Biomedical researchers at the University of Texas Medical Branch at Galveston (UTMB) have taken an important early step toward developing effective drug therapies against Venezuelan Equine Encephalitis (VEE) virus, a potential bioterrorist weapon. Their achievement: determining the precise structure of a protein that the virus requires for replication.
Outbreaks of the mosquito-borne VEE virus periodically ravage Central and South America, infecting tens of thousands of people and killing hundreds of thousands of horses, donkeys and mules. Experts also fear VEE's potential as a weapon of bioterrorism because the virus was developed into a biological weapon during the Cold War by both the United States and the Soviet Union. Analysts fret that terrorists could do likewise.
The protein the scientists focused on is known as the nsP2 protease. It acts like a pair of molecular scissors, chopping another complex of VEE proteins into specific smaller protein molecules that work together to transform living cells into VEE virus factories. "This protein is crucial to VEE virus replication, and we want to create drugs that will turn off such proteins," said Stanley W. Watowich, senior author of a paper on the research to be published in the September 12 issue of the journal Structure. The UTMB associate professor of biochemistry and molecular biology added, "Now that we know what this protease looks like, we can begin a systematic computer-based search for compounds that will inhibit its activity, stop the virus from multiplying in infected individuals, and prevent VEE outbreaks from spreading."
VEE protease inhibitors would function much like the protease inhibitors taken by people infected with HIV, Watowich said, but since human and equine immune systems could quickly overwhelm VEE viruses that were unable to replicate, infections would be eliminated instead of merely controlled, and permanent use of the medication would be unnecessary. (Those infected would also acquire immunity to VEE, just as if they had been vaccinated with a weakened form of the virus.)
Potential therapeutic compounds could be available for pre-clinical studies within two years, according to Watowich, thanks to collaborations with powerful computer centers at the University of Texas at Austin and IBM that will be able to take the UTMB protease structure and sift through "libraries" of millions of molecules, looking for those with the right structural and chemical characteristics to keep the "scissors" from closing.
To produce a detailed enough structure to begin this drug search, lead author and Watowich lab postdoctoral fellow Andrew Russo used X-ray crystallography, in which X-rays are used to scan crystallized protein samples, working both with equipment at UTMB and the high power synchrotron radiation source at Louisiana State University's Center for Advanced Microstructures and Devices in Baton Rouge. "It took about a year of hard work by Andrew, but it was worth it," Watowich said. "In the future when we're dealing with one of these periodic VEE outbreaks or a bioterrorist attack, it will be a very good thing if we have an effective medicine in the cabinet ready to use."
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