來自美國加爾維斯敦的德克薩斯州大學(xué)醫(yī)學(xué)部（University of Texas Medical Branch,，UTMB）的生物醫(yī)學(xué)研究人員已經(jīng)遷搶先在研制有效治療委內(nèi)瑞拉馬腦脊髓炎（Venezuelan Equine Encephalitis ，VEE）病毒方法方面邁出了重要的一步,。委內(nèi)瑞拉馬腦脊髓炎病毒是一種潛在的生物武器,。研究者的成就在于他們證實了該病毒復(fù)制所需要的一種蛋白的結(jié)構(gòu),。
蚊子途徑傳播的VEE病毒的爆發(fā)周期性的肆虐著美國的中部和南部，該病毒感染成千上萬的人和殺死數(shù)十萬頭牛,、驢和騾子,。VEE病毒在冷戰(zhàn)期間被美蘇兩國發(fā)展成為武器生物武器，因此專家們也害怕該病毒可能作為恐怖分子的一種潛在的生物恐怖武器,。
研究中,，科學(xué)家們將目標(biāo)聚焦到一種集名為nsP2蛋白酶的蛋白。它的作用就好像一把分子剪刀,，將另一種VEE蛋白復(fù)合體剪成特定的小蛋白分子,，然后這些小蛋白分子一起將活細(xì)胞轉(zhuǎn)變成VEE病毒工廠。“該蛋白對于VEE病毒的復(fù)制至關(guān)重要,，我們的目的是想要研制一種藥物來關(guān)閉這種蛋白,。”該研究的高級作者，Stanley W. Watowich說,。
一位UTMB生物化學(xué)與分子生物學(xué)副教授補充說“現(xiàn)在我們知道了這種蛋白酶的形狀,，我們可以開始一項系統(tǒng)的以計算機為基礎(chǔ)搜尋一種能抑制該蛋白酶活性的化學(xué)物。阻止被感染個體體內(nèi)VEE病毒的繁殖，防止VEE病毒的爆發(fā)和延伸,。”
VEE蛋白酶抑制劑與HIV的蛋白酶抑制劑的作用機理大體相似,，Watowich說，在VEE病毒不能復(fù)制的情況下,，人類和馬類動物的免疫系統(tǒng)將可以壓倒VEE病毒,，病毒感染就可以消除，而不僅僅是停留在控制住的水平,，永久性用藥將不再需要,。
根據(jù)Watowich的說法，“具有前景的治療藥物可進行為期兩年的臨床前研究,。多虧了與德州大學(xué)奧斯丁分校強大的計算機中心和IBM公司的合作,，我們能夠獲得該蛋白酶的結(jié)構(gòu)，并且可以通過在數(shù)百萬種分子組成的“庫”中尋找具有正確的結(jié)構(gòu)和化學(xué)性質(zhì)來關(guān)閉這種蛋白酶的分子,。”
為了獲得一個足夠詳細(xì)的結(jié)構(gòu)來進行藥物尋找研究,，研究人員利用X射線結(jié)晶學(xué)的方法來掃描該蛋白的結(jié)晶體樣品，研究過程中還利用了UTMB的設(shè)備和路易斯安那州立大學(xué)高級顯微結(jié)構(gòu)與設(shè)備中心的高能同步加速器資源,。
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.”
