Unité de Génomique Virale et Vaccination, Institut Pasteur, CNRS UMR3569, Paris, France.
Institut Curie, Centre de Recherche, CNRS UMR3666, INSERM U1143, Paris, France.
Antimicrob Agents Chemother. 2017 Sep 22;61(10). doi: 10.1128/AAC.00383-17. Print 2017 Oct.
pyrimidine biosynthesis is a key metabolic pathway involved in multiple biosynthetic processes. Here, we identified an original series of 3-(1-indol-3-yl)-2,3-dihydro-4-furo[3,2-]chromen-4-one derivatives as a new class of pyrimidine biosynthesis inhibitors formed by two edge-fused polycyclic moieties. We show that identified compounds exhibit broad-spectrum antiviral activity and immunostimulatory properties, in line with recent reports linking pyrimidine biosynthesis with innate defense mechanisms against viruses. Most importantly, we establish that pyrimidine deprivation can amplify the production of both type I and type III interferons by cells stimulated with retinoic acid-inducible gene 1 (RIG-I) ligands. Altogether, our results further expand the current panel of pyrimidine biosynthesis inhibitors and illustrate how the production of antiviral interferons is tightly coupled to this metabolic pathway. Functional and structural similarities between this new chemical series and dicoumarol, which was reported before to inhibit pyrimidine biosynthesis at the dihydroorotate dehydrogenase (DHODH) step, are discussed.
嘧啶生物合成是参与多种生物合成过程的关键代谢途径。在这里，我们鉴定了一系列新型的 3-(1-吲哚-3-基)-2,3-二氢-4-呋喃并[3,2-]色烯-4-酮衍生物，它们是由两个边缘融合的多环部分形成的嘧啶生物合成抑制剂。我们表明，鉴定出的化合物具有广谱抗病毒活性和免疫刺激特性，这与最近的报告一致，即嘧啶生物合成与针对病毒的先天防御机制有关。最重要的是，我们确定嘧啶剥夺可以通过细胞刺激物增强 I 型和 III 型干扰素的产生与维甲酸诱导基因 1 (RIG-I) 配体。总之，我们的结果进一步扩展了当前的嘧啶生物合成抑制剂面板，并说明了抗病毒干扰素的产生如何与该代谢途径紧密相关。该新化学系列与先前报道的嘧啶生物合成抑制剂二羟乳清酸脱氢酶 (DHODH) 步骤的二羟乳清酸脱氢酶 (DHODH) 抑制剂dicoumarol 之间存在功能和结构相似性，对此进行了讨论。
