. doi: 10.1016/j.virs.2025.05.003
Citation: Fang Yu, Qiu-Yan Zhang, Zhe-Rui Zhang, Cheng-Lin Deng, Bo Zhang. Mutational landscapes of NITD008-resistant EV71 variants revealed through population sequencing .VIROLOGICA SINICA, 2025, 40(3) : 503-505.  http://dx.doi.org/10.1016/j.virs.2025.05.003

通过种群测序揭示了EV71 NITD008耐药株的突变景观

  • 通讯作者: 张波, zhangbo@wh.iov.cn
  • 收稿日期: 2025-03-17
    录用日期: 2025-05-19
  • 肠道病毒71型(Enterovirus 71, EV71)是手足口病(Hand, foot, and mouth disease, HFMD)的主要病原体,特别是在亚太地区,对公共卫生构成严重威胁。然而,目前还没有针对EV71的有效抗病毒药物。核苷酸或核苷酸类似物已被广泛接受作为治疗药物,并在许多病毒感染的治疗中发挥主导作用。NITD008是一种腺苷酸类似物,是黄病毒和EV71的抑制剂,可阻断病毒的RNA合成。然而,在EV71复制过程中,NITD008作为诱变剂对WT和NITD008耐药株种群的突变谱影响尚不清楚。在本研究中,我们利用深度测序对有无NITD008的病毒种群进行了全基因组突变分析。在NITD008的压力下,WT EV71中2C蛋白的突变明显增加,且这些突变位于A,B和C功能基序附近,因此我们推测2C蛋白可能是NITD008抵抗EV71感染的新靶点。并且,在NITD008治疗后,相较于NITD008耐药株,WT EV71毒株发生明显的NITD008相关突变(U-to-A和U-to-C),表明诱变可能是NITD008控制EV71感染的一种作用机制。综上,这些结果为开发EV71新的广谱抗病毒药物提供了靶点,而在现代社会中,面临新发或再发传染病的风险增加,这类药物的快速干预显得尤为迫切。

Mutational landscapes of NITD008-resistant EV71 variants revealed through population sequencing

  • Corresponding author: Bo Zhang, zhangbo@wh.iov.cn
  • Received Date: 17 March 2025
    Accepted Date: 19 May 2025
  • Highlights
    1. The mutation spectra between WT population and NITD008-resistant populations during replication are compared.
    2. The 2C protein may be a new target of NITD008 as a nucleotide analogue against EV71 infection.
    3. Antiviral effect of NITD008 against EV71 is associated with increased frequency of U-to-A and U-to-C mutations.

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    4. Isakov, O., Borderia, A. V., Golan, D., Hamenahem, A., Celniker, G., Yoffe, L., Blanc, H., Vignuzzi, M., Shomron, N., 2015. Deep sequencing analysis of viral infection and evolution allows rapid and detailed characterization of viral mutant spectrum. Bioinformatics 31, 2141-2150.

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    6. Rozen-Gagnon, K., Stapleford, K. A., Mongelli, V., Blanc, H., Failloux, A. B., Saleh, M. C., Vignuzzi, M., 2014. Alphavirus mutator variants present host-specific defects and attenuation in mammalian and insect models. PLoS Pathog. 10, e1003877.

    7. Smith, E. C., Blanc, H., Surdel, M. C., Vignuzzi, M., Denison, M. R., 2013. Coronaviruses lacking exoribonuclease activity are susceptible to lethal mutagenesis: evidence for proofreading and potential therapeutics. PLoS Pathog. 9, e1003565.

    8. Stapleford, K. A., Rozen-Gagnon, K., Das, P. K., Saul, S., Poirier, E. Z., Blanc, H., Vidalain, P. O., Merits, A., Vignuzzi, M., 2015. Viral polymerase-helicase complexes regulate replication fidelity to overcome intracellular nucleotide depletion. J. Virol. 89, 11233-11244.

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    11. Wu, Y., Lou, Z., Miao, Y., Yu, Y., Dong, H., Peng, W., Bartlam, M., Li, X., Rao, Z., 2010. Structures of EV71 RNA-dependent RNA polymerase in complex with substrate and analogue provide a drug target against the hand-foot-and-mouth disease pandemic in China. Protein Cell 1, 491-500.

    12. Xia, H., Wang, P., Wang, G. C., Yang, J., Sun, X., Wu, W., Qiu, Y., Shu, T., Zhao, X., Yin, L., Qin, C. F., Hu, Y., Zhou, X, 2015. Human enterovirus nonstructural protein 2CATPase functions as both an RNA helicase and ATP-independent RNA chaperone. PLoS Pathog. 11, e1005067.

    13. Yin, Z., Chen, Y. L., Schul, W., Wang, Q. Y., Gu, F., Duraiswamy, J., Kondreddi, R. R., Niyomrattanakit, P., Lakshminarayana, S. B., Goh, A. et al., 2009. An adenosine nucleoside inhibitor of dengue virus. Proc. Natl. Acad. Sci. U S A. 106, 20435-20439.

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    Mutational landscapes of NITD008-resistant EV71 variants revealed through population sequencing

      Corresponding author: Bo Zhang, zhangbo@wh.iov.cn
    • a. State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China;
    • b. University of Chinese Academy of Sciences, Beijing, 100049, China

    Abstract: Highlights
    1. The mutation spectra between WT population and NITD008-resistant populations during replication are compared.
    2. The 2C protein may be a new target of NITD008 as a nucleotide analogue against EV71 infection.
    3. Antiviral effect of NITD008 against EV71 is associated with increased frequency of U-to-A and U-to-C mutations.

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