来自美国加尔维斯敦的德克萨斯州大学医学部（University of Texas Medical Branch，UTMB）的生物医学研究人员已经迁抢先在研制有效治疗委内瑞拉马脑脊髓炎（Venezuelan Equine Encephalitis ，VEE）病毒方法方面迈出了重要的一步。委内瑞拉马脑脊髓炎病毒是一种潜在的生物武器。研究者的成就在于他们证实了该病毒复制所需要的一种蛋白的结构。
蚊子途径传播的VEE病毒的爆发周期性的肆虐着美国的中部和南部，该病毒感染成千上万的人和杀死数十万头牛、驴和骡子。VEE病毒在冷战期间被美苏两国发展成为武器生物武器，因此专家们也害怕该病毒可能作为恐怖分子的一种潜在的生物恐怖武器。
研究中，科学家们将目标聚焦到一种集名为nsP2蛋白酶的蛋白。它的作用就好像一把分子剪刀，将另一种VEE蛋白复合体剪成特定的小蛋白分子，然后这些小蛋白分子一起将活细胞转变成VEE病毒工厂。“该蛋白对于VEE病毒的复制至关重要，我们的目的是想要研制一种药物来关闭这种蛋白。”该研究的高级作者，Stanley W. Watowich说。
一位UTMB生物化学与分子生物学副教授补充说“现在我们知道了这种蛋白酶的形状，我们可以开始一项系统的以计算机为基础搜寻一种能抑制该蛋白酶活性的化学物。阻止被感染个体体内VEE病毒的繁殖，防止VEE病毒的爆发和延伸。”
VEE蛋白酶抑制剂与HIV的蛋白酶抑制剂的作用机理大体相似，Watowich说，在VEE病毒不能复制的情况下，人类和马类动物的免疫系统将可以压倒VEE病毒，病毒感染就可以消除，而不仅仅是停留在控制住的水平，永久性用药将不再需要。
根据Watowich的说法，“具有前景的治疗药物可进行为期两年的临床前研究。多亏了与德州大学奥斯丁分校强大的计算机中心和IBM公司的合作，我们能够获得该蛋白酶的结构，并且可以通过在数百万种分子组成的“库”中寻找具有正确的结构和化学性质来关闭这种蛋白酶的分子。”
为了获得一个足够详细的结构来进行药物寻找研究，研究人员利用X射线结晶学的方法来扫描该蛋白的结晶体样品，研究过程中还利用了UTMB的设备和路易斯安那州立大学高级显微结构与设备中心的高能同步加速器资源。
英文原文：
New VEE virus protein structure marks first step to developing effective therapy
Biomedical researchers at 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 published in the Sept. 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.”
