what we've learned to fight SARS, before it threatens us again," he says.

The study was funded by grants from the National Institutes of Health and the Irma T. Hirschl Trust.

Co-authors include lead researchers Dr. Yiqun Deng and Dr. Jie Liu, as well as Dr. Qi Zheng and Wei Yong -- all of Weill Cornell Medical College in New York City.

Source: Weill Cornell Medical College

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