在法匹拉韦存在的情况下培养的脊髓灰质炎病毒的易感性变异体的特征。
Characterization of susceptibility variants of poliovirus grown in the presence of favipiravir.
机构信息
Department of Virology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan; Department of Microbiology, Faculty of Pharmaceutical Sciences, Hokuriku University, 1-1 Taiyogaoka, Kanazawa 920-1180, Japan.
Laboratory of Structural Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
出版信息
J Microbiol Immunol Infect. 2018 Oct;51(5):581-586. doi: 10.1016/j.jmii.2017.03.004. Epub 2017 Jun 29.
BACKGROUND
T-705 (favipiravir) is a potent inhibitor of RNA-dependent RNA polymerases of influenza viruses and no favipiravir-resistant virus has been isolated. Poliovirus RNA polymerase has been well characterized and isolation of resistant virus was examined in poliovirus.
METHODS
Susceptibility variants of poliovirus I (Sabin strain) were isolated during passages in the presence of favipiravir and characterized for their susceptibility and the sequence of RNA polymerase.
RESULTS
Five variants with 0.47-1.88 times the 50% inhibitory concentration for plaque formation of the parent poliovirus had amino acid variations in the 3D gene of the RNA polymerase. The distribution of amino acid variations was not related to ribavirin resistance, and two amino acid variation sites were found near the finger domain.
CONCLUSION
Favipiravir as a chain terminator would not be incorporated and replicate to cause lethal mutagenesis as a mutagen like ribavirin, and resistant mutants were not isolated. A high replication level would generate mutations leading to favipiravir resistance as ribavirin resistance was generated, but generated mutations would be lethal to the RNA polymerase function.
背景
T-705（法匹拉韦）是一种有效的流感病毒 RNA 依赖性 RNA 聚合酶抑制剂，尚未分离到对法匹拉韦耐药的病毒。脊髓灰质炎病毒 RNA 聚合酶已得到很好的表征，并在脊髓灰质炎病毒中对耐药病毒的分离进行了研究。
方法
在法匹拉韦存在的情况下，对脊髓灰质炎病毒 I（Sabin 株）进行传代，分离出对其敏感的变异株，并对其敏感性和 RNA 聚合酶序列进行了表征。
结果
在形成蚀斑的 50%抑制浓度（IC50）方面，有 5 个变异株相对于亲本脊髓灰质炎病毒的变化率为 0.47-1.88，其 RNA 聚合酶的 3D 基因存在氨基酸变异。氨基酸变异的分布与利巴韦林耐药性无关，并且在手指结构域附近发现了两个氨基酸变异位点。
结论
作为链终止剂的法匹拉韦不会被掺入并复制，从而像利巴韦林那样引起致命的诱变，因此未分离到耐药突变体。高复制水平会产生导致法匹拉韦耐药的突变，但产生的突变会对 RNA 聚合酶功能产生致命影响。
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