《自然》子刊：为什么瑞德西韦不能完全阻止冠状病毒

编辑翻译：菁菁

译文校对：奇奇

文献在2020年1月的美国医学学术期刊《自然通讯》（Nature Communications）首次刊发，文献介绍了瑞德西韦（Redesivir）的药理机制，并解释了该药物为何不能完全阻止新冠病毒复制。

瑞德西韦（Remdesivir）是第一款在欧洲和美国获得有条件批准的、用于治疗COVID-19的药物。病毒复制主要依赖RNA聚合酶完成。瑞德西韦的生效机制即为通过阻断RNA聚合酶，抑制SARS-CoV-2病毒在人细胞中的快速复制。位于哥根廷的马克斯·普朗克生化研究所（MPI）和维尔茨堡大学的研究人员在一项研究中阐明了瑞德西韦如何在病毒复制过程中干扰其聚合酶，以及瑞德西韦为什么不能完全抑制病毒聚合酶。

马克斯·普朗克研究所的主任Patrick Cramer说：“经过复杂的研究，我们得出一个简单的结论。瑞德西韦在生效时确实会干扰聚合酶，但是有延迟。而且，该药物不能完全阻止聚合酶发挥作用。” 

新冠大流行初期，MPI生化研究所的Cramer团队阐述了冠状病毒如何复制其RNA基因组。病毒基因组包含30000个RNA构建基块，这使得它特别长。因此，对于病原体而言，复制RNA是一项艰巨的任务。为了探索瑞德西韦的作用机制，Cramer团队与维尔茨堡大学的Claudia Hobartner团队开展了合作。Hobartner团队提供了用于结构和功能研究的特殊RNA分子。Hobartner教授解释说：“瑞德西韦的结构类似于RNA构件。这将误导聚合酶，使聚合酶将该药物编入正在生长的RNA链中。”

暂停而不是阻止

在将瑞德西韦编入病毒基因组后，研究人员使用生化方法和低温电子显微镜检查了聚合酶-RNA复合物。他们发现，在瑞德西韦被编入基因组后，当基因组中生成三个构建基块时，复制过程就会暂停。“聚合酶不允许基因组安装第四个构建基块。复制暂停的原因是，在聚合酶的特定位点，瑞德西韦结构中只有两个原子钩，瑞德西韦不能完全阻断RNA的产生。通常，聚合酶将在纠正错误后继续工作。”Cramer实验室的研究助理Goran Kokic 解释说。Kokic与Hillen，Tegunov，Dienemann和Seitz一起进行了关键实验。他们都是最近发表在《自然通讯》杂志上一系列与这一研究相关文献的第一作者。 

关于瑞德西韦作用机制的研究为科学家攻克这一病毒提供了新的机会。Cramer说：“现在，我们探明了瑞德西韦如何抑制冠状病毒的聚合酶。我们将致力于改善这一药物及其生效机制。此外，我们还想寻找阻止病毒复制的新化合物。”

“目前正在进行的疫苗接种对于控制疾病流行至关重要。但是，我们还需要开发有效的药物，以缓解COVID-19感染时的疾病进展。”

【英文原文】

Why Remdesivir Does not Fully Stop the Coronavirus

The Covid-19 drug remdesivir (purple) is incorporated into the new RNA chain during the copying process and suppresses the duplication of the coronavirus genome.   

Remdesivir is the first drug against COVID-19 to be conditionally approved in Europe and the United States. The drug is designed to suppress the rapid replication of the SARS-CoV-2 virus in human cells by blocking the viral copying machine, called RNA polymerase. Researchers at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen and the University of Würzburg have now elucidated how remdesivir interferes with the viral polymerase during copying and why it does not inhibit it completely.

"After complicated studies, we come to a simple conclusion," Max Planck Director Patrick Cramer says. "Remdesivir does interfere with the polymerase while doing its work, but only after some delay. And the drug does not fully stop the enzyme." 

At the pandemic's beginning, Cramer's team at the MPI for Biophysical Chemistry had elucidated how the coronavirus duplicates its RNA genome. For the pathogen this is a colossal task as its genome comprises around 30,000 RNA building blocks, making it particularly long. To elucidate remdesivir's mechanism of action, Cramer's team collaborated with Claudia Höbartner's group. The latter produced special RNA molecules for the structural and functional studies. "Remdesivir's structure resembles that of RNA building blocks," explains Höbartner, a professor of chemistry at the University of Würzburg. The polymerase is thereby misled and integrates the substance into the growing RNA chain.

Pausing Instead of Blocking

After remdesivir had been incorporated into the viral genome, the researchers examined the polymerase-RNA complexes using biochemical methods and cryo-electron microscopy. They discovered that the copying process pauses precisely when three more building blocks have been added after remdesivir was incorporated into the RNA chain. "The polymerase does not allow the installation of a fourth one. This pausing is caused by only two atoms in the structure of remdesivir that get hooked at a specific site on the polymerase. However, remdesivir does not fully block RNA production. Often, the polymerase continues its work after correcting the error," explains Goran Kokic, a research associate in Cramer's lab, who together with Hauke Hillen, Dimitry Tegunov, Christian Dienemann, and Florian Seitz, had conducted the crucial experiments. They all are first authors of the publication about this work recently published in the scientific magazine Nature Communications. 

Understanding how remdesivir works opens up new opportunities for scientists to tackle the virus. "Now that we know how remdesivir inhibits the corona polymerase, we can work on improving the substance and its effect. In addition, we want to search for new compounds that stop the viral copying machine," Max Planck Director Cramer says. "The vaccinations now underway are essential to bring the pandemic under control. But we also need to develop effective drugs that mitigate COVID-19 disease progression in the event of infection." 

参考文献：

Goran Kokic et al. Mechanism of SARS-CoV-2 polymerase stalling by remdesivir, Nature Communications (2021). DOI: 0.1038/s41467-020-20542-0 

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