Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors
Anti-influenza virus activities of 4-substituted 2,4-dioxobutanoic acid inhibitors
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DOI：
10.1128/aac.40.5.1304
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发表时间：
1996-05-01
影响因子：
4.9
通讯作者：
Tomassini, JE
中科院分区：
文献类型：
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作者：
Hastings, JC;Selnick, H;Tomassini, JE
我们先前鉴定了一系列特异性抑制流感A和B病毒转录的化合物（J. Tomassini，H. Selnick，M. E.戴维斯，M。E.作者声明：J. Bourgeois，J. Hastings，D. Hazuda，J.刘易斯，W. McClements，G. Ponticello，E. Radzilowski，G.史密斯，A. Tebben和A.沃尔夫，抗微生物。探员Chemother 38：2827-2837，1994）。化合物4-取代的2，4-二氧代丁酸选择性靶向转录酶复合物的帽依赖性核酸内切酶活性。此外，在细胞培养试验中，这些化合物中的几种有效抑制流感病毒的复制，但不抑制其他病毒的复制。在这里，我们报告的抗流感病毒活性的其他有效的衍生物的系列在体外和体内感染性试验中进行评估。这些化合物在产量降低试验中抑制流感病毒的复制，50%抑制浓度范围为0.18 - 0.71 μ M。这些50%抑制浓度与体外转录抑制（0.32至0.54 μ M）所观察到的浓度相似。一种选定的化合物还在上呼吸道激发后引起对小鼠中流感病毒复制的剂量依赖性抑制。这些研究证明了这种抑制剂类的抗病毒功效，从而确立了流感病毒核酸内切酶作为化疗靶标的效用。
We previously identified a series of compounds which specifically inhibited the transcription of influenza A and B viruses (J. Tomassini, H. Selnick, M. E. Davies, M. E. Armstrong, J. Baldwin, M. Bourgeois, J. Hastings, D. Hazuda, J. Lewis, W. McClements, G. Ponticello, E. Radzilowski, G. Smith, A. Tebben, and A. Wolfe, Antimicrob. Agents Chemother. 38:2827-2837, 1994). The compounds, 4-substituted 2,4-dioxobutanoic acids, selectively targeted the cap-dependent endonuclease activity of the transcriptase complex. Additionally, several of these compounds effectively inhibited the replication of influenza virus but not other viruses in cell culture assays. Here, we report on the anti-influenza virus activities of other potent derivatives of the series evaluated in both in vitro and in vivo infectivity assays. These compounds inhibited the replication of influenza virus in yield reduction assays, with 50% inhibitory concentrations ranging from 0.18 to 0.71 mu M. These 50% inhibitory concentrations were similar to those observed for inhibition of in vitro transcription (0.32 to 0.54 mu M). One selected compound also elicited a dose-dependent inhibition of influenza virus replication in mice following an upper respiratory tract challenge. These studies demonstrate the antiviral efficacy of this inhibitor class and thereby establish the utility of influenza virus endonuclease as a chemotherapeutic target.