科学家解析流感病毒RNA聚合酶结构 为新的抗流感药物打开通道
2012-08-06 23:33:29   来源： 丁香园   作者：  评论：0 点击：

1.Researchers at the European Molecular BiologyLaboratory (EMBL) in Grenoble, France, have determined the detailed3-dimensional structure of part of the flu virus' RNA polymerase, an enzymethat is crucial for influenza virus replication. This important finding ispublished in PLoS Pathogens. The research was done on the 2009 pandemicinfluenza strain but it will help scientists to design innovative drugs againstall the different influenza strains, and potentially lead to a new class ofanti-flu drugs in the next 5-10 years.

欧洲分子生物学实验室（EMBL）的研究人员发现了 部分流感病毒RNA聚合酶的三维结构，RNA聚合酶是对于流感病毒复制很重要的酶类。这项重要的发现发表在PLoSPathogens刊物上。这项研究是 在2009年流感大爆发的时候开展的，但是它同样有助于科学家开发出针对不同流感病毒的创新型药物。这项研究有可能使科学家们在未来5-10年的时间内研 究出一系列新型抗流感病毒药物。

2.The scientistsfocused on the endonuclease part of the viral RNA polymerase. The endonuclease isresponsible for a unique mechanism called 'cap-snatching' thatallows the virus to trick its host cell into producing viral proteins. Inhuman cells the translation of messenger RNA (mRNA) strands into proteinsrequires a special structure, called the "cap", at the beginning ofeach mRNA. When the influenza virus infects a host cell its endonuclease"snatches" that cap from the cell's own mRNA. Another part of its RNApolymerase then uses it as the starting point for synthesizing viral mRNA. Withthe correct cap structure at the beginning, viral mRNA can then hijack theprotein-production machinery of the infected cell to make viral proteins, whichassemble into new viruses that will spread the infection.

科 学家们主要关注病毒RNA聚合酶的核酸内切酶部分，核酸内切酶在“戴帽”过程中发挥作用。病毒“戴帽”的过程可以使宿主细胞合成病毒蛋白。在人类细胞中， 信使RNA转化为蛋白质需要一段特殊的结构，这段结构位于RNA 的头端，我们称之为“帽子”结构。当流感病毒感染宿主细胞时，病毒自身的核酸内切酶会“抢”走宿主细胞mRNA的“帽子”结构，这是病毒RNA聚合酶的其 余部分会利用“帽子”结构作为合成病毒mRNA的起点。由于具有病毒mRNA具有宿主细胞mRNA的帽子结构，因此病毒mRNA就会干扰宿主细胞的蛋白合 成过程，并使宿主细胞合成病毒蛋白，这样就会组装出新的病毒使感染扩散。
3.The team led byStephen Cusack, Head of EMBL Grenoble, analyzed crystals of endonuclease fromthe 2009 pandemic influenza strain using the high intensity X-ray beams at theEuropean Synchrotron Radiation Facility (ESRF). The researchers were able todetermine the 3D atomic structure of the enzyme and to visualize how severaldifferent small molecule inhibitors bind to and block its active site. If theactive site of the endonuclease is blocked by an inhibitor the enzyme cannotbind its normal substrate, the host cell mRNA, and viral replication isprevented.
这个研究小组组长是EMBL 负责人StephenCusack，他在欧洲同步辐射实验室(ESRF)利用高密度的X射线分析了导致2009年那场大爆发流感的病毒核酸内切酶的晶体结 构。研究人员能够确定核酸内切酶的三维原子结构，并且可以观察到一些小的分子抑制剂是如何附着在活性中心并使其活动中心失活的。如果核酸内切酶的活性中心 被抑制剂结合，那么核酸内切酶就不能与宿主mRNA正常结合，病毒复制就被阻止了。
4.The active site ofthe endonuclease is shaped like a cave with two metal ions at the bottom.Cusack and colleagues found that all the inhibitors they studied bind to thosetwo metal ions but, depending on their shapes, different inhibitors binddifferently to the amino-acids of the cave's walls.
核酸内切酶的活性中心形状类似于洞穴，在活性中心的底部有两个金属离子。Cusack和他的同事们发现他们所观察的所有的抑制剂均是结合到这两个金属离子上，但是由于形状不同，这些不同的抑制剂会分别与“洞穴”墙壁上的氨基酸类化合物结合。

5."Based on thisdetailed structural information we can now design new synthetic chemicals whichbind even more tightly to the endonuclease active site and thus willpotentially be more potent inhibitors of influenza virus replication,"explains Stephen Cusack. "We can even try to build in anti-drug resistanceby making sure the inhibitors only contact those amino acids that the viruscannot mutate since they are essential for the normal activity of thepolymerase."
Stephen Cusack说：“基于这么详细的结构信息，我们现在可以设计新的合成药物。这些药物可以与核酸内切酶的活性部位结合的更加紧密，因此也会更有效的抑制病 毒复制。我们甚至就可以尝试建立一种抗耐药机制，比如病毒的活性中心是保持聚合酶活性的基础，病毒不能在这些活性中心产生突变，那么我们就可以使这些抑制 剂只与那些活性中心的氨基酸类化合物结合，这样就可以减少病毒耐药的产生。
6.Because thecap-snatching mechanism is common to all influenza strains, new potentendonuclease inhibitors should be effective against seasonal flu, novel pandemicstrains or highly pathogenic H5N1 bird flu. EMBL scientists are working withEMBL's spin-off company Savira pharmaceuticals, in partnership with Roche, tofurther develop influenza inhibitors. Promising candidates will be tested firstfor efficacy in cell culture, ultimately moving into clinical trials on humans.

因为“抢帽“机制在所有的流感病 毒种类中都很常见，因此新的核酸内切酶抑制剂应该对季节性流感、新型流行毒株、高致病性的禽流感病毒均有效。EMBL的科学家们正在与EMBL下属的制药 公司Savira，以及制药公司Roche合作来进一步开发流感病毒抑制剂。开发出的新药首先会在细胞培养基上检测它的有效性，最后会再人体上进行临床试 验。