Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity.
Inhibition of pyrimidine biosynthesis pathway suppresses viral growth through innate immunity.
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DOI：
10.1371/journal.ppat.1003678
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发表时间：
2013
期刊：
影响因子：
6.7
通讯作者：
Vidalain PO
中科院分区：
文献类型：
--
作者：
Lucas-Hourani M;Dauzonne D;Jorda P;Cousin G;Lupan A;Helynck O;Caignard G;Janvier G;André-Leroux G;Khiar S;Escriou N;Desprès P;Jacob Y;Munier-Lehmann H;Tangy F;Vidalain PO
寻找先天性抗病毒反应的刺激物是开发抗病毒感染的新疗法的一种有吸引力的方法。在这里，我们建立了一个基于细胞的报告分析，以确定刺激干扰素诱导的抗病毒基因的表达的化合物。DD264是从41，353种化合物中选出的，具有免疫刺激和抗病毒特性。在寻找其作用机制的同时，我们将DD264鉴定为嘧啶生物合成途径的抑制剂。这种代谢途径最近被确定为广谱抗病毒分子的主要靶点，但我们的数据揭示了与先天免疫的未知联系。事实上，我们发现DD264或布喹那（一种众所周知的嘧啶生物合成途径抑制剂）都能增强人类细胞中抗病毒基因的表达。此外，发现DD264或布喹那的抗病毒活性严格依赖于细胞基因转录、核输出机制和所需的IRF1转录因子。总之，嘧啶生物合成抑制剂的抗病毒特性不是病毒机制上嘧啶剥夺的直接结果，而是涉及细胞免疫应答的诱导。我们治疗病毒性疾病的治疗手段非常有限，并且迫切需要可以用于对抗多种病毒的分子。在可能的策略中，人们对刺激细胞防御机制的分子越来越感兴趣。我们最近开发了一种功能测定来鉴定抗病毒基因的刺激物，并使用这种方法从化学库中选择化合物DD 264。在寻找其作用模式的同时，我们将这种分子鉴定为嘧啶生物合成的抑制剂，嘧啶生物合成是一种代谢途径，为细胞提供用于DNA和RNA合成的嘧啶核碱基。有趣的是，最近的研究表明，这种代谢途径的抑制剂可以阻止RNA病毒的复制。在这里，我们建立了嘧啶生物合成途径和诱导抗病毒基因之间的功能联系，并证明嘧啶生物合成抑制剂如DD 264或布喹那严重依赖于细胞免疫反应来抑制病毒生长。因此，嘧啶剥夺并不直接负责嘧啶生物合成抑制剂的抗病毒活性，而是涉及诱导代谢应激和随后触发细胞防御机制。
Searching for stimulators of the innate antiviral response is an appealing approach to develop novel therapeutics against viral infections. Here, we established a cell-based reporter assay to identify compounds stimulating expression of interferon-inducible antiviral genes. DD264 was selected out of 41,353 compounds for both its immuno-stimulatory and antiviral properties. While searching for its mode of action, we identified DD264 as an inhibitor of pyrimidine biosynthesis pathway. This metabolic pathway was recently identified as a prime target of broad-spectrum antiviral molecules, but our data unraveled a yet unsuspected link with innate immunity. Indeed, we showed that DD264 or brequinar, a well-known inhibitor of pyrimidine biosynthesis pathway, both enhanced the expression of antiviral genes in human cells. Furthermore, antiviral activity of DD264 or brequinar was found strictly dependent on cellular gene transcription, nuclear export machinery, and required IRF1 transcription factor. In conclusion, the antiviral property of pyrimidine biosynthesis inhibitors is not a direct consequence of pyrimidine deprivation on the virus machinery, but rather involves the induction of cellular immune response. Our therapeutic arsenal to treat viral diseases is extremely limited, and there is a critical need for molecules that could be used against multiple viruses. Among possible strategies, there is a growing interest for molecules stimulating cellular defense mechanisms. We recently developed a functional assay to identify stimulators of antiviral genes, and selected compound DD264 from a chemical library using this approach. While searching for its mode of action, we identified this molecule as an inhibitor of pyrimidine biosynthesis, a metabolic pathway that fuels the cell with pyrimidine nucleobases for both DNA and RNA synthesis. Interestingly, it was recently shown that inhibitors of this metabolic pathway prevent the replication of RNA viruses. Here, we established a functional link between pyrimidine biosynthesis pathway and the induction of antiviral genes, and demonstrated that pyrimidine biosynthesis inhibitors like DD264 or brequinar critically rely on cellular immune response to inhibit virus growth. Thus, pyrimidine deprivation is not directly responsible for the antiviral activity of pyrimidine biosynthesis inhibitors, which rather involves the induction of a metabolic stress and subsequent triggering of cellular defense mechanisms.
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影响因子：
7.6
作者：
Evers, DL;Wang, X;Huang, ES
通讯作者：
Huang, ES
影响因子：
3.5
作者：
Contreras-Sanz, Alberto;Scott-Ward, Toby S.;Gill, Hardyal S.;Jacoby, Jennifer C.;Birch, Rebecca E.;Malone-Lee, James;Taylor, Kevin M. G.;Peppiatt-Wildman, Claire M.;Wildman, Scott S. P.
通讯作者：
Wildman, Scott S. P.
影响因子：
3.5
作者：
Baum, Alina;Garcia-Sastre, Adolfo
通讯作者：
Garcia-Sastre, Adolfo
影响因子：
64.5
作者：
Dixit E;Boulant S;Zhang Y;Lee AS;Odendall C;Shum B;Hacohen N;Chen ZJ;Whelan SP;Fransen M;Nibert ML;Superti-Furga G;Kagan JC
通讯作者：
Kagan JC
影响因子：
2.1
作者：
Kimura, T;Kadokawa, Y;Taniguchi, T
通讯作者：
Taniguchi, T