INHIBITION OF CAP (M(7)GPPPXM)-DEPENDENT ENDONUCLEASE OF INFLUENZA-VIRUS BY 4-SUBSTITUTED 2,4-DIOXOBUTANOIC ACID COMPOUNDS
INHIBITION OF CAP (M(7)GPPPXM)-DEPENDENT ENDONUCLEASE OF INFLUENZA-VIRUS BY 4-SUBSTITUTED 2,4-DIOXOBUTANOIC ACID COMPOUNDS
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DOI：
10.1128/aac.38.12.2827
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发表时间：
1994-12-01
影响因子：
4.9
通讯作者：
WOLFE, A
中科院分区：
文献类型：
--
作者：
TOMASSINI, J;SELNICK, H;WOLFE, A
流感病毒mRNA的合成由加帽和甲基化（cap 1，m（7）GpppXm）RNAs引发，病毒通过核酸内切裂解从宿主细胞中的RNA聚合酶II转录物获得所述RNA。内切核酸裂解加工的保守性质为流感病毒的抗病毒剂的开发提供了独特的靶标。一系列4-取代的2，4-二氧代丁酸化合物已被鉴定为甲型和B型流感病毒中该活性的选择性抑制剂。这些抑制剂表现出在0.2至29.0 μ M范围内的帽依赖性流感病毒转录的50%抑制浓度，并在100至500倍高浓度测试时，对其他病毒和细胞聚合酶的活性没有影响。这些化合物不抑制流感病毒mRNA合成的起始或延长，但特异性抑制流感病毒核酸内切酶对加帽RNA的切割，并且不抑制其他核酸酶的活性。此外，所述化合物特异性抑制细胞培养物中甲型和B型流感病毒的复制，其效力与转录获得的50%抑制浓度相当。
Synthesis of influenza virus mRNA is primed by capped and methylated (cap 1, m(7)GpppXm) RNAs which the virus derives by endonucleolytic cleavage from RNA polymerase II transcripts in host cells. The conserved nature of the endonucleotytic processing provides a unique target for the development of antiviral agents for influenza viruses. A series of 4-substituted 2,4-dioxobutanoic acid compounds has been identified as selective inhibitors of this activity in both influenza A and B viruses. These inhibitors exhibited 50% inhibitory concentrations in the range of 0.2 to 29.0 mu M for cap-dependent influenza virus transcription and had no effect on the activity of other viral and cellular polymerases when tested at 100- to 500-fold higher concentrations. The compounds did not inhibit the initiation or elongation of influenza virus mRNA synthesis but specifically inhibited the cleavage of capped RNAs by the influenza virus endonuclease and were not inhibitory to the activities of other nucleases. Additionally, the compounds specifically inhibited replication of influenza A and B viruses in cell culture with potencies comparable to the 50% inhibitory concentrations obtained for transcription.