Restriction of SARS-CoV-2 replication by targeting programmed -1 ribosomal frameshifting.
Restriction of SARS-CoV-2 replication by targeting programmed -1 ribosomal frameshifting.
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DOI：
10.1073/pnas.2023051118
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发表时间：
2021-06-29
影响因子：
11.1
通讯作者：
Guo JU
中科院分区：
文献类型：
--
作者：
Sun Y;Abriola L;Niederer RO;Pedersen SF;Alfajaro MM;Silva Monteiro V;Wilen CB;Ho YC;Gilbert WV;Surovtseva YV;Lindenbach BD;Guo JU
包括新型冠状病毒SARS-CoV-2在内的多种RNA病毒都含有特定的RNA结构，这些RNA结构可以促进程序性核糖体移码（PRF）来调节病毒基因表达。从高通量化合物筛选中，我们鉴定了SARS-CoV-2的PRF抑制剂，并发现它显著阻碍了培养细胞中的病毒复制。有趣的是，该化合物不仅可以靶向SARS-CoV-2，还可以靶向其他使用类似RNA结构促进移码的冠状病毒。这些结果表明，靶向PRF是SARS-CoV-2和其他冠状病毒的一种合理、有效和广谱的抗病毒策略。严重急性呼吸综合征冠状病毒2型（SARS-CoV-2）中开放阅读框1b（ORF 1b）的翻译需要由RNA假结促进的程序性-1核糖体移码（-1 PRF）。SARS-CoV-2复制对-1 PRF效率变化的敏感程度目前尚不清楚。通过一个无偏见的，基于细菌的高通量化合物筛选，我们确定了meraflavine，一种氟喹诺酮类抗菌药物，作为SARS-CoV-2的-1 PRF抑制剂。meraflavine的移码抑制作用对假结区域内的突变具有稳健性，对其他β冠状病毒的−1 PRF也同样有效。与−1 PRF在病毒基因表达中的重要作用一致，meraflavine阻碍SARS-CoV-2在Vero E6细胞中的复制，从而为靶向−1 PRF作为SARS-CoV-2和其他冠状病毒的合理有效的抗病毒策略提供了原理证明。
A large variety of RNA viruses, including the novel coronavirus SARS-CoV-2, contain specific RNA structures that promote programmed ribosomal frameshifting (PRF) to regulate viral gene expression. From a high-throughput compound screen, we identified a PRF inhibitor for SARS-CoV-2 and found that it substantially impeded viral replication in cultured cells. Interestingly, the compound could target not only SARS-CoV-2 but also other coronaviruses that use similar RNA structures to promote frameshifting. These results suggest targeting PRF is a plausible, effective, and broad-spectrum antiviral strategy for SARS-CoV-2 and other coronaviruses. Translation of open reading frame 1b (ORF1b) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires a programmed −1 ribosomal frameshift (−1 PRF) promoted by an RNA pseudoknot. The extent to which SARS-CoV-2 replication may be sensitive to changes in −1 PRF efficiency is currently unknown. Through an unbiased, reporter-based high-throughput compound screen, we identified merafloxacin, a fluoroquinolone antibacterial, as a −1 PRF inhibitor for SARS-CoV-2. Frameshift inhibition by merafloxacin is robust to mutations within the pseudoknot region and is similarly effective on −1 PRF of other betacoronaviruses. Consistent with the essential role of −1 PRF in viral gene expression, merafloxacin impedes SARS-CoV-2 replication in Vero E6 cells, thereby providing proof-of-principle for targeting −1 PRF as a plausible and effective antiviral strategy for SARS-CoV-2 and other coronaviruses.
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影响因子：
17.3
作者：
Dinman, JD;Ruiz-Echevarria, MJ;Peltz, SW
通讯作者：
Peltz, SW
影响因子：
5.4
作者：
DINMAN, JD;WICKNER, RB
通讯作者：
WICKNER, RB
影响因子：
4
作者：
Chen, Yanqiong;Tao, Huan;Fu, Xinyuan
通讯作者：
Fu, Xinyuan
影响因子：
9.8
作者：
Plant EP;Pérez-Alvarado GC;Jacobs JL;Mukhopadhyay B;Hennig M;Dinman JD
通讯作者：
Dinman JD
影响因子：
64.8
作者：
Namy O;Moran SJ;Stuart DI;Gilbert RJ;Brierley I
通讯作者：
Brierley I