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中国科学院微生物所施一、高福等研究人员合作解析出埃博拉病毒聚合酶复合物结构。2022年9月28日，《自然》杂志在线发表了这项成果。

研究人员表示，丝状病毒，包括埃博拉病毒，对公众健康构成了越来越大的威胁。尽管两种治疗性单克隆抗体已被批准用于治疗埃博拉病毒疾病，但目前还没有被批准的广泛反应性药物来控制多样化的丝状病毒感染。丝状病毒有一个大型聚合酶（L）蛋白和辅助因子病毒蛋白35（VP35），它们构成了负责病毒基因组RNA合成的基本功能单元。由于其保守性，L-VP35聚合酶复合物是广泛反应性抗病毒药物的一个有望靶标。

研究人员用冷冻电镜确定了埃博拉病毒L蛋白与四聚体VP35复合物的结构（状态1）。结构分析显示，埃博拉病毒L拥有一个丝状病毒特异性插入元件，对RNA的合成至关重要，而且VP35四聚体的三个原聚体与L的N端区域有广泛的相互作用。值得注意的是，研究人员在第二种构象中捕捉到了具有明确引物环和支持螺旋的复合结构，其远离聚合酶活性部位（状态2）。此外，研究人员证明了百年老药苏拉明可以在酶促试验中抑制埃博拉病毒聚合酶的活性。L-VP35-苏拉明复合物的结构显示，苏拉明可以在高度保守的NTP进入通道处结合，阻止底物进入活性部位。这些发现揭示了埃博拉病毒的复制机制，并可能指导开发出更强大的抗飞沫病毒药物。

附：英文原文

Title: Structure of the Ebola virus polymerase complex

Author: Yuan, Bin, Peng, Qi, Cheng, Jinlong, Wang, Min, Zhong, Jin, Qi, Jianxun, Gao, George F., Shi, Yi

Issue&Volume: 2022-09-28

Abstract: Filoviruses, including Ebola virus, pose an increasing threat to the public health. Although two therapeutic monoclonal antibodies have been approved to treat the Ebola virus disease1,2, there are no approved broadly reactive drugs to control diverse filovirus infection. Filovirus has a large polymerase (L) protein and the cofactor viral protein 35 (VP35), which constitute the basic functional unit responsible for virus genome RNA synthesis3. Owing to its conservation, the L–VP35 polymerase complex is a promising target for broadly reactive antiviral drugs. Here we determined the structure of Ebola virus L protein in complex with tetrameric VP35 using cryo-electron microscopy (state 1). Structural analysis revealed that Ebola virus L possesses a filovirus-specific insertion element that is essential for RNA synthesis, and that VP35 interacts extensively with the N-terminal region of L by three protomers of the VP35 tetramer. Notably, we captured the complex structure in a second conformation with the unambiguous priming loop and supporting helix away from polymerase active site (state 2). Moreover, we demonstrated that the century-old drug suramin could inhibit the activity of the Ebola virus polymerase in an enzymatic assay. The structure of the L–VP35–suramin complex reveals that suramin can bind at the highly conserved NTP entry channel to prevent substrates from entering the active site. These findings reveal the mechanism of Ebola virus replication and may guide the development of more powerful anti-filovirus drugs.

DOI: 10.1038/s41586-022-05271-2

Source: https://www.nature.com/articles/s41586-022-05271-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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